竞争性AMPA受体拮抗剂SPD 502的合成

Synthesis of Competitive AMPA Receptor Antagonist SPD 502

5-溴异喹啉经硝化、甲基化和还原得到8-氨基-5-溴-2-甲基-1,2,3,4-四氢异喹啉(4),再经Sandmeyer靛红合成、Suzuki偶合得关键中间体N,N-二甲基-4-(8-甲基-2,3-二氧-2,3,6,7,8,9-六氢-1H-吡咯并[3,2-h]异喹啉-5-基)苯磺酰胺(8)。最后与2-氨氧基-1,4-γ-丁内酯盐酸盐缩合并经碱性开环制得竞争性AMPA受体拮抗剂SPD 502,总收率约10%。

5-Bromoisoquinoline was nitrated, methylated and reduced to give 8-amino-5-bromo-2-methyl- 1,2,3,4-tetrahydroisoquinoline （4）. After Sandmeyer isatin synthesis and Suzuki coupling, the key intermediate N,N- dimethyl-4- （8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro- 1H-pyrrolo [3,2-h] isoquinolin-5-yl） benzenesulfonamide （8） was obtained. The AMPA receptor antagonist SPD 502 was synthesized from compound 8 and 2-（aminooxy）- 1,4-γ- butyrolactone hydrochloride by condensation, followed by basic hydrolysis. The overall yield was about 10 %.