Processes for preparing calcium salt forms of statins
OwnerValerie Niddam-Hildesheim, Revital Lifshitz-Liron +1inventors
InventorsValerie Niddam-Hildesheim, Revital Lifshitz-Liron, Rami Lidor-Hadas
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Abstract
Processes for preparing a calcium salt of a statin from an ester derivative or protected ester derivative of the statin by using calcium hydroxide are provided. The ester or protected ester derivative is contacted with calcium hydroxide to obtain the calcium salt. Preferred statins are rosuvastatin, pitavastatin and atorvastatin, simvastatin and lovastatin. In processes beginning with a protected statin ester derivative, the protecting group is hydrolyzed during salt formation by contact with calcium hydroxide, or is contacted with an acid catalyst followed by contact with calcium hydroxide.
Claims42
A process for preparing a calcium salt of a statin having the formula:
- 13
- wherein r represents an organic radical, comprising contacting an ester derivative of the statin selected from the group consisting of:
- 14
- with a sufficient amount of calcium hydroxide,
- wherein R1 is a C1 to a C8 alkyl group, and
- R2, R3 and R4 each independently represent hydrogen, or the same or different hydrolyzable protecting group, or R2 and R3, together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting group.
A process for preparing rosuvastatin calcium salt comprising contacting a C1 to a C8 ester of 7-[4-(4-fluorophenyl)-6-iso-propyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoate with a sufficient amount of calcium hydroxide.
A process for preparing rosuvastatin calcium salt comprising contacting lactone form of rosuvastatin with a sufficient amount of calcium hydroxide.
A process for preparing pitavastatin calcium salt comprising contacting a C1 to a C8 ester of (E)-3,5-dihodroxy-7-[4′-(4″-fluorophenyl)-2′-(1″-cyclopropyl)-quinolin-3′-yl]-hept-6-enoate with a sufficient amount of calcium hydroxide.
A process for preparing pitavastatin calcium salt comprising contacting lactone form of pitavastatin with a sufficient amount of calcium hydroxide.
A process for preparing a calcium salt of a statin having the formula:
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- wherein R represents an organic radical, comprising the steps of:
- a) adding calcium hydroxide and an ester derivative of the statin selected from the group consisting of:
- 17
- to a mixture of water and a C1 to a C4 alcohol,
- wherein R1 is a C1 to a C8 alkyl group, and
- R2, R3 and R4 each independently represent hydrogen, or the same or different hydrolyzable protecting group, or R2 and R3, together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting group;
- b) heating the mixture;
- c) precipitating the calcium salt of the statin;
- and
- d) separating the calcium salt.
Dependencies are inferred from the claim text.