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Enantioselective synthesis of glucocorticoids by the indan synthon method and its application to the preparation of the multi-labeled glucocorticoids with stable isotopes

茚满合成子法对映选择性合成糖皮质激素及其在制备稳定同位素多标记糖皮质激素中的应用

基本信息

批准号：
12672068
负责人：
FURUTO Takashi
金额：
$ 2.11万
依托单位：
Tokyo University of Pharmacy and Life Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672068/
关键词：
corticosteroids cortisol cortisone 6β-hydroxycortisol carbone-13 stable isotopes indan synthon method GC MS prednisolone deuterium

项目摘要

A method is described for the preparation of multi-labeled cortisol and cortisone with 13C and 2H via the indan synthon method, starting from chiral 11-oxoindanylpropionic acid. The dihydroxy acetone group at C-17 of prednisone was protected as the bismethylendioxy (BMD) derivative to give prednisone-BMD, which was then degradated to the ring C/D fragment, chiral 11-oxoindanylpropionic acid, by Birch reduction followed by ozonolysis. Treatment of 13C-and/or 2H-labeled acetone trisylhydrazone with n-BuLi generated the corresponding labeled isopropenyl anion. The reaction of labeled isopropenyl anion with chiral 11-oxoindanylpropionic acid followed by dehydration, cyclization, and ozonolysis produced the labeled triketone. Cyclization of the triketone in KOH/MeOH gave the 13C-and/or 2H-labeled cortisone-BMD, which upon reduction with KBH_4 gave the 13C-and/or 2H-labeled cortisol. In this study, [1,3-13C_2]acetone was used for the syntheses of [1,2,4,19-13C_4]cortisol (cortisol-13C_4) and [1,2,4,19-13C_4]cortisone (cortisone-13C_4), and [1,3-13C_2, 1,1,1,3,3,3-2H_6]acetone was for [1,2,4,19-13C_4,1,1,19,19,19-2H_5]cortisol (cortisol-13C_4, 2H_5) and [1,2,4,19-13C_4,1,1,19,19,19-2H_5]cortisone (cortisone-13C_4, 2H_5). The introduction of double bond a C-1/C-2 was achieved by oxidation of cortisone-13C_4-BMD using selenium dioxide, followed by hydrolysis of the BMD acetal to give [1,2,4,19-13C_4]prednisone. Reduction of the C-11 carbonyl group with KBH_4 gave [1,2,4,19-13C_4]prednisolone.A method is also described for the preparation of two types of multi-labeled 6β-hydroxycortisol containing either five deuterium atoms at C-19 methyl and C-1 methylene (6β-hydroxy-[1,1,19,19,19-2H_5]cortisol) and four 13C atoms at C-1,C-2, C-4, and C-19 in addition to the five deuterium atoms (6β-hydroxy-[1,2,4,19-13C_4,1,1,19,19,19-2H_5]cortisol) for use analytical internal standards for GC-MS.

以手性11-氧代茚满基丙酸为原料，通过茚满合成子法制备了13 C和2 H标记的多标记皮质醇和可的松。将泼尼松的C-17位的二羟基丙酮保护为双亚甲二氧基（BMD）衍生物，得到泼尼松-BMD，然后通过Birch还原和臭氧分解降解为环C/D片段手性11-氧代茚满基丙酸。用n-BuLi处理13 C-和/或2 H-标记的丙酮三酰腙产生相应的标记异丙烯基阴离子。标记的异丙烯基阴离子与手性11-氧代茚满基丙酸反应，然后脱水，环化和臭氧分解产生标记的三酮。三酮在KOH/MeOH中环化得到~（13）C和/或~ 2 H标记的皮质醇-BMD，后者经KBH_4还原得到~（13）C和/或~ 2 H标记的皮质醇。本研究以[1，3 - 13 C_2]丙酮为原料合成[1，2，4，19 - 13 C_4]皮质醇[1，2，4，19 -13C_4]可的松[1，2，4，19 - 13C_4，1，1，19，19，19 -2H_5]皮质醇为丙酮[1，2，4，19 - 13C_4，1，1，19，19，19 -2H_5]可的松（Cortisone-13C_4，2H_5）。用二氧化硒氧化可的松-13 C_4-BMD，然后水解BMD缩醛，得到[1，2，4，19 - 13 C_4]泼尼松。用KBH_4还原C-11羰基得到[1，2，4，19 -13C_4]泼尼松龙，并报道了两种多标记的6β-羟基皮质醇的制备方法（6β-羟基-[1，1，19，19，19 -2H_5]皮质醇）和C-1、C-2、C-4和C-19处的4个13 C原子以及5个氘原子（6β-羟基-[1，2，4，19 - 13C_4，1，1，19，19，19 -2H_5]皮质醇）作为GC-MS分析内标。