Process for the preparation of a statin precursor
Inventors
De Lange, Ben • Heemskerk, Dennis • Bessembinder, Karin Henderika Maria
Assignees
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Publication Number
US-8987478-B2
Publication Date
2015-03-24
Expiration Date
Abstract
The present invention relates to a process for the preparation of a precursor for the synthesis of hexanoic acid derived statins and to the use of said precursor in the manufacture of a medicament.
Core Innovation
Hexanoic acid derived statins require chiral intermediates of general formula (2), wherein R4 is a carboxylic acid protecting group attached to the chiral intermediate of general formula (2). The disclosure addresses the need for R4 substitution on the chiral intermediate of general formula (2) and overcomes shortcomings associated with prior methyl-protected precursors.
A method is provided to prepare compounds of general formula (2) by acid-catalyzed contacting of a halogenated starting material of general formula (3) with an alcohol of general formula R4–OH and an acetal, an alkoxy-alkene, or a ketone. The contacting is conducted in the presence of an acid, with X defined as halogen in the halogenated starting material of general formula (3). The approach enables the introduction of diverse R4 groups.
Compared with alternative sequences involving methyl ester formation, hydrolysis/activation, and conversion to a different ester, the single-step introduction of R4 provides higher yields and purity and minimizes methanol contamination. Compounds of general formula (2) are used for manufacturing antilipemic medicaments by converting to statins of general formula (1), and the document additionally describes downstream transformations to obtain further statin derivatives, including thiol substitution to thio-ethers, optional oxidation to sulfones, and aldehyde coupling.
Claims Coverage
The disclosed independent claim covers a method for preparing compounds of general formula (2) by acid-catalyzed contacting of a halogenated general formula (3) with an alcohol R4–OH and a selected acetal, alkoxy-alkene, or ketone, with constraints on X, R2, and R3. The dependent claims further narrow the alcohol component (R4) and specify example reactants and tighter definitions for X, R2, and R3.
Acid-catalyzed contacting to form general formula (2) with specified R4
A method for preparing a compound of general formula (2) by contacting a compound of general formula (3) with an alcohol of general formula R4–OH and an acetal or an alkoxy-alkene or a ketone in the presence of an acid, characterized in that X is halogen, R2 and R3 each independently stand for an alkyl/alkenyl/cycloalkyl/cycloalkenyl/aryl/aralkyl group, optionally substituted and optionally forming a ring with the bound carbon, and R4 is an alkyl or alkenyl group with 2 to 6 carbon atoms.
Restricting the R4 alcohol to specific alkyl or alkenyl substituents
The method further defines that R4 is selected from listed alkyl or alkenyl groups including allyl, iso-butenyl, n-butyl, sec-butyl, tert-butyl, ethyl, 2-methyl-3-pentyl, 4-methyl-1-pentyl, 4-methyl-2-pentyl, n-propyl, iso-propyl, and vinyl.
Specifying the acetal, alkoxy-alkene, and ketone reactants
The method specifies that the acetal can be dimethoxypropane, the alkoxy-alkene can be 2-ethoxypropene or 2-methoxypropene, and the ketone can be acetone, cyclohexanone, cyclopentanone, or 3-pentanone.
Restricting halogen X and fixing R2 and R3 to methyl
The method further specifies that X is bromine or chlorine and that R2 and R3 are methyl.
Overall claim coverage centers on forming the chiral intermediate of general formula (2) via acid-catalyzed contacting of general formula (3) with an R4–OH alcohol and an acetal, alkoxy-alkene, or ketone, with R4 restricted to 2–6 carbon alkyl or alkenyl groups; the dependent claims then narrow R4 to listed substituents, specify particular reactants, and optionally restrict X to bromine or chlorine while setting R2 and R3 to methyl.
Stated Advantages
Introducing diverse R4 groups in a single step.
Higher yields and purity compared with alternative sequences.
Minimizing methanol contamination.
Documented Applications
Manufacturing antilipemic medicaments by converting compounds of general formula (2) to statins of general formula (1).
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