Process for the preparation of diol sulfones
Inventors
De Lange, Ben • Riebel, Peter Hans • Wolberg, Michael • Heemskerk, Dennis • Mink, Daniel
Assignees
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Publication Number
US-9150562-B2
Publication Date
2015-10-06
Expiration Date
Abstract
The present invention relates to a process for the preparation of a diol sulfone derivative comprising reaction of a halomethyl substrate with a thio-aryl compound to obtain a thio-ether compound, and oxidizing the thio-ether compound to the corresponding sulfone. In case of a chiral halomethyl substrate, the resulting chiral diol sulfone derivative is suitable as a building block for statin type compounds.
Core Innovation
The invention relates to preparation of sulfone-substituted tetrahydropyranone/acetate derivatives by reacting a halomethyl substrate with 2-mercapto-1H-benzothiazole or a compound of general formula R6—S—X to form a thioether intermediate. The thioether intermediate is then oxidized to provide a sulfone derivative. The halomethyl substrate is described with substituents R1, R2, R3, R4, and R5, and the sequence is described with protected chiral halomethyl substrates and benzothiazole-containing intermediates.
The disclosed sequence includes further synthetic variants toward a dimethyl-dioxane acetate series and formation of a sulfone N intermediate, which is used in coupling or condensation. A sulfone intermediate is coupled or condensed with a pyrimidine aldehyde to form an (E)-vinylated product with a pyrimidin-5-yl vinyl linkage. The document also links the sulfone intermediates to subsequent Julia–Kocienski olefination with aldehydes.
The transformations are presented with reported yields, purities, and product identities for key intermediates and final products. The description further states that the approach avoids hazardous alcohol-activating agents by forming a thioether intermediate before oxidation to the corresponding sulfone.
Claims Coverage
The consolidated claim coverage includes two independent claims: one directed to a process for preparing a sulfone and one directed to a compound defined by a general formula. The process claims two inventive features, and the compound claim defines a structural scaffold with specified substituent radicals and ring or heteroatom constraints.
Halomethyl-to-thioether intermediate followed by oxidation to sulfone
Reacting a halomethyl substrate of general formula (1a) or (1b) with a compound of general formula R6—S—X to obtain a compound of general formula (3a) or (3b), respectively, and subjecting the compound of general formula (3a) or (3b) to oxidation to thereby provide a sulfone of general formula (4a) or (4b), respectively.
General formula compound defined by substituent radicals and ring constraints
A compound of general formula (3b) or (4b) wherein R5 is hydrogen or an alcohol protecting group, and R6 is a radical of general formula R6′ or R6″, wherein A-B is C—C or N—N or wherein A-B is part of an aromatic five- or six-membered ring, optionally substituted, wherein Y is sulfur or an alkyl-substituted nitrogen, and wherein Z is nitrogen or CH.
The claim coverage is centered on forming a thioether intermediate from a halomethyl substrate and oxidizing it to a sulfone, together with a compound definition based on R5, R6, A-B, Y, and Z constraints.
Stated Advantages
Avoids hazardous alcohol-activating agents by providing the sulfone via thioether formation and subsequent oxidation.
Unexpected feasibility of nucleophilic thiol attack is described for substrates with small or unhindered ester groups, with high yield and low degradation.
Base-dependent E/Z selectivity is described, including E-favored outcomes associated with NaHMDS.
Documented Applications
Use of the disclosed sulfone intermediates in subsequent Julia–Kocienski olefination with aldehydes toward statins, including production of statin precursors associated with cerivastatin, fluvastatin, pitavastatin, and rosuvastatin.
A sulfone intermediate is coupled or condensed with a pyrimidine aldehyde to form an (E)-vinylated product with a pyrimidin-5-yl vinyl linkage.
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