Method for preparing rosuvastatin salts

A method for the preparation of a rosuvastatin product, which method is one of the following methods I to V:

• I) for the preparation of rosuvastatin ammonium salt of the general Formula (II),
• wherein R1, R2 and R3 independently represent hydrogen or a straight, branched or cyclic saturated alkyl group comprising 1 to 6 carbons atoms or NR1R2 together represents a saturated heterocyclic group having 5, 6 or 7 carbon atoms and one nitrogen atom,
• which comprises
• reacting a rosuvastatin amide of the general Formula (III)
• wherein R4 and R5 independently from each other represent hydrogen or a straight, branched or cyclic alkyl group comprising 1 to 6 carbon atoms or NR4R5 together represents a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom,
• in water or in a homogeneous mixture of water and a water-miscible organic solvent, preferably in a mixture of an aliphatic alcohol having 1 to 6 carbon atoms and water with an amine of the general Formula (X)
• wherein R1, R2 and R3 independently from each other represent hydrogen or a straight, branched or cyclic alkyl group or R1 and R2 with the nitrogen attached thereto comprises a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom;
• or
• II) for the preparation of rosuvastatin calcium salt of the Formula (IV)
• which comprises
• a) reacting a rosuvastatin amide of the general Formula (III), wherein R4 and R5 independently represents hydrogen or a straight, branched or cyclic saturated alkyl group comprising 1 to 6 carbon atoms or NR4R5 together forms a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom,
• in water or in a homogeneous mixture of water and a water-miscible organic solvent, preferably in water or in a mixture of an aliphatic alcohol having one to six carbon atoms and water with an amine of the general Formula (X) wherein R1, R2 and R3 independently represent hydrogen or a straight, branched or cyclic alkyl group comprising 1 to 6 carbon atoms or R1 and R2 together with a nitrogen atom attached thereto forms a saturated 5,6 or 7-membered heterocyclic group having one nitrogen;
• b) transforming the rosuvastatin ammonium salt of the general Formula (II) obtained in step a), wherein R1, R2 and R3 independently from each other represents hydrogen or a straight, branched or cyclic saturated alkyl group comprising 1 to 6 carbon atoms or R1 and R2 together with the nitrogen attached thereto forms a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom into rosuvastatin calcium salt of the Formula (IV) or a hydrate form thereof;
• or
• III) for the preparation of rosuvastatin zinc (2:1) salt of the Formula (V)
• which comprises
• a) reacting a rosuvastatin amide of the general Formula (III), wherein R4 and R5 independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or NR4R5 together represents a saturated 5-, 6- or 7-membered heterocyclic group having one nitrogen
• in water or in a homogeneous mixture of water and a water-miscible organic solvent, preferably in a mixture of water and an aliphatic alcohol having 1 to 6 carbon atoms with an amine of the general Formula (X) wherein R1, R2 and R3 independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having one to six carbon atoms or R1 and R2 with a nitrogen atom attached thereto form a saturated 5, 6 or 7-membered heterocyclic group having one nitrogen atom;
• b) transforming rosuvastatin ammonium salt of the general Formula (II) obtained in step a) wherein R1, R2 and R3 independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or R1 and R2 together with the nitrogen atom attached thereto forms a saturated 5, 6 or 7-membered heterocycylic group having one nitrogen atom into rosuvastatin zinc (2:1) salt of the Formula (IV);
• or
• IV) for the preparation of rosuvastatin TBA salt of the Formula (IIa) in crystalline Form II
• which comprises
• a) Reacting a rosuvastatin amide of the general Formula (III), wherein R4 and R5 independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or wherein NR4R5 together represents a saturated 5-, 6- or 7-membered heterocyclic group having one nitrogen atom in water or in a homogeneous mixture of water and a water-miscible solvent, preferably in a mixture of water and an aliphatic alcohol having 1 to 6 carbon atoms with an amine of the general Formula (X) wherein R1, R2 and R3 independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or wherein R1 and R2 together with the nitrogen atom attached thereto forms a saturated 5, 6 or 7-membered heterocycylic group having one nitrogen,
• b) Purifying crude rosuvastatin TBA salt obtained in step a) by crystallization;
• c) Mixing the aqueous suspension of the purified rosuvastatin TBA salt of the Formula (IIa) thus obtained with tert-butylamine and
• d) Crystallizing rosuvastatin TBA salt crystalline Form (II) of the Formula (IIa) fractionally;
• or
• V) for the preparation of rosuvastatin TBA salt of the Formula (IIa),
• which comprises reacting a rosuvastatin amide of the general Formula (III), wherein R4 and R5 independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or wherein NR4R5 together represents a saturated 5-, 6- or 7-membered heterocyclic group having one nitrogen atom in water or in a homogeneous mixture of water and a water-miscible solvent, preferably in a mixture of water and an aliphatic alcohol having 1 to 6 carbon atoms with an amine of the general Formula (X) wherein R1, R2 and R3 independently from each other represents hydrogen or a straight, branched or cyclic alkyl group having 1 to 6 carbon atoms or wherein R1 and R2 together with the nitrogen atom attached thereto forms a saturated 5, 6 or 7-membered heterocycylic group having one nitrogen.