Efficient Synthesis of 8-Oxa-3-aza-bicyclo[3.2.1]octane Hydrochloride

被引：55

作者：

Connolly, Terrence J. ^{[1
]}

Considine, John L. ^{[1
]}

Ding, Zhixian ^{[1
]}

Forsatz, Brian ^{[1
]}

Jennings, Mellard N. ^{[1
]}

MacEwan, Michael F. ^{[1
]}

McCoy, Kevin M. ^{[1
]}

Place, David W. ^{[1
]}

Sharma, Archana ^{[1
]}

Sutherland, Karen ^{[1
]}

机构：

[1] Wyeth Res, Chem Dev, Pearl River, NY 10965 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2010年 / 14卷 / 02期

关键词：

D O I：

10.1021/op9002642

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

A four-step process to generate 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride starting with 5-hydroxymethyl-2-furfuraldehyde is described. Raney nickel-mediated reduction of 5-hydroxymethyl-2-furfuraldehyde afforded 2,5-bis(hydroxymethyl)tetrahydrofuran with a predominantly cis configuration. Conversion of the diol to a ditosylate, followed by cyclization with benzylamine generated the 8-oxa-3-aza-bicyclo[3.2.1]octane core. The title compound was prepared via hydrogenolysis of the N-benzyl group with Pearlman's catalyst and isolated as the hydrochloride salt front it mixture of 2-propanol and heptane. The overall yield for the process was 43-64%. An impurity generated during scale tip highlighted the need for a strict in-process specification for acetonitrile content prior to performing the final hydrogenolysis. Ethanol conditioning of all processing equipment that had acetonitrile contact prior to the introduction of the substrate stock solution is highly recommended.

引用

页码：459 / 465

页数：7

共 15 条

[1] Stereoselective synthesis of a MCHr1 antagonist [J].