化合物4的制备研究
路线一：一步法
路线二：两步法
目标物的稳定性
酸性条件，包括柱层析的硅胶条件，会变成化合物7
工艺采用路线一
主要杂质信息
TMP和正丁基锂的用量研究
后续氧化步骤的研究
实验操作
(1R,2R,5S)-Bicyclo[3.1.0]hexan-2-ol 4. (R)-1,2-Epoxyhex-5-ene (7.5 kg, 1 equiv) was charged to the vessel containing MTBE (75 L, 10 volumes). To this solution was added tetramethylpiperidine (5.4 kg, 0.5 equiv), and the reaction mixture was cooled to between -5 and 0 °C. n-BuLi (2.5 M in hexanes, 1.1 equiv) was added at such a rate so as to maintain the temperature between -5 and 0 °C (12 h total addition time). The resulting pale orange reaction mixture was maintained at 小于0度，overnight after which all starting epoxide had been consumed (assay for 86% yield by GC).
The reaction was then quenched by the addition of 3 N HCl (40.8 L, 122.3 mol, 1.6 equiv). The aqueous phase was cut and retained. The organic phase was washed again with 3 M HCl (12.7 L, 38.2 mol, 0.5 equiv). The combined aqueous cuts were then back extracted twice, first with 38 L of MTBE (5 volumes) and finally with 19 L (2.5 volumes). The organic phases were combined and concentrated by vacuum distillation at a 小于30度 pot temperature to give the alcohol as a solution in approximately 38 L of total volume. This pale yellow oil was assayed for 6.2 kg of (1R,2R,5S)-bicyclo- [3.1.0]hexan-2-ol 4 (82% yield) and was used directly in the oxidation step. N.B. there was found to be 3% in the distillate and 1% in the aqueous cut by assay.
参考文献
A Practical and Scaleable Synthesis of 1R,5S-Bicyclo[3.1.0]hexan-2-one: The Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP) Mediated Intramolecular Cyclopropanation of (R)-1,2-Epoxyhex-5-ene
Organic Process Research & Development 2007, 11, 637−641
