BIRA-0596, -Drug Synthesis Database

【结构式】

【药物名称】BIRA-0596

【化学名称】2-(2,6-Dichlorophenylamino)-6,7-dimethyl-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-9-one

【CA登记号】333455-11-1

【分子式】C₁₈H₁₄Cl₂N₄O

【分子量】373.24448

【开发单位】Boehringer Ingelheim (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants, Lck Kinase Inhibitors, Src Kinase Inhibitors

合成路线1 合成路线2

合成路线1

Alkylation of (2-cyanophenyl)acetonitrile (I) with iodomethane under phase-transfer conditions leads to the alpha,alpha-dimethyl nitrile (II), which is further cyclized to imide (III) with 90% H2SO4. Subsequent nitration of homophthalimide (III) with HNO3/H2SO4 furnishes (IV) (1). Nitrophthalimide (IV) is reduced to the corresponding amine (V) by hydrogenation in the presence of Pd/C. This is then converted into acetamide (VI) by treatment with Ac2O. A second nitration reaction with cold HNO3 leads to the nitro amide (VII), which is further hydrolyzed with H2SO4 to the nitro amine (VIII). Hydrogenation of (VIII) over PtO2 furnishes diamine (IX). Coupling of (IX) with 2,6-dichlorophenyl isothiocyanate (X) gives thiourea (XI). Ring closure of amino thiourea (XI) to the benzimidazole derivative (XII) is carried out by treatment with DCC in refluxing THF. Partial reduction of the imide function of (XII) with NaBH4 in moist THF affords (XIII). Finally, rearrangement of (XIII) in concentrated H2SO4 at room temperature gives rise to the title compound (1,2).

参考文献中间体

【1】 Snow, R.J.; Cardozo, M.G.; Morwick, T.M.; Bussacca, C.A.; Dong, Y.; Eckner, R.J.; Jacober, S.; Jakes, S.; Kapadia, S.; Lukas, S.; Panzenbeck, M.; Peet, G.W.; Peterson, J.D.; Prokopowicz, A.S. III; Sellati, R.; Tolbert, R.M.; Tschantz, M.A.; Moss, N.; Discovery of 2-phenylamino-imidazo[4,5-h]isoquinolin-9-ones: A new class of inhibitors of lck kinase. J Med Chem 2002, 45, 16, 3394.
【2】 Goldberg, D.; Cardozo, M.G.; Tschantz, M.A.; Moss, N.; Morwick, T.; Prokopowicz, A.S. III; Snow, R.J.; Patel, U.R.; Wang, X.-J.; Hammach, A.; Takahashi, H. (Boehringer Ingelheim Pharmaceuticals Inc.); Heterocyclic cpds. useful as inhibitors of tyrosine kinases. WO 0125238 .

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)	21593	2-(cyanomethyl)benzonitrile	3759-28-2	C₉H₆N₂	详情	详情
(II)	65069	2-(1-cyano-1-methylethyl)benzonitrile		C₁₁H₁₀N₂	详情	详情
(III)	21594	4,4-dimethyl-1,3(2H,4H)-isoquinolinedione		C₁₁H₁₁NO₂	详情	详情
(IV)	65072	4,4-dimethyl-7-nitro-1,3(2H,4H)-isoquinolinedione		C₁₁H₁₀N₂O₄	详情	详情
(V)	65071	7-amino-4,4-dimethyl-1,3(2H,4H)-isoquinolinedione		C₁₁H₁₂N₂O₂	详情	详情
(VI)	65070	N-(4,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydro-7-isoquinolinyl)acetamide		C₁₃H₁₄N₂O₃	详情	详情
(VII)	65073	N-(4,4-dimethyl-8-nitro-1,3-dioxo-1,2,3,4-tetrahydro-7-isoquinolinyl)acetamide		C₁₃H₁₃N₃O₅	详情	详情
(VIII)	65074	7-amino-4,4-dimethyl-8-nitro-1,3(2H,4H)-isoquinolinedione		C₁₁H₁₁N₃O₄	详情	详情
(IX)	65075	7,8-diamino-4,4-dimethyl-1,3(2H,4H)-isoquinolinedione		C₁₁H₁₃N₃O₂	详情	详情
(X)	52344	2,6-Dichlorophenyl isothiocyanate	6590-95-0	C₇H₃Cl₂NS	详情	详情
(XI)	65077	N-(8-amino-4,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydro-7-isoquinolinyl)-N'-(2,6-dichlorophenyl)thiourea		C₁₈H₁₆Cl₂N₄O₂S	详情	详情
(XII)	65076	2-(2,6-dichloroanilino)-6,6-dimethyl-1H-imidazo[4,5-h]isoquinoline-7,9(6H,8H)-dione		C₁₈H₁₄Cl₂N₄O₂	详情	详情
(XIII)	65078	2-(2,6-dichloroanilino)-7-hydroxy-6,6-dimethyl-1,6,7,8-tetrahydro-9H-imidazo[4,5-h]isoquinolin-9-one		C₁₈H₁₆Cl₂N₄O₂	详情	详情

合成路线2

In an alternative method, 2,6-dichloro-3-nitrobenzonitrile (I) is heated with ethanolic ammonia in a sealed vessel to produce the 2-amino benzonitrile (II). Subsequent condensation of 2-amino-6-chloro-3-nitrobenzonitrile (II) with ethyl methylacetoacetate (III) in the presence of K2CO3 leads to the aryl methyl acetoacetate ester (IV). Decarboxylation and cyclization of (IV) under acidic conditions then produces isoquinolinone (V). Nitro group reduction in (V) with H2 and Pd/C leads to diamine (VI), which is further coupled with 2,6-dichlorophenyl isothiocyanate (VII), yielding thiourea (VIII). Finally, ring closure of amino thiourea (VIII) with DCC in hot DMF affords the target tricyclic compound (2).

参考文献中间体

【1】 Goldberg, D.; Cardozo, M.G.; Tschantz, M.A.; Moss, N.; Morwick, T.; Prokopowicz, A.S. III; Snow, R.J.; Patel, U.R.; Wang, X.-J.; Hammach, A.; Takahashi, H. (Boehringer Ingelheim Pharmaceuticals Inc.); Heterocyclic cpds. useful as inhibitors of tyrosine kinases. WO 0125238 .

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)	52340	2,6-Dichloro-3-nitrobenzonitrile	5866-98-8	C₇H₂Cl₂N₂O₂	详情	详情
(II)	65079	2-amino-6-chloro-3-nitrobenzonitrile		C₇H₄ClN₃O₂	详情	详情
(III)	10362	ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate	609-14-3	C₇H₁₂O₃	详情	详情
(IV)	65080	ethyl 2-(3-amino-2-cyano-4-nitrophenyl)-2-methyl-3-oxobutanoate		C₁₄H₁₅N₃O₅	详情	详情
(V)	65082	8-amino-3,4-dimethyl-7-nitro-1(2H)-isoquinolinone		C₁₁H₁₁N₃O₃	详情	详情
(VI)	65081	7,8-diamino-3,4-dimethyl-1(2H)-isoquinolinone		C₁₁H₁₃N₃O	详情	详情
(VII)	52344	2,6-Dichlorophenyl isothiocyanate	6590-95-0	C₇H₃Cl₂NS	详情	详情
(VIII)	65083	N-(8-amino-3,4-dimethyl-1-oxo-1,2-dihydro-7-isoquinolinyl)-N'-(2,6-dichlorophenyl)thiourea		C₁₈H₁₆Cl₂N₄OS	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)