Intermediates for the preparation of hmg coa reductase inhibitors and processes for the preparation thereof

A compound of Formula (2),

• wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
• R is selected from:
• wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
• Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
• Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
• Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms.

A compound of Formula (5),

• wherein R is selected from:
• wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
• Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
• Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
• Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms.

A compound of Formula (6),

• wherein R is selected from:
• wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
• Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
• Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
• Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms.

A compound of Formula (8),

• wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
• Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms;
• R10 is a hydrophobic anchor or a residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula (a) to (i),
• wherein R1 and R2 are same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl and cycloheteroalkyl;
• R4 is H, halogen, CF3, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano;
• and
• X1 is CH2, O, S or NR7,
• wherein R7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl.

A compound of Formula (8B),

• wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
• R10 is a hydrophobic anchor or a residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula (a) to (i),
• wherein R1 and R2 are same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl and cycloheteroalkyl;
• R4 is H, halogen, CF3, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano;
• and
• X1 is CH2, O, S or NR7,
• wherein R7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl.

A compounds of Formula (11),

• wherein R is selected from:
• wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
• Rc is selected from H, alkyl, aryl, alkoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
• Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S.

A process for the preparation of a compound of Formula (8B2),

• the process comprising the steps of:
• (a) reacting chiral sulfide diol of Formula (5a),
• with 2,2-dimethoxypropane to obtain a compound of Formula (2a-B);
• (b) oxidizing the compound of formula (2a-B) with a suitable oxidizing agent to provide a compound of the Formula (1a-B);
• (c) condensing the compound of Formula (1a-B) with an aldehyde compound of Formula,
• wherein R10 is, a hydrophobic anchor or a residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula,
• in the presence of a base selected from the group consisting of sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in a suitable organic solvent to obtain the compound of Formula (8B2).

A process for the preparation of an HMG-CoA reductase inhibitor of Formula (9),

• wherein
• Y is selected from the group consisting of Na+, K+, Li+, Mg2+, Ca2+, Zn2+, Ba2+, Sr2+;
• and amine and
• R10 is a hydrophobic anchor or residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula (a) to (i),
• wherein R1 and R2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl and cycloheteroalkyl;
• R4 is selected from H, halogen, CF3, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, and cyano;
• X1 is selected from CH2, O, S and NR7, wherein R7 is selected from H, alkyl, aryl, alkanoyl, aroyl, and alkoxycarbonyl, the process comprising:
• (a) condensing a compound of Formula (1)
• wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
• R is selected from:
• wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
• Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
• Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
• Ra and Rb are same or different and each represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, with an aldehyde compound,
• wherein R10 is as defined above, in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in an inert organic solvent to obtain a compound of Formula (8);
• (b) hydrolyzing the compound of Formula (8) under acidic conditions to obtain a compound of Formula (8A);
• (c) treating the compound of Formula (8A) with an alkali metal hydroxide to form the corresponding alkali metal salt of Formula (9),
• (d) optionally treating the alkali metal salt of Formula (9) with a source of cation;
• and
• (e) isolating the HMG-CoA reductase inhibitors of Formula (9).

A process for the preparation of an HMG-CoA reductase inhibitor of general Formula (9),

• wherein
• Y is selected from the group consisting of Na+, K+, Li+, Mg2+, Ca2+, Zn2+, Ba2+, Sr2+;
• and amine and
• R10 is a hydrophobic anchor or residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula (a) to (i),
• wherein R1 and R2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl and cycloheteroalkyl;
• R4 is selected from H, halogen, CF3, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, and cyano;
• X1 is selected from CH2, O, S and NR7, wherein R7 is selected from H, alkyl, aryl, alkanoyl, aroyl, and alkoxycarbonyl, the process comprising:
• (a) condensing a compound of Formula (1B)
• wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
• R is selected from:
• wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
• Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
• Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
• Ra and Rb are same or different and each represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, with an aldehyde compound,
• wherein R10 is as defined above, in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in an inert organic solvent to obtain a compound of Formula (8B);
• (b) hydrolyzing the compound of Formula (8B) under acidic conditions to obtain a compound of Formula (8A);
• (c) treating the compound of Formula (8A) with an alkali metal hydroxide to form the corresponding alkali metal salt of Formula (9),
• (d) optionally treating the alkali metal salt of Formula (9) with a source of cation;
• and
• (e) isolating the HMG-CoA reductase inhibitor of Formula (9).

A process for the preparation of rosuvastatin calcium of Formula (9a),

• the process comprising:
• (a) condensing a compound of Formula (1a-B),
• with an aldehyde compound of Formula,
• wherein R10 is
• in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in a suitable organic solvent to obtain a compound of Formula (8B2);
• (b) hydrolyzing the compound of Formula (8B2) under acidic conditions to obtain a compound of Formula (8B2-b);
• (c) treating the compound of Formula (8B2-b) with an alkali metal hydroxide to form the corresponding alkali metal salt of Formula (9B);
• wherein, Y is selected from Na+, K+, and Li+;
• (d) treating the alkali metal salt of rosuvastatin of Formula (9) with a source of calcium to obtain a calcium salt of rosuvastatin;
• and
• (e) isolating the rosuvastatin calcium of Formula (9a).

A process for the preparation of 2-((4R,6S)-6-(E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dimethylacetamide of Formula (8B2),

• the process comprising the steps of:
• (a) condensing a compound of Formula (1a-B),
• with an aldehyde compound of Formula,
• wherein R10 is
• in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in a suitable organic solvent to obtain a compound of Formula (8B2);
• (b) extracting the compound of Formula (8B2) with a water immiscible organic solvent;
• (c) removing the water immiscible organic solvent to obtain a residue;
• (d) treating the residue with a suitable organic solvent;
• (e) heating reaction mixture of step (d) at an elevated temperature;
• (f) cooling the reaction mixture to ambient temperature;
• and
• (g) isolating 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl-sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dimethylacetamide in crystalline form.

A compound selected from:

• (S)-ethyl 3-hydroxy-4-(1-phenyl-1H-tetrazol-5-ylthio)butanoate (11a);
• (S)-5-hydroxy-N,N-dimethyl-3-oxo-6-(1-phenyl-1H-tetrazol-5-ylthio)hexanamide (6a);
• (3R,5S)-3,5-dihydroxy-N,N-dimethyl-6-(1-phenyl-1H-tetrazol-5-ylthio)hexanamide (5a);
• 2-((4R,6S)-2,2-diethyl-6-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (2a-A);
• 2-((4R,6S)-2,2-dimethyl-6-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (2a-B);
• N,N-dimethyl-2-((2R,4S)-4-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetamide (2a-C);
• 2-((4R,6S)-2-ethyl-2-methyl-6-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (2a-D);
• 2-((4R,6S)-2,2-diethyl-6-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (1a-A);
• 2-((4R,6S)-2,2-dimethyl-6-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (1a-B);
• N,N-dimethyl-2-((2R,4S)-4-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetamide (1a-C);
• 2-((4R,6S)-2-ethyl-2-methyl-6-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (1a-D);
• 2-((4R,6S)-6-(E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dimethylacetamide (8B2);
• and
• 2-((2R,4S)-4-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-1,5-dioxaspiro[5.5]undecan-2-yl)-N,N-dimethylacetamide (8B3).