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【结 构 式】 
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【分子编号】58808 【品名】tert-butyl 3-amino-5-methoxybenzyl[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]carbamate 【CA登记号】 |
【 分 子 式 】C29H46N4O6Si 【 分 子 量 】574.7931 【元素组成】C 60.6% H 8.07% N 9.75% O 16.7% Si 4.89% |
合成路线1
该中间体在本合成路线中的序号：(XII)The condensation of 4-chloro-2,6-pyridinedicarboxylic acid (I) with morpholine (II) afforded the morpholinopyridinedicarboxylic acid (III), which was further esterified with MeOH and HCl to produce diester (IV). Reduction of (IV) with NaBH4 and CaCl2 gave hydroxy ester (V). After protection of the hydroxyl group of (V) as the trimethylsilylethoxymethyl derivative (VII), the ester group was hydrolyzed under basic conditions yielding acid (VIII). This was then subjected to a Curtius rearrangement with DPPA in the presence of tert-butanol to generate the tert-butyl carbamate (IX). Alkylation of carbamate (IX) with 3-methoxy-5-nitrobenzyl bromide (X) and NaH furnished the N-benzyl carbamate derivative (XI). The nitro group of (XI) was then reduced to amine (XII) by catalytic hydrogenation over Pd/C.
| 【1】 Fukami, T.; Mase, T.; Tsuchiya, Y.; Kanatani, A.; Fukuroda, T. (Banyu Pharmaceutical Co., Ltd.); Aminopyridine derivs.. EP 0889034; US 6011039; WO 9734873 . |
| 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) | 58799 | 4-chloro-2,6-pyridinedicarboxylic acid | C7H4ClNO4 | 详情 | 详情 | |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 58800 | 4-(4-morpholinyl)-2,6-pyridinedicarboxylic acid | C11H12N2O5 | 详情 | 详情 | |
| (IV) | 58801 | dimethyl 4-(4-morpholinyl)-2,6-pyridinedicarboxylate | C13H16N2O5 | 详情 | 详情 | |
| (V) | 58802 | ethyl 6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinecarboxylate | C13H18N2O4 | 详情 | 详情 | |
| (VI) | 27243 | [2-(chloromethoxy)ethyl](trimethyl)silane | 76513-69-4 | C6H15ClOSi | 详情 | 详情 |
| (VII) | 58803 | ethyl 4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinecarboxylate | C19H32N2O5Si | 详情 | 详情 | |
| (VIII) | 58804 | 4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinecarboxylic acid | C17H28N2O5Si | 详情 | 详情 | |
| (IX) | 58805 | tert-butyl 4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinylcarbamate | C21H37N3O5Si | 详情 | 详情 | |
| (X) | 58806 | 3-(bromomethyl)-5-nitrophenyl methyl ether; 1-(bromomethyl)-3-methoxy-5-nitrobenzene | C8H8BrNO3 | 详情 | 详情 | |
| (XI) | 58807 | tert-butyl 3-methoxy-5-nitrobenzyl[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]carbamate | C29H44N4O8Si | 详情 | 详情 | |
| (XII) | 58808 | tert-butyl 3-amino-5-methoxybenzyl[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]carbamate | C29H46N4O6Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Amine (XII) was converted into allyl carbamate (XIII) by reaction with allyl chloroformate. The silylethoxymethyl protecting group of (XIII) was then removed by acidic treatment to provide alcohol (XIV), which was further activated as the corresponding mesylate (XV). Condensation of mesylate (XV) with 5-ethyl-2-mercaptothiazole (XVI) gave thioether (XVII). The N-Boc group of (XVII) was finally cleaved by treatment with trifluoroacetic acid to yield the title compound.
| 【1】 Fukami, T.; Mase, T.; Tsuchiya, Y.; Kanatani, A.; Fukuroda, T. (Banyu Pharmaceutical Co., Ltd.); Aminopyridine derivs.. EP 0889034; US 6011039; WO 9734873 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 58808 | tert-butyl 3-amino-5-methoxybenzyl[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]carbamate | C29H46N4O6Si | 详情 | 详情 | |
| (XIII) | 58809 | allyl 3-({(tert-butoxycarbonyl)[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate | C33H50N4O8Si | 详情 | 详情 | |
| (XIV) | 58810 | allyl 3-({(tert-butoxycarbonyl)[6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate | C27H36N4O7 | 详情 | 详情 | |
| (XV) | 58811 | [6-[(3-{[(allyloxy)carbonyl]amino}-5-methoxybenzyl)(tert-butoxycarbonyl)amino]-4-(4-morpholinyl)-2-pyridinyl]methyl methanesulfonate | C28H38N4O9S | 详情 | 详情 | |
| (XVI) | 58812 | 5-ethyl-1,3-thiazol-2-ylhydrosulfide; 5-ethyl-1,3-thiazole-2-thiol | C5H7NS2 | 详情 | 详情 | |
| (XVII) | 58813 | allyl 3-({(tert-butoxycarbonyl)[6-{[(5-ethyl-1,3-thiazol-2-yl)sulfanyl]methyl}-4-(4-morpholinyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate | C32H41N5O6S2 | 详情 | 详情 |