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【结 构 式】 
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【药物名称】L-371257 【化学名称】1-[1-[4-(1-Acetylpiperidin-4-yloxy)-2-methoxybenzoyl]piperidin-4-yl]-2,4-dihydro-1H-3,1-benzoxazin-2-one 【CA登记号】162042-44-6 【 分 子 式 】C28H33N3O6 【 分 子 量 】507.59171 |
【开发单位】Merck & Co. (Originator) 【药理作用】ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Tocolytics, Uterine Stimulants and Tocolytics, Oxytocin Antagonists |
合成路线1
Condensation of 2-(hydroxymethyl)aniline (I) with N-Boc-4-piperidone (II), followed by reduction with NaBH3CN provided anilinopiperidine (III). Cyclization of aminoalcohol (III) with triphosgene gave benzoxazinone (IV), which was deprotected by acidic treatment to yield piperidinylbenzoxazinone (V). Methyl 2,4-dihydroxybenzoate (VI) was selectively alkylated on the 4-position by coupling with N-Boc-4-piperidinol (VII) under Mitsunobu conditions to give ether (VIII). Then, the remaining 2-OH group was methylated with MeI and NaH to give (IX), which was saponified to provide the benzoic acid derivative (X). Coupling of amine (V) and acid (X) using EDC and HOBt produced amide (XI). Then, removal of the tert-butoxycarbonyl group by acid treatment, followed by acetylation of the resulting piperidine (XII) with Ac2O, furnished the target compound.
| 【1】 Williams, P.D.; et al.; 1-[1-[4-[(N-Acetyl-4-piperidinyl)oxy]-2-methoxybenzoyl]piperidin-4-yl]-4H-3,1-benzoxazin-2(1H)-one (L-371, 257): A new, orally bioavailable, non-peptide oxytocin antagonist. J Med Chem 1995, 38, 23, 4634. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (II) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (III) | 18621 | tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate | C17H26N2O3 | 详情 | 详情 | |
| (IV) | 18622 | tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate | C18H24N2O4 | 详情 | 详情 | |
| (V) | 18623 | 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride | C13H17ClN2O2 | 详情 | 详情 | |
| (VI) | 16623 | methyl 2,4-dihydroxybenzoate | 2150-47-2 | C8H8O4 | 详情 | 详情 |
| (VII) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (VIII) | 19423 | tert-butyl 4-[3-hydroxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate | C18H25NO6 | 详情 | 详情 | |
| (IX) | 18627 | tert-butyl 4-[3-methoxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate | C19H27NO6 | 详情 | 详情 | |
| (X) | 18628 | 4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-methoxybenzoic acid | C18H25NO6 | 详情 | 详情 | |
| (XI) | 18629 | tert-butyl 4-[3-methoxy-4-([4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinyl]carbonyl)phenoxy]-1-piperidinecarboxylate | C31H39N3O7 | 详情 | 详情 | |
| (XII) | 18630 | 1-[1-[2-methoxy-4-(4-piperidinyloxy)benzoyl]-4-piperidinyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride | C26H32ClN3O5 | 详情 | 详情 |