简单高效合成缩丙酮保护的N-保护的左旋多巴衍生物

Simple and Efficient Synthesis of Acetonide-Protected and N-Protected L-DOPA Derivatives

采用先保护羧基再保护氨基的策略,优化了美国专利中Tfa-DOPA-Ome的合成方法:以L-DOPA为原料,利用SOCl 2/MeOH酯化反应代替原路线的CH 3I/KHCO 3/DMF酯化反应,然后通过与三氟乙酸甲酯的酯-酰胺交换反应,实现了简单高效、一锅法保护L-DOPA的羧基和氨基的目标。接着,利用2,2-二甲氧基丙烷的高反应活性和CaCl 2对甲醇与水的强吸附性质,成功制备了缩丙酮保护的L-DOPA中间体。最后,利用一次性脱去氨基与羧基保护再转接上其它N-保护基的方法或利用选择性脱甲酯的方法,制得了Boc-DOPA(Acetonide)-OH、Fmoc-DOPA(Acetonide)-OH和另外两种新的缩丙酮保护的L-DOPA试剂。报道的合成策略避免了使用高沸点溶剂,不产生含碘废物,并且具有产物易分离纯化、产率高、低成本的优点。

This article optimized the synthesis of Tfa-DOPA-OMe in the US patent by adopting an alternative strategy of protecting the carboxyl first and then the amino group.Taking L-DOPA as the raw material,a simple one-pot protection of both the carboxyl and the amino groups of L-DOPA was achieved by methyl esterification with SOCl 2/MeOH instead of CH 3I/KHCO 3/DMF in the original route,followed by an ester-amide exchange reaction with methyl trifluoroacetate.Subsequently,an acetonide-protected L-DOPA intermediate was successfully prepared using 2,2-dimethoxypropane as a high reactive reagent and CaCl 2 as a strong absorbent that removes methanol and water.Finally,Boc-DOPA(Acetonide)-OH,Fmoc-DOPA(Acetonide)-OH and two new acetonide-protected L-DOPA derivatives were produced using the method of simultaneous removal of the amino and carboxyl protecting groups followed by re-installation of another N-protecting group or using the method of selective demethylation.The synthetic strategy reported in this article avoids the use of high-boiling solvents and the production of iodine-containing wastes and has the advantages of easy purification,high yields,and low costs.