Process for preparing statin precursor
Inventors
De Lange, Ben • Bessembinder, Karin Henderika Maria • Heemskerk, Dennis
Assignees
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Publication Number
US-10246423-B2
Publication Date
2019-04-02
Expiration Date
Abstract
The present invention relates to a process for preparing a statin precursor, which process comprises a first reaction step, wherein a hydroxy-pyrimidine-carbonitrile is reacted with an organic sulfonyl halide to form the sulfonate-pyrimidine-carbonitrile; a second reaction step, wherein the sulfonate-pyrimidine-carbonitrile is reacted with N-methylmethane sulfonamide to form a pyrimidinyl-sulfonamide; and optionally a third reaction step, wherein the pyrimidinyl-sulfonamide is reacted with a reducing agent. All steps are conducted in toluene as the main solvent.
Core Innovation
The invention provides a multi-step process for preparing the compound of formula (IV) using toluene as the organic solvent. A starting mixture comprising the compound of formula (II) and toluene is contacted with an organic sulfonyl halide to form an intermediate mixture comprising the compound of formula (III). During the first reaction step, the first reaction mixture is kept at a first temperature of below 110 °C.
In a second reaction step, the intermediate mixture is contacted with N-methylmethane sulfonamide to form a second mixture comprising the compound of formula (IV). The second reaction step is carried out while keeping the second reaction mixture at a second temperature. The process emphasizes formation of the sulfonamide-linked pyrimidine intermediate and then conversion to the pyrimidinyl-sulfonamide.
The document further emphasizes that using a single solvent system, predominantly toluene across the steps, supports solvent integration and solvent recovery/handling strategies. It also addresses low substrate solubility/suspension by enabling the reactions despite such conditions, and it describes strategies to reduce dimer formation during formation of the pyrimidinyl-sulfonamide, including temperature control below about 110 °C and a dosing protocol for contacting/addition.
Claims Coverage
The document provides one independent claim directed to a process for preparing the compound of formula (IV), with dependent claims refining reaction participants, temperature constraints, solvent composition, and the contacting of the intermediate with N-methylmethane sulfonamide. The overall disclosure also includes an optional reduction step to prepare a compound of formula (I).
Toluene starting mixture and sulfonylation to form intermediate (III)
A process for preparing the compound of formula (IV) wherein a starting mixture comprising the compound of formula (II) and toluene is contacted with an organic sulfonyl halide, and the first reaction mixture is kept at a first temperature of below 110 °C to form an intermediate mixture comprising the compound of formula (III).
N-methylmethane sulfonamide conversion to pyrimidinyl-sulfonamide (IV)
The intermediate mixture is contacted with N-methylmethane sulfonamide and the second reaction mixture is kept at a second temperature to form a second mixture comprising the compound of formula (IV).
Independent claim coverage centers on preparing an intermediate mixture of formula (III) by contacting formula (II) in toluene with an organic sulfonyl halide under a first temperature below 110 °C, and converting that intermediate to a second mixture containing formula (IV) by contacting with N-methylmethane sulfonamide under a second temperature constraint. Dependent refinements include specified ranges and composition requirements, defined selections of sulfonyl halides and bases, and a defined contacting protocol for the second step, plus an optional reduction step to formula (I) as described in the disclosure.
Stated Advantages
Improved solvent recovery/integration by using a single solvent (toluene) across steps.
Surprisingly enables reactions despite low substrate solubility/suspension.
Strategies to reduce dimer formation.
Documented Applications
No documented applications found
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