WO2020016903A1 - An improved and commercially viable process for preparation of pyrrole derivatives with improved impurity profile & minimisation of unit operations. - Google Patents

An improved and commercially viable process for preparation of pyrrole derivatives with improved impurity profile & minimisation of unit operations. Download PDF

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WO2020016903A1
WO2020016903A1 PCT/IN2019/050463 IN2019050463W WO2020016903A1 WO 2020016903 A1 WO2020016903 A1 WO 2020016903A1 IN 2019050463 W IN2019050463 W IN 2019050463W WO 2020016903 A1 WO2020016903 A1 WO 2020016903A1
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formula
phenyl
fluorophenyl
dimethyl
cis
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PCT/IN2019/050463
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French (fr)
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Ajit Annu Kamath
Ashish Mohan Ujagare
Bhausaheb Nana Ghogare
Sanjay Gulab Shilewant
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Arch Pharmalabs 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • TITLE An improved and commercially viable process for preparation of pyrrole derivatives with improved impurity profile & minimization of unit operations.
  • the present invention relates to an improved process for the preparation of a pyrrole derivative as a racemic mixture, an enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof and pharmaceutically acceptable salts thereof and intermediates involved therein.
  • Particularly invention is directed to improved processes for the preparation of pyrrole derivatives such as [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid particularly calcium salt and its hydrate presented by Formulae I/IA respectively; wherein formation of the impurities is either eliminated or minimized in the corresponding intermediaries.
  • pyrrole derivatives such as [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid particularly calcium salt and its hydrate presented by Formulae I/IA respectively; wherein formation of the impurities is either eliminated or minimized in
  • the present invention more particularly relates to an improved process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula (IV) comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III using ammonia, Ho, Raney Nickel, an alicyclic hydrocarbon preferably cyclohexane and water wherein intermediary tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-
  • I,3-dioxan-4-yl] acetate represented by formula IIIA is not isolated but converted insitu into (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV by performing reaction with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula
  • Unique key feature of the present invention is the use of a single solvent selected from alicyclic hydrocarbon for two reactions namely“catalytic hydrogenation of a cyano compound” and “Paal-Knorr synthesis”; wherein hydrogenated compound is not isolated and reacted further with a diketone in presence of an acid resulting into a pyrrole derivative.
  • the key feature of the present invention is the use of a single solvent selected from alicyclic hydrocarbon for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester popularly known as ATV-lof formula IV comprising catalytic hydrogenation tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III; wherein hydrogenated product viz.tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl]
  • Astonishing facts of using single solvent selected from alicyclic hydrocarbon not only controls the impurities especially dimer/amide impurities in tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate and concerned intermediaries thereof but also is characterized by the fact the end product[R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts and hydrates thereof of formula VIA with improved impurity profile meets with pharmacopeial purity parameters without making extra efforts but also minimizes some of unit operations.
  • Another interesting feature of the present process is the right choice of an alicyclic hydrocarbon which is not only a common solvent for the catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2- cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III and also for Paal-Knorr synthesis producing (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV; but is further characterized by the fact that during the catalytic hydrogenation; formation of impurity of formula Illb gets controlled thereby eliminating or minimizing other dimer/amide impurities of formulae IVa, Va
  • the chosen single solvent selected from alicyclic hydrocarbon plays vital and unique dual role for the two reactions namely catalytic hydrogenation and Paal-Knorr synthesis by avoiding or minimizing the formation of trouble some impurity especially dimer/ amide impurities which creates hell of the problems in going further for the preparation of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-
  • the unique solvent chosen for the dual purpose in the present invention is the most recommended solvent for the Paal-Knorr synthesis. Hence it facilitates further insitu reaction by performing reaction with 4- (4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II generating compound of formula IV with better dimer/ amide impurity profile.
  • the present invention fully justifies the very popular proverb in the field of chemistry“ Garbage In Garbage Out” abbreviated as“gigo”as explained below:
  • Inventors of the present invention have also focused on the control or minimization of the dimer / amide impurity formed at the various stages as mentioned herein below:
  • dimer impurity represented by formula Illb refers to dimer impurity of tert-butyl [(4R,Cis)-6- (2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA. This dimer impurity is formed during the reduction of compound of formula III into compound of formula IIIA.
  • dimer impurity represented by formula IVa refers to dimer impurity of ATV-li.e.(4R,cis)-6- [2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester.
  • dimer impurity represented by formula Va refers to dimer impurity of ATV-2 i.e.(4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrol-l-yl]ethyl]-2,2-dimethyl-l,3-dihydroxy-4-acetate.
  • This impurity is formed during the acid hydrolysis of compound of formula IV contaminated with impurity of formula IVa.
  • dimer impurity represented by formula Via refers to dimer impurity of Atorvastatin, wherein R is H or Ca. This impurity is formed during alkaline hydrolysis of compound of formula V contaminated with impurity of formula Va.
  • tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA generated by catalytic hydrogenation of corresponding cyano compound of formula III using alicyclic hydrocarbon (like cyclohexane as per the process of the present invention) is not even isolated and reacted further with compound of formula II resulting into formation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV controls or minimizes or eliminates the formation of the impurities of formulae Illb, IVa, Va and Via
  • Impurity formation especially dimer impurities of formulae Illb, IVa, VA and Via wherein R is H or Ca respectively.
  • US4681893 discloses method of preparation of racemic trans-5-(4-fluorophenyl)-2-( 1 - methylethyl)-N, 4-diphenyl- 1 - [2-tetrahydro-4-4- hydroxy- 6-oxo- 2H-pyran-2-yl) ethyl] -1H- pyrrole- carboxamide ("racemic [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid lactone”) or its hydroxy acid form or pharmaceutically acceptable salts thereof and methods for its preparation thereof.
  • US5273995 discloses [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid , the pure [R(R*,R*)] enantiomer of 2-(4- fluorophenyl) - b, d-dihydroxy- 5 - ( 1 -methylethyl) - 3 -phenyl-4- [(phenylamino) carbonyl] - 1 H- pyrrole- 1 -heptanoic acid.
  • US5969156 discloses [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid hemi calcium crystalline forms I, II and IV and their preparation process.
  • [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium can contain extraneous compounds or impurities that can come from many sources.
  • the source of these impurities includes unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. Impurities introduced during commercial manufacturing processes must be limited to very small amounts and are preferably substantially absent.
  • the Food and Drug Administration guidelines recommend that the amounts of some unknown individual impurities be limited to less than 0.1 percent.
  • the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
  • W02004/046105A2 discloses Paal-Knorr reaction comprising condensation between a 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideand amine under acidic conditions at elevated temperatures and in a solvent system comprising tetrahydrofuran.
  • W02006/032959 discloses Paal-Knorr reaction comprising condensation between a 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideand amine in the presence of n- heptanoic acid and/or 2,2-dimethylbutanoic acid in solvents selected from aliphatic hydrocarbons, aromatic hydrocarbons, and mixtures thereof preferably n- heptane: tetrahydrofuran: toluene (10:5:2.2), reflux, 8h.
  • WO2007/88553 discloses Paal-Knorr reaction comprising condensation between a 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideand amine in cyclohexane in presence of Pivalic acid as catalyst.
  • WO2006/3944l also discloses Paal-Knorr reaction comprising condensation between a 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide and an amine in cyclohexane in presence of Pivalic acid as catalyst.
  • tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA discloses preparation of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula IIIA comprising hydrogenation of tert-butyl isopropylidene(TIBIN), 28% ammonia solution, isopropanol using sponge Ni as catalyst.
  • WO2012/32035 discloses preparation of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula IIIA comprising catalytic hydrogenation of corresponding nitrile of formula III using aqueous ammonia, Raney Nickel as catalyst and isopropanol as solvent.
  • US5298627 discloses a process for preparing [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid in one convergent step using a 3,5-heptanoic acid side chain.
  • a precursor of the side chain of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l- heptanoic acid was made by Claisen condensation of N,N-diphenyl acetamide and 4-cyano-3-hydroxybutanoic acid ethyl ester. The resulting 6-cyano-3, 5-dihydroxy hexanoic acid amide was protected with 2,2-dimethoxypropane.
  • US5216174 teaches generally that the Paal-Knorr synthesis can be performed on an acetonide- protected 7-amino-3, 5-dihydroxy heptanoic acid tert. -butyl ester in an inert solvent or solvents such as, for example, hexane, toluene and the like for about 24 hours at about reflux temperature of the solvents.
  • the product is not isolated but is treated directly with acid to remove the protecting group.
  • the said process comprises the step of condensing 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo- N-phenyl-butanamideof formula II, with (4R,Cis)-l,l-dimethylethyl-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxane-4-acetate of formula IIIA, in the presence of a catalytic amount of an acid in the presence of a solvent system, preferably a binary solvent system, to obtain the desired compound (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV.
  • the said dimer/amide impurity of formula IVa is formed when either (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV is further reacted with the unreacted compound of formula IIIA, or it reacts with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl- 4-oxo-N-phenyl-butanamide of formula II.
  • ether impurity of Atorvastatin calcium is generated; when (4R,cis)-6-[2-[3-phenyl- 4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV is subjected for acid hydrolysis using in alcohol like methanol for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- b,d- dihydroxy-5-(l-methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid ester of formula V and somehow the reaction gets prolonged resulting into the concentration of the reaction mass.
  • binary solvent systems that includes an alcohol solvent was used during the preparation of compound (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethylj-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV.
  • IPCOM000225989D discloses the synthesis of compound (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl- acetic acid-tertiary butyl ester of formula IV in the presence of catalytic amount of amidine base [e.g., l,8-diazabicycloundec-7-ene or l,5-diazabicyclo(4.3.0)non-5- ene] to achieve a purity of 99.5% having dimer impurity of formula IVa not more than 0.1%.
  • the dimer impurity of formula IVa was present in the level of about 0.2 to 0.4% and required additional purifications to minimize the impurity to not more than 0.1%.
  • W02017060885A1 discloses an improved process for minimizing the impurities of [R-(R*, R*]- 2-(4-fluorophenyl)- b, d-di hydroxy-5-(l-meth yl ethyl )-3-phenyl-4-[(phenylamino)carbonylJ-lH- pyrrole-l- heptanoic acid and pharmaceutical salts there from comprising the key feature of treating the aqueous solution of sodium salt of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid of formula I with a solvent that is immiscible or slightly miscible in water.
  • Inventors of the present invention specifically selected ammonia and water in combination or aqueous ammonia for the purpose. They have collected negative outputs towards the restriction of anhydrous ammonia.
  • the key feature of the present invention is the choice of alicyclic hydrocarbon specifically cyclohexane falls under the category of nonpolar solvents and therefore ammonia (anhydrous) does not get dissolved to sufficient extent providing required concentration for conducting the reaction. Secondly using liquid ammonia may pressurize the reaction which is not favorable.
  • Raney Nickel to be used is to be made free from water needs number of methanol washing which inherently increases the risk of making it pyrophoric.
  • the present invention takes the advantage of differences in the relative reaction rates of the intermediates and/or impurities and provides an improved process for preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts and hydrates thereof to circumvent yield loss for e.g. during the preparation of compound IV, multiple crystallizations are required to reduce the impurity IVa.
  • the inventors of the present invention have thought in the view of the role of a solvent in terms of reaction rates, time of possession of the reaction mass, polarity of the solvent, role of minute amount of water, use of single common solvent for two reactions comprising catalytic hydrogenation and the Paal-Knorr synthesis.
  • present invention fulfill the need in the art and provides an improved process for preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts and hydrates represented by formula I /IA by avoiding/eliminating/minimising the formation of the impurities (especially dimer/amide)formed during the synthesis of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid or pharmaceutically acceptable salts thereof and circumvent disadvantages associated with prior art, proved to be advantageous from industrial point of view and also fulfill purity criteria's led
  • present invention provides a process for controlling impurities with special reference to dimer / amide impurities of formulae Illb, IVa, Va and Via (wherein R is H or Ca) at the various stage during preparation of a compound of formula (I)/(I)A.
  • the inventors of the present invention come up with an improved or modified process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)- 5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: use of single solvent selected from alicyclic hydrocarbon for catalytic hydrogenation of (4R,Cis)- 1 , 1 -dimethylethyl-6-(2-cyanomethyl)-2, 2-dimethyl- 1 ,3-dioxane-4- acetate of formula III in an using water, Raney Nickel, ammonia and H2wherein hydrogenated product viz amino intermediary i.e.
  • Impurities of Atorvastatin consist of:
  • impurities A, B, C, D and E are specified pharmacopieal impurities fall under category of related substances, while F, G and H are detectable pharmacopieal impurities.
  • impurity of formula IVa is considered as dimer impurity of (4R,cis)-6-[2-[3- phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl] -2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester), impurity of formula IVb, impurity of formula Va, Dimer impurity of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate, Dimer impurity of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phen
  • Impurities discussed herein after or before; if once are formed are difficult to remove from desired product by routine crystallization procedures as their solubility index is similar those of desired products. Furthermore these impurities are functionally similar to those of desired products and would undergo chemical transformations in similar way in the subsequent reaction steps.
  • the chemistry of the impurities formation is already discussed herein above.
  • the inventors of the present invention have developed a process to achieve high purity profile of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising the use of a single solvent selected from alicyclic hydrocarbon for two reactions namely catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III and for Paal-Knorr synthesis for the preparation of (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluor
  • the said process of the present invention comprises catalytic hydrogenation of (4R,Cis)-l,l- dimethylethyl-6-(2-cyanomethyl)-2, 2-dimethyl- l,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and 3 ⁇ 4 characterized by the fact that generated amino intermediary tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4- yl] acetate represented by formula IIIA containing minimized dimer/amide impurity represented by formula Illb is used as such( without isolation) for Paal-Knorr synthesis by performing further reaction with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II resulting into high quality (4R,cis)-6-[2-[3-pheny
  • ADVANTAGES OF THE PRESENT INVENTION i. Use of single solvent selected from alicyclic hydrocarbon for two different reactions namely catalytic hydrogenation and Paal-Knorr synthesis; wherein hydrogenated product is not isolated.
  • Process of the present invention controls the impurities especially dimer/amide of formulae Illb, IVa, Va and Via (wherein R is H or Ca)formed at various stages of Atorvastatin and its salt.
  • the present invention relates to an improved process for preparation of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid and pharmaceutically acceptable salts thereof represented by formula VIA with high purity particularly [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA wherein the impurities formed are either minimized or eliminated.
  • the present invention particularly relates to an improved or modified process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole- l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: catalytic hydrogenation of (4R,Cis)- 1,1 -dimethylethyl-6-(2-cyanomethyl)-2, 2-dimethyl- 1,3- dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and H 2 characterized by the fact that generated amino intermediary i.e.
  • the key feature of the present invention is the use of a single solvent selected from alicyclic hydrocarbon for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester popularly known as ATV-l of formula IV comprising catalytic hydrogenation tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III; wherein hydrogenated product viz tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl
  • Impurities discussed herein above; if once are formed are difficult to remove from desired product by routine crystallization procedures as their solubility index is similar those of desired products. Furthermore these impurities are functionally similar to those of desired products and would undergo chemical transformations in similar way in the subsequent reaction steps as depicted herein below.
  • the first aspect of the present invention is to use a single solvent selected from alicyclic hydrocarbon for two reactions namely catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2- cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III and Paal-Knorr synthesis for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester popularly known as ATV-l of formula IV wherein hydrogenated product tert-butyl [(4R,Cis)-6- (2-aminoethyl)-2,2-dimethyl-l,3-d
  • the second aspect of the present invention is to use a single solvent selected from alicyclic hydrocarbon for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester popularly known as ATV-l of formula IV comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III; wherein hydrogenated product viz tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl
  • the third aspect of the invention is to provide a process for the preparation of Atorvastatin and its pharmaceutical acceptable salt of formula I/IA comprising improved impurity profile wherein the key intermediate of formula IIIA is not isolated and is reacted further with 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II resulting into (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV followed by its conversion into Atorvastatin and its pharmaceutically acceptable salts of formula VIA.
  • the fourth aspect of the present invention is to provide a process for the preparation of Atorvastatin and its pharmaceutical acceptable salt of formula I/IA meeting with pharmaceutical specifications comprising none of the extra purifications of (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl- acetic acid-tertiary butyl ester of formula IV.
  • the fifth aspect of the present invention is to provide a process for controlling impurities during preparation of a compound of formula (I)/(I)A involving an improved or modified process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[ l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: catalytic hydrogenation of (4R,Cis)-l, l-dimethylethyl-6-(2-cyanomethyl)-2,2- dimethyl-l ,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and 3 ⁇ 4 characterized by the fact that generated amino intermediary i.e.
  • tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula TTTA containing minimized (dimer/amide impurity of formula Illb) is not isolated and used as such for Paal-Knorr synthesis by performing further reaction with 4-(4-fluorophenyl)-2-isobutyryl-3- phenyl-4-oxo-N-phenyl-butanamideof formula II.
  • said impurities consists of:
  • One specific aspect of the present invention is to provide an improved process for controlling impurities especially dimer impurities of the formulae given herein below during preparation of compounds namely tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate(IIIA), (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester (IV), (4R-cis)- tert-butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4-[(phenyla
  • Atorvastatin calcium Various dimer impurities which are formed during the entire synthesis of Atorvastatin calcium are:
  • Formula IVa Dimer impurity of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester (ATV-l)
  • Formula G/ Formula Via (wherein R is H or Ca): Dimer impurity of Atorvastatin or its Ca salt.
  • the present invention provides an improved process for generating high purity tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA comprising use of alicyclic hydrocarbon as hydrogenating solvent resulting with minimized dimer/amide impurity of formula Illb; wherein the said intermediary is not isolated; but the purity is determined by the GC analysis as an evidential proof to prove the superiority of catalytic hydrogenation of the present process over the conventional process.
  • the said process comprises: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan- 4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ammonia and 3 ⁇ 4 b) in the meanwhile, reaction mass containing tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate represented by IIIA is given for analysis by Gas Chromatography. The GC results are reported on the basis of Relative Retention Time (RRT).
  • RRT Relative Retention Time
  • IIIA (not isolated): Tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4- yl] acetate
  • the present invention provides an improved process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV having impurities less than 0.l%(w/w, as measured by HPLC), of compound of Formula IVa popularly known as amide or dimer impurity of formula IVa corresponding Relative Retention Time of 0.57and other unknown impurity corresponding Relative Retention Time of 0.42 respectively (refer to Table - 2) wherein process comprises: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3- dioxan-4-
  • the present invention provides a process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof of formula I comprising: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, 3 ⁇ 4 and ammonia
  • the present invention provides an improved process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof having less than 0.1% by wt of dimer/amide impurity of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium of Formula Via wherein R is calcium as measured by HPLC comprising: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l
  • in the present invention for Paal-Knorr synthesis compound of formula II could be prepared by any of the ROS depicted herein below and reacting it with unisolated intermediary tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4- yl] acetate of formula TTTA resulting into (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV.
  • the present invention provides an improved process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof of formula I/IA comprising: a) catalytic hydrogenation of (4R,Cis)-l,l-dimethylethyl-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and 3 ⁇ 4
  • the present invention provides an improved process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutically acceptable salts thereofof formula I/IA comprising: a) catalytic hydrogenation of (4R,Cis)-l,l-dimethylethyl-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and 3 ⁇ 4
  • the present invention provides an improved process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutically acceptable salts and hydrates thereof comprising: a) catalytic hydrogenation of (4R,Cis)-l,l-dimethylethyl-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and 3 ⁇ 4
  • the present invention provides a process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof of formula I comprising: a) treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA
  • the present invention provides a process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof of formula RIA comprising: a) treating cation salt of formula I; wherein cation M is Hydrogen, [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH- pyrrole-l- heptanoic acid is treated with strong base like alkali metal hydroxide to obtain alkali metal salt which is then further treated with calcium salt to obtain [R-(R*, R*]-2- (4-fluorophen
  • a process for controlling impurities is evaluated on the basis (% w/w)especially with reference to amide/ dimer impurities of formulae Illb, IVa, Va and VIa( wherein R is H or Ca) formed during the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid/ calcium more particularly of the formula
  • a process for controlling impurities(%w/w) formed during the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts thereof of formula I/IA wherein individual other unknown impurities at the various RRTs are either not detected or less than 0.05%; while the limit is NMT 0.1% for each one.
  • impurity “Atorvastatin related compound E” is not even detected in Atorvastatin and its pharmaceutically acceptable salts.
  • Atorvastatin or its pharmaceutically acceptable salts prepared by the process of the present invention is thus comparable, commercially viable and superior over than that prepared by the conventional process as discussed in details above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising therapeutically effective amount of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof, preferably [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium salt of formula IA prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • starting compounds of Formula II, III and IIIA are known in the art and can be prepared by any known methods, for example, starting compounds of Formula (II) may be synthesized according to US 5, 124,482 or WO 03/004457or W02006/021968 or US7872154 and compound of Formula III may be synthesized according to US 5,003,080 or US 6,001,615; and precursor of formula II by the process of EP2874992which are incorporated herein by reference.
  • the first step of the foregoing process may include catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III in alicyclic hydrocarbon as solvent, catalyst, ammonia and hydrogen to obtain tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA, removing the catalyst from the reaction mass by filtration followed its reaction with 4-(4-fluorophenyl)-2-isobutyryl-3- phenyl-4-oxo-N-phenyl-butanamide of formula II according to Paal-Knorr pyrrole synthesis in the presence of an acid as catalyst, an amine and phase transfer catalyst as reaction promoting catalyst.
  • Hydrocarbon used in the catalytic hydrogenation is preferably selected from alicycl
  • the hydrogenation catalyst used for the purpose is selected from the group comprising Raney Nickel, sponge Nickel, Molybdenum doped Raney and the like having the similar functionality preferably Raney Nickel.
  • Ammonia used for the purpose is selected from group comprising anhydrous ammonia, ammonia and water preferably water and ammonia.
  • anhydrous ammonia due to its low solubility in alicyclic hydrocarbon preferably cyclohexane due to its non-polar nature.
  • Second using liquid ammonia could raise the pressure during the reaction imparting to unfavorable condition; hence not preferred.
  • the acid catalyst used during Paal-Knorr reaction is selected from any one or more from group comprising pivalic acid, formic acid, acetic acid, butyric acid, valeric acid, isovaleric acid, malic acid, succinic acid, malonic acid, citric acid, benzoic acid, oxalic acid, n-butyric acid and the like or mixtures thereof, preferably pivalic acid or acetic acid or mixtures thereof.
  • Amine required for the reaction is selected from the group comprising primary, secondary amine, tertiary amine preferably di-isopropyl amine.
  • the phase transfer catalyst is selected from group of quaternary ammonium, pyridinium salts and like tetra butyl ammonium salts comprising tetra butyl ammonium chloride/bromide/iodide preferably tetra butyl ammonium sulphate.
  • the order and manner of combining the reactants at any stage of the process are not critical and it may be varied.
  • the reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, any of the reactants may be dissolved together, or their solutions may be combined in any order.
  • Suitable solvents used herein for step a) i.e. for preparing tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III and Paal-Knorr reaction (as tert- butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate is not isolated but used as such), include but are not limited to aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as heptanes, hexane, cyclohexane, and the like; ethers such as methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether and the like; cyclic ethers
  • the step of catalytic hydrogenation is carried out at a temperature at about 35-38°C over a period of 8hrs to 10 hrs.
  • the resultant reaction mass is filtered off to remove the catalyst under the Nitrogen and filtrate is collected; wherein hydrogenated product is not isolated.
  • purity of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan- 4-yl] acetate of formula IIIA is checked on GC which comes out to be at least 99.5% with impurity profile are depicted in comparison table -1 with their relative retention time herein above.
  • [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid ester compound of Formula IV thus formed contains amide/dimer impurity of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of Formula IVa to an appreciably less extent of about 0.034% which is suitable for regulatory standards.
  • the inventors of the present invention have converted the ester compound of Formula IV containing amide impurity of Formula IVa in trace amount is further converted to [R-(R*, R*]-2- (4-fluorophenyl)- b, d-di hydroxy-5-(l-meth yl ethyl )-3-phenyl-4-[(phenylamino)carbonyl]-lH- pyrrole-l- heptanoic acid according to the current process as described herein after, provided high purity [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof in good yields and suitable for regulatory standards.
  • Next step of the aforementioned process involves deprotection of the hydroxy protecting groups by treatment with a suitable acid such as hydrochloric acid, acetic acid, sulfuric acid, oxalic acid, trifluoroacetic acid, phosphoric acid and formic acid in a suitable organic solvent.
  • a suitable acid such as hydrochloric acid, acetic acid, sulfuric acid, oxalic acid, trifluoroacetic acid, phosphoric acid and formic acid in a suitable organic solvent.
  • the organic solvent includes, but is not limited to halogenated solvents such as dichloromethane, chloroform and the like; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, t- butanol and the like; ether solvents such as tetrahydrofuran, diethyl ether and the like; ketone solvents such as methyl ethyl ketone, acetone and the like; ester solvents such as methyl acetate, ethyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; water and mixtures thereof.
  • the suitable acid is hydrochloric acid and the suitable solvent is selected from the group comprising methanol, isopropanol, t-butanol, acetonitrile or mixtures of any of these solvents with water.
  • the deprotection reaction may be carried out at a temperature in the range of about l0°C to about 75 °C, preferably about l5°C to about 65 °C more preferably at RT.
  • the reaction mixture is maintained for 1 hr to about 8 hrs or until completion of the reaction, preferably 3-6 hrs.
  • Formula V can be processed directly in the same reaction medium to prepare the [R-(R*, R*]-2- (4-fluorophenyl)- b, d-di hydroxy-5-(l-meth yl ethyl )-3-phenyl-4-[(phenylamino)carbonyl]-lH- pyrrole-l- heptanoic acid or a cation salt thereof, for example sodium salt, which process involves hydrolysis of the compound of formula V with a suitable base like alkali metal hydroxide in a suitable solvent at a temperature from about lO°C to about 75°C, preferably about 25 °C to about 65 °C.
  • Suitable alkali metal hydroxides include but are not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; preferably sodium hydroxide.
  • Selection of suitable organic solvents used for the alkaline (breaking tert butyl group) reaction can be same as solvents used for the deprotection reaction (acid hydrolysis).
  • suitable solvent is selected from the group comprising methanol, isopropanol, t-butanol, acetonitrile or mixtures of any of these solvents with water.
  • high purity [R-(R*, R*]-2-(4-fluorophenyl)- b,d-dihydroxy- 5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium is obtained having a chemical purity of at least about 98%, as measured by HPLC, preferably at least about 99%, as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC.
  • the present invention provides I R-(R*.
  • the present invention can be best understood from the following examples that also includes examples as per the conventional mode for the preparation of tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate and ATV-l, ATV-2 and Atorvastatin Calcium.
  • the dried filtrate is then charged with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide 0.369 mole (l54.0g), pivalic acid (33.70 g) 0.329 mole, Di-isopropyl amine (25.93 g) 0.256 mole and tetra butyl ammonium hydrogen sulphate (18.58 gm) 0.0547 mole .
  • the contents are heated to reach at 78-85°C and stirring is continued for about 40 hrs till the reaction gets completed as monitored on HPLC.
  • Example-2 Preparation of(4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester:
  • the dried filtrate is then charged with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide 0.36 mole (l54.0g), pivalic acid (33.70 g) 0.329 mole, Di-isopropyl amine (25.93 g) 0.256 mole and tetra butyl ammonium hydrogen sulphate( 18.58 g) 0.0547 mole .
  • the contents are heated to reach at 78- 85 °C and stirring is continued for about 40 hrs till the reaction gets completed as monitored on HPLC.
  • the reaction mass is gradually cooled to and washed with 8% sodium bicarbonate solution followed by water washing.
  • Reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 1000 ml water and 500ml Methyl tert-butyl ether.
  • the aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 at about 40°C using dilute acetic acid followed by addition of solution containing calcium acetate (18 gm, 0.112 mol) in 225 ml water at about 40°C.Slurry was agitated for 30 min at about 50°C and cooled to 45°C, maintained for 120 min and filtered, washed the cake with 50 ml water.
  • Example-4 Preparation of [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate:
  • Mass is subjected for the cooling under stirring till the maximum precipitation.
  • the product is filtered off washed with chilled isopropanol. Dry the product under vacuum at 50-55°C to obtain l lOg of first purified material (99.41 %).Dimer/amide impurity 0.17% and an unknown impurity 0.35%.
  • Second purification (P2) A well equipped 1 lt four neck flask is charged with 110 g Pl (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester followed by the addition of 440 ml isopropanol and the contents were heated at around 70°C till the solution becomes clear. Mass is subjected for the cooling under stirring till the maximum precipitation.
  • the product is filtered off washed with chilled isopropanol. Dry the product under vacuum at 50-55 °C to obtain 102 g of second purified material (99.49%). Dimer/amide impurity 0.12% and an unknown impurity 0.27%.
  • Example-6 Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate (Crude ATV-l to Atorvastatin calcium trihydrate):
  • reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 1000ml water and 500 ml Methyl tert-butyl ether.
  • the aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 at about 40°C using dilute acetic acid followed by addition of solution containing calcium acetate 18 gm, 0.112 mol) in 450ml water at about 40°C. Slurry was agitated for 30 min at about 50°C and cooled to 45 °C, maintained for 120 min and filtered, washed the cake with 50 ml water.
  • Example-7 Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate (ATV-l Pl to Atorvastatin calcium trihydrate):
  • Reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 1000 ml water and 500 ml Methyl tert-butyl ether.
  • the aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 at about 40°C using dilute acetic acid followed by addition of solution containing calcium acetate (18 gm, 0.112 mol) in 450 ml water at about 40°C.
  • Slurry was agitated for 30 min at about 50°C and cooled to 45 °C, maintained for 120 min and filtered, washed the cake with 50 ml water.
  • Example-8 Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate (ATV-l P2 to Atorvastatin calcium trihydrate):
  • Example-9 Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate (ATV-l P3to Atorvastatin calcium trihydrate):

Abstract

The present invention relates to improved process for the preparation of a pyrrole derivative as a racemic mixture, an enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof or a pharmaceutically acceptable salt and hydrates thereof and also intermediates involved therein. Particularly invention is directed to improved processes for the preparation of pyrrole derivatives such as (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(1-methyl-ethyl)-pyrrole-1-yl]-2,2-dimethyl-[1,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV followed by its conversion into [R-(R*, R*]-2-(4-fluorophenyl)- β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1- heptanoic acid particularly calcium salt and its hydrate represented by Formulae I/IA respectively wherein formation of the impurities is either eliminated or minimized in the corresponding intermediaries.

Description

TITLE: An improved and commercially viable process for preparation of pyrrole derivatives with improved impurity profile & minimization of unit operations.
TECHNICAL FIELD: The present invention relates to an improved process for the preparation of a pyrrole derivative as a racemic mixture, an enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof and pharmaceutically acceptable salts thereof and intermediates involved therein. Particularly invention is directed to improved processes for the preparation of pyrrole derivatives such as [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid particularly calcium salt and its hydrate presented by Formulae I/IA respectively; wherein formation of the impurities is either eliminated or minimized in the corresponding intermediaries.
Figure imgf000003_0001
Formula IA
The present invention more particularly relates to an improved process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula (IV) comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III using ammonia, Ho, Raney Nickel, an alicyclic hydrocarbon preferably cyclohexane and water wherein intermediary tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-
I,3-dioxan-4-yl] acetate represented by formula IIIA is not isolated but converted insitu into (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV by performing reaction with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula
II.
Figure imgf000004_0001
Formula IV
Figure imgf000004_0002
Formula III
Figure imgf000004_0003
Unique key feature of the present invention is the use of a single solvent selected from alicyclic hydrocarbon for two reactions namely“catalytic hydrogenation of a cyano compound” and “Paal-Knorr synthesis”; wherein hydrogenated compound is not isolated and reacted further with a diketone in presence of an acid resulting into a pyrrole derivative.
The key feature of the present invention is the use of a single solvent selected from alicyclic hydrocarbon for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester popularly known as ATV-lof formula IV comprising catalytic hydrogenation tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III; wherein hydrogenated product viz.tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate represented by formula IIIA is not isolated and taken ahead as such for Paal- Knorr synthesis by performing reaction with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide of formula II.
Astonishing facts of using single solvent selected from alicyclic hydrocarbon not only controls the impurities especially dimer/amide impurities in tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate and concerned intermediaries thereof but also is characterized by the fact the end product[R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts and hydrates thereof of formula VIA with improved impurity profile meets with pharmacopeial purity parameters without making extra efforts but also minimizes some of unit operations.
Another interesting feature of the present process is the right choice of an alicyclic hydrocarbon which is not only a common solvent for the catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2- cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III and also for Paal-Knorr synthesis producing (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV; but is further characterized by the fact that during the catalytic hydrogenation; formation of impurity of formula Illb gets controlled thereby eliminating or minimizing other dimer/amide impurities of formulae IVa, Va and Via in the upcoming intermediaries and final product. The chosen single solvent selected from alicyclic hydrocarbon plays vital and unique dual role for the two reactions namely catalytic hydrogenation and Paal-Knorr synthesis by avoiding or minimizing the formation of trouble some impurity especially dimer/ amide impurities which creates hell of the problems in going further for the preparation of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-
1- heptanoic acid and its pharmaceutically acceptable salts of formula I especially [R-(R*, R*]-
2-(4-fluorophenyl)- b, d-di hydroxy-5-(l-meth yl ethyl )-3-phenyl-4-[(phenylamino)carbonyl]4H- pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA. The chosen single solvent is alicyclic hydrocarbon preferably cyclohexane. Process of the present invention neither requires solvent distillation/ recovery of the solvent nor the isolation of tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA. Since the unique solvent chosen for the dual purpose in the present invention is the most recommended solvent for the Paal-Knorr synthesis. Hence it facilitates further insitu reaction by performing reaction with 4- (4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II generating compound of formula IV with better dimer/ amide impurity profile.
The present invention fully justifies the very popular proverb in the field of chemistry“ Garbage In Garbage Out” abbreviated as“gigo”as explained below:
Explanation: Tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA prepared by conventional process* *having inferior quality with unwanted impurities (difficult for removal, refer to table 1), which all reflects in further reactions of [R- (R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid .
**Here it is to be noted that the phrase“conventional process” used hereinafter indicates that the tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate that is used for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid is produced by the process comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III using methanolic ammonia (anhydrous ammonia in methanol), Raney Ni and Hydrogen. The said concept is useful for the similar problems with structural related chemical or stereo chemical impurities encountered in other statin and statin intermediates as well.
Chemical names used herein in the specification are popularly abbreviated as given herein below: tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula III: (cyano ketal)/ATS-8 tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA: (amino ketal)/ATS-9/AMN-4
4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide represented by formula II: (DKT 3), DKT-III, 1, 4-diketone.
(4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester or (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester popularly known as ATV-l represented by formula IV.
(4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4- [(phenylamino)carbon yl]-lH-pyrrol-l-yl]ethyl]-2, 2-dimethyl- l,3-dihydroxy-4-acetate popularly known as ATV-2 represented by formula V.
Inventors of the present invention have also focused on the control or minimization of the dimer / amide impurity formed at the various stages as mentioned herein below:
For the present invention the term amide or dimer impurity is used in the context of the following compounds and all of them contribute towards the dimer impurity of Atorvastatin/calcium salt: i) dimer impurity represented by formula Illb refers to dimer impurity of tert-butyl [(4R,Cis)-6- (2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA. This dimer impurity is formed during the reduction of compound of formula III into compound of formula IIIA.
Figure imgf000008_0001
Formula III b ii) dimer impurity represented by formula IVa refers to dimer impurity of ATV-li.e.(4R,cis)-6- [2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester. This impurity is formed during Paal- Knorr reaction when impurity Illb reacts with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo- N-phenyl-butanamide of formula II.
(Also refer to scheme A)
Figure imgf000008_0002
iii) dimer impurity represented by formula Va refers to dimer impurity of ATV-2 i.e.(4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrol-l-yl]ethyl]-2,2-dimethyl-l,3-dihydroxy-4-acetate.This impurity is formed during the acid hydrolysis of compound of formula IV contaminated with impurity of formula IVa.
(Also refer to scheme B)
Figure imgf000008_0003
iv) dimer impurity represented by formula Via refers to dimer impurity of Atorvastatin, wherein R is H or Ca. This impurity is formed during alkaline hydrolysis of compound of formula V contaminated with impurity of formula Va.
Figure imgf000009_0001
i.e. when R is H the impurity is:
Figure imgf000009_0002
and when R is Ca and the impurity is:
Figure imgf000009_0003
SEOUENCIAL CONVERSION OF DIMER IMPURITIES AT THE VARIOUS STAGES:
Figure imgf000010_0001
As per the sequence shown above it is clearly understood that for the formation of dimer/amide impurity of Atorvastatin/calcium salt; the impurities of formulae Illb, IVa, Va acts as precursors.
It has been observed by the present inventors that when tert-butyl [(4R,Cis)-6-(2-aminoethyl)- 2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA prepared by the conventional methods is converted into(4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV, it results in the formation of some prominent impurities of formulae Illb, IVa, Va and Via where in R is H or Ca which are reflected in the final product of formula VIA.
On the other hand; tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA generated by catalytic hydrogenation of corresponding cyano compound of formula III using alicyclic hydrocarbon (like cyclohexane as per the process of the present invention) is not even isolated and reacted further with compound of formula II resulting into formation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV controls or minimizes or eliminates the formation of the impurities of formulae Illb, IVa, Va and Via hence results in superior purity of intermediaries of formulae IV, V and thereby by producing [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and salts thereof directly meeting with pharmacopeial specifications.
ENTIRE SCHEMATIC REPRESENTATION OF THE PRESENT INVENTION IS DEPICTED HEREIN BELOW:
Figure imgf000011_0001
BACKGROUND OF THE INVENTION: Pyrrole derivative [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium is used as a lipid-lowering agent, for treating hypercholesterolemia. The chemical name is [R-(R*,R*)]-2-(4-fluorophenyl)- b, d-dihydroxy- 5-(l-methylethyl)- 3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l- heptanoic acid, calcium salt (2: 1). [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium has the following chemical structure:
Figure imgf000011_0002
In the present specification; the background is viewed & discussed under the three headings: 1. Paal-Knorr reaction.
2. Use of alicyclic hydrocarbon as single solvent for two reactions namely catalytic hydrogenation of compound of formula III and Paal-Knorr synthesis resulting into compound of formula IV, wherein hydrogenated product is not isolated
3. Preparation and insitu use of intermediary tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA in alicyclic hydrocarbon without isolation for Paal-Knorr synthesis.
4. Impurity formation especially dimer impurities of formulae Illb, IVa, VA and Via wherein R is H or Ca respectively.
Figure imgf000012_0001
US4681893 discloses method of preparation of racemic trans-5-(4-fluorophenyl)-2-( 1 - methylethyl)-N, 4-diphenyl- 1 - [2-tetrahydro-4-4- hydroxy- 6-oxo- 2H-pyran-2-yl) ethyl] -1H- pyrrole- carboxamide ("racemic [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid lactone") or its hydroxy acid form or pharmaceutically acceptable salts thereof and methods for its preparation thereof. US5273995 discloses [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid , the pure [R(R*,R*)] enantiomer of 2-(4- fluorophenyl) - b, d-dihydroxy- 5 - ( 1 -methylethyl) - 3 -phenyl-4- [(phenylamino) carbonyl] - 1 H- pyrrole- 1 -heptanoic acid. Also disclosed are hemi calcium , hemimagnesium, hemizinc, monosodium, monopotassium, N-methylglucamine and l-deoxy-l- (methylamino)-D-glucitol salts of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid .
US5969156 discloses [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid hemi calcium crystalline forms I, II and IV and their preparation process. There are several routes to [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid disclosed in the art but the most prominent approach available till date is the pyrrole ring construction (Paal-Knorr pyrrole synthesis), which involves reacting tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula TTTA with 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II to obtain diol protected [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid ester of formula IV, followed by deprotection of the diol functionality and carboxylic acid functional group and then conversion in to [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid , for example, in US 5,003,080, WO 2005/092852 and many other references.
Like any synthetic compound, [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium can contain extraneous compounds or impurities that can come from many sources. Impurities in [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l- heptanoic acid hemi-calcium salts or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The source of these impurities includes unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. Impurities introduced during commercial manufacturing processes must be limited to very small amounts and are preferably substantially absent.
In the United States, the Food and Drug Administration guidelines recommend that the amounts of some unknown individual impurities be limited to less than 0.1 percent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
Stach et al in Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229-246 discloses Synthesis of some impurities and/or degradation products of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid , calcium (3R,5R)-7- [2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol- l-yl]-3,5-dihydroxyheptanoate,. These include its desfluoro analog, the corresponding (3S,5S)- and (3S,5R)-epimers, [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid lactone, and some other potential impurities. The synthesized compounds as well as the corresponding intermediates were characterized by 1H NMR, 13C NMR and MS; but is silent about the removal of these impurities from [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or its pharmaceutically acceptable salts.
Wade et al in Organic Process Research & Development 1997, 1, 320-324 disclosed a rework process for the preparation of high purity [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid by converting [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid sodium salt in to lactone form, crystallizing the lactone from toluene and converting the pure lactone to [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium. This process introduced additional steps of lactone crystallization and isolation to obtain the final product with high purity, which increases the manufacturing cost. Baumann, K. L. et al., Tet. Lett. 1992, 33, 2283-2284 disclosed a process for preparing [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonylJ- lH-pyrrole-l- heptanoic acid which involves preparing a pyrrole intermediate in 75% yield from (4R,Cis)-l,l-dimethylethyl-6-(2-aminoethyl)-2, 2-dimethyl- l,3-dioxane-4-acetate but does not describe the quality of the condensed product. The Paal-Knorr reaction is carried out in a ternary solvent mixture of toluene-heptane-tetrahydrofuran (THF) (1:4: 1) in the presence of pivalic acid as catalyst.
W02004/046105A2 discloses Paal-Knorr reaction comprising condensation between a 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideand amine under acidic conditions at elevated temperatures and in a solvent system comprising tetrahydrofuran.
W02006/032959 discloses Paal-Knorr reaction comprising condensation between a 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideand amine in the presence of n- heptanoic acid and/or 2,2-dimethylbutanoic acid in solvents selected from aliphatic hydrocarbons, aromatic hydrocarbons, and mixtures thereof preferably n- heptane: tetrahydrofuran: toluene (10:5:2.2), reflux, 8h.
WO2007/88553discloses Paal-Knorr reaction comprising condensation between a 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideand amine in cyclohexane in presence of Pivalic acid as catalyst.
WO2006/3944lalso discloses Paal-Knorr reaction comprising condensation between a 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide and an amine in cyclohexane in presence of Pivalic acid as catalyst.
The prior art cited herein above discloses Paal- Knorr reaction comprising condensation between 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II and tert- butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA (a primary amine) in various solvent, binary solvent system or ternary solvent system in presence of an acid as catalyst.
Looking at the various process those are available in the prior art for the preparation of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA. WO2007/29216 discloses preparation of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula IIIA comprising hydrogenation of tert-butyl isopropylidene(TIBIN), 28% ammonia solution, isopropanol using sponge Ni as catalyst.
WO2012/32035 discloses preparation of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula IIIA comprising catalytic hydrogenation of corresponding nitrile of formula III using aqueous ammonia, Raney Nickel as catalyst and isopropanol as solvent.
Tetrahedron Letters, Vol 33, No.l7 (1992), p-2283-2284 disclosed the process for the preparation of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of the formula IIIA by hydrogenation comprising the reaction of corresponding nitrile of formula (III) , ¾, anhydrous ammonia, Molybdenum doped Raney Nickel in methanol. It also discloses hydrogenation comprising ¾, anhydrous ammonia, trimethyl acetic acid, Molybdenum doped Raney Nickel in tetrahydrofuran, methanol, n-heptane, toluene.
US5298627 discloses a process for preparing [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid in one convergent step using a 3,5-heptanoic acid side chain. A precursor of the side chain of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l- heptanoic acid was made by Claisen condensation of N,N-diphenyl acetamide and 4-cyano-3-hydroxybutanoic acid ethyl ester. The resulting 6-cyano-3, 5-dihydroxy hexanoic acid amide was protected with 2,2-dimethoxypropane. The nitrile was hydrogenated with Raney nickel and the resulting (4R,Cis)- 1,1 -dimethylethyl-6-(2-aminoethyl)-2, 2-dimethyl- l,3-dioxane- 4-acetate of formula IIIA. This was reacted with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4- oxo-N-phenyl-butanamidethe compound of formula II, in 2:2: 1 n-heptane: toluenedetrahydrofuran, a ternary solvent system, in the presence of pivalic acid as a catalyst. The intermediate acetonide is hydrolyzed to the carboxylic acid with sodium hydroxide to give [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl] -lH-pyrrole-l- heptanoic acid as the sodium salt.
US5216174 teaches generally that the Paal-Knorr synthesis can be performed on an acetonide- protected 7-amino-3, 5-dihydroxy heptanoic acid tert. -butyl ester in an inert solvent or solvents such as, for example, hexane, toluene and the like for about 24 hours at about reflux temperature of the solvents. The product is not isolated but is treated directly with acid to remove the protecting group.
It also discloses the hydrogenation of compound of formula III with hydrogen in the presence of catalyst such as Raney Nickel, Raney Cobalt and the like in finely divided form in an inert solvent such as methanol, ethanol, isopropanol, tetrahydrofuran and the like with saturated anhydrous ammonia or saturated with aqueous ammonium hydroxide.
US2009/081801 discloses that during the Paal-Knorr pyrrole synthesis, an amide impurity of formula IVa referred as dimer impurity of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester, which is very difficult to remove. It also discloses an improved process for preparing (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV. The said process comprises the step of condensing 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo- N-phenyl-butanamideof formula II, with (4R,Cis)-l,l-dimethylethyl-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxane-4-acetate of formula IIIA, in the presence of a catalytic amount of an acid in the presence of a solvent system, preferably a binary solvent system, to obtain the desired compound (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV. It also relates to an improved process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl- acetic acid-tertiary butyl ester of the formula IV with dimer impurity of formula IVa content of less than 0.16%.
Figure imgf000017_0001
In the entire synthesis of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof, the“Paal-knorr” reaction could be treated as a back bone reaction. The reaction of the tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II is known as the Paal-Knorr Pyrrole synthesis. It involves addition of a primary amine to both keto groups of the 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide and elimination of two moles of water to form the pyrrole.
The synthesis of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid by comprising Paal-Knorr pyrrole synthesis followed by its further conversion into [R-(R*, R*]-2-(4-fluorophenyl)- b,d-dihydroxy- 5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium is presented herein below:
Figure imgf000018_0001
However, it has been known that some of the impurities formed during the synthesis of atorvastatin and THESEARE:
Figure imgf000018_0002
Figure imgf000019_0001
Figure imgf000020_0001
Once these impurities are formed it’s very difficult to remove from desired product by routine crystallization procedures as their solubility index is similar to those of desired products. Furthermore these impurities (especially dimer/amide) are functionally similar to those of desired products and would undergo chemical transformations in similar way in the subsequent reaction steps. Also refer to Sequential conversion of dimer impurities.
Refer to below given schemes:
PLAUSIBLE WAYS OF DIMER IMPURITY FORMATION:
There occurs formation of dimer of tert-butyl [(4R, 6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate represented by formula Illb during the synthesis of compound of formula TTTA. This impurity of formula Illb if not controlled at the stage of catalytic hydrogenation of compound of formula III holds responsible formation of rest of the dimer/amide impurities.
The said dimer/amide impurity of formula IVa is formed when either (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV is further reacted with the unreacted compound of formula IIIA, or it reacts with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl- 4-oxo-N-phenyl-butanamide of formula II.
Formation of Dimer/amide Impurity of ATV-l represented by formula IVa can be best understood by the reaction sequence given herein below: SCHEME A:
Figure imgf000021_0001
The possible reason for the formation of impurity could be attributed to factors like prolonged time for the completion of the reaction, presence of unreacted reactants, role of the solvents during Pall -Knorr reaction etc.
For example; ether impurity of Atorvastatin calcium is generated; when (4R,cis)-6-[2-[3-phenyl- 4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV is subjected for acid hydrolysis using in alcohol like methanol for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- b,d- dihydroxy-5-(l-methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid ester of formula V and somehow the reaction gets prolonged resulting into the concentration of the reaction mass.
It has been observed that when compound (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV if remains contaminated with dimer impurity of formula IVa; and used as such, results into formation of an impurity of Formula Va along with unreacted compound of formula IV is likely formed in the acid hydrolysis step for the preparation of [R- (R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid ester of formula V. Further, when compound V thus formed is hydrolyzed with strong alkaline condition, both compound V and impurity Va gets converted to the [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid sodium salt of formula VI, while unreacted compound IV transforms to another impurity of formula IVb which is again difficult to remove once formed and is precipitated along with [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium .
Refer to below given schemes:
DIMER/AMIDE IMPURITY FORMATION CAN BE BEST UNDERSTOOD BY THE REACTION SEQUENCE GIVEN HEREIN BELOW:
Acid Hydrolysis of contaminated (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester/IV followed by strong base hydrolysis oriented impurities:
It has been observed that (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester contaminated with Dimer impurity of formula IVa is taken for the acid hydrolysis to break the ketal it results into the formation of required dihydroxy compound (4R-cis)- tert-Butyl -6- [2- [2- (4-fluorophenyl)-5-( 1 - methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrol- 1- yl]ethyl]-2,2-dimethyl-l,3-dihydroxy-4-acetate as major product, however compound of formula Va and unreacted (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester remains as impurities.
When this (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4- [(phenylamino)carbonyl]- lH-pyrrol- l-yl]ethyl]-2, 2-dimethyl- l,3-dihydroxy-4-acetateof formula V contaminated with unreacted (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl )-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl esterof formula IV and impurity of formula Va s taken further for strong base hydrolysis e.g. NaOH it results into the formation of sodium salt of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonylJ-lH-pyrrole- 1- heptanoic acid as major products that remains contaminated with impurity of formula Vb and impurity of formula Va.
The whole sequence could be best understood by following set of reactions:
SCHEME B:
Figure imgf000023_0001
Mild base hydrolysis of contaminated ATV-2 oriented impurities:
When (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4- [(phenylamino)carbon yl]-lH-pyrrol-l-yl]ethyl]-2, 2-dimethyl- l,3-dihydroxy-4-acetate of formula V contaminated with impurity Va along with unreacted compound IV is subjected to mild alkaline conditions, the compound Va gets converted in to compound Via while the unreacted compound IV remains unaltered.
SCHEME C:
Figure imgf000024_0001
To reduce this dimer impurity of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl )-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV, multiple crystallizations/purifications are required leading to significant product loss and increase in manufacturing cost.
As per US2009/081801 measures are taken to minimize its content not more than 0.16%, binary solvent systems that includes an alcohol solvent was used during the preparation of compound (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethylj-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV.
(4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethylj-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV prepared by the conventional process contains approximately 0.4 to 0.5% of the amide impurity or so called dimer impurity of compound IV represented by formula IVa requires further purification from organic solvents to reduce the impurity to 0.16%. Such crystallization processes though feasible in laboratory scale are not suitable for large-scale manufacturing processes as it increases the production cost.
IPCOM000225989D discloses the synthesis of compound (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl- acetic acid-tertiary butyl ester of formula IV in the presence of catalytic amount of amidine base [e.g., l,8-diazabicycloundec-7-ene or l,5-diazabicyclo(4.3.0)non-5- ene] to achieve a purity of 99.5% having dimer impurity of formula IVa not more than 0.1%. Although, the process is reproducible, the dimer impurity of formula IVa was present in the level of about 0.2 to 0.4% and required additional purifications to minimize the impurity to not more than 0.1%.
W02017060885A1 discloses an improved process for minimizing the impurities of [R-(R*, R*]- 2-(4-fluorophenyl)- b, d-di hydroxy-5-(l-meth yl ethyl )-3-phenyl-4-[(phenylamino)carbonylJ-lH- pyrrole-l- heptanoic acid and pharmaceutical salts there from comprising the key feature of treating the aqueous solution of sodium salt of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid of formula I with a solvent that is immiscible or slightly miscible in water. It also discloses that the said process results all the below given specified impurities the level of 0.1 % by wt as determine by HPLC in [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof.
In view of the above observations, an improved process for the preparation of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid and pharmaceutically acceptable salts and hydrates thereof is required which is free of above mentioned drawbacks.
None of the prior art cited herein above teaches or motivates to a skilled person in the art to suggest“an improved or modified process for the preparation of (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: Use of a single solvent selected from alicyclic hydrocarbon for the preparation of (4R,cis)-6-[2- [3 -phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester popularly known as ATV-l of formula IV comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl- l,3-dioxan-4-yl] acetate of formula III; wherein hydrogenated product viz tert-butyl [(4R,Cis)-6- (2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula TTTA is not isolated and taken ahead as such for Paal-Knorr synthesis by performing reaction with 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II.
Catalytic hydrogenation of (4R,Cis)- 1,1 -dimethylethyl-6-(2-cyanomethyl)-2, 2-dimethyl- 1,3- dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and Hois characterized by the fact that generated amino intermediary i.e.tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA containing minimized impurity of formula Illb is not isolated and used as such for Paal-Knorr synthesis by performing further reaction with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl- hiitan amide of formula II with improved purity profile over that prepared by the conventional mode of preparation wherein multiple crystallizations are required” (Refer to table 2).This better purity profile ultimately results into [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts and hydrates thereof meeting with pharmacopeial requirements without taking extra efforts.
Inventors of the present invention specifically selected ammonia and water in combination or aqueous ammonia for the purpose. They have collected negative outputs towards the restriction of anhydrous ammonia. As per their observation the key feature of the present invention is the choice of alicyclic hydrocarbon specifically cyclohexane falls under the category of nonpolar solvents and therefore ammonia (anhydrous) does not get dissolved to sufficient extent providing required concentration for conducting the reaction. Secondly using liquid ammonia may pressurize the reaction which is not favorable.
Moreover in the conventional mode during the catalytic hydrogenation of (4R,Cis)-l, l- dimethylethyl-6-(2-cyanomethyl)-2, 2-dimethyl- l,3-dioxane-4-acetate of formula III using methanolic ammonia, Raney Nickel to be used is to be made free from water needs number of methanol washing which inherently increases the risk of making it pyrophoric.
The present invention takes the advantage of differences in the relative reaction rates of the intermediates and/or impurities and provides an improved process for preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts and hydrates thereof to circumvent yield loss for e.g. during the preparation of compound IV, multiple crystallizations are required to reduce the impurity IVa. The inventors of the present invention have thought in the view of the role of a solvent in terms of reaction rates, time of possession of the reaction mass, polarity of the solvent, role of minute amount of water, use of single common solvent for two reactions comprising catalytic hydrogenation and the Paal-Knorr synthesis. Incidentally it so happened that the selection of the solvent kept the check on the unknown impurity represented by formula Illb formed in tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA (not isolated) that is responsible further for the formation of dimer/ amide impurities of formulae IVa, Vaand Via respectively in the upcoming products.
Figure imgf000027_0001
Dimer of of tert-butyl [(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate
Figure imgf000027_0002
Dimer/ Amide impurity of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester
Figure imgf000028_0001
Dimer impurity of ATV-2 (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl] ethyl]-2,2-dimethyl-l,3-dihydroxy-4-acetate.
Figure imgf000028_0002
Dimer/ Amide impurity of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium.
Schematic presentation of the present invention can be depicted as given herein below:
Figure imgf000028_0003
Therefore, present invention fulfill the need in the art and provides an improved process for preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts and hydrates represented by formula I /IA by avoiding/eliminating/minimising the formation of the impurities (especially dimer/amide)formed during the synthesis of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid or pharmaceutically acceptable salts thereof and circumvent disadvantages associated with prior art, proved to be advantageous from industrial point of view and also fulfill purity criteria's led by various regulatory authorities.
In view of the drawbacks of the reported processes, present invention provides a process for controlling impurities with special reference to dimer / amide impurities of formulae Illb, IVa, Va and Via (wherein R is H or Ca) at the various stage during preparation of a compound of formula (I)/(I)A. The inventors of the present invention come up with an improved or modified process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)- 5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: use of single solvent selected from alicyclic hydrocarbon for catalytic hydrogenation of (4R,Cis)- 1 , 1 -dimethylethyl-6-(2-cyanomethyl)-2, 2-dimethyl- 1 ,3-dioxane-4- acetate of formula III in an using water, Raney Nickel, ammonia and H2wherein hydrogenated product viz amino intermediary i.e. tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate represented by formula IIIA with minimized amide impurity is not isolated and used as such for Paal-Knorr synthesis by performing further reaction with 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in presence of an acid and an amine along with phase transfer catalyst affording the (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV with better purity profile. (Refer to table 1 & 2)
(4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl esterof formula IV thus obtained is then taken for the acid hydrolysis affording (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl]-2, 2-dimethyl- 1,3- dihydroxy-4-acetate of formula V followed by alkaline/base hydrolysis to get the compound of formula I/IA wherein M is Na or Ca.
Impurities of Atorvastatin consist of:
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Among these impurities A, B, C, D and E are specified pharmacopieal impurities fall under category of related substances, while F, G and H are detectable pharmacopieal impurities.
Other than these; impurity of formula IVa (is considered as dimer impurity of (4R,cis)-6-[2-[3- phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl] -2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester), impurity of formula IVb, impurity of formula Va, Dimer impurity of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate, Dimer impurity of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium of formula Via wherein R is Ca and ether impurity of Atorvastatin are the impurities which falls under the category of unknown individual impurities and are formed during the formation of [R-(R*, R*]- 2-(4-fluorophenyl)- b, d-di hydroxy-5-(l-meth yl ethyl )-3-phenyl-4-[(phenylamino)carbonyl]-lH- pyrrole-l- heptanoic acid. As per the international pharmacopeia the limit for any unknown individual impurity should not be more than 0.1%.
Impurities discussed herein after or before; if once are formed are difficult to remove from desired product by routine crystallization procedures as their solubility index is similar those of desired products. Furthermore these impurities are functionally similar to those of desired products and would undergo chemical transformations in similar way in the subsequent reaction steps. The chemistry of the impurities formation is already discussed herein above.
Here it becomes important to emphasize that among these impurities; especially Dimer/amide impurities of Illb, IVa, Vaand VIa(wherein R is H or Ca)given herein below are most troublesome as once they are formed they are very difficult to remove. Hence one has to think a way by which their formation is prohibited.
Figure imgf000033_0001
TECHNICAL PROBLEM ASSOCIATED WITH PRIOR ART:
Low purity profile of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA prepared by conventional process comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III using anhydrous ammonia, methanol as solvent, Raney Ni and ¾ followed by its isolation as an oily residue. Conducting Paal - Knorr reaction comprising oily residue of formula IIIA and 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II using cyclohexane as most recommended solvent in presence of an acid results into (4R,cis)-6- [2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV with inferior quality hence affecting the quality of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts of formula VIA. Therefore to meet with required purity profile, multiple crystallizations (at least three) of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester are needed.
The most troublesome impurity during Paal-Knorr reaction is the dimer impurity represented by formula IVa, the precursor of which seems to be impurity of formula Illb (also refer to Scheme A and Table 1).
CONTRIBUTING FACTORS TOWARDS LOW PURITY:
In the view of inventors of the present invention; attributing factors towards low purity of tert- butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate thereby of(4R,cis)-6-[2- [3 -phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester, and associated products prepared by the conventional process could be: i. Choice of solvent
ii. Polarity of solvent chosen
iii. Nature of ammonia used
iv. Rate of reaction
v. Duration for the completion of the reaction
vi. Digestion period given to the reaction mass before isolation of the product from the reaction mass.
TECHNICAL SOLUTION:
The inventors of the present invention have developed a process to achieve high purity profile of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising the use of a single solvent selected from alicyclic hydrocarbon for two reactions namely catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III and for Paal-Knorr synthesis for the preparation of (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester popularly known as ATV-l of formula IV wherein hydrogenated product tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4- yl] acetate represented by formula IIIA is not isolated and used as such.
The said process of the present invention comprises catalytic hydrogenation of (4R,Cis)-l,l- dimethylethyl-6-(2-cyanomethyl)-2, 2-dimethyl- l,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and ¾ characterized by the fact that generated amino intermediary tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4- yl] acetate represented by formula IIIA containing minimized dimer/amide impurity represented by formula Illb is used as such( without isolation) for Paal-Knorr synthesis by performing further reaction with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II resulting into high quality (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)- 5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV and hence that of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts of formula VIA there upon.
Choice of alicyclic hydrocarbon preferably cyclohexane as a single solvent for the catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III resulting into tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA wherein hydrogenated product of formula represented by IIIA is not isolated; and also for Paal-Knorr synthesis for the preparation of (4R,cis)-6-[2-[3- phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl] -2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV not only controls the impurity formation in itself and further products thereof but also contributes towards minimization of the unit operations those required in conventional process mentioned herein below: i. No distillation of alcoholic solvent, use of multiple solvents from binary or ternary solvent system is required.
ii. No isolation of hydrogenated product viz.tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate is required as in conventional process.
iii. No transferring the tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4- yl] acetate obtained in the second step into cyclohexane as it is already existing solvent used for the catalytic hydrogenation and most recommended solvent in the most of the prior art for the Paal-Knorr reaction in presence of acid as catalyst preferably Pivalic acid.
iv. No multiple crystallizations required for purifying (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester to achieve the desired purity.
ADVANTAGES OF THE PRESENT INVENTION: i. Use of single solvent selected from alicyclic hydrocarbon for two different reactions namely catalytic hydrogenation and Paal-Knorr synthesis; wherein hydrogenated product is not isolated.
ii. Tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate though not isolated possesses high purity containing lesser unknown individual especially dimer/impurities than those formed in conventional process.
iii. Use of a single solvent selected from alicyclic hydrocarbon for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl-ethyl)- pyrrole- l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester popularly known as ATV-l of formula IV comprising catalytic hydrogenation tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III; wherein hydrogenated product viz tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA is not isolated and taken ahead as such for Paal-Knorr synthesis by performing reaction with 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II yielding ATV - 1 with high purity and improved impurity profile.
iv. Use of alicyclic hydrocarbon as solvent furnishes high purity profile of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA(not isolated)over the prior art methods comprising polar solvents like methanol, ethanol, isopropanol, tetrahydrofuran and like.
v. Use of multiple solvent as binary solvent system or ternary solvent used for Paal- Knorr reaction is avoided.
vi. Minimization of unit operations as discussed herein above. vii. Process of the present invention controls the impurities especially dimer/amide of formulae Illb, IVa, Va and Via (wherein R is H or Ca)formed at various stages of Atorvastatin and its salt.
viii. Highly pure tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate generated therein imparts high purity to (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester(resulting after Paal-Knorr reaction) and consequently [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-
3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutically acceptable salts then after.
ix. High purity profile of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-
4-yl] acetate of formula IIIA and hence purity profile of subsequent products gets enhanced and the final products reaches at the pharmacopeial passing quality without making more efforts making process commercially viable.
x. Multiple crystallizations of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester are avoided thereby minimizing yield loss.
Accordingly, there is a need for a process of synthesis for preparing [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid and its pharmaceutically acceptable salts of formula VIA, wherein the impurities especially dimer/amide formed are either minimized or eliminated.
SUMMARY OF THE INVENTION:
The present invention relates to an improved process for preparation of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid and pharmaceutically acceptable salts thereof represented by formula VIA with high purity particularly [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA wherein the impurities formed are either minimized or eliminated.
Figure imgf000038_0001
Formula I Formula IA
The present invention particularly relates to an improved or modified process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole- l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: catalytic hydrogenation of (4R,Cis)- 1,1 -dimethylethyl-6-(2-cyanomethyl)-2, 2-dimethyl- 1,3- dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and H2 characterized by the fact that generated amino intermediary i.e. tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA(not isolated) with minimized dimer/amide impurity of formula Illbis used as such for Paal-Knorr synthesis by performing further reaction with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl- butanamideof formula II and catalyst.
The key feature of the present invention is the use of a single solvent selected from alicyclic hydrocarbon for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester popularly known as ATV-l of formula IV comprising catalytic hydrogenation tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III; wherein hydrogenated product viz tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate represented by formula IIIA is not isolated and taken ahead as such for Paal- Knorr synthesis by performing reaction with4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide of formula II.
This (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV is converted via subsequent steps into [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof of formula V IA with improved impurity profile meeting with pharmacopeial requirements without making extra efforts as required in the conventional process available in the prior art like multiple crystallizations.
Impurities discussed herein above; if once are formed are difficult to remove from desired product by routine crystallization procedures as their solubility index is similar those of desired products. Furthermore these impurities are functionally similar to those of desired products and would undergo chemical transformations in similar way in the subsequent reaction steps as depicted herein below.
SEQUENTIAL CONVERSION OF DIMER IMPURITIES FROM THE VARIOUS STAGES:
Figure imgf000039_0001
DETAILED DISCREPTION OF THE INVENTION:
The preferred embodiments described herein detail for illustrative purposes are subject to many variations. It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient but are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
The term“first”,“second” and the like, herein do not denote any order, quantity or importance, but rather are used to distinguish one element from another, and the terms“a” and“an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.
Along with the main aspect of the invention as discussed below and above; all other aspects of the present invention are discussed herein after in details via different embodiments.
The first aspect of the present invention is to use a single solvent selected from alicyclic hydrocarbon for two reactions namely catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2- cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III and Paal-Knorr synthesis for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester popularly known as ATV-l of formula IV wherein hydrogenated product tert-butyl [(4R,Cis)-6- (2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula TTTA is not isolated and used as such.
The second aspect of the present invention is to use a single solvent selected from alicyclic hydrocarbon for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester popularly known as ATV-l of formula IV comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III; wherein hydrogenated product viz tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate represented by formula IIIA is not isolated and taken ahead as such for Paal- Knorr synthesis by performing reaction with4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide of formula II.
The third aspect of the invention is to provide a process for the preparation of Atorvastatin and its pharmaceutical acceptable salt of formula I/IA comprising improved impurity profile wherein the key intermediate of formula IIIA is not isolated and is reacted further with 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II resulting into (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV followed by its conversion into Atorvastatin and its pharmaceutically acceptable salts of formula VIA.
The fourth aspect of the present invention is to provide a process for the preparation of Atorvastatin and its pharmaceutical acceptable salt of formula I/IA meeting with pharmaceutical specifications comprising none of the extra purifications of (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl- acetic acid-tertiary butyl ester of formula IV.
The fifth aspect of the present invention is to provide a process for controlling impurities during preparation of a compound of formula (I)/(I)A involving an improved or modified process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[ l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: catalytic hydrogenation of (4R,Cis)-l, l-dimethylethyl-6-(2-cyanomethyl)-2,2- dimethyl-l ,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and ¾ characterized by the fact that generated amino intermediary i.e. tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula TTTA containing minimized (dimer/amide impurity of formula Illb) is not isolated and used as such for Paal-Knorr synthesis by performing further reaction with 4-(4-fluorophenyl)-2-isobutyryl-3- phenyl-4-oxo-N-phenyl-butanamideof formula II. (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl- acetic acid- tertiary butyl ester of formula IV thus obtained is then taken for the acid hydrolysis affording (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4- [(phenylamino)carbon yl]-lH-pyrrol-l-yl]ethyl]-2, 2-dimethyl- l,3-dihydroxy-4-acetate of formula V followed by alkaline hydrolysis to get the compound of formula I/IA where in cation is M.
Figure imgf000041_0001
O LLLL
Formula III
Figure imgf000042_0001
Figure imgf000043_0001
Formula IA
Wherein said impurities consists of:
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000045_0003
One specific aspect of the present invention is to provide an improved process for controlling impurities especially dimer impurities of the formulae given herein below during preparation of compounds namely tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate(IIIA), (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester (IV), (4R-cis)- tert-butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrol-l-yl]ethyl]-2,2-dimethyl-l,3-dihydroxy-4-acetate (V) and[R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid and its pharmaceutically acceptable salts especially [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium .
Various dimer impurities which are formed during the entire synthesis of Atorvastatin calcium are:
Figure imgf000045_0001
Formula Illb
Formula Illb: Dimer impurity of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan- 4-yl] acetate (IIIA)
Figure imgf000045_0002
Formula IVa: Dimer impurity of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester (ATV-l)
Figure imgf000046_0001
Formula Va: Dimer impurity of(4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl - ethyl)-3-phen yl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl]-2, 2-dimethyl- 1, 3-dihydroxy- 4-acetate (ATV-2)
Figure imgf000046_0002
Or as calcium salt shown below
Figure imgf000046_0003
Formula G/ Formula Via (wherein R is H or Ca): Dimer impurity of Atorvastatin or its Ca salt.
In accordance with first embodiment, the present invention provides an improved process for generating high purity tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA comprising use of alicyclic hydrocarbon as hydrogenating solvent resulting with minimized dimer/amide impurity of formula Illb; wherein the said intermediary is not isolated; but the purity is determined by the GC analysis as an evidential proof to prove the superiority of catalytic hydrogenation of the present process over the conventional process.
The said process comprises: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan- 4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ammonia and ¾ b) in the meanwhile, reaction mass containing tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate represented by IIIA is given for analysis by Gas Chromatography. The GC results are reported on the basis of Relative Retention Time (RRT).
Figure imgf000047_0001
The comparison table- 1 given herein below clearly indicates the superiority of the process of the present invention over the conventional process available in the prior art for the preparation of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA. The GC purity of the said compound of formula IIIA is studied with respect to two unknown individual impurities corresponding to RRT of 0.55 and 0.91 respectively.
Comparison Table-1
Figure imgf000047_0002
Figure imgf000048_0002
wherein: IIIA (not isolated): Tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4- yl] acetate
Figure imgf000048_0001
The tabular representation as depicted herein above (Ref:Table-l) clearly indicates that the process of present invention is superior over the conventional process.
Looking at individual GC impurity profile; the impurity corresponding to RRT of 0.55 and 0.91 becomes nil.
Looking at GC purity of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA prepared and isolated by conventional process as depicted in the comparison table is 99.35%, while process of present invention imparts 99.70%.
Therefore the concept of using alicyclic hydrocarbon preferably cyclohexane as a single solvent for the reaction comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)- 2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III, water, ammonia and Raney Ni and ¾ shows its inventive feature, making the process non obvious to a person skilled in the art.
According to second embodiment of the present invention, an improved or modified process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ammonia and ¾;
b) wherein hydrogenated product is not isolated
c) using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with minimized dimer/ amide impurity of formula Illb
d) adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV
Figure imgf000049_0001
The following comparison table-2 clearly indicates the superiority of the process of the present invention over the conventional process available in the prior art for the preparation of (4R,cis)- 6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV via performing insitu reaction of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl- but an amide of formula II in the existing solvent wherein existing alicyclic solvent is cyclohexane.
Comparison Table-2
Figure imgf000050_0002
Figure imgf000050_0001
Figure imgf000050_0003
Figure imgf000050_0004
Figure imgf000050_0009
Figure imgf000050_0010
Figure imgf000050_0011
Figure imgf000050_0012
Figure imgf000050_0013
Figure imgf000050_0006
Figure imgf000050_0007
Figure imgf000050_0008
Figure imgf000050_0005
Wherein
IV: (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester
Figure imgf000051_0001
IVa: Dimmer/ amide imp of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)- 5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester:
Figure imgf000051_0002
The tabular representation as depicted herein above (Ref:Table-2) clearly indicates that the process of present invention is superior over the conventional process as it differs remarkably in their purity and impurity profile.
When compound of formula IV prepared by conventional process comprising isolated tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula TTTA (involving catalytic hydrogenation of compound of formula III using methanolic anhydrous ammonia) is reacted with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl- biitanamideof formula II resulting into crude (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV(99.25% pure) contains 0.40% an unknown impurity(RRT:0.42)and 0.24% dimer/amide impurity of formula IV (RRT:0.57) represented by formula IVa. To bring the impurities upto a permissible limit, at least three crystallizations are required which not only increases the no of unit operations but also contributes the yield loss by 6-8 % per crystallization there by making the process non-viable. Therefore, conventional process leads to substantial decline of product yield. Furthermore; in spite of having three purifications of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester the unknown individual impurity corresponding to RRT of 0.42 does not result into lesser than 0.21% (whereas limit for any unknown individual impurity NMT 0.1%) and dimer impurity reaches to 0.06%.
On the contrary(4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV prepared by process of the present invention comprising use of single solvent selected from alicyclic hydrocarbon for catalytic hydrogenation of [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl- l,3-dioxan-4-yl] acetate of formula III resulting into tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA(kept unisolated) and for Paal- Knorr synthesis wherein unisolated IIIA is reacted further with 4-(4-fluorophenyl)-2-isobutyryl-
3-phenyl-4-oxo-N-phenyl-butanamideof formula II resulting into crude(4R,cis)-6-[2-[3-phenyl-
4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester(99.66% pure) devoid of impurity corresponding to (RRT:0.42) while dimer impurity of formula IVa to be 0.034% against 0.06% obtained by conventional mode and three purifications performed; therefore shows its inventive feature, making the process non obvious to a person skilled in the art for Paal-Knorr synthesis of compound of formula IV.
In accordance with another embodiment, the present invention provides an improved process for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV having impurities less than 0.l%(w/w, as measured by HPLC), of compound of Formula IVa popularly known as amide or dimer impurity of formula IVa corresponding Relative Retention Time of 0.57and other unknown impurity corresponding Relative Retention Time of 0.42 respectively (refer to Table - 2) wherein process comprises: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ammonia and H2; b) wherein hydrogenated product is not isolated
c) using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA with minimized dimer/ amide impurity of formula Illb
d) adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6-[2- [3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]- 2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV
e) isolating (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV with minimized dimer/ amide impurity of formula IV a
Figure imgf000053_0001
In accordance with another embodiment, the present invention provides a process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof of formula I comprising: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ¾ and ammonia
b) wherein the hydrogenated compound is not isolated
c) using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with minimized dimer/ amide impurity of formula Illb
d) adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6- [2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l- yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV with minimized dimer/ amide impurity of formula IVa
e) hydrolyzing the compound of formula IV in a suitable solvent in the presence of an acid to obtain (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3- phenyl-4-[(phenylamino)carbon yl]-lH-pyrrol- l-yl]ethyl]-2, 2-dimethyl- 1,3- dihydroxy-4-acetate of formula V with minimized dimer/ amide impurity of formula Va;
f) hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof;
g) treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA with minimized dimer/ amide impurity of Atorvastin or its Ca salt
Figure imgf000054_0001
In accordance with another embodiment, the present invention provides an improved process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof having less than 0.1% by wt of dimer/amide impurity of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium of Formula Via wherein R is calcium as measured by HPLC comprising: a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ¾ and ammonia
b) wherein the hydrogenated compound is not isolated
c) using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA with minimized dimer/ amide impurity of formula Illb
d) adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6- [2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l- yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV with minimized dimer/ amide impurity of formula IVa
e) hydrolyzing the compound of formula IV in a suitable solvent in the presence of an acid to obtain (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl]-2, 2-dimethyl- 1,3- dihydroxy-4-acetate of formula V with minimized dimer/ amide impurity of formula Va
f) hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof;
g) treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA with minimized dimer/ amide impurity of Atorvastin or its Ca salt.
Figure imgf000055_0001
Dimer/amide impurity of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3 -phenyl -4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or its calcium salt
The following comparison table-3 clearly indicates the superiority of the process of the present invention over the conventional process available in the prior art for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l- heptanoic acid calcium of formula IA using the process of the present invention.
The tabular representation as depicted herein below (Ref: Table-3) clearly indicates that the process of present invention is superior over the conventional process as it differs remarkably in their purity and impurity profile. Crude compound of formula IV obtained by the conventional process requires at least two to three purifications to meet with the dimer impurity in [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l- heptanoic acid calcium final in passing limit.
Comparison Table-3
Figure imgf000056_0001
Figure imgf000057_0005
Figure imgf000057_0006
Figure imgf000057_0003
Figure imgf000057_0004
Figure imgf000057_0002
On the contrary compound of formula IV crude itself obtained by the process of the present invention results in very much satisfactory range of dimer impurity of [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium final meets as per the pharmacopeial limit for the said impurity.
From the above [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium analysis; it is clearly understood that in spite having the two to three additional purifications of compound of formula IV, % impurity in Atorvastain or its calcium salt does not even meet with that obtained from present invention.
In accordance with one more embodiment, in the present invention for Paal-Knorr synthesis compound of formula II could be prepared by any of the ROS depicted herein below and reacting it with unisolated intermediary tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4- yl] acetate of formula TTTA resulting into (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV.
US5124482 (Warner Lambert):
Figure imgf000057_0001
W02006/021968 (Biocon):
Figure imgf000058_0001
WO 03/004457(Ciba)and US7872154 (Arch)
Figure imgf000058_0002
In accordance with another embodiment, the present invention provides an improved process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof of formula I/IA comprising: a) catalytic hydrogenation of (4R,Cis)-l,l-dimethylethyl-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and ¾
b) wherein hydrogenated product is not isolated
c) using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula TTTA d) adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV; wherein 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamideof formula II is prepared by the process depicted in the scheme herein below
e) hydrolyzing the compound of formula IV in a suitable solvent in presence of an acid to obtain (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)- 3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrol- l-yl]ethyl]-2, 2-dimethyl- 1,3- dihydroxy-4- acetate of formula V
f) hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof;
g) treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- b,d- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA
Figure imgf000059_0001
In accordance with similar embodiment, the present invention provides an improved process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutically acceptable salts thereofof formula I/IA comprising: a) catalytic hydrogenation of (4R,Cis)-l,l-dimethylethyl-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and ¾
b) wherein hydrogenated product is not isolated
c) using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula TTTA d) adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV; wherein 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide of formula II is prepared by the process depicted in the scheme herein below
e) hydrolyzing the compound of formula IV in a suitable solvent in presence of an acid to obtain (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)- 3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrol- l-yl]ethyl]-2, 2-dimethyl- 1,3- dihydroxy-4- acetate of formula V
f) hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof;
g) treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- b,d- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA
Figure imgf000060_0001
In accordance with similar embodiment, the present invention provides an improved process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutically acceptable salts and hydrates thereof comprising: a) catalytic hydrogenation of (4R,Cis)-l,l-dimethylethyl-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxane-4-acetate of formula III in an alicyclic hydrocarbon, water, Raney Nickel, ammonia and ¾
b) wherein hydrogenated product is not isolated
c) using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula TTTA d) adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV; wherein 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide of formula II is prepared by the process depicted in the scheme herein below
e) hydrolyzing the compound of formula IV in a suitable solvent in presence of an acid to obtain (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)- 3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrol- l-yl]ethyl]-2, 2-dimethyl- 1,3- dihydroxy-4-acetate of formula V
f) hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof;
g) treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- b,d- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA
Figure imgf000062_0001
In accordance with one embodiment, the present invention provides a process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof of formula I comprising: a) treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA
Figure imgf000062_0002
In accordance with one embodiment, the present invention provides a process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and pharmaceutical salts thereof of formula RIA comprising: a) treating cation salt of formula I; wherein cation M is Hydrogen, [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH- pyrrole-l- heptanoic acid is treated with strong base like alkali metal hydroxide to obtain alkali metal salt which is then further treated with calcium salt to obtain [R-(R*, R*]-2- (4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA
Figure imgf000063_0001
According to yet another embodiment of the present invention, provided is a process for controlling impurities is evaluated on the basis (% w/w)especially with reference to amide/ dimer impurities of formulae Illb, IVa, Va and VIa( wherein R is H or Ca) formed during the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid/ calcium more particularly of the formula
Figure imgf000063_0002
According to yet another embodiment of the present invention, provided is a process for controlling impurities(%w/w) formed during the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts thereof of formula I/IA devoid of Atorvastatin Related Compound B (Isomer), Atorvastatin Related Compound C (Difluoro), Atorvastatin Related Compound D (Epoxide), Methyl ester (other known imp), Oxo impurity(other known imp), Atorvastatin related compound E(Enantiomeric impurity) and Ether imp of Atorvastatin.
According to yet another embodiment of the present invention, provided is a process for controlling impurities(%w/w) formed during the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts thereof of formula I/IA wherein dimer/amide impurities of formulae Illb, IVa,Va and VIa(wherein R is H or Ca) respectively are less than
O.05% in the intermediates of formulae III, IV, V and Atorvastatin and its pharmaceutically acceptable salts, while the limit is NMT 0.1% for each one.
According to yet another embodiment of the present invention, provided is a process for controlling impurities(%w/w) formed during the preparation of [R-(R*, R*]-2-(4-fluorophenyl)-
P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts thereof of formula I/IA wherein any other known impurities are either not detected or are less than 0.07%;while the limit is NMT 0.1% for each one.
According to yet another embodiment of the present invention, provided is a process for controlling impurities(%w/w) formed during the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts thereof of formula I/IA wherein individual other unknown impurities at the various RRTs are either not detected or less than 0.05%; while the limit is NMT 0.1% for each one.
According to yet another embodiment of the present invention, provided is a process for controlling impurities(%w/w) formed during the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid and its pharmaceutically acceptable salts thereof of formula I/IA wherein total impurity(not including Atorvastatin related compound E) is 0.28% against 0.28% by conventional mode achieved after three purifications of compound of formula IV. However it becomes important to emphasize here that impurity “Atorvastatin related compound E” is not even detected in Atorvastatin and its pharmaceutically acceptable salts.
Therefore it is seen here that Atorvastatin or its pharmaceutically acceptable salts prepared by the process of the present invention is thus comparable, commercially viable and superior over than that prepared by the conventional process as discussed in details above.
In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising therapeutically effective amount of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof, preferably [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium salt of formula IA prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
The starting compounds of Formula II, III and IIIA are known in the art and can be prepared by any known methods, for example, starting compounds of Formula (II) may be synthesized according to US 5, 124,482 or WO 03/004457or W02006/021968 or US7872154 and compound of Formula III may be synthesized according to US 5,003,080 or US 6,001,615; and precursor of formula II by the process of EP2874992which are incorporated herein by reference.
Figure imgf000065_0001
The first step of the foregoing process may include catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III in alicyclic hydrocarbon as solvent, catalyst, ammonia and hydrogen to obtain tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA, removing the catalyst from the reaction mass by filtration followed its reaction with 4-(4-fluorophenyl)-2-isobutyryl-3- phenyl-4-oxo-N-phenyl-butanamide of formula II according to Paal-Knorr pyrrole synthesis in the presence of an acid as catalyst, an amine and phase transfer catalyst as reaction promoting catalyst. Hydrocarbon used in the catalytic hydrogenation is preferably selected from alicyclic hydrocarbon selected from the group comprising cyclohexane, and the like preferably cyclohexane.
The hydrogenation catalyst used for the purpose is selected from the group comprising Raney Nickel, sponge Nickel, Molybdenum doped Raney and the like having the similar functionality preferably Raney Nickel.
Ammonia used for the purpose is selected from group comprising anhydrous ammonia, ammonia and water preferably water and ammonia. The limitation observed in using anhydrous ammonia due to its low solubility in alicyclic hydrocarbon preferably cyclohexane due to its non-polar nature. Second using liquid ammonia could raise the pressure during the reaction imparting to unfavorable condition; hence not preferred.
The acid catalyst used during Paal-Knorr reaction is selected from any one or more from group comprising pivalic acid, formic acid, acetic acid, butyric acid, valeric acid, isovaleric acid, malic acid, succinic acid, malonic acid, citric acid, benzoic acid, oxalic acid, n-butyric acid and the like or mixtures thereof, preferably pivalic acid or acetic acid or mixtures thereof.
Amine required for the reaction is selected from the group comprising primary, secondary amine, tertiary amine preferably di-isopropyl amine.
The phase transfer catalyst is selected from group of quaternary ammonium, pyridinium salts and like tetra butyl ammonium salts comprising tetra butyl ammonium chloride/bromide/iodide preferably tetra butyl ammonium sulphate.
The order and manner of combining the reactants at any stage of the process are not critical and it may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, any of the reactants may be dissolved together, or their solutions may be combined in any order.
Examples of suitable solvents used herein for step a) i.e. for preparing tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III and Paal-Knorr reaction (as tert- butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate is not isolated but used as such), include but are not limited to aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as heptanes, hexane, cyclohexane, and the like; ethers such as methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether and the like; cyclic ethers such as tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers such as 2- methyl tetrahydrofuran and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; ketones such as acetone, methyl ethyl ketone and the like; dialkylformamides such as dimethyl formamide and the like, dialkylacetamides such as dimethyl acetamide and the like; dialkylsulfoxides such as dimethyl sulfoxide and the like. Preferably, the suitable organic solvent is cyclohexane.
The step of catalytic hydrogenation is carried out at a temperature at about 35-38°C over a period of 8hrs to 10 hrs. After completion of the reaction, the resultant reaction mass is filtered off to remove the catalyst under the Nitrogen and filtrate is collected; wherein hydrogenated product is not isolated. Meanwhile purity of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan- 4-yl] acetate of formula IIIA is checked on GC which comes out to be at least 99.5% with impurity profile are depicted in comparison table -1 with their relative retention time herein above.
This organic layer obtained from step b) containing tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA(not isolated) is given the water washing and taken ahead as such without isolating product for further reaction by the addition of 4-(4- fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II, acid as catalyst, amine and phase transfer catalyst. After completion of the reaction in about 40 hrs at about 75°Cthe resultant compound of Formula IV is isolated by known techniques. No additional purification is required as it provides excellent quality product which not only minimizes the unit operations but also avoids the yield loss, thereby making the process viable in all aspects. (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV is dried according to any of the methods known in the art such as a tray dryer, vacuum oven, air oven and the like. [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid ester compound of Formula IV thus formed contains amide/dimer impurity of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of Formula IVa to an appreciably less extent of about 0.034% which is suitable for regulatory standards.
The inventors of the present invention have converted the ester compound of Formula IV containing amide impurity of Formula IVa in trace amount is further converted to [R-(R*, R*]-2- (4-fluorophenyl)- b, d-di hydroxy-5-(l-meth yl ethyl )-3-phenyl-4-[(phenylamino)carbonyl]-lH- pyrrole-l- heptanoic acid according to the current process as described herein after, provided high purity [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof in good yields and suitable for regulatory standards.
Next step of the aforementioned process involves deprotection of the hydroxy protecting groups by treatment with a suitable acid such as hydrochloric acid, acetic acid, sulfuric acid, oxalic acid, trifluoroacetic acid, phosphoric acid and formic acid in a suitable organic solvent.
The organic solvent includes, but is not limited to halogenated solvents such as dichloromethane, chloroform and the like; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, t- butanol and the like; ether solvents such as tetrahydrofuran, diethyl ether and the like; ketone solvents such as methyl ethyl ketone, acetone and the like; ester solvents such as methyl acetate, ethyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; water and mixtures thereof. Preferably, the suitable acid is hydrochloric acid and the suitable solvent is selected from the group comprising methanol, isopropanol, t-butanol, acetonitrile or mixtures of any of these solvents with water.
The deprotection reaction may be carried out at a temperature in the range of about l0°C to about 75 °C, preferably about l5°C to about 65 °C more preferably at RT. The reaction mixture is maintained for 1 hr to about 8 hrs or until completion of the reaction, preferably 3-6 hrs. The resultant (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4- [(phenylamino)carbon yl]-lH-pyrrol-l-yl]ethyl]-2, 2-dimethyl- l,3-dihydroxy-4-acetate of
Formula V can be processed directly in the same reaction medium to prepare the [R-(R*, R*]-2- (4-fluorophenyl)- b, d-di hydroxy-5-(l-meth yl ethyl )-3-phenyl-4-[(phenylamino)carbonyl]-lH- pyrrole-l- heptanoic acid or a cation salt thereof, for example sodium salt, which process involves hydrolysis of the compound of formula V with a suitable base like alkali metal hydroxide in a suitable solvent at a temperature from about lO°C to about 75°C, preferably about 25 °C to about 65 °C.
Suitable alkali metal hydroxides include but are not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; preferably sodium hydroxide. Selection of suitable organic solvents used for the alkaline (breaking tert butyl group) reaction can be same as solvents used for the deprotection reaction (acid hydrolysis). Preferably, suitable solvent is selected from the group comprising methanol, isopropanol, t-butanol, acetonitrile or mixtures of any of these solvents with water.
After completion of the ester hydrolysis of the reaction mixture containing [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid sodium may be treated with a suitable carbon followed by treating with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof formula IA.
According to the present invention, high purity [R-(R*, R*]-2-(4-fluorophenyl)- b,d-dihydroxy- 5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium is obtained having a chemical purity of at least about 98%, as measured by HPLC, preferably at least about 99%, as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC.The present invention provides I R-(R*. R*1-2-(4-fluorophenyl)- B.b-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl1-lH-pyrrole-l- heptanoic acid calcium, obtained by the process described herein, having all the unknown detectable individual impurities less than 0.05% Inventors of the present invention emphasize here that isolation of the tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula IIIA prepared by the catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate of formula III in alicyclic hydrocarbon preferably cyclohexane and using further for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole- l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester comprising the reaction with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in cyclohexane in presence of acid and catalyst if any falls under the scope of the present invention.
The present invention can be best understood from the following examples that also includes examples as per the conventional mode for the preparation of tert-butyl [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate and ATV-l, ATV-2 and Atorvastatin Calcium.
Preparation of Atorvastatin and its pharmaceutically acceptable salts:
MODE OF THE PRESENT INVENTION:
Example 1: Preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester:
A mixture oftert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate 100.0 g (0.371 mole), 7 vol. cyclohexane, 1 vol of ammonia dispersed in water having 20-24% concentration and 20% by weight of pre washed Raney Ni is charged in an autoclave and hydrogenation is continued at about 30-40°C at a pressure around 5 kg/cm till the absorption of hydrogen is ceased to absorb. GC analysis revealed completion of the reaction (99.70%)The reaction mass is cooled to 25-30°C and the catalyst was removed by filtration under Nitrogen blanket. Filtrate so collected was dehydrated to make it free from water.
The dried filtrate is then charged with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide 0.369 mole (l54.0g), pivalic acid (33.70 g) 0.329 mole, Di-isopropyl amine (25.93 g) 0.256 mole and tetra butyl ammonium hydrogen sulphate (18.58 gm) 0.0547 mole .The contents are heated to reach at 78-85°C and stirring is continued for about 40 hrs till the reaction gets completed as monitored on HPLC. The reaction mass is gradually cooled to and washed with 8% sodium bicarbonate solution followed by water washing cyclohexane is distilled of under the reduced pressure. Traces of solvent are removed by using isopropanol. Finally (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester is isolated by using water as antisolvent. Product is filtered off washed with water. Dry the product under vacuum at 50-55° to obtain (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester as off-white solid material (200 gm, 82.30% yield) HPLC purity 99.6% , Dimer/amide impurity 0.034%.
Example-2: Preparation of(4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester:
A mixture of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate . (0.371 mole), 7 vol. cyclohexane, 1 vol of ammonia dispersed in water having 20-24% concentration and 25% by weight of pre washed Raney Ni is charged in an autoclave and hydrogenation is continued at about 30-40°C at a pressure around 5 kg/cm till the absorption of hydrogen is ceased to absorb. GC analysis revealed completion of the reaction. The reaction mass was cooled to 25-30°C and the catalyst was removed by filtration under Nitrogen blanket. Filtrate so collected was dehydrated to make it free from water. The dried filtrate is then charged with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide 0.36 mole (l54.0g), pivalic acid (33.70 g) 0.329 mole, Di-isopropyl amine (25.93 g) 0.256 mole and tetra butyl ammonium hydrogen sulphate( 18.58 g) 0.0547 mole .The contents are heated to reach at 78- 85 °C and stirring is continued for about 40 hrs till the reaction gets completed as monitored on HPLC.The reaction mass is gradually cooled to and washed with 8% sodium bicarbonate solution followed by water washing. Cyclohexane is distilled of under the reduced pressure. Traces of solvent are removed by using isopropanol. Finally (4R,cis)-6-[2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl- acetic acid-tertiary butyl ester is isolated by using water as antisolvent. Product is filtered off washed with water. Dry the product under vacuum at 50-55° to obtain (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2, 2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester as off-white solid material (200 gm, 82.30% yield) HPLC purity 99.2% , Dimer/amide impurity 0.035% Example-3 Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate:
100 g (O. l52mole) of crude (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester obtained from (example 1) is dissolved in methanol 13 vol (w/v) at 40-50 °C till complete dissolution, hydrochloric acid (26 g of 36.5% in 87 ml water solution was added to the reaction mass at 25-30°C. After stirring the contents at 25-30°C until the completion of the reaction as monitored on HPLC. Methanol is distilled off under the reduced pressure. Concentrated reaction mass is poured into sodium hydroxide solution (19.55 g in 650 ml water) and stirred till the completion of the reaction as monitored by HPLC resulting into [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid sodium salt. Reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 1000 ml water and 500ml Methyl tert-butyl ether. The aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 at about 40°C using dilute acetic acid followed by addition of solution containing calcium acetate (18 gm, 0.112 mol) in 225 ml water at about 40°C.Slurry was agitated for 30 min at about 50°C and cooled to 45°C, maintained for 120 min and filtered, washed the cake with 50 ml water. Dry the product under vacuum at 50-55 °C for 12-14 hr to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate having purity 99.7%+, and dimer impurity 0.03%.
CONVENTIONAL MODE:
Example-4: Preparation of [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate:
A mixture oftert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate 60.0 g (0.223 mole), 13 vol. methanol, 5-6 vol of methanolic ammonia having concentration 12-16% and 15 g of Raney Ni is charged in an autoclave and hydrogenation is continued at about 30- 40°C at a pressure around 5 kg/cm till the absorption of hydrogen is ceased to absorb. GC analysis revealed completion of the reaction. The reaction mass was cooled to 25-30°C and the catalyst was removed by filtration under Nitrogen blanket. Filtrate collected is concentrated under the reduced pressure till an thick oily material is obtained. Wt. of 58 g (99.35%), with two unknown impurities at RRTs of 0.55 and 0.91 are found to be 0.48 and 0.18 respectively.
Example-5: Preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester:
A well equipped 1 lt four neck flask is charged with 60g (0.219 mole) [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate prepared as per the method of example 4, followed by 400 ml cyclohexane followed by 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo- N-phenyl-butanamide96.0g(0.230 mole), pivalic acid 20.22 g(0. l97 mole), Di-isopropyl amine 15.56 g(0.l53 mole) and tetra butyl ammonium hydrogen sulphate 11.15 gm(0.0338 mole).The contents are heated to reach at 78-85°C and are continued for about 40 hrs till the reaction gets completed as monitored on HPLC. The reaction mass is gradually cooled to and washed with 8% sodium bicarbonate solution followed by water washing. Cyclohexane is distilled of under the reduced pressure. Traces of solvent are removed by using isopropanol. Finally (4R,cis)-6-[2-[3- phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl] -2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester is isolated by using water as antisolvent. Product is filtered off washed with sufficient water. Dry the product under vacuum at 50-55 °C to obtain (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester as off-white solid crude material 120 gm, HPLC purity 99.25%, Dimer/amide impurity 0.24% and an unknown impurity 0.40%.
First purification (PI): A well equipped2 lt four neck flask is charged with 120 g crude (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester followed by the addition of 750 ml isopropanol and the contents were heated at around 70°C till the solution becomes clear. If required the solution is filtered hot and concentrated under the reduced pressure to get the sufficient consistency. Mass is subjected for the cooling under stirring till the maximum precipitation. The product is filtered off washed with chilled isopropanol. Dry the product under vacuum at 50-55°C to obtain l lOg of first purified material (99.41 %).Dimer/amide impurity 0.17% and an unknown impurity 0.35%. Second purification (P2): A well equipped 1 lt four neck flask is charged with 110 g Pl (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 - yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester followed by the addition of 440 ml isopropanol and the contents were heated at around 70°C till the solution becomes clear. Mass is subjected for the cooling under stirring till the maximum precipitation. The product is filtered off washed with chilled isopropanol. Dry the product under vacuum at 50-55 °C to obtain 102 g of second purified material (99.49%). Dimer/amide impurity 0.12% and an unknown impurity 0.27%.
Third purification (P3): A well equipped 1 lt four neck flask is charged with 100 g P2 (4R,cis)- 6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester followed by the addition of 400 ml isopropanol and the contents were heated at around 70°C till the solution becomes clear. Mass is subjected for the cooling under stirring till the maximum precipitation. The product is filtered off washed with chilled isopropanol. Dry the product under vacuum at 50-55°C to obtain 96 g of third purified material 96 g (99.6l%).Dimer/amide impurity 0.06% and an unknown impurity 0.21%.
Example-6:Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate (Crude ATV-l to Atorvastatin calcium trihydrate):
100 g (O. l52mole) of crude (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester obtained from (example 5) is dissolved in methanol 13 vol (w/v) at 40-50 till complete dissolution, hydrochloric acid (26 g of 36.5% ) in 87 ml water solution was added to the reaction mass at 25-30°. After stirring the contents at 25-30°C until the completion of the reaction as monitored on HPLC. Methanol is distilled off under the reduced pressure and reaction mass is poured into sodium hydroxide solution (19.55 g in 650 ml water) and stirred till the completion of the reaction as monitored by HPLC resulting into [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid sodium salt. Reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 1000ml water and 500 ml Methyl tert-butyl ether. The aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 at about 40°C using dilute acetic acid followed by addition of solution containing calcium acetate 18 gm, 0.112 mol) in 450ml water at about 40°C. Slurry was agitated for 30 min at about 50°C and cooled to 45 °C, maintained for 120 min and filtered, washed the cake with 50 ml water. Dry the product under vacuum at 50-55°C for 12-14 hr to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate 84 g having and dimer impurity of Atorvastatin of formula Via (wherein R is H) to be 0.15% and dimer/amide impurity of formula IVa to be 0.24%.
Example-7: Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate (ATV-l Pl to Atorvastatin calcium trihydrate):
100 g (O. l52mole) of crude (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5- (l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester obtained from (example 5, Pl) is dissolved in methanol 13 vol (w/v) at 40- 50°C till complete dissolution, hydrochloric acid (26 g of 36.5% ) in 87 ml water solution was added to the reaction mass at 25-30°C. After stirring the contents at 25-30°C until the completion of the reaction as monitored on HPLC. Methanol is distilled off under the reduced pressure and reaction mass is poured into sodium hydroxide solution (19..55 g in 650 ml water) and stirred till the completion of the reaction as monitored by HPLC resulting into [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonylJ-lH-pyrrole- 1- heptanoic acid sodium salt. Reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 1000 ml water and 500 ml Methyl tert-butyl ether. The aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 at about 40°C using dilute acetic acid followed by addition of solution containing calcium acetate (18 gm, 0.112 mol) in 450 ml water at about 40°C. Slurry was agitated for 30 min at about 50°C and cooled to 45 °C, maintained for 120 min and filtered, washed the cake with 50 ml water. Dry the product under vacuum at 50-55°C for 12-14 hr to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate 83.5 g having dimer impurity of Atorvastatin of formula Via (wherein R is H) to be 0.11 % and dimer/amide impurity of formula IVa to be 0.17%. Example-8:Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate (ATV-l P2 to Atorvastatin calcium trihydrate):
50 g (0.076mole) of P2 (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester obtained from (example 5, P2) is dissolved in methanol 6.5 vol (w/v) at 40- 50°C till complete dissolution, hydrochloric acid (13 g of 36.5% ) in 45 ml water solution was added to the reaction mass at 25-30°C over about 30-45 minutes. After stirring the contents at 25-30°C until the completion of the reaction as monitored on HPLC. Methanol is distilled off under the reduced pressure and reaction mass is poured into sodium hydroxide solution (9.78 g in 325 ml water) and stirred till the completion of the reaction as monitored by HPLC resulting into [R- (R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid sodium salt. Reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 500 ml water and 250 ml Methyl tert-butyl ether. The aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 atabout 40°C using dilute acetic acid followed by addition of solution containing calcium acetate (9gm, 0.056 mol) in 225 ml water at about 40°C. Slurry was agitated for 30 min at about 50°C and cooled to 45°C, maintained for 120 min and filtered, washed the cake with water.Dry the product under vacuum at 50-55°C for 12-14 hr to obtain [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium trihydrate 43 g having dimer impurity of Atorvastatin of formula Via (wherein R is H) to be 0.08 % % and dimer/amide impurity of formula IVa to be 0.12%.%.
Example-9:Preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium trihydrate (ATV-l P3to Atorvastatin calcium trihydrate):
50 g (0.076mole) of P3 (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester obtained from (example 5 P3) is dissolved in methanol 6.5 vol (w/v) at 40-50°Ctill complete dissolution, hydrochloric acid (13 g of 36.5% ) in 45 ml water solution was added to the reaction mass at 25-30°C over about 30-45 minutes. After stirring the contents at 25-30°C until the completion of the reaction as monitored on HPLC. Methanol is distilled off under the reduced pressure and reaction mass is poured into sodium hydroxide solution (9.78 g in 325 ml water) and stirred till the completion of the reaction as monitored by HPLC resulting into [R- (R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid sodium salt. Reaction mass is concentrated under reduced pressure followed by the addition of mixture containing 500ml water and 250ml Methyl tert-butyl ether. The aqueous layer is collected to adjust pH of the mass was 8.6 to 8.7 at about 40°C using dilute acetic acid followed by addition of solution containing calcium acetate (9.0 gm, 0.056 mol) in225 ml water at about 40°C. Slurry was agitated for 30 min at about 50°C and cooled to 45°C, maintained for 120 min and filtered, washed the cake with water. Dry the product under vacuum at 50-55°C for 12-14 hrs to obtain [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium 44.6 g having dimer impurity of Atorvastatin of formula Via (wherein R is H) to be 0.05 % and dimer/amide impurity of formula IVa to be 0.06%.

Claims

WE CLAIM
1. A process comprising the use of single solvent playing the dual role for the preparation of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate of formula III wherein hydrogenated product is not isolated and reacted further with 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamideof formula II in presence of an acid resulting into (4R,cis)-6-[2-[3- phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV.
Figure imgf000078_0001
2. A process for the preparation of pyrrole derivative comprising the use of single solvent for two reactions namely catalytic hydrogenation of a cyano compound and Paal-Knorr synthesis wherein a primary amine reacts with a diketone in presence of an acid resulting into formation of a pyrrole ring characterized by the fact that the hydrogenated product (amine) is not isolated. Pyrrole derivative thus obtained is then further converted into intermediates involved therein further for the preparation of medicinally important pyrrole derivative and pharmaceutically acceptable salts and hydrates thereof.
3. The process of claim 1 and 2 further comprising converting (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester into Atorvastatin and its pharmaceutically acceptable salts and hydrates thereof; wherein single solvent used therein is selected from alicyclic hydrocarbon is preferably cyclohexane.
4. A process for the preparation of Atorvastatin and its pharmaceutically acceptable salts and hydrates thereof of formula EIA with more stringent specifications than pharmacopeial specifications wherein known impurities (% w/w); Atorvastatin related compound E (NMT 0.2%), Atorvastatin related compounds A, B & C (NMT 0.15%), Atorvastatin related compound D (NMT 0.10%), any other known impurity (NMT 0.10%), any unknown impurity (NMT 0.1%) comprising none of the extra purification of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l -methyl-ethyl)- pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV; wherein the process comprises:
Figure imgf000079_0001
Figure imgf000080_0001
Formula IA a. catalytic hydrogenation of tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl- l,3-dioxan-4-yl] acetate of formula III in an alicyclic solvent; wherein hydrogenated product is not isolated and reacted further with 4-(4-fluorophenyl)- 2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in presence of an acid and catalyst, b. (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl- ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV obtained from the step a) is then hydrolyzed using a solvent in presence of an acid resulting into (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)- 5-(l- methyl-ethyl)-3 -phenyl-4- [(phenylamino)carbonyl]-lH-pyrrol-l-yl] ethyl] -
2, 2-dimethyl- l,3-dihydroxy-4-acetate of formula V,
c. (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4- [(phenylamino)carbonyl]- lH-pyrrol- 1 -yl]ethyl]-2, 2-dimethyl- 1 ,3-dihydroxy-4- acetate of formula V from the step b is the hydrolyzed in the presence of a base resulting into cation salt of Atorvastatin.
d. cation salt of Atorvastatin from step c) is then reacted with calcium salt resulting into Atorvastatin salt of calcium and hydrates thereof formula 1/1 A.
Figure imgf000080_0002
5. A process for controlling impurities during preparation of a [R-(R*, R*]-2-(4- fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonylJ-lH- pyrrole-l- heptanoic acid or its pharmaceutically acceptable salts of formula (I)/(I)A involving an improved or modified process for the preparation of (4R,cis)-6-[2-[3- phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2- dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising: a. catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ¾ and ammonia
b. wherein the hydrogenated compound is not isolated
c. using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with minimized dimer/ amide impurity of formula Illb
d. adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV with minimized dimer/ amide impurity of formula IVa
e. hydrolyzing the compound of formula IV in a suitable solvent in presence of an acid to obtain (4R-cis)- tert-butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl- ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl]-2,2- dimethyl-l,3-dihydroxy-4-acetate of formula V with minimized dimer/ amide impurity of formula Va
f. hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof;
g. treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- b,d- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium and hydrates thereof of formula IA with minimized dimer/ amide impurity of Atorvastatin or its Ca salt and its hydrate of formula IA.
Figure imgf000082_0001
Formula IV
Figure imgf000082_0002
Figure imgf000083_0001
Formula IA
wherein said impurities comprises of:
Figure imgf000083_0002
Figure imgf000084_0001
Figure imgf000085_0001
6. A process for controlling impurities during the preparation of (4R,cis)-6-[2-[3-phenyl-4- (phenyl-carbamoyl)-2-(4-fluorophenyl)-5-( 1 -methyl-ethyl)-pyrrole- 1 -yl]-2,2-dimethyl- [l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV comprising:
a. catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ¾ and ammonia
b. wherein the hydrogenated compound is not isolated
c. using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with minimized dimer/ amide impurity of formula Illb d. adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl- butanamideof formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)- 5-( 1 -methyl-ethyl) -pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV with minimized dimer/ amide impurity of formula IVa.
7. A process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts and hydrates thereof having less than 0.1% by wt of dimer/amide impurities represented by the formulae Illb, IVa, Va and Via (wherein R is H or Ca) formed during the entire synthesis of [R-(R*, R*]-2-(4-fluorophenyl)- b,d- dihydroxy-5-(l-methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl] -lH-pyrrole-l- heptanoic acid calcium of Formula Via wherein R is calcium as measured by HPLC comprising:
a) catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2-dimethyl-l,3- dioxan-4-yl] acetate of formula Illusing alicyclic hydrocarbon, water, Raney Ni, H2 and ammonia
b) wherein the hydrogenated compound is not isolated
c) using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with minimized dimer/ amide impurity of formula Illb
d) adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamideof formula II in the organic layer from step c,acid and catalyst to obtain the (4R,cis)-6- [2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l- yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IVwith minimized dimer/ amide impurity of formula IVa
e) hydrolyzing a compound of formula IV in a suitable solvent in presence of an acid to obtain (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4- [(phenylamino)carbonyl]- lH-pyrrol- 1 -yl]ethyl]-2, 2-dimethyl- 1 ,3-dihydroxy-4-acetate of formula Vwith minimized dimer/ amide impurity of formula Va f) hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof;
g) treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof of formula IA with minimized dimer/ amide impurity of Atorvastin or its Ca salt:
wherein; various dimer impurities which are formed during the entire synthesis of Atorvastatin calcium are:
Figure imgf000087_0001
Formula Illb: Dimer impurity of tert-butyl [(4R,Cis)-6-(2-aminoethyl)-2,2-dimethyl- l,3-dioxan-4-yl] acetate
Figure imgf000087_0002
Formula IVa: Dimer impurity of (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4- fluorophenyl)-5-(l-methyl-ethyl)-pyrrole-l-yl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-tertiary butyl ester (ATV-l)
Figure imgf000087_0003
Formula Va: Dimer impurity of (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl]-2,2- dimethyl- 1 ,3-dihydroxy-4-acetate (ATV-2)
Figure imgf000088_0001
Or as calcium salt shown below
Figure imgf000088_0002
Formula G/ Formula Via (wherein R is H or Ca): Dimer impurity of Atorvastatin or its Ca salt.
8. A process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts and hydrates thereof comprising:
a. catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, H2 and ammonia
b. wherein the hydrogenated compound is not isolated
c. using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with minimized dimer/ amide impurity of formula Illb
d. adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butanamide of formula II in the organic layer from step c, acid as catalyst to obtain the (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(l- methyl-ethyl)-pyrrole- 1 -yl] -2,2-dimethyl- [ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV; wherein 4-(4-fluorophenyl)-2-isobutyryl-3- phenyl-4-oxo-N-phenyl-butanamide of formula II is prepared by any of the process and 4-methyl -3-oxo-N-phenylpentamidedepicted in the schemes herein below:
Figure imgf000089_0001
f. hydrolyzing the compound of formula IV in a suitable solvent in presence of acid to obtain (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl- ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl] ethyl]-2,2- dimethyl-l,3-dihydroxy-4-acetate of formula V
g. hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof; treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium and hydrates thereof of formula VIA.
9. A process for the preparation of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof with controlled impurities therein comprising: a. catalytically hydrogenating tert-butyl [(4R,Cis)-6-(2-cyanomethyl)-2,2- dimethyl-l,3-dioxan-4-yl] acetate of formula III using alicyclic hydrocarbon, water, Raney Ni, ¾ and ammonia
b. wherein the hydrogenated compound is not isolated
c. using the organic layer obtained from the step b) containing [(4R,Cis)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate represented by formula IIIA with minimized dimer/ amide impurity of formula Illb
d. adding 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N-phenyl- butanamideof formula II in the organic layer from step c, acid and catalyst to obtain the (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)- 5-( 1 -methyl-ethyl) -pyrrole- 1 -yl]-2,2-dimethyl-[ 1 ,3]dioxane-4-yl-acetic acid- tertiary butyl ester of formula IV with minimized dimer/ amide impurity of formula IVa
e. treating a compound of formula IV in a suitable solvent in presence of an acid to obtain (4R-cis)- tert-Butyl -6-[2-[2-(4-fluorophenyl)-5-(l- methyl-ethyl)-3- phenyl-4-[(phenylamino)carbonyl]- lH-pyrrol- 1 -yl] ethyl] -2,2-dimethyl- 1,3- dihydroxy-4-acetate of formula V with minimized dimer/ amide impurity of formula Va
f. hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula I or a cation salt thereof;
g. treating cation salt of formula I; wherein cation M is sodium, the sodium salt is treated with Calcium salt to obtain [R-(R*, R*]-2-(4-fluorophenyl)- b,d- dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole- 1- heptanoic acid calcium and hydrates thereof of formula IAwith minimized dimer/ amide impurity of Atorvastatin or its Ca salt; wherein; compound of formula I/IA is devoid of Atorvastatin Related Compound B (Isomer), Atorvastatin Related Compound C (Difluoro), Atorvastatin Related Compound D (Epoxide), Methyl ester (other known imp), Oxo impurity (other known imp),Atorvastatin related compound E (Enantiomeric impurity), ether impurity of Atorvastatin(other known imp), while dimer/amide impurities of formulae Illb, IVa,Va and Via wherein R is H or Ca respectively are less than 0.05% in the intermediates of formulae III, IV, V and Atorvastatin and its pharmaceutically acceptable salts, individual other unknown impurities at the various RRTs are either not detected or less than 0.05%; (while the limit is NMT 0.1% for each one) and last but not least total impurity(not includingAtorvastatin related compound E) is 0.28%.
10. The process as per any of preceding claims (4-9); wherein alicyclic hydrocarbon preferably cyclohexane is the common solvent for the catalytic hydrogenation of compound of formula III and for the Paal-Knorr reaction.
11. The process as per any of preceding claims (4-9) the acid catalyst used during Paal-Knorr reaction is selected from group comprising pivalic acid, formic acid, acetic acid, butyric acid, valeric acid, isovaleric acid, malic acid, succinic acid, malonic acid, citric acid, benzoic acid, oxalic acid, n-butyric acid and the like or mixtures thereof, preferably pivalic acid or acetic acid or mixtures thereof. The catalyst used for the purpose comprising an amine and a phase transfer catalyst wherein; amine is selected from the group comprising primary, secondary amine, tertiary amine preferably di-isopropyl amine. The phase transfer catalyst is selected from group of quaternary ammonium, pyridinium salts and the like, tetra butyl ammonium salts comprising tetra butyl ammonium chloride/bromide/iodide preferably tetra butyl ammonium sulphate.
12. The process of the claims(4-9), wherein the alkaline base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and the like preferably sodium hydroxide.
13. The process of the preceding claims related to preparation of Atorvastatin calcium; wherein calcium source for the preparation of calcium salt of formula IA; wherein the source of Calcium is selected from group consisting calcium hydroxide, calcium chloride or calcium acetate.
14. A pharmaceutical composition comprising therapeutically effective amount of [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid or pharmaceutically acceptable salts thereof, preferably [R-(R*, R*]-2-(4-fluorophenyl)- P,5-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l- heptanoic acid calcium salt of formula IA prepared by the processes of the present invention having less than 0.1% by wt of dimer/amide impurities represented by the formulae Illb, IVa, Va and Via (wherein R is H or Ca) and at least one pharmaceutically acceptable excipient.
PCT/IN2019/050463 2018-07-18 2019-06-19 An improved and commercially viable process for preparation of pyrrole derivatives with improved impurity profile & minimisation of unit operations. WO2020016903A1 (en)

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CN113373187A (en) * 2021-05-26 2021-09-10 江苏阿尔法药业股份有限公司 Nitrogen heterocyclic compound C27H30FNO6Enzyme-catalyzed synthesis method of
CN114195670A (en) * 2021-12-31 2022-03-18 河南豫辰药业股份有限公司 Refining method of atorvastatin mother nucleus M4

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WO2017060885A1 (en) * 2015-10-09 2017-04-13 Laurus Labs Private Limited An improved process for preparation of atorvastatin or pharmaceutically acceptable salts thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017060885A1 (en) * 2015-10-09 2017-04-13 Laurus Labs Private Limited An improved process for preparation of atorvastatin or pharmaceutically acceptable salts thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113373187A (en) * 2021-05-26 2021-09-10 江苏阿尔法药业股份有限公司 Nitrogen heterocyclic compound C27H30FNO6Enzyme-catalyzed synthesis method of
CN113373187B (en) * 2021-05-26 2023-11-10 江苏阿尔法药业股份有限公司 Nitrogen heterocyclic compound C 27 H 30 FNO 6 Is a method for enzymatic synthesis of (a)
CN114195670A (en) * 2021-12-31 2022-03-18 河南豫辰药业股份有限公司 Refining method of atorvastatin mother nucleus M4
CN114195670B (en) * 2021-12-31 2024-03-15 河南豫辰药业股份有限公司 Refining method of atorvastatin mother nucleus M4

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