Synthetic Route of C9H12N2O2On September 28, 2017 ,《Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders》 was published in Journal of Medicinal Chemistry. The article was written by Mikami, Satoshi; Nakamura, Shinji; Ashizawa, Tomoko; Nomura, Izumi; Kawasaki, Masanori; Sasaki, Shigekazu; Oki, Hideyuki; Kokubo, Hironori; Hoffman, Isaac D.; Zou, Hua; Uchiyama, Noriko; Nakashima, Kosuke; Kamiguchi, Naomi; Imada, Haruka; Suzuki, Noriko; Iwashita, Hiroki; Taniguchi, Takahiko. The article contains the following contents:
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer’s disease through upregulation of cyclic nucleotides in the brain, and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of the authors’ recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clin. candidate 36 (I) (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochem. properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3′,5′-cGMP levels in mouse brains, and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clin. trials. The experimental part of the paper was very detailed, including the reaction process of Ethyl 2-(3-aminopyridin-2-yl)acetate(cas: 295327-27-4Synthetic Route of C9H12N2O2)
Ethyl 2-(3-aminopyridin-2-yl)acetate(cas: 295327-27-4) belongs to anime. The reaction of alkyl halides, R―X, where X is a halogen, or analogous reagents with ammonia (or amines) is useful with certain compounds. Not all alkyl halides are effective reagents; the reaction is sluggish with secondary alkyl groups and fails with tertiary ones. Its usefulness is largely confined to primary alkyl halides (those having two hydrogen atoms on the reacting site).Synthetic Route of C9H12N2O2