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【结 构 式】 
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【药物名称】R-116010 【化学名称】N-[4-[2(S)-(Dimethylamino)-1(S)-(1H-imidazol-1-yl)propyl]phenyl]benzothiazol-2-amine 【CA登记号】201410-54-0 ((R*,R*)-isomer), 201411-20-3 (undefined isomer) 【 分 子 式 】C21H23N5S 【 分 子 量 】377.51496 |
【开发单位】Janssen (Originator) 【药理作用】ONCOLYTIC DRUGS |
合成路线1
Friedel-Crafts acylation of acetanilide (I) with 2-chloropropionyl chloride (II) in the presence of AlCl3 provided ketone (III). The chlorine atom of (III) was then displaced with dimethylamine to afford amino ketone (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. Treatment of alcohol (V) with carbonyl diimidazole furnished the imidazolyl derivative (VI). The acetamido group of (VI) was then hydrolyzed with 3N HCl to give aniline (VII). This compound was converted to isothiocyanate (VIII) by treatment with thiophosgene and NaOH. Alternatively, aniline (VII) was treated with carbon disulfide and NaOH and then with iodomethane to give the bis(methylthio)methyleneamino derivative (IX). The condensation of either (VIII) or (IX) with 2-aminothiophenol (X) produced the target benzothiazole (XI) as a mixture of isomers. Then, separation of the diastereoisomers by column chromatography, followed by resolution by chiral HPLC, furnished the title (S,S)-isomer.
| 【1】 Venet, M.; Van Wauwe, J.; Mabire, D.; Sanz, G.; Poignet, H.; Wouters, J.; Synthesis of R116010, a retinoic acid (RA) metabolism inhibitor with antitumoral effects. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PC-60. |
| 【2】 Venet, M.G.; Mabire, D.J.-P.; Lacrampe, J.F.A.; Sanz, G.C. (Janssen Pharmaceutica NV); N-[4-(heteroarylmethyl)phenyl]-heteroarylamines. EP 0907650; JP 2000503670; US 6124330; WO 9749704 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 46351 | N-[4-[(1R,2S)-2-(dimethylamino)-1-hydroxypropyl]phenyl]acetamide | C13H20N2O2 | 详情 | 详情 | |
| (Vb) | 46352 | N-[4-[(1S,2S)-2-(dimethylamino)-1-hydroxypropyl]phenyl]acetamide | C13H20N2O2 | 详情 | 详情 | |
| (VIa) | 46353 | N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]acetamide | C16H22N4O | 详情 | 详情 | |
| (VIb) | 46354 | N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]acetamide | C16H22N4O | 详情 | 详情 | |
| (VIIa) | 46355 | N-[(1S,2R)-2-(4-aminophenyl)-2-(1H-imidazol-1-yl)-1-methylethyl]-N,N-dimethylamine; 4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]aniline | C14H20N4 | 详情 | 详情 | |
| (VIIb) | 46356 | N-[(1S,2S)-2-(4-aminophenyl)-2-(1H-imidazol-1-yl)-1-methylethyl]-N,N-dimethylamine; 4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]aniline | C14H20N4 | 详情 | 详情 | |
| (VIIIa) | 46357 | (1R,2S)-1-(1H-imidazol-1-yl)-1-(4-isothiocyanatophenyl)-N,N-dimethyl-2-propanamine; N-[(1S,2R)-2-(1H-imidazol-1-yl)-2-(4-isothiocyanatophenyl)-1-methylethyl]-N,N-dimethylamine | C15H18N4S | 详情 | 详情 | |
| (VIIIb) | 46358 | N-[(1S,2S)-2-(1H-imidazol-1-yl)-2-(4-isothiocyanatophenyl)-1-methylethyl]-N,N-dimethylamine; (1S,2S)-1-(1H-imidazol-1-yl)-1-(4-isothiocyanatophenyl)-N,N-dimethyl-2-propanamine | C15H18N4S | 详情 | 详情 | |
| (IXa) | 46359 | 1-[(1R,2S)-1-(4-[[bis(methylsulfanyl)methylene]amino]phenyl)-2-(dimethylamino)propyl]-1H-imidazole | C17H24N4S2 | 详情 | 详情 | |
| (IXb) | 46360 | 1-[(1S,2S)-1-(4-[[bis(methylsulfanyl)methylene]amino]phenyl)-2-(dimethylamino)propyl]-1H-imidazole | C17H24N4S2 | 详情 | 详情 | |
| (XIa) | 46361 | N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-1,3-benzothiazol-2-amine; N-(1,3-benzothiazol-2-yl)-N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]amine | C21H23N5S | 详情 | 详情 | |
| (XIb) | 46362 | N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-1,3-benzothiazol-2-amine; N-(1,3-benzothiazol-2-yl)-N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]amine | C21H23N5S | 详情 | 详情 | |
| (I) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (II) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (III) | 46349 | N-[4-(2-chloropropanoyl)phenyl]acetamide | C11H12ClNO2 | 详情 | 详情 | |
| (IV) | 46350 | N-[4-[2-(dimethylamino)propanoyl]phenyl]acetamide | C13H18N2O2 | 详情 | 详情 | |
| (X) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
合成路线2
In an alternative procedure, 2-aminothiophenol (X) was condensed with phenyl isothiocyanate (XII) to produce N-phenyl-2-aminobenzothiazole (XIII). Subsequent Friedel-Crafts acylation of (XIII) with acid chloride (II) gave chloro ketone (XIV), which was converted to amino ketone (XV) upon treatment with dimethylamine. After ketone (XV) reduction with NaBH4, the resulting amino alcohol (XVI) was treated with carbonyl diimidazole, and the mixture of isomers was chromatographically separated as above.
| 【1】 Venet, M.; Van Wauwe, J.; Mabire, D.; Sanz, G.; Poignet, H.; Wouters, J.; Synthesis of R116010, a retinoic acid (RA) metabolism inhibitor with antitumoral effects. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PC-60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIa) | 46367 | (1R,2S)-1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanol | C18H21N3OS | 详情 | 详情 | |
| (XVIb) | 46368 | (1S,2S)-1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanol | C18H21N3OS | 详情 | 详情 | |
| (X) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (XI) | 46363 | benzenesulfenyl cyanide | C7H5NS | 详情 | 详情 | |
| (XII) | 46364 | N-(1,3-benzothiazol-2-yl)-N-phenylamine; N-phenyl-1,3-benzothiazol-2-amine | C13H10N2S | 详情 | 详情 | |
| (XIII) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (XIV) | 46365 | 1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-chloro-1-propanone | C16H13ClN2OS | 详情 | 详情 | |
| (XV) | 46366 | 1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanone | C18H19N3OS | 详情 | 详情 |
合成路线3
The cyclization of 1,3-diphenylthiourea (I) with Br2 and HBr in water gives N-(benzothiazol-2-yl)-N-phenylamine (II), which is condensed with 2-chloropropionyl chloride (III) by means of AlCl3 in dichloromethane to yield the propiophenone (IV). The reaction of (IV) with dimethylamine in isopropanol affords the racemic alpha-(dimethylamino) propiophenone (V), which is optically resolved by means of (+)(D)-di-p-toluoyltartaric acid providing the (S)-enantiomer (VI) with a 80% ee. The reduction of (VI) with NaBH4 and NaOH in isopropanol gives the (S,S)-enantiomer (VII) with a 85% ee. Finally, this compound is condensed with CDI and imidazole to afford the target compound that is purified by crystallization in ethyl acetate up to a 99% ee.
| 【1】 Aelterman, W.; et al.; Conversion of the laboratory synthetic route of the N-aryl-2-benzothiazolamine R116010 to a manufacturing method. Org Process Res Dev 2001, 5, 5, 467. |
| 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) | 56953 | 1,3-Diphenyl-2-thiourea; 1,3-Diphenylthiourea; N,N'-Diphenylthiourea; S-Diphenylthiocarbamide; sym-Diphenylthiourea; Thiocarbanilide | 102-08-9 | C13H12N2S | 详情 | 详情 |
| (II) | 46364 | N-(1,3-benzothiazol-2-yl)-N-phenylamine; N-phenyl-1,3-benzothiazol-2-amine | C13H10N2S | 详情 | 详情 | |
| (III) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (IV) | 46365 | 1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-chloro-1-propanone | C16H13ClN2OS | 详情 | 详情 | |
| (V) | 46366 | 1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanone | C18H19N3OS | 详情 | 详情 | |
| (VI) | 56954 | (2S)-1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanone | C18H19N3OS | 详情 | 详情 | |
| (VII) | 46368 | (1S,2S)-1-[4-(1,3-benzothiazol-2-ylamino)phenyl]-2-(dimethylamino)-1-propanol | C18H21N3OS | 详情 | 详情 |