Methods for making thiazolypyrazole carboxylic acids and intermediates therefor
Inventors
Cooper, Alan • O'Shea, Paul • Anantha, Narayanan
Assignees
Bantam Pharmaceutical LLC • Exemplify Biopharma Inc • Bantam Pharamceutical LLC
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Publication Number
US-12358905-B2
Publication Date
2025-07-15
Expiration Date
Abstract
This disclosure relates generally to improved methods of preparing pyrazolylthiazole-containing compounds and their intermediates.
Core Innovation
The invention relates to improved syntheses of ring-substituted pyrazolylthiazole carboxylic acid derivatives of formula (I). The route prepares pyrazolylthiazoles of formula (Ia) by forming a hydrazone from thiazolylhydrazines of formula (Ib) and diones of formula (II), followed by alkylhalogenide-mediated cyclization or contacting with a compound of formula X1-CH2-Q1 to obtain the halopyrazolylthiazole of formula (Ia).
The thiazolylhydrazines of formula (Ib) are prepared from dihalothiazoles by reacting with aqueous hydrazine to obtain a crude product, and then crystallizing the crude product from a hydrocarbon solvent to obtain the thiazolylhydrazine (Ib). The partial content indicates that the coupling is a Suzuki coupling.
The halopyrazolylthiazole of formula (Ia) is then coupled with an organoboron comprising an R5 moiety to obtain the compound of formula (I), yielding the ring-substituted pyrazolylthiazole carboxylic acid derivatives, with exemplified intermediates and final products.
Claims Coverage
The partial claim set includes four independent claims covering three transformation motifs and one compound claim: hydrazone formation/cyclization to halopyrazolylthiazoles, crystallization of thiazolylhydrazines from crude hydrazine reaction products, organoboron coupling from halopyrazolylthiazoles to formula (I), and a halopyrazolylthiazole compound of formula (Ia).
Hydrazone formation and alkylhalogenide-mediated cyclization to halopyrazolylthiazole of formula (Ia)
Reacting a thiazolylhydrazine of formula (Ib) with a dione of formula (II), optionally in a solvent, under conditions sufficient to form a hydrazone, and contacting the hydrazone with a compound of formula X1-CH2-Q1 to obtain the halopyrazolylthiazole of formula (Ia).
Halopyrazolylthiazole compound of formula (Ia)
A halopyrazolylthiazole of formula (Ia) wherein X is a halogen; L1 and Q1 are selected from specified bond/heteroatom/linker and substituent patterns; R1 is selected from C1-C8 alkyl, C1-C8 alkenyl and C1-C8 alkynyl each unsubstituted or fluorinated; R3 is phenyl or heteroaryl with optional substituent patterns; and R4 and R6 are selected from defined groups.
Organoboron coupling of halopyrazolylthiazole of formula (Ia) to compound of formula (I)
Coupling a halopyrazolylthiazole of formula (Ia) with an organoboron comprising an R5 moiety to obtain the compound of formula (I), optionally as a pharmaceutically acceptable salt or N-oxide and/or a solvate or hydrate, where the coupling is described as a Suzuki coupling.
Dihalothiazole reaction with aqueous hydrazine to thiazolylhydrazine of formula (Ib), followed by hydrocarbon crystallization
Reacting a dihalothiazole with an aqueous solution of hydrazine to obtain a crude product, and crystallizing the crude product from a hydrocarbon solvent to obtain the thiazolylhydrazine of formula (Ib).
Across the independent claims, the inventive subject matter is centered on conversion of thiazolylhydrazines and diones into halopyrazolylthiazoles via hydrazone formation and alkylhalogenide-mediated cyclization, preparation of thiazolylhydrazines from dihalothiazoles by aqueous hydrazine reaction and hydrocarbon crystallization, and organoboron coupling of halopyrazolylthiazoles to compounds of formula (I).
Stated Advantages
Higher overall yield (reported as >30% versus 2.5% in a cited prior method).
High purity (reported as ≥98%).
Potential to avoid chromatography.
Documented Applications
Not explicitly described in patent.
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