Practical and Scalable Synthesis of S1P1 Receptor Agonist ACT-209905

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• 作者：Gunther Schmidt ; Stefan Reber ; Martin H. Bolli ; Stefan Abele
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：April 20, 2012
• 年：2012
• 卷：16
• 期：4
• 页码：595-604
• 全文大小：430K
• 年卷期：v.16,no.4(April 20, 2012)
• ISSN：1520-586X

文摘

A practical and scalable route for the fast delivery of 12 kg of S1P₁ agonist (ACT-209905) has been developed. ACT-209905 is composed of an amino pyridine group, an oxadiazole spacer, a 2-ethyl-5-methylphenol moiety and a chiral 1-amino-2-propanol side chain. The convergent synthesis consists of 16 steps with 9 isolated intermediates and is chromatography-free. Key building blocks are accessed from low-cost starting materials, such as acetone, diethyl oxalate, cyanoacetamide, and 2-ethyl-5-methyl aniline. A Negishi coupling that was troubled by the use of metal reagents and concomitant metal waste streams has been replaced by a less expensive Guareschi鈥揟horpe reaction to build up an amino isonicotinic acid. The chiral 1-amino-2-propanol moiety was secured by selective ring-opening of an epoxide with lithium hexamethyldisilazide as an ammonia surrogate, thus omitting the notorious double alkylated byproduct.