Novel Process for Statins and its Pharmaceutically Acceptable Salts Thereof

2) One-pot synthesis for the preparation of statins and their pharmaceutically acceptable salts thereof represented by general formula-1

• Wherein R is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor, which is selected from the following formula-A/B/C,
• Wherein M is H, Na+, K+, Mg+2, Ca+2
• Herein after the above compounds of formula A, B and C are referred to as ‘R’;
• Which comprises of the following steps
• a) Reacting the sulfone compound of general formula-3
• Wherein R is defined as above which is linked to sulphur atom with a methylene group (—CH2—) and R2 is
• Wherein
• R3 is alkyl, aryl, arylalkyl or cycloalkyl,
• R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
• R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
• And
• X is O,N—H,N-alkyl or S;
• with an amide compound of general formula-7
• Wherein R6 and R7 are C1-C10 straight or branched chain alkyl or cycloalkyl or cycloalkyl with one heteroatom,
• in presence of an alkali and alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate preferably potassium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixtures thereof, preferably dimethyl sulfoxide to provide the compound of general formula-8,
• which in-situ reacting with suitable acid such as hydrochloric acid, acetic acid, sulfuric acid in a suitable solvent to give the diol compound of general formula-9,
• which upon treating with an alkali base such as sodium hydroxide, potassium hydroxide and lithium hydroxide to form the corresponding alkali salt then further treating with suitable organic amine base to give organic amine compound of general formula-5, optionally drying the organic amine compound of general formula-5,
• Organic amine selected from methyl amine, ethyl amine, tertiarybutyl amine, diisopropyl amine, dicyclohexyl amine, isobutyl amine, n-butylamine, (+/−) 2-butyl amine, phenyl ethyl amine, morpholine and pyrrolidine preferably tertiarybutyl amine or n-butyalmine,
• b) Converting the corresponding organic amine compound of general Formula-5 into its pharmaceutically acceptable salts of general formula-1 by treating the organic amine compound of general Formula-5 with an alkali base such as sodium hydroxide, potassium hydroxide and lithium hydroxide preferably sodium hydroxide and setting the pH of the reaction mixture to 9.1 by extracting the organic amine salt compound of general Formula-5 with tertiary butyl acetate or by direct distillation of the reaction mixture,
• c) Optionally isolating the corresponding alkali salt compound of general formula-6,
• wherein M is Na+, K+
• d) Adding the aqueous phase of the reaction mixture or an aqueous solution of isolated alkali salt compound of general formula-6 to a solution of calcium chloride or calcium acetate in a suitable solvent such as water.

3) One-pot synthesis for the preparation of statins and their pharmaceutically acceptable salts thereof represented by general formula-1

• Wherein R is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor, which is selected from the following formula A/B/C,
• Wherein M is H, Na+, K+, Mg+2, Ca+2
• Herein after the above compounds of formula A, B and C are referred to as ‘R’;
• Which comprises of the following steps
• a) Reacting the sulfone compound of general formula-3
• Wherein R is defined as above which is linked to sulphur atom with a methylene group (—CH2—) and R2 is
• Wherein
• R3 is alkyl, aryl, arylalkyl or cycloalkyl,
• R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
• R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
• And
• X is O,N—H,N-alkyl or S;
• With an aldehyde compound of formula-4
• in presence of an alkali and alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate preferably potassium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethyl acetamide or mixtures thereof, preferably dimethyl sulfoxide to provide condensed compound, which in-situ reacting with trifluoroacetic acid to give the lactone compound, which is further reacting with suitable organic amine to give an amide compound of general formula-10,
• Wherein R8 and R9 are C1-C10 straight or branched chain alkyl or cycloalkyl or cycloalkyl with one heteroatom,
• b) Reacting the corresponding amide compound of general formula-10 with an alkali base such as sodium hydroxide, potassium hydroxide and lithium hydroxide preferably sodium hydroxide followed by treating with suitable organic amine base to give organic amine compound of general formula-5, optionally drying the organic amine compound of general formula-5,
• Organic amine selected from methyl amine, ethyl amine, tertiarybutyl amine, diisopropyl amine, dicyclohexyl amine, isobutyl amine, n-butylamine, (+/−) 2-butyl amine, phenyl ethyl amine, morpholine and pyrrolidine preferably tertiarybutyl amine or n-butyalmine,
• c) Converting the corresponding organic amine compound of general formula-5 into its pharmaceutically acceptable salts of general formula-1 by treating the organic amine salt compound of general formula-5 with an alkali base such as sodium hydroxide, potassium hydroxide and lithium hydroxide preferably sodium hydroxide and setting the pH of the reaction mixture to 9.1 by extracting the organic amine salt compound of general Formula-5 with tertiary butyl acetate or by direct distillation of the reaction mixture,
• d) Optionally isolating the corresponding alkali salt compound of general formula-6,
• wherein M is Na+, K+
• e) Adding the aqueous phase of the reaction mixture or an aqueous solution of isolated alkali salt compound of general Formula-6 to a solution of calcium chloride or calcium acetate in a suitable solvent such as water.

4) One-pot synthesis for the preparation of statins and their pharmaceutically acceptable salts thereof represented by general formula-1

• Wherein R is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor, which is selected from the following formula A/B/C,
• Wherein M is H, Na+, K+, Mg+2, Ca+2
• Herein after the above compounds of formula A, B and C are referred to as ‘R’;
• Which comprises of the following steps
• a) Reacting the sulfone compound of general formula-3
• Wherein R is defined as above which is linked to sulphur atom with a methylene group (—CH2—) and R2 is
• Wherein
• R3 is alkyl, aryl, arylalkyl or cycloalkyl,
• R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
• R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
• And
• X is O,N—H,N-alkyl or S;
• with an aldehyde compound of Formula-4
• in presence of an alkali and alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate preferably potassium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixtures thereof, preferably dimethyl sulfoxide to provide the compound of general formula-11,
• which in-situ reacting with suitable acid such as hydrochloric acid, acetic acid, sulfuric acid in a suitable solvent to give the diol compound of general formula-12,
• which upon treating with an alkali base such as sodium hydroxide, potassium hydroxide and lithium hydroxide preferably sodium hydroxide to form the corresponding alkali base salt then further treating with an suitable organic amine base to give organic amine compound of general formula-5, optionally drying the organic amine compound of general formula-5,
• Organic amine selected from methyl amine, ethyl amine, tertiarybutyl amine, diisopropyl amine, dicyclohexyl amine, isobutyl amine, n-butylamine, (+/−) 2-butyl amine, phenyl ethyl amine, morpholine and pyrrolidine preferably tertiarybutyl amine or n-butylamine,
• b) Converting the corresponding organic amine compound of general formula-5 into its pharmaceutically acceptable salts of general formula-1 by treating the organic amine compound of general formula-5 with an alkali base such as sodium hydroxide, potassium hydroxide and lithium hydroxide preferably sodium hydroxide and setting the pH of the reaction mixture to 9.1 by extracting the organic amine salt compound of general formula-5 with tertiary butyl acetate or by direct distillation of the reaction mixture,
• c) Optionally isolating the corresponding alkali salt compound of general formula-6,
• wherein M is Na+, K+
• d) Adding the aqueous phase of the reaction mixture or an aqueous solution of isolated alkali salt compound of general formula-6 to a solution of calcium chloride or calcium acetate in a suitable solvent such as water.

17) A process for the preparation of olefinic dihydroxy acids and their pharmaceutically acceptable salt compound of formula-2,

• Wherein R1 is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor, which is selected from the following formula a/b/c/d/e/f/g/h,
• wherein denotes single or double bond and M is H, Na+, K+, Mg+2, Ca+2
• which comprises of the following steps
• a) Reacting a sulfone compound of general formula-13
• Wherein R1 is defined as above which is linked to sulphur atom with a methylene group (—CH2—) and R2 is
• Wherein
• R3 is alkyl, aryl, arylalkyl or cycloalkyl,
• R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
• R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
• And
• X is O,N—H,N-alkyl or S;
• Herein after the above compounds of general formula (i), (j) and (k) are referred as ‘R2’ with an aldehyde compound of general formula-14
• wherein R10 is alkyl,cycloalkyl,arylalkyl,aryl or carbonylbenzyloxy (cbz), preferably alkyl, more preferably tertiary butyl,
• in presence of an alkali and alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate preferably cesium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixtures thereof, preferably dimethyl sulfoxide to provide olefin compound of general formula-15,
• b) The olefin compound of general formula-15 may be used to form a dihydroxy acid HMG CoA reductase inhibitor by subjecting olefin compound of formula-15 to acidic conditions such as using hydrochloric acid, acetic acid, sulfuric acid to remove the acetonide and form diol compound, which upon treating with an alkali base such as sodium hydroxide to form the corresponding sodium salt then further treating with suitable organic amine base to give organic amine compound of formula-16,
• Organic amine selected from methyl amine, ethyl amine, tertiarybutyl amine, diisopropyl amine, dicyclohexyl amine, isobutyl amine, n-butylamine, (+/−) 2-butyl amine, phenyl ethyl amine, morpholine and pyrrolidine, preferably tertiarybutyl amine or n-butylamine,
• c) Converting the corresponding organic amine salt compound of formula-16 into free acid compound of formula-21 by treating the compound of formula-16 with an acid such as trifluoro acetic acid, hydrochloric acid, acetic acid, preferably acetic acid to give acid compound of formula-21,
• d) The alkenyl double bond in acid compound of formula-21 may be hydrogenated (H2/Pd/C) to provide the saturated alkyl acid compound of formula-22,
• e) Converting the corresponding organic amine salt compound into pharmaceutically acceptable salts of olefin dihydroxy acid compound of general formula-2 by treating the organic amine compound of general formula-16 with an alkali base such as sodium hydroxide followed by treating with corresponding alkali or alkaline earth metal salts like calcium chloride, calcium acetate, sodium hydroxide preferably calcium acetate in a suitable solvent such as water.
• where M is H, Na+, K+, Mg+2, Ca+2.

18) A process for the preparation of olefinic dihydroxy acids and their pharmaceutically acceptable salt compound of formula-1,

• Wherein R1 is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor, which is selected from the following formula a/b/c/d/e/f/g/h, is linked to sulphur atom with a methylene group (—CH2—);
• wherein denotes single or double bond and M is H, Na+, K+, Mg+2, Ca+2
• Which comprises of the following steps
• a) Reacting sulfoxide compound of general formula-17
• Wherein R1 is defined as above which is linked to sulphur atom with a methylene group (—CH2—) and R2 is defined as above.
• with an aldehyde compound of general Formula-14
• wherein R10 is alkyl,cycloalkyl,arylalkyl,aryl or carbonylbenzyloxy (cbz), preferably alkyl, more preferably tertiary butyl,
• in presence of strong base like amide bases such as sodium bis(trimethyl silyl) amide, potassium bis(trimethyl silyl) amide, lithium bis(trimethyl silyl) amide in a suitable polar aprotic solvents like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixtures thereof, preferably dimethyl sulfoxide to provide olefin compound of general formula-15,
• b) The olefin compound of general formula-15 may be used to form a dihydroxy acid HMG CoA reductase inhibitor by subjecting olefin compound of general formula-15 to acidic conditions such as using hydrochloric acid, sulfuric acid, acetic acid to remove the acetonide and form diol compound, which upon treating with an alkali base such as sodium hydroxide to form the corresponding sodium salt then further treating with suitable organic amine base compound to give the organic amine compound of general formula-16,
• Organic amine selected from methyl amine, ethyl amine, tertiarybutyl amine, diisopropyl amine, dicyclohexyl amine, isobutyl amine, n-butylamine, (+/−) 2-butyl amine, phenyl ethyl amine, morpholine and pyrrolidine preferably tertiarybutyl amine or n-butylamine,
• c) Converting the corresponding organic amine compound of general formula-16 into its pharmaceutically acceptable salts of general formula-2 by treating the organic amine compound of general formula-16 with an alkali base such as sodium hydroxide followed by treating with corresponding alkali or alkaline earth metal salts like calcium chloride, calcium acetate, sodium hydroxide in a suitable solvent such as water.
• where M is H, Na+, K+, Mg+2, Ca+2.

35) A process for the preparation of novel sulfone and sulfoxide derivatives having the general formula-13 and formula-17,

• Wherein R is defined as above which is linked to sulphur atom with a methylene group (—CH2—) and R2 is
• Wherein
• R3 is alkyl, aryl, arylalkyl or cycloalkyl,
• R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
• R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
• And
• X is O,N—H,N-alkyl or S;
• Which comprises of the following steps
• a) Treating a solution of the compound of general formula-18
• R1-L Formula-18
• Wherein L is a leaving group such as halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, preferably halogen, more preferably bromo and R1 is defined as above which is linked to leaving group with a methylene group (—CH2—), with a thiol compound of general formula-19
• R2SH Formula-19
• wherein R2 is defined as above
• in presence of a suitable base like sodium hydroxide with or without a suitable solvent, a suitable solvent selected from chloro solvents like methylene chloride, chloroform, carbon tetrachloride, keto solvents like acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone, ester solvents like ethyl acetate, methyl acetate, tertiary butyl acetate, polar solvents like dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, water or mixtures thereof, preferably keto solvents, more preferably acetone to provide a novel sulfide compound of formula-20,
• wherein R1 is as defined above which is linked to sulphur atom with a methylene group (—CH2—) and R2 are defined as above
• b) And oxidizing a sulfide compound of formula-20 with an oxidizing agent like metachloro per benzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydro peroxide, preferably hydrogen peroxide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chloro solvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chloro solvents, more preferably methylene chloride to provide the novel sulfone compound of general formula-13 and a novel sulfoxide compound of formula-17 can be prepared by controlled oxidation of sulfide.

36) Novel sulfide compounds having general formula-20,

• Wherein R1 is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor, which is selected from the following formula a/b/d/e/f/g/h, is linked to sulphur atom with a methylene group (—CH2),
• R2 is
• Wherein
• R3 is alkyl, aryl, arylalkyl or cycloalkyl,
• R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
• R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
• And
• X is O,N—H,N-alkyl or S.

37) Novel sulfone compounds having general Formula-13,

• Wherein R1 is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor, which is selected from the following formula a/b/c/d/e/f/g/h, is linked to a sulphur atom with a methylene group (—CH2—),
• and R2 is
• Wherein
• R3 is alkyl, aryl, arylalkyl or cycloalkyl,
• R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
• R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
• And
• X is O,N—H,N-alkyl or S.

38) Novel sulfoxide compounds having general formula-17,

• Wherein R1 is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor, which is selected from the following formula a/b/c/d/e/f/g/h, is linked to a sulphur atom with a methylene group (—CH2—)
• and R2 is
• Wherein
• R3 is alkyl, aryl, arylalkyl or cycloalkyl,
• R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
• R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy
• And X is O,N—H,N-alkyl or S.

41) A process for the preparation of calcium salt compounds of statins of general formula-1 which comprises of;

• Wherein M is Calcium, R and R1 is defined as above.
• Which comprises of the following steps
• a) Converting the organic amine salt compound of general formula-5 or Formula-16 into its sodium salt by treating with sodium hydroxide,
• b) Setting the reaction mixture pH to 8.0 to 9.2 by evaporating the solvent containing organic amine under nitrogen atomosphere followed by extracting the reaction mixture with a suitable solvent such as ester solvents like ethyl acetate, methyl acetate, tertiary butyl acetate or by extracting the organic amine with a suitable solvent like ester solvents ethyl acetate, methyl acetate, tertiary butyl acetate, preferably tertiary butyl acetate to remove organic amine or by adding an acid like hydrochloric acid,
• c) Adding the aqueous phase of the reaction mixture to a calcium source in a suitable solvent like water to give free flow calcium salt compound of general formula-1 or formula-2 respectively.