Methyltetrazole sulfides and sulfones
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Publication Number
US-8865900-B2
Publication Date
2014-10-21
Expiration Date
Abstract
The present invention relates to a process for the preparation of a 1-methyl-1H-tetrazole-5-thio derivative comprising reaction of a halomethyl substrate with 1-methyl-H-tetrazole-5-thiol 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 a process for preparing a sulfone. The process reacts a halomethyl substrate of general formula (1a) or (1b), where R1 is halogen, with 1-methyl-1H-tetrazole-5-thiol (MTT) or a salt thereof to obtain a compound of general formula (2a) or (2b), and thereafter oxidizes the compound of general formula (2a) or (2b) to give a sulfone of general formula (3a) or (3b). The halomethyl substrates include protected forms in which R4 is an alcohol protecting group.
A key aspect is the use of 1-methyl-1H-tetrazole-5-thiol (MTT) in the synthesis leading from thio-ether intermediates to sulfone building blocks. The described approach addresses drawbacks associated with prior-art sulfonyl-activating agents and limitations in ester scope by enabling compatibility with smaller or unhindered carboxyl protecting groups, while producing thio-ether derivatives (2a/2b) that can be converted into sulfone derivatives (3a/3b).
The document further describes that MTT is compatible with a modified Julia-Kocienski olefination using aldehydes to form olefination products, and it reports that sodium-comprising bases can strongly favor E/Z ratios relevant for E-configuration. Representative embodiments include downstream conversion to statin-type vinyl products after olefination using aldehyde-containing compounds.
Claims Coverage
The document contains one independent claim that defines the core process steps for forming sulfones, followed by dependent claims that refine substrate scope, specify oxidation reagents, add isolation steps, and extend the process to subsequent olefination/condensation steps with aldehydes using sodium-containing bases.
Halomethyl-to-tetrazole-thiol thio-ether formation then oxidation to sulfone
A process for preparing a sulfone by reacting a halomethyl substrate of general formula (1a) or (1b) with 1-methyl-1H-tetrazole-5-thiol or a salt thereof to obtain a compound of general formula (2a) or (2b), and thereafter oxidizing the compound of general formula (2a) or (2b) to give a sulfone of general formula (3a) or (3b).
Specified halogen and substituent scope for R1–R5 in the halomethyl substrate
A process according to the claim limited to halomethyl substrates in which R1 is halogen and R4 is an alcohol protecting group, with additional defined options for the remaining substituents.
Oxidizing step using one or more specified oxidizing agents
The process of oxidizing the compound of general formula (2a) or (2b) is performed using one or more specified oxidizing agents.
Isolation of intermediate and/or sulfone compounds
The process includes isolating a compound belonging to one of the specified general-formula groups (2a/2b) and/or (3a/3b).
Sulfonyl intermediate reacted with aldehyde-containing R6-CHO reactants
A further step comprises reacting a sulfone of general formula (3a) or (3b) with a compound of general formula R6-CHO to form a compound of general formula (4a) or (4b), respectively.
Use of a sodium-comprising base including sodium hexamethyldisilazane
The process uses a sodium-comprising base, exemplified by sodium hexamethyldisilazane.
Across the independent claim and dependent refinements, the inventive theme is formation of sulfone building blocks via reaction of halomethyl substrates with 1-methyl-1H-tetrazole-5-thiol (MTT) to produce thio-ether intermediates followed by oxidation to sulfones, with further specified oxidation agents, isolation of intermediates/sulfones, and optional downstream reaction with defined aldehyde-containing reactants under sodium-comprising base conditions.
Stated Advantages
Overcomes prior-art drawbacks associated with hazardous or expensive sulfonyl-activating agents.
Enables use with smaller or unhindered carboxyl protecting groups, addressing limitations in ester scope.
Reports unexpected compatibility of MTT in a modified Julia-Kocienski olefination context.
Sodium-comprising bases strongly favor E/Z ratios relevant to E-configuration.
Documented Applications
Preparation of sulfone building blocks that support olefination to form statin-type vinyl products, including embodiments linked to statins such as cerivastatin, fluvastatin, pitavastatin, and rosuvastatin.
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