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1.
Mol Pharm ; 21(4): 1933-1941, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38502549

RESUMO

Islatravir, a highly potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) for the treatment of HIV, has great potential to be formulated as ethylene-vinyl acetate (EVA) copolymer-based implants via hot melt extrusion. The crystallinity of EVA determines its physical and rheological properties and may impact the drug-eluting implant performance. Herein, we describe the systematic analysis of factors affecting the EVA crystallinity in islatravir implants. Differential scanning calorimetry (DSC) on EVA and solid-state NMR revealed drug loading promoted EVA crystallization, whereas BaSO4 loading had negligible impact on EVA crystallinity. The sterilization through γ-irradiation appeared to significantly impact the EVA crystallinity and surface characteristics of the implants. Furthermore, DSC analysis of thin implant slices prepared with an ultramicrotome indicated that the surface layer of the implant was more crystalline than the core. These findings provide critical insights into factors affecting the crystallinity, mechanical properties, and physicochemical properties of the EVA polymer matrix of extruded islatravir implants.


Assuntos
Desoxiadenosinas , Etilenos , Polivinil , Compostos de Vinila , Polivinil/química
2.
Mol Pharm ; 20(7): 3380-3392, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37279175

RESUMO

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all the possible crystalline solid forms of small-molecule active pharmaceutical ingredients. We have used a CSP-based cocrystal prediction method to rank ten potential cocrystal coformers by the energy of the cocrystallization reaction with an antiviral drug candidate, MK-8876, and a triol process intermediate, 2-ethynylglyclerol. For MK-8876, the CSP-based cocrystal prediction was performed retrospectively and successfully predicted the maleic acid cocrystal as the most likely cocrystal to be observed. The triol is known to form two different cocrystals with 1,4-diazabicyclo[2.2.2]octane (DABCO), but a larger solid form landscape was desired. CSP-based cocrystal screening predicted the triol-DABCO cocrystal as rank one, while a triol-l-proline cocrystal was predicted as rank two. Computational finite-temperature corrections enabled determination of relative crystallization propensities of the triol-DABCO cocrystals with different stoichiometries and prediction of the triol-l-proline polymorphs in the free-energy landscape. The triol-l-proline cocrystal was obtained during subsequent targeted cocrystallization experiments and was found to exhibit an improved melting point and deliquescence behavior over the triol-free acid, which could be considered as an alternative solid form in the synthesis of islatravir.


Assuntos
Química Farmacêutica , Estudos Retrospectivos , Cristalização
3.
J Org Chem ; 87(4): 2120-2128, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-34582192

RESUMO

Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.


Assuntos
Bloqueadores dos Canais de Cálcio , Ródio , Aminação , Bloqueadores dos Canais de Cálcio/farmacologia , Catálise , Hidrogenação , Estereoisomerismo
4.
J Am Chem Soc ; 140(46): 15596-15600, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30384591

RESUMO

An operationally simple protocol for a palladium-catalyzed 13CO and 14CO exchange with activated aliphatic and benzoic carbonyls is presented. Several 13C and 14C building blocks, natural product derivatives, and pharmaceuticals have been prepared to showcase the method for late-stage carbon isotope incorporation and its functional group compatibility.

5.
J Org Chem ; 74(12): 4547-53, 2009 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-19456171

RESUMO

A practical and efficient synthesis of bradykinin B(1) antagonist 1 is described. A convergent strategy was utilized which involved synthesis of three fragments: 3, 6, and 7. Cross coupling of fragments 6 and 7 followed by amidation with 3 enabled efficient synthesis of 1 in 19 steps total, a 35% overall yield from commercially available pyridine 10. The key to the success of the synthesis was the development of a fluorodenitration step to install the fluorine in pyridine 7 and a catalytic enantioselective hydrogenation of N-acyl enamide 9 to set the stereochemistry.


Assuntos
Amidas/síntese química , Antagonistas de Receptor B1 da Bradicinina , Piridinas/síntese química , Amidas/química , Amidas/farmacologia , Aminas/síntese química , Aminas/química , Azóis/síntese química , Azóis/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrogenação , Metilação , Piridinas/química , Piridinas/farmacologia , Estereoisomerismo
6.
Org Lett ; 8(22): 5161-4, 2006 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-17048868

RESUMO

Aryl carboxylic esters were synthesized by Pd-catalyzed carbonylation of aryl p-fluorobenzenesulfonates or -tosylates. A unique Josiphos ligand was discovered through high-throughput catalyst screening, which was the key for the successful carbonylation of various substrates. This catalyst is effective and works well for both electron-rich and electron-poor aryl arenesulfonates. Isolated yields of up to 90% were obtained for aryl p-fluorobenzenesulfonates and -tosylates. [reaction: see text]


Assuntos
Sulfonatos de Arila/química , Hidrocarbonetos Fluorados/química , Compostos de Tosil/química , Catálise , Técnicas de Química Combinatória , Ésteres , Estrutura Molecular , Paládio
7.
Org Lett ; 7(16): 3405-8, 2005 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-16048303

RESUMO

A novel and highly enantioselective Ru-catalyzed hydrogenation of N-sulfonylated-alpha-dehydroamino acids has been discovered and demonstrated in the synthesis of an anthrax lethal factor inhibitor (LFI). Herein, this methodology is used to prepare N-sulfonylated amino acids in up to 98% ee. This unprecedented hydrogenation uses a chiral Ru catalyst rather than Rh as typical for acylated dehydroamino acids and esters, and this work reports the first asymmetric hydrogenation of a tetrasubstituted dehydroamino acid derivative using a Ru catalyst. [reaction: see text]


Assuntos
Aminoácidos/síntese química , Toxinas Bacterianas/antagonistas & inibidores , Rutênio/química , Aminoácidos/química , Aminoácidos/farmacologia , Antígenos de Bactérias , Bacillus anthracis/química , Bacillus anthracis/patogenicidade , Catálise , Hidrogenação , Estereoisomerismo
8.
Org Lett ; 4(17): 2969-72, 2002 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-12182601

RESUMO

[reaction: see text] Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).


Assuntos
Dimetilaminas/síntese química , Compostos Heterocíclicos/síntese química , Vimblastina/síntese química , Química Farmacêutica , Fluorocarbonos/química , Iminas/química , Vimblastina/análogos & derivados , Compostos de Vinila/química
9.
J Org Chem ; 73(4): 1639-42, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18186647

RESUMO

Asymmetric hydrogenation of allylic dimethylcarbinamide 2 with 1 mol % of cationic Rh(I)-Josiphos complex in THF under 500 psi of H2 generated the corresponding tertiary carbinamide 1 in 98.5% assay yield and a 94:6 enantiomeric ratio. Upon crystallization, the product was isolated in 91% isolated yield and 95:5 enantiomeric ratio.


Assuntos
Amidas/química , Hidrogênio/química , Rênio/química , Catálise , Cristalização , Espectroscopia de Ressonância Magnética , Espectrofotometria Infravermelho
10.
Acc Chem Res ; 40(12): 1320-6, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18020425

RESUMO

This Account outlines the efforts of Merck scientists toward implementing asymmetric hydrogenation as a core competency within Merck Research Laboratories. Several key factors are discussed including (i) a focus on efficient chemical synthesis, (ii) implementation of high throughput screening (HTS) techniques, (iii) demonstration of robustness on scale, and (iv) diligence to ensure freedom of operation and catalyst supply for manufacturing. Several examples of the development of efficient asymmetric hydrogenation processes are described.


Assuntos
Indústria Farmacêutica/métodos , Hidrogenação , Pirazinas/síntese química , Pirazinas/química , Fosfato de Sitagliptina , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Triazóis/síntese química , Triazóis/química
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