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[PMID]: | 18239303 |
[Au] Autor: | Araya I; Kanazawa S; Akita H |
[Ad] Endereço: | Research Center, Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Shimotsuga-gun, Tochigi, Japan. ichirou.araya@mb.kyorin-pharm.co.jp |
[Ti] Título: | Process development and large-scale synthesis of NK1 antagonist. |
[So] Source: | Chem Pharm Bull (Tokyo);56(2):176-80, 2008 Feb. | [Is] ISSN: | 0009-2363 |
[Cp] País de publicação: | Japan |
[La] Idioma: | eng |
[Ab] Resumo: | A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a neurokinin (NK)(1) antagonist. The key step in the synthesis is the intramolecular cyclization of N-[3,5-bis(trifluoromethyl)phenylmethyl]-N-(3-hydroxypropyl)-4-chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxamide (15) which was obtained by amide formation between 4-(2-methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (8) and 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3). Treatment of 15 with 1,8-diazabicyclo[5,4,0]undec-7-ene provided 6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (6). This intermediate (6) is transformed into the candidate compound (1) by two steps; oxidation, and substitution reaction of the resultant sulfone (7) with 1-acetylpiperazine. This synthetic method is free of chromatographic purification and is amenable to large scale synthesis. |
[Mh] Termos MeSH primário: |
Antagonistas do Receptor de Neuroquinina-1 Oxazocinas/síntese química
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[Mh] Termos MeSH secundário: |
Cromatografia Líquida de Alta Pressão Análise Custo-Benefício Ciclização Indicadores e Reagentes Oxazocinas/economia Espectrometria de Massas por Ionização por Electrospray Espectrometria de Massas de Bombardeamento Rápido de Átomos Espectrofotometria Ultravioleta
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Indicators and Reagents); 0 (KRP-103); 0 (Neurokinin-1 Receptor Antagonists); 0 (Oxazocines) |
[Em] Mês de entrada: | 0803 |
[Cu] Atualização por classe: | 131121 |
[Lr] Data última revisão:
| 131121 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 080202 |
[St] Status: | MEDLINE |
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