6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one -Drug Synthesis Database

【结构式】

【分子编号】40806

【品名】6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one

【CA登记号】

【分子式】C₆H₆N₄O

【分子量】150.14

【元素组成】C 48% H 4.03% N 37.32% O 10.66%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(X)

4-Methyl-5-nitroimidazole (I) is condensed with benzaldehyde (II) in the presence of piperidine to produce the 4-styryl imidazole (III). Alkylation of imidazole (III) with benzyl chloride leads to a 3:1 mixture of regioisomeric N-benzyl imidazoles (IV) and (V). Ozonolysis of this mixture, followed by oxidative work-up of the ozonide with performic acid, allows isolation of the desired imidazolecarboxylic acid (VI) by employing a differential precipitation technique. Activation of acid (VI) with CDI, and further treatment of the resultant imidazolide with potassium methanenitronate gives rise to nitro ketone (VII). Both nitro groups of (VII) are then reduced by SnCl2 in concentrated HCl to furnish diamine (VIII). Then, removal of the N-benzyl group of (VIII) by catalytic hydrogenation over Pd/C yields imidazole (IX). Ring closure of (IX) in the presence of triethyl orthoformate produces the imidazodiazepinone (X)

参考文献中间体

合成目标

【1】 Chan, E.; et al.; Total synthesis of (8R)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin), the potent inhibitor of adenosine deaminase. J Org Chem 1982, 47, 18, 3457.
【2】 Baker, D.C.; Putt, S.R.; A total synthesis of pentostatin, the potent inhibitor of adenosine deaminase. J Am Chem Soc 1979, 101, 20, 6127.
【3】 Baker, D.C.; Putt, S.R. (Pfizer Inc.); 2-Amino-1-(5-amino-1H-imidazol-4-yl)ethanone and method of preparation. DE 2835144; ES 472478; ES 479618; GB 2005661; GB 2013680; US 4117229 .
【4】 Baker, D.C.; Putt, S.R. (Pfizer Inc.); Imidazole cpds., methods for their production and conversion of said cpds. into (R)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazol[4,5-d][1,3]diazepin-8-ol. US 4195176 .

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)	62513	4-methyl-5-nitro-1H-imidazole		C₄H₅N₃O₂	详情	详情
(II)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(III)	62514	5-nitro-4-[(E)-2-phenylethenyl]-1H-imidazole		C₁₁H₉N₃O₂	详情	详情
(IV)	62515	1-benzyl-4-nitro-5-[(E)-2-phenylethenyl]-1H-imidazole		C₁₈H₁₅N₃O₂	详情	详情
(V)	62516	1-benzyl-5-nitro-4-[(E)-2-phenylethenyl]-1H-imidazole		C₁₈H₁₅N₃O₂	详情	详情
(VI)	62517	1-benzyl-4-nitro-1H-imidazole-5-carboxylic acid		C₁₁H₉N₃O₄	详情	详情
(VII)	62518	1-(1-benzyl-4-nitro-1H-imidazol-5-yl)-2-nitro-1-ethanone		C₁₂H₁₀N₄O₅	详情	详情
(VIII)	62519	2-amino-1-(4-amino-1-benzyl-1H-imidazol-5-yl)-1-ethanone		C₁₂H₁₄N₄O	详情	详情
(IX)	62520	2-amino-1-(5-amino-1H-imidazol-4-yl)-1-ethanone		C₅H₈N₄O	详情	详情
(X)	40806	6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one		C₆H₆N₄O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

After silylation of the imidazodiazepinone (X) employing bis(trimethylsilyl)trifluoroacetamide, glycosylation with 2-deoxy-3,5-di-p-toluoyl-D-erythro-pentofuranosyl chloride (XI) leads to a mixture of glycoside anomers (XII) and (XIII), from which the desired beta-anomer (XII) can be isolated by either column chromatography or by fractional crystallization. The toluoyl ester groups of (XII) are then removed by methanolysis in the presence of NaOMe to afford (XIV). Finally, reduction of ketone (XIV) gives rise to a 60:40 mixture of the target (R)-hydroxy imidazodiazepine along with its (S)-epimer (XV), which are separated by reverse-phase preparative HPLC

参考文献中间体

合成目标

【1】 Baker, D.C.; Putt, S.R.; A total synthesis of pentostatin, the potent inhibitor of adenosine deaminase. J Am Chem Soc 1979, 101, 20, 6127.
【2】 Chan, E.; et al.; Total synthesis of (8R)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin), the potent inhibitor of adenosine deaminase. J Org Chem 1982, 47, 18, 3457.
【3】 Baker, D.C.; Putt, S.R. (Pfizer Inc.); Imidazole cpds., methods for their production and conversion of said cpds. into (R)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazol[4,5-d][1,3]diazepin-8-ol. US 4195176 .
【4】 Baker, D.C.; Putt, S.R. (Pfizer Inc.); 2-Amino-1-(5-amino-1H-imidazol-4-yl)ethanone and method of preparation. DE 2835144; ES 472478; ES 479618; GB 2005661; GB 2013680; US 4117229 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	40806	6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one		C₆H₆N₄O	详情	详情
(XI)	37194	(2R,3S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate	4330-21-6	C₂₁H₂₁ClO₅	详情	详情
(XII)	62522	{(2R,3S,5R)-3-[(4-methylbenzoyl)oxy]-5-[8-oxo-7,8-dihydroimidazo[4,5-d][1,3]diazepin-3(6H)-yl]tetrahydro-2-furanyl}methyl 4-methylbenzoate		C₂₇H₂₆N₄O₆	详情	详情
(XIII)	62521	{(2R,3S,5S)-3-[(4-methylbenzoyl)oxy]-5-[8-oxo-7,8-dihydroimidazo[4,5-d][1,3]diazepin-3(6H)-yl]tetrahydro-2-furanyl}methyl 4-methylbenzoate		C₂₇H₂₆N₄O₆	详情	详情
(XIV)	62523	3-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one		C₁₁H₁₄N₄O₄	详情	详情
(XV)	62524	(8S)-3-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol		C₁₁H₁₆N₄O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Dibenzyl malonate (I) was alkylated with 3-(trifluoromethyl)benzyl bromide (II) in the presence of Na in DMF to yield the 3-(trifluoromethyl)benzylmalonate (III). Further alkylation of (III) with 1,4-dibromobutane (IV) provided the bromobutyl derivative (V). Condensation of the known 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8-one (VI) with bromide (V) in the presence of NaH and NaI furnished adduct (VII). The keto group of (VII) was then reduced to alcohol (VIII) employing NaBH4 in MeOH-CH2Cl2. Finally, hydrogenolysis of the benzyl ester groups of (VIII) in the presence of Pd/C and Et3N afforded the title dicarboxylate triethylammonium salt.

参考文献中间体

合成目标

【1】 Bookser, B.C.; Kasibhatla, S.R.; Erion, M.D.; AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues: N3-alkylmalonates as ribose 5'-monophosphate mimetics. J Med Chem 2000, 43, 8, 1519.

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)	16013	dibenzyl malonate	15014-25-2	C₁₇H₁₆O₄	详情	详情
(II)	40803	1-(bromomethyl)-3-(trifluoromethyl)benzene	402-23-3	C₈H₆BrF₃	详情	详情
(III)	40804	dibenzyl 2-[3-(trifluoromethyl)benzyl]malonate		C₂₅H₂₁F₃O₄	详情	详情
(IV)	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
(V)	40805	dibenzyl 2-(4-bromobutyl)-2-[3-(trifluoromethyl)benzyl]malonate		C₂₉H₂₈BrF₃O₄	详情	详情
(VI)	40806	6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one		C₆H₆N₄O	详情	详情
(VII)	40807	dibenzyl 2-[4-[8-oxo-7,8-dihydroimidazo[4,5-d][1,3]diazepin-3(6H)-yl]butyl]-2-[3-(trifluoromethyl)benzyl]malonate		C₃₅H₃₃F₃N₄O₅	详情	详情
(VIII)	40808	dibenzyl 2-[4-[8-hydroxy-7,8-dihydroimidazo[4,5-d][1,3]diazepin-3(6H)-yl]butyl]-2-[3-(trifluoromethyl)benzyl]malonate		C₃₅H₃₅F₃N₄O₅	详情	详情

Extended Information