|
【结 构 式】 
|
【分子编号】18650 【品名】1-naphthalenesulfonyl chloride 【CA登记号】85-46-1 |
【 分 子 式 】C10H7ClO2S 【 分 子 量 】226.68308 【元素组成】C 52.99% H 3.11% Cl 15.64% O 14.12% S 14.15% |
合成路线1
该中间体在本合成路线中的序号：(II)By condensation of 2,4-dimethyl-1-(2-aminoethyl)pyrrolidine (I) with 1-naphtalenesulfonyl chloride (II) in refluxing benzene, followed by a treatment with fumaric acid (III) in absolute ethanol.
| 【1】 Josic, L.; Anti-arrythmic sulphonamide compositions. EP 0021580; JP 56161373; US 4372955; US 4436908 . |
| 【2】 Castaner, J.; Thorpe, P.; BRL-31660 A. Drugs Fut 1985, 10, 10, 810. |
合成路线2
该中间体在本合成路线中的序号：(VI)Title compound was prepared by two related ways: N-(Benzyloxycarbonyl)-L-tryptofanol (I) was deprotected by hydrogenolysis in the presence of Pd/C. The resulting tryptofanol (II) was then coupled with N-(benzyloxycarbonyl)-L-isoleucine (III), using 1-(3-diethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to provide (IV). Subsequent hydrogenolytic deprotection gave amine (V), which was condensed with 1-naphthalenylsulfonyl chloride (VI) in the presence of 4-(dimethylamino)pyridine to afford sulfonamide (VII). Finally, oxidation with DMSO in the presence of SO3-pyridine complex yielded the aldehyde.
| 【1】 Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T.; Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J Med Chem 1998, 41, 22, 4301. |
| 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) | 18645 | benzyl (1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethylcarbamate | C19H20N2O3 | 详情 | 详情 | |
| (II) | 18646 | (2S)-2-amino-3-(1H-indol-3-yl)-1-propanol | C11H14N2O | 详情 | 详情 | |
| (III) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (IV) | 18648 | benzyl (1S,2S)-1-([[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]amino]carbonyl)-2-methylbutylcarbamate | C25H31N3O4 | 详情 | 详情 | |
| (V) | 18649 | (2S,3S)-2-amino-N-[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]-3-methylpentanamide | C17H25N3O2 | 详情 | 详情 | |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |
| (VII) | 18651 | (2S,3S)-N-[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]-3-methyl-2-[(1-naphthylsulfonyl)amino]pentanamide | C27H31N3O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Alternatively, N-(benzyloxycarbonyl)-L-Trp (VIII) was condensed with N,O-dimethylhydroxylamine in the presence of EDC and HOBt to give N-(methoxy)amide (IX). Hydrogenolytic deprotection produced amine (X), which was coupled with Z-Ile (III) to afford dipeptide (XI). Subsequent deprotection, and coupling of the resulting amine (XII) with sulfonyl chloride (VI) gave sulfonamide (XIII). Then, reduction of the N-(methoxy)amide with diisobutylaluminum hydride furnished the target aldehyde
| 【1】 Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T.; Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J Med Chem 1998, 41, 22, 4301. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |
| (VIII) | 18652 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid | 7432-21-5 | C19H18N2O4 | 详情 | 详情 |
| (IX) | 18653 | benzyl (1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate | C21H23N3O4 | 详情 | 详情 | |
| (X) | 18654 | (2S)-2-amino-3-(1H-indol-3-yl)-N-methoxy-N-methylpropanamide | C13H17N3O2 | 详情 | 详情 | |
| (XI) | 18655 | benzyl (1S,2S)-1-[([(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]amino)carbonyl]-2-methylbutylcarbamate | C27H34N4O5 | 详情 | 详情 | |
| (XII) | 18656 | (2S,3S)-2-amino-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]-3-methylpentanamide | C19H28N4O3 | 详情 | 详情 | |
| (XIII) | 18657 | (2S,3S)-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]-3-methyl-2-[(1-naphthylsulfonyl)amino]pentanamide | C29H34N4O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The intermediate sulfonamide (VII) was prepared by two synthetic routes starting from trans 4-(aminomethyl)cyclohexanecarboxylic acid (I). 1.- The N-Boc derivative (II) was converted to the mixed anhydride with ClCOOMe and then reduced to alcohol (III) using NaBH4. Subsequent conversion of (III) to tosylate, followed by reaction with NaN3, provided azide (IV), which was reduced to amine (V) by hydrogenation over PtO2 (1). Coupling of (V) with 1-naphthalenesulfonyl chloride (VI) produced the corresponding sulfonamide, which by further acid deprotection of the Boc group gave (VII). 2.- In a related procedure, amino acid (I) was coupled with sulfonyl chloride (VI) to afford sulfonamide (VIII). The carboxylic acid of (VIII) was activated as the mixed anhydride with ClCOOEt and then treated with ammonia to provide amide (IX). Reduction of this amide with BH3 in THF then furnished intermediate (VII). 3.- Quinazolindione (X) was treated with phosphoryl chloride in the presence of N,N-dimethylaniline to produce 2,4-dichloroquinazoline (XI). Selective amination of (XI) at position 4 with ammonia yielded (XII), which was finally condensed with amine (VII) to afford the title compound, which was isolated as the hydrochloride salt.
| 【1】 Rigollier, P.; Whitebread, S.; Yamaguchi, Y.; Rüeger, H.; Chiesi, M.; Schilling, W.; Criscione, L.; Synthesis and SAR of CGP 71683A, a potent and sele. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.239. |
| 【2】 Yamaguchi, Y.; Rigollier, P.; Rueeger, H.; et al.; Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y5 receptor antagonists. Bioorg Med Chem Lett 2000, 10, 11, 1175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 23058 | 4-(aminomethyl)cyclohexanecarboxylic acid | 1197-18-8 | C8H15NO2 | 详情 | 详情 |
| (II) | 23346 | 4-[[(tert-butoxycarbonyl)amino]methyl]cyclohexanecarboxylic acid | C13H23NO4 | 详情 | 详情 | |
| (III) | 23347 | tert-butyl [4-(hydroxymethyl)cyclohexyl]methylcarbamate | C13H25NO3 | 详情 | 详情 | |
| (IV) | 23348 | Trans-N-[4-(Aminomethyl)cyclohexylmethyl]carbamic acid tert-butyl ester | C13H26N2O2 | 详情 | 详情 | |
| (V) | 23349 | tert-butyl [4-(aminomethyl)cyclohexyl]methylcarbamate | C13H26N2O2 | 详情 | 详情 | |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |
| (VII) | 23351 | N-[[4-(aminomethyl)cyclohexyl]methyl]-1-naphthalenesulfonamide | C18H24N2O2S | 详情 | 详情 | |
| (VIII) | 23352 | 4-[[(1-naphthylsulfonyl)amino]methyl]cyclohexanecarboxylic acid | C18H21NO4S | 详情 | 详情 | |
| (IX) | 23353 | 4-[[(1-naphthylsulfonyl)amino]methyl]cyclohexanecarboxamide | C18H22N2O3S | 详情 | 详情 | |
| (X) | 23354 | 2,4-Dihydroxyquinazoline;Benzoyleneurea; 2,4(1H,3H)-quinazolinedione; quinazoline-2,4-dione | 86-96-4 | C8H6N2O2 | 详情 | 详情 |
| (XI) | 23355 | NSC 75192;2,4-dichloroquinazoline | 607-68-1 | C8H4Cl2N2 | 详情 | 详情 |
| (XII) | 23356 | 2-chloro-4-quinazolinamine; 2-chloro-4-quinazolinylamine | C8H6ClN3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The reaction of 6-bromo-1H-indole (I) with Tips-Cl and NaH in DMF gives the N-silylated indole (II), which is condensed with 1,4-diazabicyclo[4,3,0]nonane (III) by means of tBu-ONa, Pd(OAc)2 and tBu3P in hot xylene to yield the corresponding adduct (IV). The desilylation of (IV) by means of TBAF in THF affords the deprotected indole (V), which is finally sulfonated with 1-naphthylsulfonyl chloride and NaHMDS in THF.
| 【1】 Isaac, M.; et al.; 6-Bicyclopiperazinyl-1-araylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potent, and selective 5-HT6 receptor antagonists. Bioorg Med Chem Lett 2000, 10, 15, 1719. |
| 【2】 Isaac, M.; Slassi, A.; Xin, T. (NPS Allelix Corp.); Cpds. having 5-HT6 receptor antagonist activity. WO 0132660 . |
| 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) | 30014 | 6-Bromoindole; 6-Bromo-1H-indole | 52415-29-9 | C8H6BrN | 详情 | 详情 |
| (II) | 47471 | 6-bromo-1-(triisopropylsilyl)-1H-indole | C17H26BrNSi | 详情 | 详情 | |
| (III) | 40336 | octahydropyrrolo[1,2-a]pyrazine | C7H14N2 | 详情 | 详情 | |
| (IV) | 47472 | 2-[1-(triisopropylsilyl)-1H-indol-6-yl]octahydropyrrolo[1,2-a]pyrazine | C24H39N3Si | 详情 | 详情 | |
| (V) | 47473 | 2-(1H-indol-6-yl)octahydropyrrolo[1,2-a]pyrazine | C15H19N3 | 详情 | 详情 | |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |