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【结 构 式】 
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【分子编号】32916 【品名】ethyl 2-azidoacetate 【CA登记号】637-81-0 |
【 分 子 式 】C4H7N3O2 【 分 子 量 】129.1186 【元素组成】C 37.21% H 5.46% N 32.54% O 24.78% |
合成路线1
该中间体在本合成路线中的序号：Thermal cyclization of the azidocinnamate (II), obtained from O-benzylsalicylaldehyde (I) by methoxide condensation with ethyl azidoacetate, provides methyl 4-benzyloxyindol-2-carboxylate (III). Debenzylation by catalytic hydrogenolysis and alkylation of the phenol with (2S)-glycidyl tosylate gives the chiral oxirane (IV). Ring opening of (IV) followed by protection of the secondary amine by reaction with di-tert-butyldicarbonate and saponification of the methyl ester gives the key (S)-beta-blocker synthon (V). The required ACE inhibitor svnthon (VIII) is assembled from tert-butyl-N'-benzyloxycarbonyl-(S)-lysinate (VI). Alkylation of the alpha-amino group with the triflate of methyl (R)-lactate and saponification of the methyl ester gives N-[5-benzyloxycarbonylamino-1-(S)-tert-butyloxycarbonylpent-1-yl-(S)-alanine (VII). Condensation of (VII) with tert-butyl-(S)-prolinate. mediated by dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, followed by hydrogenolytic removal of the benzyloxycarbonyl group, provides tert-butyl-N-[5-amino-1-(S)-tert-butyloxycarbonylpent-1-yl]-(S)-alanyl-(S)-prolinate (VIII). Coupling of (V) with (VIII) using dicyclohexylcarbodiimide-1-hydroxybenzotriazole and removal of the tert-butyl protecting groups by acidolysis in trifluoroacetic acid, with ethyl methyl sulfide as a scavenger, gives crude BW-8385C as the bistrifluoroacetate salt. Purification is achieved by ion exchange chromatography on DE52 cellulose, followed by reverse-phase desalting to provide pure BW-B385C as the zwitterionic trihydrate.
| 【1】 Allan, G.; Hardy, G.W.; BW-B385C. Drugs Fut 1988, 13, 3, 203. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 | |
| 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | ||
| 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 | |
| 32916 | ethyl 2-azidoacetate | 637-81-0 | C4H7N3O2 | 详情 | 详情 | |
| 63428 | 3-methyl-1H-indole | C9H9N | 详情 | 详情 | ||
| (I) | 21874 | 2-(benzyloxy)benzaldehyde | 5896-17-3 | C14H12O2 | 详情 | 详情 |
| (II) | 21875 | methyl (Z)-2-azido-3-[2-(benzyloxy)phenyl]-2-propenoate | C17H15N3O3 | 详情 | 详情 | |
| (III) | 21876 | methyl 4-(benzyloxy)-1H-indole-2-carboxylate | C17H15NO3 | 详情 | 详情 | |
| (IV) | 21877 | methyl 4-[(2R)oxiranylmethoxy]-1H-indole-2-carboxylate | C13H13NO4 | 详情 | 详情 | |
| (V) | 21878 | 4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indole-2-carboxylic acid | C20H28N2O6 | 详情 | 详情 | |
| (VI) | 21879 | tert-butyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate | C18H28N2O4 | 详情 | 详情 | |
| (VII) | 21880 | (2S)-2-[[(1S)-5-[[(benzyloxy)carbonyl]amino]-1-(tert-butoxycarbonyl)pentyl]amino]propionic acid | C21H32N2O6 | 详情 | 详情 | |
| (VIII) | 21881 | tert-butyl (2S)-1-((2S)-2-[[(1S)-5-amino-1-(tert-butoxycarbonyl)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate | C22H41N3O5 | 详情 | 详情 | |
| (IX) | 21882 | tert-butyl (2S)-1-((2S)-2-[[(1S)-1-(tert-butoxycarbonyl)-5-([[4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indol-2-yl]carbonyl]amino)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate | C42H67N5O10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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 |
合成路线3
该中间体在本合成路线中的序号：(VII)The intermediate benzyl 5,7-dimethylindole-2-carboxylate (X) was prepared by several procedures. Diazotization of 2,4-dimethylaniline (I), followed by Japp-Klingemann condensation of the diazonium salt (II) with ethyl 2-methyl-3-oxobutyrate (III) furnished hydrazone (IV). Subsequent Fischer indole synthesis in formic acid at 75 C provided ethyl 5,7-dimethylindole-2-carboxylate (V). An alternative route to indole (V) involved condensation of 3,5-dimethylbenzaldehyde (VI) with ethyl azidoacetate (VII) in ethanolic NaOEt, followed by thermal cyclization of the resulting azidocinnamate ester (VIII). Basic hydrolysis of ethyl ester (V) gave carboxylic acid (IX), which was converted to the benzyl ester (X) upon treatment with benzyl bromide and DBU.
| 【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 32911 | 2,4-dimethylaniline; 2,4-dimethylphenylamine | 95-68-1 | C8H11N | 详情 | 详情 |
| (II) | 32912 | 2,4-dimethylbenzenediazonium | C8H9N2 | 详情 | 详情 | |
| (III) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (IV) | 32913 | ethyl 2-[(Z)-2-(2,4-dimethylphenyl)hydrazono]propanoate | C13H18N2O2 | 详情 | 详情 | |
| (V) | 32914 | ethyl 5,7-dimethyl-1H-indole-2-carboxylate | C13H15NO2 | 详情 | 详情 | |
| (VI) | 32915 | 3,5-dimethylbenzaldehyde | 5779-95-3 | C9H10O | 详情 | 详情 |
| (VII) | 32916 | ethyl 2-azidoacetate | 637-81-0 | C4H7N3O2 | 详情 | 详情 |
| (VIII) | 32917 | ethyl (Z)-2-azido-3-(3,5-dimethylphenyl)-2-propenoate | C13H15N3O2 | 详情 | 详情 | |
| (IX) | 32918 | 5,7-dimethyl-1H-indole-2-carboxylic acid | C11H11NO2 | 详情 | 详情 | |
| (X) | 32919 | benzyl 5,7-dimethyl-1H-indole-2-carboxylate | C18H17NO2 | 详情 | 详情 |