|
【结 构 式】 
|
【分子编号】31423 【品名】tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate 【CA登记号】 |
【 分 子 式 】C13H20N2O4S 【 分 子 量 】300.37888 【元素组成】C 51.98% H 6.71% N 9.33% O 21.31% S 10.68% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of L-asparagine (I) with benzenesulfonyl chloride (II) in the presence of NaOH gave sulfonamide (III). Subsequent Hofmann rearrangement of (III) employing sodium hypobromite produced the diaminopropionic acid derivative (IV), which was protected as the tert-butyl ester (V) using isobutylene in the presence of H2SO4. Condensation of methyl 4-aminobenzoate (VI) with bis(2-chloroethyl)amine (VII) in refluxing butanol yielded the arylpiperazine (VIII), which was protected with di tert-butyl dicarbonate to give the corresponding carbamate (IX). Basic hydrolysis of the methyl ester of (IX) provided carboxylic acid (X). This was then coupled with amine (V) using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) to afford amide (XI). Finally, deprotection of the tert-butyl ester and BOC group of (XI) with trifluoroacetic acid furnished the title compound.
| 【1】 Egbertson, M.S.; Turchi, L.M.; Hartman, G.D.; Halczenko, W.; Whitman, D.B.; Perkins, J.J.; Krause, A.E.; Ihle, N.; Claremon, D.A.; Hoffman, W.; Duggan, M.E. (Merck & Co., Inc.); Fibrinogen receptor antagonists. EP 0673247; JP 1996504194; WO 9412181 . |
| 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) | 25972 | S-(+)-Asparagine; S-(+)-2-Aminosuccinamic acid; L-Asparagine | 70-47-3 | C4H8N2O3 | 详情 | 详情 |
| (II) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
| (III) | 25973 | (2S)-4-amino-4-oxo-2-[(phenylsulfonyl)amino]butyric acid | C10H12N2O5S | 详情 | 详情 | |
| (IV) | 31422 | (2S)-3-amino-2-[(phenylsulfonyl)amino]propionic acid | C9H12N2O4S | 详情 | 详情 | |
| (V) | 31423 | tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C13H20N2O4S | 详情 | 详情 | |
| (VI) | 20537 | methyl 4-aminobenzoate | 619-45-4 | C8H9NO2 | 详情 | 详情 |
| (VII) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (VIII) | 31424 | methyl 4-(1-piperazinyl)benzoate | C12H16N2O2 | 详情 | 详情 | |
| (IX) | 31425 | tert-butyl 4-[4-(methoxycarbonyl)phenyl]-1-piperazinecarboxylate | C17H24N2O4 | 详情 | 详情 | |
| (X) | 31426 | 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzoic acid | C16H22N2O4 | 详情 | 详情 | |
| (XI) | 31427 | tert-butyl 4-[4-[([(2S)-3-(tert-butoxy)-3-oxo-2-[(phenylsulfonyl)amino]propyl]oxy)carbonyl]phenyl]-1-piperazinecarboxylate | C29H39N3O8S | 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 4-hydroxypiperidine (I) with methyl 3,4-difluorobenzoate (II) in DMSO yields derivative (III), which is first mesylated with methanesulfonyl chloride (MsCl) and Et3N in CH2Cl2 and then subjected to reaction with NaN3 in DMF to provide azido derivative (IV). Hydrogenation of (IV) over Pd/C in HOAc/H2O/dioxane affords amino derivative (V), which is then condensed with 2-bromopyrimidine (VI) in DMSO in the presence of DIEA, yielding derivative (VII). Methyl ester group of (VII) is then subjected to saponification by means of aqueous NaOH in THF/MeOH, and the resulting carboxylic acid is coupled to diaminopropionate derivative (VIII) in DMF by means of EDC, HOBt and N-methylmorpholine (NMM) to furnish amide (IX). Hydrolysis of the t-butyl ester group of (IX) by treatment with TFA in CH2Cl2 affords carboxylic acid (X), which is finally hydrogenated over Pd/C in dioxane/H2O to give the target compound.
| 【1】 Ajito, K.; Katano, K.; Kubota, D.; Ishikawa, M.; Murakami, S.; Hachisu, M.; Yamamoto, M. (Meiji Seika Kaisha, Ltd.); Aminopiperidine derivs. as integrin alphavbeta3 antagonists. EP 1074543; WO 9952872 . |
| 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) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (II) | 45450 | methyl 3,4-difluorobenzoate | 369-25-5 | C8H6F2O2 | 详情 | 详情 |
| (III) | 45451 | methyl 3-fluoro-4-(4-hydroxy-1-piperidinyl)benzoate | 107-82-4 | C13H16FNO3 | 详情 | 详情 |
| (IV) | 45452 | methyl 4-(4-azido-1-piperidinyl)-3-fluorobenzoate | C13H15FN4O2 | 详情 | 详情 | |
| (V) | 45453 | methyl 4-(4-amino-1-piperidinyl)-3-fluorobenzoate | C13H17FN2O2 | 详情 | 详情 | |
| (VI) | 45454 | 2-bromopyrimidine | 4595-60-2 | C4H3BrN2 | 详情 | 详情 |
| (VII) | 45455 | methyl 3-fluoro-4-[4-(2-pyrimidinylamino)-1-piperidinyl]benzoate | C17H19FN4O2 | 详情 | 详情 | |
| (VIII) | 31423 | tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C13H20N2O4S | 详情 | 详情 | |
| (IX) | 45456 | tert-butyl (2S)-3-([3-fluoro-4-[4-(2-pyrimidinylamino)-1-piperidinyl]benzoyl]amino)-2-[(phenylsulfonyl)amino]propanoate | C29H35FN6O5S | 详情 | 详情 | |
| (X) | 45457 | (2S)-3-([3-fluoro-4-[4-(2-pyrimidinylamino)-1-piperidinyl]benzoyl]amino)-2-[(phenylsulfonyl)amino]propionic acid | C25H27FN6O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)6-Methylnicotinonitrile (I) is oxidized by means of SeO2 in refluxing dioxane to furnish aldehyde (II). Subsequent condensation of (II) with dimethyl 2-(diethoxyphosphoryl)succinate (III) gives rise to the quinolizine derivative (IV). The cyano group of (IV) is then reduced to the primary amine (V) by catalytic hydrogenation over Pd/C. After protecting amine (V) as the corresponding N-Boc derivative (VI), alkaline hydrolysis of the methyl ester group provides acid (VII) (1). Coupling of acid (VII) with (S) t-butyl 3-amino-2-(benzenesulfonylamino)propionate (VIII) by means of HATU leads to amide (IX) (1,2).
| 【1】 Rej, R.; Lamothe, S.; Zacharie, B.; Labrecque, D.; Courchesne, M.; Falardeau, G.; Abbot, S.; Wang, W.; Chan, L.; Meerovitch, K.; Bergeron, F.; Attardo, G.; Synthesis and in vitro potency of quinolizinone-based alphavbeta3 receptor antagonists. Proc Am Assoc Cancer Res 2002, 43. |
| 【2】 Attardo, G.; Lamothe, S.; Rej, R.; Zacharie, B.; Falardeau, G.; Labrecque, D.; Courchesne, M.; Abbott, S. (Shire BioChem Inc.); Quinolizinones as integrin inhibitors. EP 1115724; US 6630488; WO 0017197 . |
| 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) | 63672 | 6-methylnicotinonitrile | C7H6N2 | 详情 | 详情 | |
| (II) | 63673 | 6-formylnicotinonitrile | C7H4N2O | 详情 | 详情 | |
| (III) | 63674 | dimethyl 2-(diethoxyphosphoryl)succinate | C10H19O7P | 详情 | 详情 | |
| (IV) | 63675 | methyl 7-cyano-4-oxo-4H-quinolizine-2-carboxylate | C12H8N2O3 | 详情 | 详情 | |
| (V) | 63676 | methyl 7-(aminomethyl)-4-oxo-4H-quinolizine-2-carboxylate | C12H12N2O3 | 详情 | 详情 | |
| (VI) | 63677 | methyl 7-{[(tert-butoxycarbonyl)amino]methyl}-4-oxo-4H-quinolizine-2-carboxylate | C17H20N2O5 | 详情 | 详情 | |
| (VII) | 63678 | 7-{[(tert-butoxycarbonyl)amino]methyl}-4-oxo-4H-quinolizine-2-carboxylic acid | C16H18N2O5 | 详情 | 详情 | |
| (VIII) | 31423 | tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C13H20N2O4S | 详情 | 详情 | |
| (IX) | 63679 | tert-butyl (2S)-3-{[(7-{[(tert-butoxycarbonyl)amino]methyl}-4-oxo-4H-quinolizin-2-yl)carbonyl]amino}-2-[(phenylsulfonyl)amino]propanoate | C29H36N4O8S | 详情 | 详情 |