Morie T, Kato S, Harada H, Yoshida N, Matsumoto J
Exploratory Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1994 Apr;42(4):877-82. doi: 10.1248/cpb.42.877.
The enantiomers, (S)-(-)-1 and (R)-(+)-1, of (+/-)-4-amino-5-chloro-2-ethoxy- N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride) [(+/-)-1], a new and selective gastroprokinetic agent, were prepared from optically active [4-(4-fluorobenzyl)-2-morpholinyl]methylamines (S)-(-)-4 and (R)-(+)-4, respectively. The requisite (S)-(-)-4 and (R)-(+)-4 were prepared by optical resolution of [4-(4-fluorobenzyl)-2-morpholinyl]methyl p-toluenesulfonate [(+/-)-5] using (-)- and (+)-N-(p-toluenesulfonyl)glutamic acids, followed by amination of the tosyloxy groups of (R)-(-)-5 and (S)-(+)-5, respectively. The absolute configurations of (R)-(-)-5 and (S)-(+)-5 were determined on the basis of an asymmetric synthesis of (R)-(-)-5 from (S)-(+)-benzyl glycidyl ether [(S)-(+)-11]. Mosapride and its enantiomers, (S)-(-)-1 and (R)-(+)-1, were essentially equipotent in serotonin 5-HT4 receptor agonistic activity on the electrically evoked contractions in isolated guinea pig ileum.
新型选择性促胃肠动力药（±）-4-氨基-5-氯-2-乙氧基-N-[[4-（4-氟苄基）-2-吗啉基]甲基]苯甲酰胺（莫沙必利）[（±）-1]的对映体（S）-（-）-1和（R）-（+）-1分别由旋光性的[4-（4-氟苄基）-2-吗啉基]甲胺（S）-（-）-4和（R）-（+）-4制备。所需的（S）-（-）-4和（R）-（+）-4通过用（-）-和（+）-N-（对甲苯磺酰基）谷氨酸对[4-（4-氟苄基）-2-吗啉基]甲基对甲苯磺酸酯[（±）-5]进行拆分制备，然后分别对（R）-（-）-5和（S）-（+）-5的甲苯磺酰氧基进行胺化。（R）-（-）-5和（S）-（+）-5的绝对构型是基于由（S）-（+）-苄基缩水甘油醚[（S）-（+）-11]不对称合成（R）-（-）-5确定的。莫沙必利及其对映体（S）-（-）-1和（R）-（+）-1对豚鼠离体回肠电诱发收缩的5-羟色胺5-HT4受体激动活性基本相当。
