RESUMO
We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.
Assuntos
Alcenos/química , Carbono/química , Cinamatos/química , Cinamatos/síntese química , Indazóis/química , Indazóis/síntese química , Receptores de Estrogênio/metabolismo , Técnicas de Química Sintética , Cinamatos/farmacologia , Indazóis/farmacologia , Cetonas/química , EstereoisomerismoRESUMO
A concise asymmetric synthesis has been developed to prepare idasanutlin, a small molecule MDM2 antagonist. Idasanutlin is currently being investigated as a potential treatment for various solid tumors and hematologic malignancies. The highly congested pyrrolidine core, containing four contiguous stereocenters, was constructed via a Cu(I)/(R)-BINAP catalyzed [3+2]-cycloaddition reaction. This optimized copper(I)-catalyzed process has been used to produce more than 1500 kg of idasanutlin. The manufacturing process will be described, highlighting the exceptionally selective and consistent cycloaddition/isomerization/hydrolysis sequence. The excellent yields, short cycle times and reduction in waste streams result in a sustainable production process with low environmental impact.
Assuntos
Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/síntese química , para-Aminobenzoatos/síntese química , Catálise , Cobre , Reação de Cicloadição , Hidrólise , IsomerismoRESUMO
[reaction: see text] The two novel bisindole alkaloid structures shown can be synthesized in a few steps from the canthiphytine derivative 9.
Assuntos
Alcaloides Indólicos/química , Alcaloides Indólicos/síntese química , Apocynaceae/química , Cristalografia por Raios X , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Plantas Medicinais/químicaRESUMO
Highly enantioselective and very short syntheses of the bioactive forms of estrone (3) and desogestrel (4) are described using a chiral oxazaborolidinium catalyst (2) in the key initial step. Enantiomerically pure estrone was synthesized in eight steps from the readily available starting materials diene 5 and alpha,beta-enal 6 via intermediates 8 and 9. Desogestrel was synthesized using a similar strategy from diene 5 and alpha,beta-enal 11 via intermediates 12-17. The efficient syntheses of the chiral catalyst 2 and its enantiomer are also presented.
Assuntos
Desogestrel/síntese química , Estrona/síntese química , Congêneres da Progesterona/síntese química , Amino Álcoois/química , Catálise , Indicadores e Reagentes , EstereoisomerismoRESUMO
A concise, highly efficient formal total synthesis of dl-physostigmine is described, using a relatively simple method that should be adaptable to the synthesis of homologous members of this type of alkaloid. The key step in the synthesis is a new vicarious nucleophilic substitution reaction between p-nitroanisole and a C-silylated derivative of N-methylpyrrolidinone. Subsequent conversion of the initial adduct to the tricyclic framework of physostigmine follows a well-established protocol and provides the key intermediate 8 in high yield. The vicarious nucleophilic substitution reaction has also been extended to six-membered lactams, with encouraging results.
Assuntos
Inibidores da Colinesterase/síntese química , Fisostigmina/síntese química , Bromo/química , Catálise , Cristalografia por Raios X , Fabaceae/química , Cromatografia Gasosa-Espectrometria de Massas , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Estereoisomerismo , Streptomyces/metabolismoRESUMO
In Lewis-basic solvents, alkynyl carbons bonded to iodine have chemical shifts approximately 12-15 ppm higher in frequency than the corresponding shifts in CDCl3. We offer computational evidence that this solvent effect comes directly from polarization of the iodoalkyne triple bond. Hartree-Fock and Density Functional Theory calculations reproduce the change in chemical shift for a gas-phase complex between the iodoalkyne and dimethyl sulfoxide as Lewis base. The amount of spin-orbit coupling from the adjacent iodine does not change appreciably in the complex, according to the calculations.