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【结 构 式】 
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【分子编号】16490 【品名】4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol 【CA登记号】1193-02-8 |
【 分 子 式 】C6H7NS 【 分 子 量 】125.19432 【元素组成】C 57.56% H 5.64% N 11.19% S 25.61% |
合成路线1
该中间体在本合成路线中的序号：(I)The acylation of 4-aminothiophenol (I) with ethyl chloroformate (II) is performed in a nitrogen atmosphere in the presence of NaHCO3 in CH2Cl2 / water medium giving ethyl (4-mercaptophenyl)carbamate (III). This compound is condensed with cis-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dixolan-4-yl]methyl methanesulfonate (IV) in the presence of K2CO3 in refluxing acetone under nitrogen, affording the title compound, which is converted to the monohydrochloride with i-PrOH / HCl in 4-methyl-2-pentanone.
| 【1】 Heeres, J.; Van der Veken, L.J.E.; Novel (2-aryl-4-phenylthioalkyl-1,3-dioxolan-2-yl-methyl)azole derivatives. DE 3166517D; EP 0052905 . |
| 【2】 Van Ginckel, R.; Geuens, G.; Heeres, J.; Tubulozole Hydrochloride. Drugs Fut 1984, 9, 12, 911. |
| 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) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (II) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (III) | 13295 | ethyl 4-sulfanylphenylcarbamate | C9H11NO2S | 详情 | 详情 | |
| (IV) | 34328 | 1-[[(2S,4S)-2-(2,4-dichlorophenyl)-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazole | C17H20Cl2N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Reaction of the Grignard reagent derived from 4-chlorobenzyl bromide (I) with allyl bromide (II) gives 4-(4-chlorophenyl)but-1-ene (III), which is epoxidized with peracetic acid in dichloromethane to yield 4-(4-chlorophenyl)-1,2-epoxybutane (IV). Opening of (IV) with the anion of imidazole (V) gives 1-[4-(4-chlorophenyl)-2-hydroxybutyl]imidazole (VI), which is oxidized under Swern conditions to 4-(4-chlorophenyl)-1-(1-imidazolyl)-2-butanone (VII). Ketone (VII) is then reacted with (S)-solketal tosylate [(S)-1,2-O-isopropylideneglycerol-3-O-tosylate] (VIII) in the presence of p-toluenesulfonic acid in toluene to give a mixture of stereoisomers, and (2S,4S)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-ylmethyl)-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolane (IX) is then separated by crystallization. Finally, (IX) is treated with 4-aminothiophenol (X) in the presence of potassium carbonate in acetone.
| 【1】 Dyson, N.H.; Gardner, J.O.; Prince, A.; Kertesz, D.J. (Syntex (USA), Inc.); Process for preparing 1,3-dioxolane derivs. JP 1995508002; US 5208331 . |
| 【2】 Walker, K.A.; Burton, P.M.; Swinney, D.C. (Syntex (USA), Inc.); 1,3-Dioxolane derivs. as cholesterol lowering agents. JP 1992308588; US 5158949 . |
| 【3】 Walker, K.A.M.; Rotstein, D.M.; Kertesz, D.J.; et al.; Selective inhibition of mammalian lanosterol 14alpha-demethylase: A possible strategy for cholesterol lowering. J Med Chem 1993, 36, 15, 2235-7. |
| 【4】 Prous, J.; Mealy, N.; Castañer, J.; RS-21607-197. Drugs Fut 1994, 19, 2, 125. |
| 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) | 16481 | 1-(bromomethyl)-4-chlorobenzene | 622-95-7 | C7H6BrCl | 详情 | 详情 |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 16483 | 1-(3-butenyl)-4-chlorobenzene | C10H11Cl | 详情 | 详情 | |
| (IV) | 16484 | 2-(4-chlorophenethyl)oxirane | C10H11ClO | 详情 | 详情 | |
| (V) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (VI) | 16486 | 4-(4-chlorophenyl)-1-(1H-imidazol-1-yl)-2-butanol | C13H15ClN2O | 详情 | 详情 | |
| (VII) | 16487 | 4-(4-chlorophenyl)-1-(1H-imidazol-1-yl)-2-butanone | C13H13ClN2O | 详情 | 详情 | |
| (VIII) | 16488 | (2S)-2,3-dihydroxypropyl 4-methylbenzenesulfonate | C10H14O5S | 详情 | 详情 | |
| (IX) | 16489 | [(2S,4S)-2-(4-chlorophenethyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | C23H25ClN2O5S | 详情 | 详情 | |
| (X) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Coupling of the chiral auxiliary (R)-proline (I) with methacryloyl chloride (II) under Schotten-Baumann conditions provided amide (III). This was converted to bromolactone (IV) by asymmetric bromolactonization in the presence of N-bromosuccinimide. Subsequent acid hydrolysis yielded the chiral (R)-bromoacid (V), that was converted to acid chloride (VI) and then coupled with 4-amino-2-trifluoromethylbenzonitrile (VII) in DMA at low temperature to afford anilide (VIII). Coupling with 4-aminothiophenol (IX) using NaH in THF produced sulfide (X). Finally, conversion of the aniline precursor (X) to the target isothiocyanate was achieved by reaction with thiophosgene in the presence of NaHCO3.
| 【1】 Mukherjee, A.; et al.; Affinity labeling of the androgen receptor with nosteroidal chemoaffinity ligands. Biochem Pharmacol 1999, 58, 8, 1259. |
| 【2】 Dalton, J.T.; Miller, D.D.; Kirkovsky, L.; Mukherjee, A.; Yin, D.; Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring. J Med Chem 2000, 43, 4, 581. |
| 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) | 28284 | D-proline | 344-25-2 | C5H9NO2 | 详情 | 详情 |
| (II) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (III) | 40972 | (2R)-1-methacryloyl-2-pyrrolidinecarboxylic acid | C9H13NO3 | 详情 | 详情 | |
| (IV) | 40967 | (3R,8aR)-3-(bromomethyl)-3-methyltetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione | C9H12BrNO3 | 详情 | 详情 | |
| (V) | 40968 | (2R)-3-bromo-2-hydroxy-2-methylpropionic acid | C4H7BrO3 | 详情 | 详情 | |
| (VI) | 40969 | (2R)-3-bromo-2-hydroxy-2-methylpropanoyl chloride | C4H6BrClO2 | 详情 | 详情 | |
| (VII) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (VIII) | 40970 | (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C12H10BrF3N2O2 | 详情 | 详情 | |
| (IX) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (X) | 40971 | (2R)-3-[(4-aminophenyl)sulfanyl]-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C18H16F3N3O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Progesterone (I) was oxidized to the 6-dehydro derivative (II) using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Conjugate addition of 4-aminothiophenol (III) to dienone (II) furnished the aminophenyl sulfide (IV). The target urea was then obtained by coupling of the amino compound (IV) with (R)-alpha-methylbenzyl isocyanate (V).
| 【1】 Clarke, R.; Leonessa, F.; Ghiorghis, A.; Kulawiec, R.J.; Talebian, A.; Kim, J.-H.; Hammer, C.; C-7 analogues of progesterone as potent inhibitors of the P-glycoprotein efflux pump. J Med Chem 2002, 45, 2, 390. |
| 【2】 Clarke, R.; Talebian, A.H.; Ghiorghis, A.; Leonessa, F.; Hammer, C. (Georgetown University); Progesterone analogs to reverse multidrug resistance. WO 9700683 . |
| 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) | 55957 | (9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one; (S)-Pregn-4-en-3,20-dione; 3,20-pregnene-4; 4-Pregnene-3,20-dione; beta-progesterone; Corlutin; Corlutina; Corluvite; Corporin; Corpus luteum hormone; Flavolutan; Fologenon; Gestone; Gestormone; Glanducorpin; Homoflaveine; Hormoluton; Lipolutin; Lucorteum; Luteal hormone; Lutein; Luteinique; Luteodyn; Luteogan; Luteohormone; Luteol; Luteosan; Luteostab; Luteovis; Lutex; Lutidon; Lutocyclin; Lutocylin; Lutocylol; Lutoform; Lutogyl; Lutren; Lutromone; Piaponon; Pranone; Pregn-4-ene-3,20-dione; pregnendione; Pregnene-3,20-dione; Pregnenedione; Primolut; Progekan; Progesterol; Progesterone; Progesteronum; Progestone; Prolidon; Syntolutan | 57-83-0 | C21H30O2 | 详情 | 详情 |
| (II) | 55958 | (9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | 1162-56-7 | C21H28O2 | 详情 | 详情 |
| (III) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (IV) | 55959 | (7R,9S,10R,13S,14S,17S)-17-acetyl-7-[(4-aminophenyl)sulfanyl]-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C27H35NO2S | 详情 | 详情 | |
| (V) | 30212 | 1-[(1R)-1-isocyanatoethyl]benzene; (1R)-1-phenylethyl isocyanate | 33375-06-3 | C9H9NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XX)Synthesis of intermediate (VII):
Reaction of 4-sulfanylaniline (XX) with TFAA in the presence of Et3N in THF gives trifluoroacetamide (XXI), which then condenses with 5-(chloromethyl)-1-propylimidazole (V) using TEA in MeOH/H2O to yield thioether (XXII). Oxidation of sulfanyl derivative (XXII) by means of H2O2 in AcOH, followed by hydrolysis with NaOH affords the racemic sulfinyl derivative (XXIII), which is then submitted to optical resolution with di-p-toluoyl-D-tartaric acid to provide the desired (S)-enantiomer (VII) (1). Scheme 3.
| 【1】 Nishiguchi, A., Adachi, M., Ito, T., Ikemoto, T., Tawada, H. (Takeda Pharmaeutical Co., Ltd.). Process for producing optically active sulfoxide derivative. CA 2479071, EP 1484322, JP 2004123694, WO 2003076411. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 66041 | 5-(chloromethyl)-1-propylimidazole | C7H11ClN2 | 详情 | 详情 | |
| (VII) | 66043 | C13H17N3OS | 详情 | 详情 | ||
| (XX) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (XXI) | 66054 | 2,2,2-Trifluoro-N-(4-Mercaptophenyl)Acetamide; 2,2,2-Trifluoro-N-(4-Sulfanylphenyl)Ethanamide | 94006-35-6 | C8H6F3NOS | 详情 | 详情 |
| (XXII) | 66055 | C15H16F3N3OS | 详情 | 详情 | ||
| (XXIII) | 66056 | C13H17N3OS | 详情 | 详情 |