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【结 构 式】 
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【分子编号】28516 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid 【CA登记号】 |
【 分 子 式 】C14H18N2O6 【 分 子 量 】310.3068 【元素组成】C 54.19% H 5.85% N 9.03% O 30.94% |
合成路线1
该中间体在本合成路线中的序号：(I)Coupling of N-Boc-p-nitrophenylalanine (I) with 4-(2-fluoroethyl)piperidine (II) by means of 2-benzotriazolyl-1,1,3,3-tetramethyluronium tetrafluoborate (TBTU) gave amide (III) which, after acidic deprotection provided aminoamide (IV). 4-Chloropyridine-3-sulfonyl chloride (VI), generated from 4-hydroxy pyridine-3-sulfonic acid (V) by chlorination with PCl5/POCl3, was coupled with amine (IV) to afford sulfonamide (VII). Further condensation of (VII) with L-phenylalaninol (VIII) produced aminopyridine (IX). Conversion of the alcohol group of (IX) to the corresponding mesylate, followed by displacement with morpholine furnished the N-substituted morpholine (X). The nitro group of (X) was finally reduced to the target aniline by hydrogenation over Pd/C.
| 【1】 Ambler, J.; Baker E; Brown, L.; Butler, P.; Farr, D.; Dunnet, K.; Le Grand, D.; Janus, D.; Jones, D.; Menear, K.; Mercer, M.; Smith, G.; Talbot, M.; Tweed, M.; The discovery of orally available thrombin inhibitors: Studies towards the optimisation of CGH1668. Bioorg Med Chem Lett 1998, 8, 24, 3583. |
| 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) | 28516 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid | C14H18N2O6 | 详情 | 详情 | |
| (II) | 28517 | 4-(2-fluoroethyl)piperidine | C7H14FN | 详情 | 详情 | |
| (III) | 28518 | tert-butyl (1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethylcarbamate | C21H30FN3O5 | 详情 | 详情 | |
| (IV) | 28519 | (2S)-2-amino-1-[4-(2-fluoroethyl)-1-piperidinyl]-3-(4-nitrophenyl)-1-propanone | C16H22FN3O3 | 详情 | 详情 | |
| (V) | 28520 | 4-hydroxy-3-pyridinesulfonic acid | C5H5NO4S | 详情 | 详情 | |
| (VI) | 28521 | 4-chloro-3-pyridinesulfonyl chloride | C5H3Cl2NO2S | 详情 | 详情 | |
| (VII) | 28522 | 4-chloro-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide | C21H24ClFN4O5S | 详情 | 详情 | |
| (VIII) | 28523 | (2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol | 5267-64-1 | C9H13NO | 详情 | 详情 |
| (IX) | 28524 | 4-[[(1S)-1-benzyl-2-hydroxyethyl]amino]-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide | C30H36FN5O6S | 详情 | 详情 | |
| (X) | 28525 | 4-[[(1S)-1-benzyl-2-(4-morpholinyl)ethyl]amino]-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide | C34H43FN6O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of N-(tert-butoxycarbonyl)-4-nitro-L-phenylalanine (I) with 4-ethylpiperiine (II) by means of diisopropylethylamine (DIEA) in dichloromethane gives the corresponding protected piperidide (III), which is treated with TFA to eliminate the carbamate group yielding (IV). The sulfonation of (IV) with 4-chloropyridine-3-sulfonyl chloride (V) by means of DIEA in dichloromethane affords the sulfonamide (VI), which is condensed with 2-(2(S)-amino-3-phenylpropoxy)ethanol (VII) by means of DIEA in ethanol giving the intermediate (VIII). Finally, the reduction of the nitro group of (VIII) with H2 over Pd/C in methanol affords the target compound.
| 【1】 Brundish, D.E.; Brown, L.N.; Le Grand, D.M.; Menear, K.A.; Smith, G.P.; Allen, M.C.; Butler, P.I.; Cockroft, X.-L.; Matthews, I.T.W.; Walker, C.V.; Wathey, W.B. (Novartis AG); Thrombin inhibitors. WO 9746553 . |
| 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) | 28516 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid | C14H18N2O6 | 详情 | 详情 | |
| (II) | 30451 | 4-ethylpiperidine | C7H15N | 详情 | 详情 | |
| (III) | 30452 | tert-butyl (1S)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethylcarbamate | C21H31N3O5 | 详情 | 详情 | |
| (IV) | 30453 | (2S)-2-amino-1-(4-ethyl-1-piperidinyl)-3-(4-nitrophenyl)-1-propanone | C16H23N3O3 | 详情 | 详情 | |
| (V) | 28521 | 4-chloro-3-pyridinesulfonyl chloride | C5H3Cl2NO2S | 详情 | 详情 | |
| (VI) | 30454 | 4-chloro-N-[(1S)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide | C21H25ClN4O5S | 详情 | 详情 | |
| (VII) | 30455 | 2-[[(2S)-2-amino-3-phenylpropyl]oxy]-1-ethanol | C11H17NO2 | 详情 | 详情 | |
| (VIII) | 30456 | 4-[[(1S)-1-benzyl-2-(2-hydroxyethoxy)ethyl]amino]-N-[(1S)-2-(4-ethyl-1-piperidinyl)-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide | C32H41N5O7S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Claisen condensation of ethyl formate with N-trityl-4-piperidone (I) in the presence of NaOEt afforded the intermediate dicarbonyl enolate (II), which was subsequently condensed with ethyl hydrazinoacetate (III) to furnish the desired pyrazolopyridine (IV) accompanied by minor amounts of its regioisomer (V). After acid cleavage of the trityl protecting group of (IV), the desired isomer (VI) was isolated by recrystallization from isopropanol. Coupling of (VI) with N-Boc-L-4-nitrophenylalanine (VII) employing BOP yielded amide (VIII). Subsequent Boc group cleavage in (VIII) with trifluoroacetic acid provided amine (IX), which was coupled with 4-cyanobenzoic acid (X) using 6-chloro-2,4-dimethoxy-1,3,5-triazine (CDMT) to yield (XI). Finally, addition of hydroxylamine to the cyano group of (XI) gave the title N-hydroxyamidine.
| 【1】 Baba, K.; Tanaka, M.; Kuroki, Y.; Takata, K.; Motoyama, T.; Ueno, H. (Ube Industries, Ltd.); N-Acylamino acid amide cpds. and intermediates for preparation thereof. EP 1020467; US 6265418; WO 9906402 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 | |
| 49757 | ethyl 2-[5-[(2S)-2-amino-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C19H23N5O5 | 详情 | 详情 | ||
| 49758 | ethyl 2-[5-[(2S)-2-[(4-cyanobenzoyl)amino]-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C27H26N6O6 | 详情 | 详情 | ||
| (I) | 28590 | 2-[([[(isopropylamino)carbothioyl]disulfanyl]carbothioyl)amino]propane | C8H16N2S4 | 详情 | 详情 | |
| (II) | 49751 | sodium (4-oxo-1-trityl-3-piperidinylidene)methanolate | C25H22NNaO2 | 详情 | 详情 | |
| (III) | 49752 | ethyl 2-hydrazinoacetate | C4H10N2O2 | 详情 | 详情 | |
| (IV) | 49753 | ethyl 2-(5-trityl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)acetate | C29H29N3O2 | 详情 | 详情 | |
| (V) | 49754 | ethyl 2-(5-trityl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)acetate | C29H29N3O2 | 详情 | 详情 | |
| (VI) | 49755 | ethyl 2-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)acetate | C10H15N3O2 | 详情 | 详情 | |
| (VII) | 28516 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid | C14H18N2O6 | 详情 | 详情 | |
| (VIII) | 49756 | ethyl 2-[5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C24H31N5O7 | 详情 | 详情 |