|
【结 构 式】 
|
【药物名称】AG-2033((6R)-isomer), AG-2034 【化学名称】N-[5-[2-[2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6(S)-yl]ethyl]thien-2-ylcarbonyl]-L-glutamic acid 【CA登记号】177575-17-6 【 分 子 式 】C18H21N5O6S2 【 分 子 量 】467.52597 |
【开发单位】Agouron (Originator) 【药理作用】Oncolytic Drugs, Antimetabolites, Glycinamide Ribonucleotide Formyltransferase (GARTFase) Inhibitors |
合成路线1
Palladium-catalyzed coupling between (S)-4-ethynyl-2,2-dimethyl[1,3]dioxolane (I) and ethyl 5-bromothiophene-2-carboxylate (II) afforded the acetylene adduct (III), which was further hydrogenated to (IV) in the presence of Pd/C. Acid hydrolysis of the acetonide function of (IV) gave diol (V). In order to invert the configuration of the chiral center of (V), its primary hydroxyl group was protected as the silyl ether (VI) and the secondary alcohol was subsequently converted to mesylate (VII). After desilylation of (VII) by means of tetrabutylammonium fluoride, the resultant mesylate alcohol was cyclized to epoxide (VIII) upon treatment with NaH in THF. Epoxide ring opening in (VIII) with NaN3 furnished azido alcohol (IX). Then, azide reduction in the presence of Boc2O gave rise to the Boc-protected amine (X). Introduction of a sulfur atom was accomplished by conversion of alcohol (X) to mesylate (XI), followed by displacement with potassium thioacetate to yield (XII). Concomitant thioacetate ester (XII) hydrolysis and alkylation of the intermediate thiol with chloromalonate (XIII) provided the mercaptomalonate (XIV).
| 【1】 Varney, M.D.; et al.; Protein structure-based design, synthesis, and biological evaluation of 5-thia-2, 6-diamino-4(3H)-oxopyrimidines: Potent inhibitors of glycinamide ribonucleotide transformylase with potent cell growth inhibition. J Med Chem 1997, 40, 16, 2502. |
| 【2】 Varney, M.D.; Palmer, C.L.; Romines, W.H. (Agouron Pharmaceuticals, Inc.); Syntheses of optically pure cpds. useful as GARFT inhibitors and their intermediates. WO 9640674 . |
| 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) | 59491 | (4S)-4-ethynyl-2,2-dimethyl-1,3-dioxolane | C7H10O2 | 详情 | 详情 | |
| (II) | 59492 | ethyl 5-bromo-2-thiophenecarboxylate | C7H7BrO2S | 详情 | 详情 | |
| (III) | 59493 | ethyl 5-{2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethynyl}-2-thiophenecarboxylate | C14H16O4S | 详情 | 详情 | |
| (IV) | 59494 | ethyl 5-{2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-2-thiophenecarboxylate | C14H20O4S | 详情 | 详情 | |
| (V) | 59495 | ethyl 5-[(3S)-3,4-dihydroxybutyl]-2-thiophenecarboxylate | C11H16O4S | 详情 | 详情 | |
| (VI) | 59496 | ethyl 5-((3S)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxybutyl)-2-thiophenecarboxylate | C17H30O4SSi | 详情 | 详情 | |
| (VII) | 59497 | ethyl 5-{(3S)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(methylsulfonyl)oxy]butyl}-2-thiophenecarboxylate | C18H32O6S2Si | 详情 | 详情 | |
| (VIII) | 59498 | ethyl 5-{2-[(2R)oxiranyl]ethyl}-2-thiophenecarboxylate | C11H14O3S | 详情 | 详情 | |
| (IX) | 59499 | ethyl 5-[(3R)-4-azido-3-hydroxybutyl]-2-thiophenecarboxylate | C11H15N3O3S | 详情 | 详情 | |
| (X) | 59500 | ethyl 5-{(3R)-4-[(tert-butoxycarbonyl)amino]-3-hydroxybutyl}-2-thiophenecarboxylate | C16H25NO5S | 详情 | 详情 | |
| (XI) | 59501 | ethyl 5-{(3R)-4-[(tert-butoxycarbonyl)amino]-3-[(methylsulfonyl)oxy]butyl}-2-thiophenecarboxylate | C17H27NO7S2 | 详情 | 详情 | |
| (XII) | 59502 | ethyl 5-{(3S)-3-(acetylsulfanyl)-4-[(tert-butoxycarbonyl)amino]butyl}-2-thiophenecarboxylate | C18H27NO5S2 | 详情 | 详情 | |
| (XIII) | 59503 | dimethyl chloromalonate | 28868-76-0 | C5H7ClO4 | 详情 | 详情 |
| (XIV) | 59504 | dimethyl 2-({(1S)-1-{[(tert-butoxycarbonyl)amino]methyl}-3-[5-(ethoxycarbonyl)-2-thienyl]propyl}sulfanyl)malonate | C21H31NO8S2 | 详情 | 详情 |
合成路线2
After removal of the Boc protecting group of (XIV), the resultant free amine spontaneously cyclized to the lactam (XV) in methanolic solution. Lactam (XV) was O-alkylated with trimethyloxonium fluoroborate, yielding the lactim ether (XVI), which was condensed with guanidine (XVII) to produce the pyridothiazine (XVIII). Hydrolysis of the ethyl ester of (XVIII), followed by coupling of the resultant acid (XIX) with L-glutamic acid diethyl ester (XX), furnished amide (XXI). The ester groups of (XXI) were finally hydrolyzed with NaOH to give the title compound.
| 【1】 Varney, M.D.; et al.; Protein structure-based design, synthesis, and biological evaluation of 5-thia-2, 6-diamino-4(3H)-oxopyrimidines: Potent inhibitors of glycinamide ribonucleotide transformylase with potent cell growth inhibition. J Med Chem 1997, 40, 16, 2502. |
| 【2】 Varney, M.D.; Palmer, C.L.; Romines, W.H. (Agouron Pharmaceuticals, Inc.); Syntheses of optically pure cpds. useful as GARFT inhibitors and their intermediates. WO 9640674 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 59504 | dimethyl 2-({(1S)-1-{[(tert-butoxycarbonyl)amino]methyl}-3-[5-(ethoxycarbonyl)-2-thienyl]propyl}sulfanyl)malonate | C21H31NO8S2 | 详情 | 详情 | |
| (XV) | 59505 | methyl (6S)-6-{2-[5-(ethoxycarbonyl)-2-thienyl]ethyl}-3-oxo-2-thiomorpholinecarboxylate | C15H19NO5S2 | 详情 | 详情 | |
| (XVI) | 59506 | methyl (6S)-6-{2-[5-(ethoxycarbonyl)-2-thienyl]ethyl}-3-methoxy-5,6-dihydro-2H-1,4-thiazine-2-carboxylate | C16H21NO5S2 | 详情 | 详情 | |
| (XVII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (XVIII) | 59507 | ethyl 5-{2-[(6S)-2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl]ethyl}-2-thiophenecarboxylate | C15H18N4O3S2 | 详情 | 详情 | |
| (XIX) | 59508 | 5-{2-[(6S)-2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl]ethyl}-2-thiophenecarboxylic acid | C13H14N4O3S2 | 详情 | 详情 | |
| (XX) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (XXI) | 59509 | diethyl (2S)-2-{[(5-{2-[(6S)-2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl]ethyl}-2-thienyl)carbonyl]amino}pentanedioate | C22H29N5O6S2 | 详情 | 详情 |