BMS-243117, -Drug Synthesis Database

【结构式】

【药物名称】BMS-243117

【化学名称】2-(3-tert-Butylureido)-N-(2-chloro-6-methylphenyl)benzothiazole-6-carboxamide

【CA登记号】225521-80-2

【分子式】C₂₀H₂₁ClN₄O₂S

【分子量】416.93297

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Antiarthritic Drugs, IMMUNOMODULATING AGENTS, Treatment of Autoimmune Diseases, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Lck Kinase Inhibitors

合成路线1 合成路线2

合成路线1

Reaction of ethyl 4-aminobenzoate (I) with sodium thiocyanate and bromine in cold AcOH gives rise to the amino benzothiazole (II). Subsequent treatment of (II) with phenyl chloroformate affords the phenyl carbamate (III), which is further reacted with tert-butylamine to furnish urea (IV). After alkaline hydrolysis of the ethyl ester (IV), the resultant carboxylic acid (V) is converted to the azabenzotriazolyl active ester (VI) upon treatment with HATU in DMF. Active ester (VI) is finally coupled with 2-chloro-6-methylaniline (VII) in the presence of sodium bis(trimethylsilyl)amide to yield the target amide.

参考文献中间体

【1】 Das, J.; Barrish, J.C.; Wityak, J. (Bristol-Myers Squibb Co.); Benzothiazole protein tyrosine kinase inhibitors. EP 1037632; JP 2001522800; WO 9924035 .

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)	16498	Benzocaine; ethyl 4-aminobenzoate	94-09-7	C₉H₁₁NO₂	详情	详情
(II)	65034	ethyl 2-amino-1,3-benzothiazole-6-carboxylate		C₁₀H₁₀N₂O₂S	详情	详情
(III)	65035	ethyl 2-[(phenoxycarbonyl)amino]-1,3-benzothiazole-6-carboxylate		C₁₇H₁₄N₂O₄S	详情	详情
(IV)	65036	ethyl 2-{[(tert-butylamino)carbonyl]amino}-1,3-benzothiazole-6-carboxylate		C₁₅H₁₉N₃O₃S	详情	详情
(V)	65037	2-{[(tert-butylamino)carbonyl]amino}-1,3-benzothiazole-6-carboxylic acid		C₁₃H₁₅N₃O₃S	详情	详情
(VI)	65038	N-(tert-butyl)-N'-{6-[(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)carbonyl]-1,3-benzothiazol-2-yl}urea		C₁₈H₁₇N₇O₃S	详情	详情
(VII)	29789	2-chloro-6-methylphenylamine; 2-chloro-6-methylaniline	87-63-8	C₇H₈ClN	详情	详情

合成路线2

In an alternative method, ethyl 4-aminobenzoate (I) is treated with NaSCN/Br2 to produce the amino benzothiazole (II), which is further protected as the N-Boc derivative (III). Alkaline hydrolysis of ester (III), followed by chlorination of the resultant acid (IV) with oxalyl chloride gives rise to the acid chloride (V). This is then coupled with 2-chloro-6-methylaniline (VI) yielding amide (VII). The N-Boc protecting group of (VII) is then cleaved employing trifluoroacetic acid to produce amine (VIII), which is subsequently reacted with phenyl chloroformate producing the phenyl carbamate (IX). Finally, displacement of carbamate (IX) with tert-butylamine furnishes the title urea. (1,2)

参考文献中间体

【1】 Das, J.; Lin, J.; Moquin, R.V.; Shen, Z.; Spergel, S.H.; Wityak, J.; Doweyko, A.M.; DeFex, H.F.; Fang, Q.; Pang, S.; Pitt, S.; Shen, D.R.; Schieven, G.L.; Barrish, J.C.; Molecular design, synthesis, and structure-activity relationships leading to the potent and selective p56(lck) inhibitor BMS-243117. Bioorg Med Chem Lett 2003, 13, 13, 2145.
【2】 Das, J.; Barrish, J.C.; Wityak, J. (Bristol-Myers Squibb Co.); Benzothiazole protein tyrosine kinase inhibitors. EP 1037632; JP 2001522800; WO 9924035 .

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)	16498	Benzocaine; ethyl 4-aminobenzoate	94-09-7	C₉H₁₁NO₂	详情	详情
(II)	65034	ethyl 2-amino-1,3-benzothiazole-6-carboxylate		C₁₀H₁₀N₂O₂S	详情	详情
(III)	65039	ethyl 2-[(tert-butoxycarbonyl)amino]-1,3-benzothiazole-6-carboxylate		C₁₅H₁₈N₂O₄S	详情	详情
(IV)	65040	2-[(tert-butoxycarbonyl)amino]-1,3-benzothiazole-6-carboxylic acid		C₁₃H₁₄N₂O₄S	详情	详情
(V)	65041	tert-butyl 6-(chlorocarbonyl)-1,3-benzothiazol-2-ylcarbamate		C₁₃H₁₃ClN₂O₃S	详情	详情
(VI)	29787	2-(3-methyl-4-oxo-1,3-thiazolidin-2-ylidene)acetyl chloride		C₆H₆ClNO₂S	详情	详情
(VII)	65042	tert-butyl 6-[(2-chloro-6-methylanilino)carbonyl]-1,3-benzothiazol-2-ylcarbamate		C₂₀H₂₀ClN₃O₃S	详情	详情
(VIII)	65043	2-amino-N-(2-chloro-6-methylphenyl)-1,3-benzothiazole-6-carboxamide		C₁₅H₁₂ClN₃OS	详情	详情
(IX)	65044	phenyl 6-[(2-chloro-6-methylanilino)carbonyl]-1,3-benzothiazol-2-ylcarbamate		C₂₂H₁₆ClN₃O₃S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)