R-116010, -Drug Synthesis Database

【结构式】

【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
　　　　　　N-(2-Benzothiazolyl)-N-[4-[2(S)-(dimethylamino)-1(S)-(1H-imidazol-1-yl)propyl]phenyl]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 合成路线2 合成路线3

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.

参考文献中间体

【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.

参考文献中间体

【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.

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)