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【结 构 式】 
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【分子编号】16729 【品名】(2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C13H16N2O3 【 分 子 量 】248.28172 【元素组成】C 62.89% H 6.5% N 11.28% O 19.33% |
合成路线1
该中间体在本合成路线中的序号：(VI)1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with trimethylsulfonium iodide (II) and potassium tert-butoxide gives the epoxide (III), which is treated with benzyl alcohol and NaH to perform epoxide ring opening and simultaneous cyclization to yield the oxazolidinone (IV). The hydrolysis of (IV) with KOH affords compound (V), which is condensed with N-(benzylaminocarbonyl)-L-proline (VI) (prepared in situ with benzyl isocyanate (VII) and L-proline (VIII) in the presence of triethylamine) by means of diphenyl phosphoryl azide (DPPA) giving the dipeptide analogue (IX). The oxidation of (IX) with P2O5 in DMSO yields the benzylated JTP-4819 product (X), which is finally deprotected by hydrogenolysis with H2 over Pd/C.
| 【1】 Wroblewski, T.; Silvestre, J.S.; Castañer, J.; JTP-4819. Drugs Fut 1998, 23, 4, 384. |
| 【2】 Fujiwara, T.; Iwamoto, Y.; Uchida, I.; Shinoda, M.; Abe, H.; Toide, K.; A novel prolyl endopeptidase inhibitor, JTP-4819, for the treatment of Alzheimer's disease: Review of preclinical pharmacology. CNS Drug Rev 1996, 2, 3, 343-62. |
| 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) | 16724 | tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal | 69610-41-9 | C10H17NO3 | 详情 | 详情 |
| (II) | 16725 | trimethylsulfonium iodide | 2181-42-2 | C3H9IS | 详情 | 详情 |
| (III) | 16726 | tert-butyl (2S)-2-[(2R)oxiranyl]tetrahydro-1H-pyrrole-1-carboxylate | C11H19NO3 | 详情 | 详情 | |
| (IV) | 16727 | (1R,7aS)-1-[(benzyloxy)methyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | C14H17NO3 | 详情 | 详情 | |
| (V) | 16728 | (1R)-2-(benzyloxy)-1-[(2S)tetrahydro-1H-pyrrol-2-yl]-1-ethanol | C13H19NO2 | 详情 | 详情 | |
| (VI) | 16729 | (2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid | C13H16N2O3 | 详情 | 详情 | |
| (VII) | 16730 | 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate | 3173-56-6 | C8H7NO | 详情 | 详情 |
| (VIII) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (IX) | 16732 | (2S)-N-benzyl-2-([(2S)-2-[(1R)-2-(benzyloxy)-1-hydroxyethyl]tetrahydro-1H-pyrrol-1-yl]carbonyl)tetrahydro-1H-pyrrole-1-carboxamide | C26H33N3O4 | 详情 | 详情 | |
| (X) | 16733 | (2S)-N-benzyl-2-([(2S)-2-[2-(benzyloxy)acetyl]tetrahydro-1H-pyrrol-1-yl]carbonyl)tetrahydro-1H-pyrrole-1-carboxamide | C26H31N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)2) The reaction of tert-butoxycarbonyl-L-proline (XI) with diazomethane and triethylamine in ether gives the diazoketone (XII), which by treatment with acetic acid at 100 C yields the acetoxyketone (XIII). The deprotection of (XIII) with trifluoroacetic acid affords the unprotected alpha-hydroxyketone (XIV), which is condensed with N-(benzylaminecarbonyl)-L-proline (VI) by means of 1-hydroxybenzotriazole (HOBT) giving the acetylated dipeptide analogue (XV). Finally, this compound is deacetylated with K2CO3 in methanol/water.
| 【1】 Wroblewski, T.; Silvestre, J.S.; Castañer, J.; JTP-4819. Drugs Fut 1998, 23, 4, 384. |
| 【2】 Kobayashi, K.; Akamatsu, M.; Yata, S.; Abe, H.; Toide, K.; Kogayu, M.; Uchida, I. (Japan Tobacco Inc.; Welfide Corporation); Cpd. with prolyl endopeptidase inhibitor activity and pharmaceutical use thereof. EP 0670309; JP 1995512967; US 5536737; WO 9412474 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 16729 | (2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid | C13H16N2O3 | 详情 | 详情 | |
| (XI) | 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 | |
| (XII) | 16735 | tert-butyl (2S)-2-(2-diazoacetyl)tetrahydro-1H-pyrrole-1-carboxylate | 101130-03-4 | C11H17N3O3 | 详情 | 详情 |
| (XIII) | 16736 | tert-butyl (2S)-2-[2-(acetoxy)acetyl]tetrahydro-1H-pyrrole-1-carboxylate | C13H21NO5 | 详情 | 详情 | |
| (XIV) | 16737 | 2-oxo-2-[(2S)tetrahydro-1H-pyrrol-2-yl]ethyl acetate | C8H13NO3 | 详情 | 详情 | |
| (XV) | 16738 | 2-[(2S)-1-([(2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrol-2-yl]carbonyl)tetrahydro-1H-pyrrol-2-yl]-2-oxoethyl acetate | C21H27N3O5 | 详情 | 详情 |