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【结 构 式】 
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【分子编号】19423 【品名】tert-butyl 4-[3-hydroxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C18H25NO6 【 分 子 量 】351.39964 【元素组成】C 61.52% H 7.17% N 3.99% O 27.32% |
合成路线1
该中间体在本合成路线中的序号：(IX)1) 2-Aminobenzyl alcohol (I) was condensed with N-tert-butoxycarbonyl-4-piperidone (II) in toluene with azeotropical removal of water, and the resulting imine (III) was reduced with sodium cyanoborohydride to yield the secondary amine (IV). Further treatment of (IV) with triphosgene in the presence of N,N-diisopropyl ethylamine (DIEA) produced the benzoxazinone (V), which was then deprotected with HCl in EtOAc to give piperidine (VI).
| 【1】 Development of orally active oxytocin antagonists: Studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2-methoxybenzoyl]piperidin-4-yl)-1, 4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines. J Med Chem 1998, 41, 12, 2146. |
| 【2】 Bock, M.G.; Evans, B.E.; Hobbs, D.W.; Williams, P.D.; Anderson, P.S.; Freidinger, R.M.; Pettibone, D.J. (Merck & Co., Inc.); Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists. EP 0714299; JP 1997500134; US 5665719; WO 9502405 . |
| 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) | 19417 | tert-butyl 4-[[2-(hydroxymethyl)phenyl]imino]-1-piperidinecarboxylate | C17H24N2O3 | 详情 | 详情 | |
| (IV) | 18621 | tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate | C17H26N2O3 | 详情 | 详情 | |
| (V) | 18622 | tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate | C18H24N2O4 | 详情 | 详情 | |
| (VI) | 19420 | 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C13H16N2O2 | 详情 | 详情 | |
| (VII) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (VIII) | 16623 | methyl 2,4-dihydroxybenzoate | 2150-47-2 | C8H8O4 | 详情 | 详情 |
| (IX) | 19423 | tert-butyl 4-[3-hydroxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate | C18H25NO6 | 详情 | 详情 | |
| (X) | 18627 | tert-butyl 4-[3-methoxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate | C19H27NO6 | 详情 | 详情 | |
| (XI) | 18628 | 4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-methoxybenzoic acid | C18H25NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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 |