Oatis J E, Baker J P, McCarthy J R, Knapp D R
J Med Chem. 1983 Dec;26(12):1687-91. doi: 10.1021/jm00366a005.
One of the major metabolites of propranolol (Inderal) is the O-glucuronide. In order to further study its disposition, possible metabolism, and contribution to the antihypertensive effect of propranolol, we have synthesized and separated the two diastereomeric propranolol O-beta-D-glucuronides (9a,b). These compounds were prepared by reaction of naphthol with epichlorohydrin and treatment of the resulting (2RS)-1'-(2,3-epoxypropoxy)naphthalene (2) with sodium azide to give (2RS)-1-(1'-naphthoxy)-3-azido-2-propanol (3). Alkylation of 3 with methyl (2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranosid)uronate (4) gave methyl (2RS)-[1-(1'-naphthoxy)-3-azido-2-propyl-2",3",4"-tri-O-acetyl-beta-D- glucopyranosid]uronate (5a,b). Reductive alkylation, followed by HPLC separation of the diastereomers, gave methyl (2R)- and (2S)-[1-(1'-naphthoxy)-3-(isopropylamino)-2-propyl-2",3",4"-tri-O-acetyl- beta-D-glucopyranosid]uronate (6a,b). Hydrolytic removal of the acetyl and methyl protecting groups gave the free glucuronides, which were then converted to the sodium salts, 9a,b. The stereochemistry of the glycoside linkage was deduced from the 400-MHz 1H NMR spectra. The absolute configuration of the aglycon portion was determined after Glusulase hydrolysis by derivatization with (R)-(+)- or -(-)-alpha-methylbenzyl isocyanate and comparison of the HPLC retention volumes with those of derivatized reference (R)- and (S)-propranolols.
普萘洛尔（心得安）的主要代谢产物之一是O-葡糖醛酸苷。为了进一步研究其处置、可能的代谢以及对普萘洛尔降压作用的贡献，我们合成并分离了两种非对映体普萘洛尔O-β-D-葡糖醛酸苷（9a,b）。这些化合物是通过萘酚与环氧氯丙烷反应，然后将所得的(2RS)-1'-(2,3-环氧丙氧基)萘（2）用叠氮化钠处理得到(2RS)-1-(1'-萘氧基)-3-叠氮基-2-丙醇（3）来制备的。3与甲基(2,3,4-三-O-乙酰基-1-溴-1-脱氧-α-D-吡喃葡萄糖苷)uronate（4）烷基化得到甲基(2RS)-[1-(1'-萘氧基)-3-叠氮基-2-丙基-2",3",4"-三-O-乙酰基-β-D-吡喃葡萄糖苷]uronate（5a,b）。还原烷基化，随后通过HPLC分离非对映体，得到甲基(2R)-和(2S)-[1-(1'-萘氧基)-3-(异丙基氨基)-2-丙基-2",3",4"-三-O-乙酰基-β-D-吡喃葡萄糖苷]uronate（6a,b）。水解去除乙酰基和甲基保护基团得到游离的葡糖醛酸苷，然后将其转化为钠盐，9a,b。糖苷键的立体化学由400 MHz 1H NMR光谱推导得出。苷元部分的绝对构型在葡糖淀粉酶水解后，通过用(R)-(+)-或-(-)-α-甲基苄基异氰酸酯衍生化并将HPLC保留体积与衍生化的参比(R)-和(S)-普萘洛尔的保留体积进行比较来确定。
