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【结 构 式】

【分子编号】42257

【品名】(2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid

【CA登记号】125238-99-5

【 分 子 式 】C24H28N2O6

【 分 子 量 】440.4962

【元素组成】C 65.44% H 6.41% N 6.36% O 21.79%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(I)

Protected 2,4-diaminobutyric acid (I) is coupled with benzylamine (A) in acetonitrile in the presence of DCC and HOBt to yield (II), which is Boc deprotected by means of TFA in CH2Cl2 and loaded onto 2-Cl-trityl-Cl resin to provide (III). Treatment of (III) with piperidine/DMF to remove the Fmoc group, followed by coupling with Fmoc-3,4-difluoro-L-phenylalanine (IV) with HBTU, HOBt in DMF in and DIEA affords (V). The Fmoc group of dipeptide (V) is removed with piperidine/DMF and reaction with (X) in the presence of 4-nitrophenylchloroformate and DIEA in DCM yields (VI). Amine (X) can be obtained by treatment of indole (VII) with bromo derivative (VIII) by means of Cs2CO3 in DMF to yield (IX) followed by reduction of the nitro moiety with FeCl3?H2O, charcoal powder and Me2NNH2 in refluxing MeOH. Finally, Mannich reaction of (VI) with pyrrolidine and formaldehyde in HOAc followed by resin cleavage with TFA in CH2Cl2 furnishes the target molecule.

1 Derian, C.K.; Andrade-Gordon, P.; Maryanoff, B.E.; et al.; Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. Proceedings of the National Academy of Sciences of the United States of America 1999, 96, 22, 12257.
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) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 42257 (2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid 125238-99-5 C24H28N2O6 详情 详情
(II) 42258 9H-fluoren-9-ylmethyl (1S)-1-[(benzylamino)carbonyl]-3-[(tert-butoxycarbonyl)amino]propylcarbamate C31H35N3O5 详情 详情
(III) 42259 9H-fluoren-9-ylmethyl (1S)-3-amino-1-[(benzylamino)carbonyl]propylcarbamate C26H27N3O3 详情 详情
(IV) 42260 (2S)-3-(3,4-difluorophenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid C24H19F2NO4 详情 详情
(V) 42261 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-3-amino-1-[(benzylamino)carbonyl]propyl]amino)-1-(3,4-difluorobenzyl)-2-oxoethylcarbamate C35H34F2N4O4 详情 详情
(VI) 42262 (2S)-4-amino-N-benzyl-2-[[(2S)-2-[([[1-(2,6-dichlorobenzyl)-1H-indol-6-yl]amino]carbonyl)amino]-3-(3,4-difluorophenyl)propanoyl]amino]butanamide C36H34Cl2F2N6O3 详情 详情
(VII) 39294 6-Nitroindole; 6-Nnitro-1H-indole 4769-96-4 C8H6N2O2 详情 详情
(VIII) 40793 2-(bromomethyl)-1,3-dichlorobenzene 20443-98-5 C7H5BrCl2 详情 详情
(IX) 42263 1-(2,6-dichlorobenzyl)-6-nitro-1H-indole C15H10Cl2N2O2 详情 详情
(X) 42264 1-(2,6-dichlorobenzyl)-1H-indol-6-ylamine; 1-(2,6-dichlorobenzyl)-1H-indol-6-amine C15H12Cl2N2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

Treatment of 6-nitroindole (I) with aqueous NaNO2 and HCl affords 3-indazolecarboxaldehyde (II), which is then subjected to reductive amination with pyrrolidine (III) by means of NaBH(OAc)3 in dichloroethane/DMF in the presence of acetic acid to provide compound (IV). Alkylation of (IV) with 2,6-dichlorobenzyl bromide (V) by means of KOH in THF yields compound (VI), whose nitro group is reduced with dimethyl hydrazine (Me2NNH2), FeCl3 and charcoal in refluxing MeOH to furnish aminoindazole intermediate (VII). The synthesis of intermediate (XIII) is performed as follows: Coupling of protected diaminobutyric acid (VIII) with benzylamine (IX) by means of DCC and HOBt in acetonitrile, followed by Fmoc removal after treatment with diethylamine, gives derivative (X), which is then condensed with protected difluorophenylalanine (XI) by means of DIC and HOBt in acetonitrile to afford protected dipeptide (XII). Finally, intermediate (XIII) is obtained by Fmoc removal of (XII) by treatment with ethylamine. The desired product is finally obtained by condensation of intermediates (VII) and (XIII) by means of 4-nitrophenyl chloroformate and DIEA in dichloromethane, followed by Boc removal with TFA in dichloromethane.

1 Andrade-Gordon, P.; Zhang, H.-C.; Derian, C.K.; et al.; Discovery and optimization of a novel series of thrombin receptor (PAR-1) antagonists: Potent, selective peptide mimetics based on indole and indazole templates. J Med Chem 2001, 44, 7, 1021.
2 Zhang, H.-C.; Pandey, A.; Scarborough, R.M.; Maryanoff, B.E. (COR Therapeutics, Inc.; Ortho-McNeil Pharmaceutical, Inc.); Novel indazole peptidomimetics as thrombin receptor antagonists. WO 0100656 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(I) 39294 6-Nitroindole; 6-Nnitro-1H-indole 4769-96-4 C8H6N2O2 详情 详情
(II) 48891 6-nitro-1H-indazole-3-carbaldehyde C8H5N3O3 详情 详情
(III) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(IV) 48892 6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole C12H14N4O2 详情 详情
(V) 40793 2-(bromomethyl)-1,3-dichlorobenzene 20443-98-5 C7H5BrCl2 详情 详情
(VI) 48893 1-(2,6-dichlorobenzyl)-6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole C19H18Cl2N4O2 详情 详情
(VII) 48894 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-ylamine; 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-amine C19H20Cl2N4 详情 详情
(VIII) 42257 (2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid 125238-99-5 C24H28N2O6 详情 详情
(IX) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(X) 48895 tert-butyl (3S)-3-amino-4-(benzylamino)-4-oxobutylcarbamate C16H25N3O3 详情 详情
(XI) 42260 (2S)-3-(3,4-difluorophenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid C24H19F2NO4 详情 详情
(XII) 48896 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-1-[(benzylamino)carbonyl]-3-[(tert-butoxycarbonyl)amino]propyl]amino)-1-(3,4-difluorobenzyl)-2-oxoethylcarbamate C40H42F2N4O6 详情 详情
(XIII) 48897 tert-butyl (3S)-3-[[(2S)-2-amino-3-(3,4-difluorophenyl)propanoyl]amino]-4-(benzylamino)-4-oxobutylcarbamate C25H32F2N4O4 详情 详情
Extended Information