N-[7-Chloro-5-(2-fluorophenyl)-3H-1,3-benzodiazepin-2-yl]-N-methyl-N-nitrosoamine -Drug Synthesis Database

【结构式】

【分子编号】33559

【品名】N-[7-Chloro-5-(2-fluorophenyl)-3H-1,3-benzodiazepin-2-yl]-N-methyl-N-nitrosoamine

【CA登记号】

【分子式】C₁₆H₁₂ClFN₄O

【分子量】330.7487432

【元素组成】C 58.1% H 3.66% Cl 10.72% F 5.74% N 16.94% O 4.84%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

The reaction of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I) with methylamine by means of TiCl4 in refluxing benzene gives 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine (II), which by reaction with NaNO2 in acetic acid is converted into its N-nitroso derivative (III). The treatment of (III) with nitromethane and potassium tert-butoxide in DMF affords 7-chloro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine (IV), which is reduced with H2 over Raney-Ni in THF affording the 2-aminomethyl derivative (V).The acetylation of (V) with acetic anhydride in CH2Cl2 gives the acetamide (VI), which is cyclized with polyphosphoric acid at 150 C yielding 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (VII). The deshydrogenation of (VII) with MnO2 in refluxing toluene affords 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (VIII), which is finally treated with maleic acid (A) in hot ethanol.

参考文献中间体

合成目标

【1】 Fryer, R.I.; Walser, A.; Benzo or heterocyclic fused imidazodiazepines and pharmaceutical compositions containing them. BE 0833248; DE 2540522; FR 2303016; GB 1527131; JP 51125099 .
【2】 Dhaon, M.K. (Abbott Laboratories Inc.); Process for the preparation of midazolam. WO 0170744 .
【3】 Thorpe, P.; Castaner, J.; Midazolam Maleate. Drugs Fut 1978, 3, 11, 822.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情
(I)	33355	7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one	2886-65-9	C₁₅H₁₀ClFN₂O	详情	详情
(II)	33558	N-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]-N-methylamine; 7-chloro-5-(2-fluorophenyl)-N-methyl-3H-1,4-benzodiazepin-2-amine		C₁₆H₁₃ClFN₃	详情	详情
(III)	33559	N-[7-Chloro-5-(2-fluorophenyl)-3H-1,3-benzodiazepin-2-yl]-N-methyl-N-nitrosoamine		C₁₆H₁₂ClFN₄O	详情	详情
(IV)	33560	7-chloro-5-(2-fluorophenyl)-2-[(Z)-nitromethylidene]-1,3-dihydro-2H-1,4-benzodiazepine		C₁₆H₁₁ClFN₃O₂	详情	详情
(V)	33561	[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methanamine; [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methylamine		C₁₆H₁₅ClFN₃	详情	详情
(VI)	33562	N-[[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]methyl]acetamide		C₁₈H₁₇ClFN₃O	详情	详情
(VII)	33563	8-chloro-6-(2-fluorophenyl)-1-methyl-3a,4-dihydro-3H-imidazo[1,5-a][1,4]benzodiazepine		C₁₈H₁₅ClFN₃	详情	详情
(VIII)	33564	8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine	59467-70-8	C₁₈H₁₃ClFN₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (I) with methylamine by means of TiCl4 in refluxing benzene gives 7-chloro-5-(2-fluorophenyl)-2-(methylamino)-3H-1,4-benzodiazepine (II), which is treated with NaNO2 and HOAc to yield the nitroso derivative (III). The condensation of (III) with dimethyl malonate (IV) by means of potassium tert-butoxide in DMF affords 2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-ylidene]malonic acid dimethyl ester (V), which is monodecarboxylated with KOH in refluxing methanol, providing the corresponding acetate (VI). The reaction of (VI) with NaNO2 and HOAc gives the hydroxyimino derivative (VII), which is reduced with H2 over RaNi in hot methanol to provide the expected amino derivative (VIII). The cyclization of (VIII) with triethyl orthoacetate (IX) and HCl in refluxing ethanol affords 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester (X), which is hydrolyzed with KOH in refluxing methanol/water to provide the corresponding free acid (XI). Finally, this compound is decarboxylated by heating in refluxing ethyleneglycol to give the target compound along with some 6H-isomer that is separated by chromatography. Alternatively, the decarboxylation of (XI) can also be performed in mineral oil at 230 C to obtain a better yield of the target compound.

参考文献中间体

合成目标

【1】 Bhatia, A.V.; Dhaon, M.K.; Davis, D.A.; Esser, G.L. (Abbott Laboratories Inc.); Process for the preparation of midazolam. WO 0102402 .
【2】 Walser, A.; Fryer, R.I. (F. Hoffmann-La Roche AG); Process for the preparation of diazepine derivs.. DE 2609486; GB 1549836 .

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)	33355	7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one	2886-65-9	C₁₅H₁₀ClFN₂O	详情	详情
(II)	33558	N-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]-N-methylamine; 7-chloro-5-(2-fluorophenyl)-N-methyl-3H-1,4-benzodiazepin-2-amine		C₁₆H₁₃ClFN₃	详情	详情
(III)	33559	N-[7-Chloro-5-(2-fluorophenyl)-3H-1,3-benzodiazepin-2-yl]-N-methyl-N-nitrosoamine		C₁₆H₁₂ClFN₄O	详情	详情
(IV)	19373	dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester	108-59-8	C₅H₈O₄	详情	详情
(V)	44390	dimethyl 2-[7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene]malonate		C₂₀H₁₆ClFN₂O₄	详情	详情
(VI)	44391	methyl 2-[7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene]acetate		C₁₈H₁₄ClFN₂O₂	详情	详情
(VII)	44392	methyl 2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]-2-(hydroxyimino)acetate		C₁₈H₁₅ClFN₃O₃	详情	详情
(VIII)	44393	methyl 2-amino-2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-yl]acetate		C₁₈H₁₇ClFN₃O₂	详情	详情
(IX)	12940	1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate	78-39-7	C₈H₁₈O₃	详情	详情
(X)	44394	methyl 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate		C₂₀H₁₅ClFN₃O₂	详情	详情
(XI)	44395	8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid		C₁₉H₁₃ClFN₃O₂	详情	详情

Extended Information