|
【结 构 式】 
|
【药物名称】Variolin B, PM-01220 【化学名称】5-(2-Aminopyrimidin-4-yl)-4-hydroxypyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-9-amine 【CA登记号】 【 分 子 式 】C14H11N7O 【 分 子 量 】293.29007 |
【开发单位】University of California, Oakland (Originator), PharmaMar (Not Determined) 【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, ONCOLYTIC DRUGS, Apoptosis Inducers, CDK/Cyclin Complex Inhibitors |
合成路线1
The triarylcarbinol intermediate (IV) is obtained by two different ways: 1. The reaction of 2-chloro-4-methoxypyridine-3-carboxylic acid (I) with (COCl)2 in dichloromethane gives the acyl chloride (II), which is condensed with 2-methylsulfanylpyrimidin-4-yl lithium salt (III) in THF to yield the triarylcarbinol (IV). 2. The reaction of the lithium salt (III) with 0.4 equiv. of diethyl carbonate (V) in THF gives the symmetric ketone (VI), which is then condensed with the 2-chloro-4-methoxypyridin-3-yl lithium salt (VII) in THF to yield the desired triarylcarbinol intermediate (IV). The cyclization of the triarylcarbinol intermediate (IV) by means of Tes-H and TEA in 1,2-dichloroethane at 100 C gives the desired core structure (VIII), which is oxidized at its sulfanyl groups with MCPBA in chloroform to yield the sulfinyl derivative (IX). The reaction of (IX) with 4-methoxybenzylamine (X) at 85 ?C affords the protected diamine (XI). The demethylation of (XI) by means of EtS-Na in hot DMF provides the pyridinol (XII), which is finally N-deprotected by means of triflic acid to yield the target variolin B (1).
| 【1】 Morris, J.C.; Anderson, R.J.; Total synthesis of variolin B. Tetrahedron Lett 2001, 42, 49, 8697. |
| 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) | 55708 | 2-chloro-4-methoxynicotinic acid | C7H6ClNO3 | 详情 | 详情 | |
| (II) | 55709 | 2-chloro-4-methoxynicotinoyl chloride | C7H5Cl2NO2 | 详情 | 详情 | |
| (III) | 55710 | [2-(methylsulfanyl)-4-pyrimidinyl]lithium | C5H5LiN2S | 详情 | 详情 | |
| (IV) | 55711 | (2-chloro-4-methoxy-3-pyridinyl){bis[2-(methylsulfanyl)-4-pyrimidinyl]}methanol | C17H16ClN5O2S2 | 详情 | 详情 | |
| (V) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (VI) | 55712 | bis[2-(methylsulfanyl)-4-pyrimidinyl]methanone | C11H10N4OS2 | 详情 | 详情 | |
| (VII) | 55713 | (2-chloro-4-methoxy-3-pyridinyl)lithium | C6H5ClLiNO | 详情 | 详情 | |
| (VIII) | 55714 | 4-methoxy-9-(methylsulfanyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine; methyl 9-(methylsulfanyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-yl ether | C17H15N5OS2 | 详情 | 详情 | |
| (IX) | 55715 | 4-[4-methoxy-9-(methylsulfinyl)pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-5-yl]-2-pyrimidinyl methyl sulfoxide; 4-methoxy-9-(methylsulfinyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine | C17H15N5O3S2 | 详情 | 详情 | |
| (X) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (XI) | 55716 | N-(4-methoxybenzyl)-N-(4-{4-methoxy-9-[(4-methoxybenzyl)amino]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-5-yl}-2-pyrimidinyl)amine; 4-methoxy-N-(4-methoxybenzyl)-5-{2-[(4-methoxybenzyl)amino]-4-pyrimidinyl}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-9-amine | C31H29N7O3 | 详情 | 详情 | |
| (XII) | 55717 | 9-[(4-methoxybenzyl)amino]-5-{2-[(4-methoxybenzyl)amino]-4-pyrimidinyl}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol | C30H27N7O3 | 详情 | 详情 |
合成路线2
The condensation of 4-methoxypyridine-3-carbaldehyde (I) with 2-azidoacetic acid ethyl ester (II) by means of NaOMe in ethanol gives 2-azido-3-(4-methoxypyridin-3-yl)acrylic acid ethyl ester (III), which is cyclized in refluxing o-xylene to yield the pyrrolopyridine (IV). The reaction of the NH group of (IV) with Sem-Cl and NaH in DMF affords the N-protected compound (V), whose ester group is reduced with LiAlH4 in refluxing THF to provide the carbinol (VI). The oxidation of (VI) with MnO2 in dichloromethane gives the corresponding carbaldehyde (VII), which is condensed with 2-azidoacetic acid ethyl ester (II) as before to yield the azido acrylic ester (VIII). The condensation of (VIII) with triphenylphosphine (IX) in dichloromethane affords the iminophosphorane (X), which is N-deprotected by means of TBAF in THF to provide the deprotected iminophosphorane (XI). The cyclization of (XI) with alpha-methylbenzyl isocyanate (XII) in THF gives the tricyclic pyrimidopyrrolopyridine (XIII), which is brominated with Br2 in pyridine to yield intermediate (XIV). The reaction of (XIV) with 1-ethoxyvinyl trimethyl tin (XV) by means of PdCl2(PPh3)2 in DMF affords the acetyl derivative (XVI), which is condensed with dimethylformamide di-tert-butyl acetal (XVII) in hot DMF to provide the dimethyl enaminone (XVIII). The cyclization of (XVIII) with guanidine (XIX) by means of K2CO3 in refluxing 2-methoxyethanol gives the 2-aminopyrimidine derivative (XX), with simultaneous hydrolysis of the ester group. The decarboxylation of (XX), with simultaneous demethylation, by heating at 260 C in diphenyl ether yields the N-protected precursor (XXI), which is finally treated with triflic acid to afford the target variolin B.
| 【1】 Molina, P.; et al.; Synthesis of the potent antitumoral marine alkaloid variolin B. Tetrahedron Lett 2002, 43, 6, 1005. |
| 【2】 Fresneda, P.M.; et al.; Synthetic studies towards the 2-aminopyrimidine alkaloids variolins and meridianins from marine origin. Tetrahedron Lett 2000, 41, 24, 4777. |
| 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) | 55718 | 4-methoxynicotinaldehyde | C7H7NO2 | 详情 | 详情 | |
| (II) | 32916 | ethyl 2-azidoacetate | 637-81-0 | C4H7N3O2 | 详情 | 详情 |
| (III) | 55719 | ethyl (Z)-2-azido-3-(4-methoxy-3-pyridinyl)-2-propenoate | C11H12N4O3 | 详情 | 详情 | |
| (IV) | 55720 | ethyl 4-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate | C11H12N2O3 | 详情 | 详情 | |
| (V) | 55721 | ethyl 4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate | C17H26N2O4Si | 详情 | 详情 | |
| (VI) | 55722 | (4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol | C15H24N2O3Si | 详情 | 详情 | |
| (VII) | 55723 | 4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde | C15H22N2O3Si | 详情 | 详情 | |
| (VIII) | 55724 | ethyl (Z)-2-azido-3-(4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-propenoate | C19H27N5O4Si | 详情 | 详情 | |
| (IX) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
| (X) | 55725 | ethyl (Z)-3-(4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-[(triphenylphosphoranylidene)amino]-2-propenoate | C37H42N3O4PSi | 详情 | 详情 | |
| (XI) | 55726 | ethyl (Z)-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-[(triphenylphosphoranylidene)amino]-2-propenoate | C31H28N3O3P | 详情 | 详情 | |
| (XII) | 55734 | (S)-(-)-1-Phenylethyl isocyanate; (S)-(-)-Phenylethyl Isocyanate; Isocyanic acid (S)-(-)-alpha-phenylethyl ester; S-(-)-alpha-Methylbenzyl isocyanate | 14649-03-7 | C9H9NO | 详情 | 详情 |
| (XIII) | 55727 | ethyl 4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C22H22N4O3 | 详情 | 详情 | |
| (XIV) | 55728 | ethyl 5-bromo-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C22H21BrN4O3 | 详情 | 详情 | |
| (XV) | 55729 | ethyl 1-(trimethylstannyl)vinyl ether; (1-ethoxyvinyl)(trimethyl)stannane | C7H16OSn | 详情 | 详情 | |
| (XVI) | 55730 | ethyl 5-acetyl-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C24H24N4O4 | 详情 | 详情 | |
| (XVII) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
| (XVIII) | 55731 | ethyl 5-[(E)-3-(dimethylamino)-2-propenoyl]-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C27H29N5O4 | 详情 | 详情 | |
| (XIX) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (XX) | 55732 | 5-(2-amino-4-pyrimidinyl)-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylic acid | C24H21N7O3 | 详情 | 详情 | |
| (XXI) | 55733 | 5-(2-amino-4-pyrimidinyl)-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol | C22H19N7O | 详情 | 详情 |