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【结 构 式】 
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【分子编号】28590 【品名】2-[([[(isopropylamino)carbothioyl]disulfanyl]carbothioyl)amino]propane 【CA登记号】 |
【 分 子 式 】C8H16N2S4 【 分 子 量 】268.49252 【元素组成】C 35.79% H 6.01% N 10.43% S 47.77% |
合成路线1
该中间体在本合成路线中的序号：(IX)The reaction of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-one (I) with 1(R)-phenylethylamine (II) by means of p-toluenesulfonic acid in refluxing toluene gives the enamine (III), which is methylated with lithium diisopropylamide and methyl iodide in THF yielding the 1-methyldihydronaphthalene (IV). The cyclization of (IV) with acryloyl chloride (V) in toluene affords the benzoquinoline derivative (VI), which is treated with triethylsilane and trifluoroacetic acid to eliminate the chiral auxiliar giving intermediate (VII). The methylation of (VII) with methyllithium in THF yields the N-methyl benzoquinoline (VIII), which is treated with N,N'-diisopropylthiuram disulfide (IX) and tert-butyllithium to afford the thiol derivative (X). Finally, this compound is condensed with 2-chloro-4-ethylbenzo thiazole (XI) by means of K2CO3 in hot DMF.
| 【1】 Brennan, J.; et al.; Selective thiomethylation of benzo[f]quinolinone dianions facilitates production of a type I/II 5-alpha-reductase inhibitor (LY320236). 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst ORGN 151. |
| 【2】 Audia, J.E.; Haehl, K.L.; Kress, T.J.; McQuaid, L.A.; Neubauer, B.L.; Rocco, V.P.; Wepsiec, J.P. (Eli Lilly and Company); 5alpha-Reductase inhibitors. CA 2158609; EP 0703221; JP 1996225533; WO 9609046 . |
| 【3】 Audia, J.E.; Neubauer, B.L. (Eli Lilly and Company); Benzoquinolin-3-ones to inhibit bone loss. EP 0742010; JP 1999511739; US 5550134; WO 9635422 . |
| 【4】 Audia, J.E.; Neubauer, B.L. (Eli Lilly and Company); Use of benzoquinolin-3-ones for the treatment and prevention of prostatic cancer. CA 2172211; EP 0733365; JP 1996277220 . |
| 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) | 28584 | 6-bromo-3,4-dihydro-2(1H)-naphthalenone | 4133-35-1 | C10H9BrO | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (III) | 28585 | 6-bromo-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C18H18BrN | 详情 | 详情 | |
| (IV) | 28586 | N-(6-bromo-1-methyl-3,4-dihydro-2-naphthalenyl)-N-[(1R)-1-phenylethyl]amine | C19H20BrN | 详情 | 详情 | |
| (V) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (VI) | 28587 | (10bR)-8-bromo-10b-methyl-4-[(1R)-1-phenylethyl]-1,4,6,10b-tetrahydrobenzo[f]quinolin-3(2H)-one | C22H22BrNO | 详情 | 详情 | |
| (VII) | 28588 | (4aR,10bR)-8-bromo-10b-methyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C14H16BrNO | 详情 | 详情 | |
| (VIII) | 28589 | (4aR,10bR)-8-bromo-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H18BrNO | 详情 | 详情 | |
| (IX) | 28590 | 2-[([[(isopropylamino)carbothioyl]disulfanyl]carbothioyl)amino]propane | C8H16N2S4 | 详情 | 详情 | |
| (X) | 28591 | (4aR,10bR)-4,10b-dimethyl-8-sulfanyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H19NOS | 详情 | 详情 | |
| (XI) | 28592 | 2-chloro-4-ethyl-1,3-benzothiazole | C9H8ClNS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Claisen condensation of ethyl formate with N-trityl-4-piperidone (I) in the presence of NaOEt afforded the intermediate dicarbonyl enolate (II), which was subsequently condensed with ethyl hydrazinoacetate (III) to furnish the desired pyrazolopyridine (IV) accompanied by minor amounts of its regioisomer (V). After acid cleavage of the trityl protecting group of (IV), the desired isomer (VI) was isolated by recrystallization from isopropanol. Coupling of (VI) with N-Boc-L-4-nitrophenylalanine (VII) employing BOP yielded amide (VIII). Subsequent Boc group cleavage in (VIII) with trifluoroacetic acid provided amine (IX), which was coupled with 4-cyanobenzoic acid (X) using 6-chloro-2,4-dimethoxy-1,3,5-triazine (CDMT) to yield (XI). Finally, addition of hydroxylamine to the cyano group of (XI) gave the title N-hydroxyamidine.
| 【1】 Baba, K.; Tanaka, M.; Kuroki, Y.; Takata, K.; Motoyama, T.; Ueno, H. (Ube Industries, Ltd.); N-Acylamino acid amide cpds. and intermediates for preparation thereof. EP 1020467; US 6265418; WO 9906402 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 | |
| 49757 | ethyl 2-[5-[(2S)-2-amino-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C19H23N5O5 | 详情 | 详情 | ||
| 49758 | ethyl 2-[5-[(2S)-2-[(4-cyanobenzoyl)amino]-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C27H26N6O6 | 详情 | 详情 | ||
| (I) | 28590 | 2-[([[(isopropylamino)carbothioyl]disulfanyl]carbothioyl)amino]propane | C8H16N2S4 | 详情 | 详情 | |
| (II) | 49751 | sodium (4-oxo-1-trityl-3-piperidinylidene)methanolate | C25H22NNaO2 | 详情 | 详情 | |
| (III) | 49752 | ethyl 2-hydrazinoacetate | C4H10N2O2 | 详情 | 详情 | |
| (IV) | 49753 | ethyl 2-(5-trityl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)acetate | C29H29N3O2 | 详情 | 详情 | |
| (V) | 49754 | ethyl 2-(5-trityl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)acetate | C29H29N3O2 | 详情 | 详情 | |
| (VI) | 49755 | ethyl 2-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)acetate | C10H15N3O2 | 详情 | 详情 | |
| (VII) | 28516 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid | C14H18N2O6 | 详情 | 详情 | |
| (VIII) | 49756 | ethyl 2-[5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoyl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]acetate | C24H31N5O7 | 详情 | 详情 |