UP-2092, NSC-709119, DRH-417, D-709119, -Drug Synthesis Database

【结构式】

【药物名称】UP-2092, NSC-709119, DRH-417, D-709119

【化学名称】(11aS)-7,8-Dimethoxy-2-(4-methoxyphenyl)-5,11a-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

【CA登记号】260544-29-4

【分子式】C₂₁H₂₀N₂O₄

【分子量】364.40455

【开发单位】Spirogen (Originator), Cancer Research UK (Codevelopment), EORTC (Codevelopment)

【药理作用】ONCOLYTIC DRUGS, DNA-Damaging Drugs

合成路线1 合成路线2

合成路线1

Chlorination of 2-nitro-4,5-dimethoxybenzoic acid (I) by using oxalyl chloride and DMF provides acid chloride (II), which is subsequently coupled to hydroxyproline methyl ester (III) to yield amide (IV). Catalytic hydrogenation of the nitro group of (IV), followed by intramolecular cyclization leads to the tricyclic lactam (V). In order to protect the lactam NH of (V), the hydroxyl group is first converted into the silyl ether (VI), which is further treated with trimethylsilylethoxymethyl chloride and NaH to give the SEM-lactam (VII). Selective O desilylation of (VII) is accomplished by means of tetrabutylammonium fluoride, providing alcohol (VIII). Oxidation of (VIII) under Swern reaction conditions gives rise to ketone (IX).

参考文献中间体

【1】 Thurston, D.E.; Howard, P.W. (University of Portsmouth); Compounds. EP 1109812; WO 0012508 .

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)	31789	4,5-dimethoxy-2-nitrobenzoic acid	4998-07-6	C₉H₉NO₆	详情	详情
(II)	31790	4,5-dimethoxy-2-nitrobenzoyl chloride		C₉H₈ClNO₅	详情	详情
(III)	15796	methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate		C₆H₁₁NO₃	详情	详情
(IV)	61271	methyl (2S,4R)-1-(4,5-dimethoxy-2-nitrobenzoyl)-4-hydroxy-2-pyrrolidinecarboxylate		C₁₅H₁₈N₂O₈	详情	详情
(V)	61272	(2R,11aS)-2-hydroxy-7,8-dimethoxy-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione		C₁₄H₁₆N₂O₅	详情	详情
(VI)	61273	(2R,11aS)-2-{[tert-butyl(dimethyl)silyl]oxy}-7,8-dimethoxy-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione		C₂₀H₃₀N₂O₅Si	详情	详情
(VII)	61274	(2R,11aS)-2-{[tert-butyl(dimethyl)silyl]oxy}-7,8-dimethoxy-10-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione		C₂₆H₄₄N₂O₆Si₂	详情	详情
(VIII)	61275	(2R,11aS)-2-hydroxy-7,8-dimethoxy-10-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione		C₂₀H₃₀N₂O₆Si	详情	详情
(IX)	61276	(11aS)-7,8-dimethoxy-10-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,1-c][1,4]benzodiazepine-2,5,11(3H,10H,11aH)-trione		C₂₀H₂₈N₂O₆Si	详情	详情

合成路线2

Treatment of ketone (IX) with trifluoromethanesulfonic anhydride and pyridine produces the vinyl triflate (X). This is then subjected to Suzuki coupling with 4-methoxyphenylboronic acid (XI) to yield adduct (XII). Finally, regioselective lactam reduction in (XII) with NaBH4 furnishes the title compound.

参考文献中间体

【1】 Thurston, D.E.; Howard, P.W. (University of Portsmouth); Compounds. EP 1109812; WO 0012508 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	61276	(11aS)-7,8-dimethoxy-10-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,1-c][1,4]benzodiazepine-2,5,11(3H,10H,11aH)-trione		C₂₀H₂₈N₂O₆Si	详情	详情
(X)	61277	(11aS)-7,8-dimethoxy-5,11-dioxo-10-{[2-(trimethylsilyl)ethoxy]methyl}-5,10,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-yl trifluoromethanesulfonate		C₂₁H₂₇F₃N₂O₈SSi	详情	详情
(XI)	39246	4-methoxyphenylboronic acid	5720-07-0	C₇H₉BO₃	详情	详情
(XII)	61278	(11aS)-7,8-dimethoxy-2-(4-methoxyphenyl)-10-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione		C₂₇H₃₄N₂O₆Si	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)