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【结 构 式】 
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【分子编号】35169 【品名】(2S)-2-aminopropanamide 【CA登记号】 |
【 分 子 式 】C3H8N2O 【 分 子 量 】88.1094 【元素组成】C 40.9% H 9.15% N 31.79% O 18.16% |
合成路线1
该中间体在本合成路线中的序号：(II)Safinamide has been obtained by reductocondensation of 4-(3-fluorobenzyloxy)benzaldehyde (I) with L-alaninamide (II) by means of sodium cyanoborohydride in methanol.
| 【1】 Sorbera, L.A.; Castaner, J.; Leeson, P.A.; Safinamide mesilate. Drugs Fut 2001, 26, 8, 745. |
| 【2】 Bonsignori, A.; Pevarello, P.; Dostert, P.; et al.; Synthesis and anticonvulsant activity of a new class of 2-[arylalkyl)amino]alkanamide derivatives. J Med Chem 1998, 41, 4, 579. |
| 【3】 Dostert, P.; Pevarello, P.; Heidempergher, F.; Varasi, M.; Bonsignori, A.; Roncucci, R. (Pharmacia Corp.); N-Phenylalkyl substd. alpha-amino carboxamide derivs. and process for their preparation. EP 0400495; EP 0426816; JP 1992500215; US 5236957; US 5391577; US 5502079; WO 9014334 . |
| 【4】 Dostert, P.; Pevarello, P.; Bonsignori, A.; Varasi, M.; Synthesis and anticonvulsant activity of new benzyloxybenzylacetamide derivatives. 12th Int Symp Med Chem (Sept 13-17, Basel) 1992, Abst P-089.C. |
合成路线2
该中间体在本合成路线中的序号：(III)The compound was prepared by solid phase peptide synthesis on a p-methylbenzhydrylamine resin. Attachment of Boc-L-alanine (I) afforded resin (II). Subsequent deprotection of the Boc group of (II) gave the alanine-linked resin (III). Coupling of (III) with Boc-L-proline (IV), followed by Boc group cleavage yielded the dipeptide resin (V). Further coupling of (V) with N-Boc-(2S,3R)-3-amino-2-hydroxy-5-methylhexanoic acid (VI) furnished the tripeptide resin (VI). Finally, deprotection of the Boc group of (VI) and simultaneous cleavage from the resin by treatment with HF provided the title tripeptide amide.
| 【1】 Maggiora, L.L.; Simmons, W.H.; Orawski, A.T.; Apstatin analogue inhibitors of aminopeptidase P, a bradykinin-degrading enzyme. J Med Chem 1999, 42, 13, 2394. |
| 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) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (II) | 35168 | tert-butyl (1S)-2-amino-1-methyl-2-oxoethylcarbamate | C8H16N2O3 | 详情 | 详情 | |
| (III) | 35169 | (2S)-2-aminopropanamide | C3H8N2O | 详情 | 详情 | |
| (IV) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (V) | 35170 | (2S)-N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamide | C8H15N3O2 | 详情 | 详情 | |
| (VI) | 35171 | (2S,3R)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoic acid | C12H23NO5 | 详情 | 详情 | |
| (VII) | 35172 | tert-butyl (1R)-1-[(1S)-2-[(2S)-2-([[(1S)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-1-hydroxy-2-oxoethyl]-3-methylbutylcarbamate | C20H36N4O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Protection of the hydroxyphosphinyl function of Z-Phe(PO2)H (I) by treatment with AgNO3 and 1-adamantyl bromide (AdBr) affords protected compound (II). Treatment of (II) with ethyl methylacrylate (III) by means of hexamethyldisilazane provides compound (IV), which is then subjected to saponification with NaOH in EtOH, affording carboxylic acid (V). The Z protecting group of (V) is then removed with Pd/C and ammonium formate, and subsequent reaction with FmocCl in dioxane yields protected derivative (VI). Separately, on resin protected alanine (VII) is treated with piperidine/NMP for Fmoc removal to afford (VIII), which is then coupled with phosphinic derivative (VI) by means of HBTU/DIEA in NMP and then treated with piperidine/NMP for Fmoc removal, giving derivative (IX). Coupling between (IX) and FmocAsp(OtBu)OH by means of HBTU and DIEA in NMP followed by Fmoc removal with piperidine/NMP affords phosphinic peptide (X), which is then acetylated to give derivative (XI). Finally, the desired product is obtained after first treatment of (XI) with HOAc and trifluoroethanol (TFE) in CH2Cl2 for cleavage of the protected peptide from the resin, followed by removal of the protecting groups with TFA and scavengers (thioanisole, phenol, ethanedithiol and triisopropylsilane) in CH2Cl2/H2O and final separation of the diastereoisomeric forms of the resulting phosphinic peptides by HPLC.
| 【1】 Yiotakis, A.; et al.; Protection of the hydroxyphosphinyl function of phosphinic dipeptides by adamantyl. Application to the solid-phase synthesis of phosphinic peptides. J Org Chem 1996, 61, 19, 6601. |
| 【2】 Yiotakis, A.; Menard, J.; Dive, V.; Michaud, A.; Ezan, E.; Corvol, P.; Cotton, J.; Chauvet, M.-T.; Cuniasse, P. (Commissariat a l'Energie Atomique; INSERM (Institut National de la Sante et de la Recherche Medicale)); N-Terminal site selective inhibitors of human angiotensin conversion enzyme (ACE). EP 1091966; WO 0001706 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (I) | 49739 | (1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethylphosphinic acid | C16H18NO4P | 详情 | 详情 | |
| (II) | 49740 | 1-adamantyl (1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethylphosphinate | C26H32NO4P | 详情 | 详情 | |
| (III) | 49741 | Methacrylic acid ethyl ester; Ethyl methacrylate | 97-63-2 | C6H10O2 | 详情 | 详情 |
| (IV) | 49742 | ethyl (2S)-3-[(1-adamantyloxy)((1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)phosphoryl]-2-methylpropanoate | C32H42NO6P | 详情 | 详情 | |
| (V) | 49743 | (2S)-3-[(1-adamantyloxy)((1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)phosphoryl]-2-methylpropionic acid | C30H38NO6P | 详情 | 详情 | |
| (VI) | 49744 | (2S)-3-[(1-adamantyloxy)((1R)-1-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-phenylethyl)phosphoryl]-2-methylpropionic acid | C37H42NO6P | 详情 | 详情 | |
| (VII) | 49745 | 9H-fluoren-9-ylmethyl (1S)-2-amino-1-methyl-2-oxoethylcarbamate | C18H18N2O3 | 详情 | 详情 | |
| (VIII) | 35169 | (2S)-2-aminopropanamide | C3H8N2O | 详情 | 详情 | |
| (IX) | 49746 | 1-adamantyl (2S)-3-[[(1S)-2-amino-1-methyl-2-oxoethyl]amino]-2-methyl-3-oxopropyl[(1R)-1-amino-2-phenylethyl]phosphinate | C25H38N3O4P | 详情 | 详情 | |
| (X) | 49747 | tert-butyl (3S)-4-([(1R)-1-[(1-adamantyloxy)((2S)-3-[[(1S)-2-amino-1-methyl-2-oxoethyl]amino]-2-methyl-3-oxopropyl)phosphoryl]-2-phenylethyl]amino)-3-amino-4-oxobutanoate | C33H51N4O7P | 详情 | 详情 | |
| (XI) | 49748 | tert-butyl (3S)-3-(acetamido)-4-([(1R)-1-[(1-adamantyloxy)((2S)-3-[[(1S)-2-amino-1-methyl-2-oxoethyl]amino]-2-methyl-3-oxopropyl)phosphoryl]-2-phenylethyl]amino)-4-oxobutanoate | C35H53N4O8P | 详情 | 详情 |