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【结 构 式】 
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【分子编号】40793 【品名】2-(bromomethyl)-1,3-dichlorobenzene 【CA登记号】20443-98-5 |
【 分 子 式 】C7H5BrCl2 【 分 子 量 】239.9261 【元素组成】C 35.04% H 2.1% Br 33.3% Cl 29.55% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)In a further method for the separation of the diastereomeric mixture, (6R,S)-folinic acid (XXVIa-b) was converted to the alpha 2,6-dichlorobenzyl ester upon treatment with 2,6-dichlorobenzyl bromide (XXVII) and Na2CO3. The resultant diastereomeric esters were easily separated by column chromatography to provide the (6S)-isomer (XXVIII), which was finally converted to the title compound by saponification of the benzyl ester group.
| 【1】 Fitzhugh, A.L.; Akee, R.K. (US Department of Health & Human Services); Process for separating the diastereomers of (6R,6S)-5,6,7,8-tetrahydrofolic acid derivs.. US 5698693 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVIa) | 56836 | (2S)-2-{[4-({[(6S)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid | C20H23N7O7 | 详情 | 详情 | |
| (XXVIb) | 56837 | (2S)-2-{[4-({[(6R)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid | C20H23N7O7 | 详情 | 详情 | |
| (XXVII) | 40793 | 2-(bromomethyl)-1,3-dichlorobenzene | 20443-98-5 | C7H5BrCl2 | 详情 | 详情 |
| (XXVIII) | 56838 | (4S)-4-{[4-({[(6S)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}-5-[(2,6-dichlorobenzyl)oxy]-5-oxopentanoic acid | C27H27Cl2N7O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Coupling of N-acetyl-D-thioproline (I) with tyrosine methyl ester (II) using EDC and HOBt yielded dipeptide (III). Subsequent alkylation of the tyrosine phenolic group of (III) with 2,6-dichlorobenzyl bromide (IV) and NaH produced the dichlorobenzyl ether (V). The methyl ester group of (V) was finally hydrolyzed employing LiOH in aqueous THF.
| 【1】 Head, J.C.; Warrellow, G.J.; Archibald, S.C. (Celltech Chiroscience plc); Anti-inflammatory tyrosine derivs.. EP 0984981; US 6093696; WO 9854207 . |
| 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) | 40791 | (4S)-3-acetyl-1,3-thiazolidine-4-carboxylic acid | 24877-72-3 | C6H9NO3S | 详情 | 详情 |
| (II) | 21431 | methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 1080-06-4 | C10H13NO3 | 详情 | 详情 |
| (III) | 40792 | methyl (2S)-2-([[(4S)-3-acetyl-1,3-thiazolidin-4-yl]carbonyl]amino)-3-(4-hydroxyphenyl)propanoate | C16H20N2O5S | 详情 | 详情 | |
| (IV) | 40793 | 2-(bromomethyl)-1,3-dichlorobenzene | 20443-98-5 | C7H5BrCl2 | 详情 | 详情 |
| (V) | 40794 | methyl (2S)-2-([[(4S)-3-acetyl-1,3-thiazolidin-4-yl]carbonyl]amino)-3-[4-[(2,6-dichlorobenzyl)oxy]phenyl]propanoate | C23H24Cl2N2O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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4
该中间体在本合成路线中的序号：(V)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 |