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【结 构 式】 
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【药物名称】J-104870 【化学名称】N-[3-[6-(5-Ethylthiazol-2-ylsulfanylmethyl)-4-(4-morpholinyl)pyridin-2-ylaminomethyl]-5-methoxyphenyl]carbamic acid allyl ester 【CA登记号】196498-48-3 【 分 子 式 】C27H33N5O4S2 【 分 子 量 】555.72316 |
【开发单位】Banyu (Originator) 【药理作用】Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders, Neuropeptide Y1 (NPY Y1) Antagonists |
合成路线1
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
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 |
合成路线3
A similar method, but using a different protection strategy, has been reported. 4-Hydroxy-2,6-pyridinedicarboxylic acid (XVIII) was condensed with morpholine (II) to provide, after Fischer esterification, the morpholinopyridine diester (IV). Reduction of (IV) with calcium borohydride furnished hydroxy ester (V). Protection of (V) as the corresponding tetrahydropyranyl ether, followed by ester group saponification, afforded (XIX). Curtius rearrangement of acid (XIX) in the same conditions as above gave carbamate (XX), which was alkylated with benzyl chloride (XXI) yielding (XXII). After reduction of the nitroderivative (XXII) with iron and ammonium chloride, the resultant amine (XXIII) was acylated by allyl chloroformate to produce carbamate (XXIV). Then, acidic treatment removed the tetrahydropyranyl-protecting group to afford alcohol (XIV), which was finally processed as in the above method.
| 【1】 Haga, Y.; Tsuchiya, Y.; Mase, T.; et al.; Potent and selective aminopyridine NPY Y1 receptor antagonists. 21st Symp Med Chem (Nov 28 2001, Kyoto) 2001, Abst 2P-38. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 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 | |
| (XIV) | 58810 | allyl 3-({(tert-butoxycarbonyl)[6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate | C27H36N4O7 | 详情 | 详情 | |
| (XVIII) | 58814 | 4-hydroxy-2,6-pyridinedicarboxylic acid | C7H5NO5 | 详情 | 详情 | |
| (XIX) | 58815 | 4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinecarboxylic acid | C16H22N2O5 | 详情 | 详情 | |
| (XX) | 58816 | tert-butyl 4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinylcarbamate | C20H31N3O5 | 详情 | 详情 | |
| (XXI) | 58817 | 3-(chloromethyl)-5-nitrophenyl methyl ether; 1-(chloromethyl)-3-methoxy-5-nitrobenzene | C8H8ClNO3 | 详情 | 详情 | |
| (XXII) | 58818 | tert-butyl 3-methoxy-5-nitrobenzyl{4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}carbamate | C28H38N4O8 | 详情 | 详情 | |
| (XXIII) | 58819 | tert-butyl 3-amino-5-methoxybenzyl{4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}carbamate | C28H40N4O6 | 详情 | 详情 | |
| (XXIV) | 58820 | allyl 3-[((tert-butoxycarbonyl){4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}amino)methyl]-5-methoxyphenylcarbamate | C32H44N4O8 | 详情 | 详情 |