Process for the preparation of statins in the presence of base
Inventors
Bessembinder, Karin Henderika Maria • Heemskerk, Dennis • De Lange, Ben
Assignees
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Publication Number
US-9126975-B2
Publication Date
2015-09-08
Expiration Date
Abstract
The present invention relates to a process for the preparation of statins by means of a Julia-Kocienski reaction between an aldehyde and a sulfone derivative in the presence of an alkaline metal alkoxy base. The resulting derivatives are suitable as building blocks for statin type compounds such as cerivastatin, fluvastatin, pitavastatin and rosuvastatin.
Core Innovation
The invention relates to a process for the preparation of a compound of general formula R1—C≡C—R2 or a salt thereof. The process reacts a compound of formula R1—CH=O with a compound of formula R2—CH2—SO2—R7 in the presence of an alkaline metal alkoxy base, and the R1 and R2 radicals are defined by the specific radical formulas (A), (B), (C) and (D) for R1 and by the general formulas (E) or (F) for R2, together with further definitions of R3, R4, R5, R6, and R7.
A key feature is performing the olefination using an alkaline metal alkoxy base having a pKa value of from 16 to 21. The strategy is presented as a modified Julia–Kocienski olefination between aldehydes of the form R1—CH=O and chiral diol sulfone precursors derived via thio-ether intermediates to sulfones, and it is characterized as improving the formation of the desired E-configuration required for the statins while avoiding side-product formation observed with bases such as KHMDS, LiHMDS, and NaHMDS.
The document further specifies that R6 is an alcohol protecting group and that R7 is defined as a radical of general formula R7′ or R7″, including heteroaryl groups and benzothiazolyl structures. The described process includes subsequent deprotection and isolation to yield a related product according to a general formula (G), and the partial content explicitly associates the disclosed workflow with statins including cerivastatin, fluvastatin, pitavastatin, and rosuvastatin.
Claims Coverage
The independent claim covers a process comprising reacting an R1—CH=O aldehyde with an R2—CH2—SO2—R7 sulfone-containing precursor in the presence of an alkaline metal alkoxy base having a pKa of 16 to 21. The claim set contains 1 independent claim and dependent claims that refine the base selection, the substituent classes for R1/R2 substituents, and a deprotection/isolation outcome.
Alkaline metal alkoxy base with pKa 16 to 21
A process comprising reacting a compound of formula R1—CH=O with a compound of formula R2—CH2—SO2—R7 in the presence of an alkaline metal alkoxy base with a pKa value of from 16 to 21.
Aldehyde and sulfone precursor pair producing R1—C(=C)—R2
The process reacts an aldehyde compound of formula R1—CH=O with a compound of formula R2—CH2—SO2—R7 to prepare a compound of general formula R1—C(=C)—R2 or a salt thereof.
Defined R1, R2 substituent framework and R7 heteroaryl/benzothiazolyl radical
R1 is a radical chosen from radicals of formula (A), (B), (C) and (D), R2 is a radical of general formula (E) or (F), R6 is an alcohol protecting group, and R7 is a radical of general formula R7′ or R7″ including heteroaryl groups and benzothiazolyl structures.
Deprotection and isolation to yield compound (G) class
The process includes subsequent deprotection and isolation to yield a compound of general formula (G).
Across the claim set, the core coverage is a modified Julia–Kocienski-type process defined by the specific aldehyde/sulfone precursor reaction to form R1—C(=C)—R2, executed using an alkaline metal alkoxy base with a pKa of 16 to 21. Dependent claims narrow base identities, constrain R1/R2 substituent options, and add a deprotection/isolation outcome that yields a product class (G).
Stated Advantages
Enables high E-selectivity corresponding to the E-configuration required for the statins.
Avoids side-product formation seen with KHMDS, LiHMDS, and NaHMDS.
Documented Applications
Preparation of statins including cerivastatin, fluvastatin, pitavastatin, and rosuvastatin using the modified Julia–Kocienski olefination process.
Conversion to an E-vinyl pyrimidinyl statin precursor (compound E) as part of forming statin products.
Formation of rosuvastatin calcium salt.
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