Process for preparing tetralin compounds
Inventors
BEATTY, Joel Worley • DREW, Samuel Lawrie • EPPLIN, Matthew • FOURNIER, JEREMY • GAL, Balint • HAELSIG, Karl T. • Hardman, Clayton • Kalisiak, Jaroslaw • LAWSON, Kenneth Victor • Leleti, Manmohan Reddy • MAILYAN, Artur Karenovich • MATA, Guillaume • Rosen, Brandon Reid • Wang, Zhang • Yu, Kai
Assignees
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Publication Number
US-12145901-B1
Publication Date
2024-11-19
Expiration Date
Abstract
The present disclosure describes processes and intermediates useful for preparing a compound of Formula (Xa) or Formula (Xb). The processes and intermediates can be used to prepare the compounds of the disclosure at multigram or kilogram scale.
Core Innovation
The invention is directed to a process in which a compound of Formula (IIa) is contacted with a chiral ruthenium (II) catalyst and a hydrogen reagent to prepare a compound of Formula (Ia). The chiral ruthenium (II) catalyst is RuCl(p-cymene)[(R,R)-Ts-DPEN], and the resulting compound of Formula (Ia) has at least 90% diastereomeric purity. The Formula (Ia) compound includes substituent definitions R1 through R5, where R5 is an alcohol protecting group.
The document further describes catalyst-controlled hydrogenation in a stereoselective process for preparing fluorinated chiral compounds and substituted tetralin compounds. The hydrogen reagent is described as hydrogen gas or formic acid, and the stereochemical outcome is presented as a preferential formation of a trans-isomer and diastereomerically enriched products. The disclosure also states fluorination and deprotection sequences leading to additional compounds, including Formula (Xa).
The content additionally outlines downstream transformations involving fluorinating agents, second deprotecting agents, and oxidizing agents identified in the document. It also includes investigation of hydrogenation stereochemistry, confirmation of product structures by single-crystal X-ray diffraction for compounds identified as 8, 9, and 11, and substituted tetralin structures related to hypoxia-inducible factor pathway targets, including HIF-1α, HIF-2α, HIF-3α, ARNT, prolyl-4-hydroxylases, and von Hippel-Lindau.
Claims Coverage
The consolidated claim coverage centers on one process with a chiral ruthenium (II) catalyst system and a hydrogen reagent to prepare a diastereomerically pure compound of Formula (Ia). Across the claimed refinements, the inventive features include the catalyst identity, hydrogen reagent selection, substituent definitions for R1 through R5, downstream fluorination and deprotection, oxidizing-agent options, and a palladium impurity constraint.
Chiral ruthenium(II)-catalyzed hydrogenation to prepare Formula (Ia) with high diastereomeric purity
A process comprising contacting a compound of Formula (IIa) with a chiral ruthenium (II) catalyst and a hydrogen reagent to prepare a compound of Formula (Ia), wherein the chiral ruthenium (II) catalyst is RuCl(p-cymene)[(R,R)-Ts-DPEN], and the compound of Formula (Ia) has at least 90% diastereomeric purity.
Hydrogen reagent selection
The hydrogen reagent is either hydrogen gas or formic acid.
Alcohol protecting group selection for R5
R5 is an alcohol protecting group selected from MOM, MEM, THP, tert-butyl, allyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, and 4-methoxybenzyl.
Fluorination of Ia followed by deprotection to Xa
The process includes contacting the compound of Formula (Ia) with a fluorinating agent to form a compound of Formula (XIa), and then contacting the compound of Formula (XIa) with a second deprotecting agent to form a compound of Formula (Xa).
Specific oxidizing agents for subsequent transformations
The process includes an oxidizing agent selected from potassium permanganate, 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 2-iodoxybenzoic acid, 1-acetoxy-5-bromo-1,2-benziodoxol-3(1H)-one, oxalyl chloride-dimethyl sulfoxide, tert-butyl hydroperoxide, sodium hypochlorite, and chromium (VI) trioxide.
Low palladium impurity constraint
The process is carried out such that the compound of Formula (VI) contains less than 1000 ppm palladium.
Overall, the claims focus on a RuCl(p-cymene)[(R,R)-Ts-DPEN] chiral ruthenium(II)-catalyzed hydrogenation of Formula (IIa) to produce Formula (Ia) with at least 90% diastereomeric purity, together with dependent refinements for hydrogen reagent choice, R5 protecting-group selection, fluorination and deprotection, oxidizing agents, and a palladium impurity limit.
Stated Advantages
Produces a compound of Formula (Ia) having at least 90% diastereomeric purity.
The disclosed products are substantially free of other stereoisomers.
Process capability/quality statements are provided including yield and purity ranges.
Scalable stereoselective processes for preparing substituted tetralin compounds.
Documented Applications
Stereoselective preparation of fluorinated chiral compounds via catalyst-controlled hydrogenation to produce Formula (Ia)/(Ib), followed by fluorination and conversion steps involving Formulas (III), (IV), and (V).
Preparation of substituted tetralin compounds related to hypoxia-inducible factor (HIF) pathway targets, including HIF-1α, HIF-2α, HIF-3α, ARNT (HIF-β), prolyl-4-hydroxylases (PHDs), and von Hippel-Lindau (pVHL).
Preparation of compounds corresponding to Formula (Ia) and downstream deprotected products (Formula (Xa)/(Xb)) through a multi-step process that includes fluorination and deprotection sequences.
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