Process for producing 4,5-dihydro-1H-pyrazoles and intermediates
Inventors
Green, Jeremy • MIX, Stefan • Brunet, Vincent • Brown, Gareth • Pavlovic, Drazen
Assignees
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Publication Number
US-12595235-B2
Publication Date
2026-04-07
Expiration Date
Abstract
Described are processes for the manufacture of compounds containing a (S)-4,5-dihydro-1H-pyrazole ring. These processes include a chiral resolution step of an intermediate using selected chiral resolving agents. For example, the chiral resolving agents may be selected from (−)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(−)-2-amino-3-methyl-1-butanol, (−)-cinchonidine, (−)-spartein, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol and (1R,2S)-(+)-cis-1-amino-2-indanol.
Core Innovation
The invention relates to a process for preparing an enantiomerically enriched compound. The process provides a compound of Formula I(a) or I(b), or a tautomer thereof, that comprises a mixture of R and S isomers at the (*) carbon atom (C*), wherein the fourth atom attached to C* is hydrogen or an isotope thereof, and the compound is dissolved in a solvent to obtain a solution.
A chiral resolving agent is selected from (−)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(−)-2-amino-3-methyl-1-butanol, (−)-cinchonidine, (−)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol, and dissolved in the solution to form a precipitate and a supernatant. The dissolving and resolving steps are carried out simultaneously or sequentially.
The precipitate is separated from the supernatant, and one of the precipitate or the supernatant comprises the enantiomerically enriched compound with a higher concentration in the S-enantiomer compared to the R-enantiomer. The disclosure further includes acidic aqueous treatment to form salts and optional further processing to recover or recycle isomeric material for downstream enrichment.
The disclosure further includes guidance and example compounds for the broader chemical context involving Formula II and conversion steps to Formula III and tautomers, including S-dihydropyrazole ring-containing compound CB1 receptor inhibitors such as (S)-Ibipinabant.
Claims Coverage
The independent claim is directed to an enantiomer-enrichment process for a Formula I(a)/I(b) compound, using chiral resolving-agent addition to generate a precipitate/supernatant split with S-enrichment. The main inventive features are the Formula I(a)/I(b) substrate, the selected chiral resolving agents, the precipitate and supernatant formation, and the selection of which fraction is enriched in S.
Formula I(a)/I(b) enantiomeric substrate at C*
Providing a compound of Formula I(a) or I(b), or a tautomer thereof, comprising a mixture of R and S isomers at C* wherein the fourth atom attached to C* is hydrogen or an isotope thereof.
Solution preparation in a solvent
Dissolving the compound of Formula I(a) or I(b) in a solvent to obtain a solution.
Chiral resolving agent forming precipitate and supernatant
Dissolving a chiral resolving agent selected from (−)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(−)-2-amino-3-methyl-1-butanol, (−)-cinchonidine, (−)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol in the solution to form a precipitate and a supernatant.
Separating with S-enrichment in one fraction
Separating the precipitate from the supernatant wherein one of the precipitate or the supernatant comprises the enantiomerically enriched compound comprising a higher concentration in S-enantiomer compared to the R-enantiomer of the compound of Formula I(a) or I(b); and wherein steps (b) and (c) are carried out simultaneously or sequentially.
Across the independent claim, the coverage centers on preparing an enantiomerically enriched compound from a Formula I(a)/I(b) R/S mixture at C* by dissolving a defined chiral resolving agent to produce precipitate and supernatant, followed by separation such that either fraction is enriched in the S-enantiomer relative to the R-enantiomer.
Stated Advantages
Produces an enantiomerically enriched compound with a higher concentration of the S-enantiomer compared to the R-enantiomer.
Documented Applications
CB1 receptor inhibitors, including (S)-Ibipinabant, in connection with compounds and conversions involving Formula II and conversion to S-dihydropyrazole (Formula III) compounds.
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