|
【结 构 式】 
|
【药物名称】Covidarabine, Deoxycoformycin, Pentostatin, CL-67310465, PD-81565, YK-176, CI-825, NSC-218321, Coforin, Oncopent, Nipent 【化学名称】(R)-3-(2-Deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol 【CA登记号】53910-25-1, 59979-24-7 (deleted CAS), 63677-95-2 (deleted CAS), 69196-00-5 (deleted CAS), 70865-77-9 (deleted CAS) 【 分 子 式 】C11H16N4O4 【 分 子 量 】268.27457 |
【开发单位】SuperGen (Proprietary), Pfizer (Originator), Nippon Kayaku (Not Determined), Wyeth Pharmaceuticals (Not Determined), Abbott (Distributor) 【药理作用】Antiarthritic Drugs, ANTIINFECTIVE THERAPY, IMMUNOMODULATING AGENTS, Leukemia Therapy, Lymphoma Therapy, Non-Hodgkin's Lymphoma Therapy, Oncolytic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Septic Shock, Treatment of Transplant Rejection, Adenosine Deaminase Inhibitors, Antimetabolites |
合成路线1
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)
| 【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
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
| 【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 |