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【结 构 式】 
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【分子编号】40586 【品名】bromo[2-(tert-butoxy)-2-oxoethyl]zinc 【CA登记号】 |
【 分 子 式 】C6H11BrO2Zn 【 分 子 量 】260.44614 【元素组成】C 27.67% H 4.26% Br 30.68% O 12.29% Zn 25.11% |
合成路线1
该中间体在本合成路线中的序号：The known enol ether (I) was dihydroxylated with OsO4 and then oxidatively cleaved to the keto formate (II) by means of Pb(OAc)4. Reformatskii reaction of (II) with (tert-butoxycarbonyl)methylzinc bromide gave hydroxyester (III). Further cyclization of (III) using trifluroacetic acid produced lactone (IV). Halogenation with iodine monochloride afforded iodopyridine (V). Then, cleavage of the methyl ether of (V) employing trimethylsilyl iodide generated the pyridone lactone (VI), which was N-alkylated with 3-(trimethylsilyl)propargyl bromide (VII), yielding (VIII). Radical annulation of (VIII) with isonitrile (IX) in the presence hexamethylditin furnished the pentacyclic system (X). Finally, removal of the N-Boc protecting group of (X) yielded the title compound.
| 【1】 Bom, D.; et al.; Novel A,B,E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities. J Med Chem 1999, 42, 16, 3018. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | ||
| (I) | 35096 | 4-ethyl-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridine | C14H21NO2Si | 详情 | 详情 | |
| (II) | 35097 | [2-methoxy-4-propionyl-6-(trimethylsilyl)-3-pyridinyl]methyl formate | C14H21NO4Si | 详情 | 详情 | |
| (III) | 35098 | tert-butyl 3-[3-[(formyloxy)methyl]-2-methoxy-6-(trimethylsilyl)-4-pyridinyl]-3-hydroxypentanoate | C20H33NO6Si | 详情 | 详情 | |
| (IV) | 35099 | 5-ethyl-5-hydroxy-9-methoxy-7-(trimethylsilyl)-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C15H23NO4Si | 详情 | 详情 | |
| (V) | 35100 | 5-ethyl-5-hydroxy-7-iodo-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H14INO4 | 详情 | 详情 | |
| (VI) | 35101 | 5-ethyl-5-hydroxy-7-iodo-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H12INO4 | 详情 | 详情 | |
| (VII) | 35105 | (3-bromo-1-propynyl)(trimethyl)silane | 38002-45-8 | C6H11BrSi | 详情 | 详情 |
| (VIII) | 35106 | 5-ethyl-5-hydroxy-7-iodo-8-[3-(trimethylsilyl)-2-propynyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C17H22INO4Si | 详情 | 详情 | |
| (IX) | 35107 | Carbamic acid, (4-cyanophenyl)-, 1,1-dimethylethyl ester (9CI); tert-butyl 4-cyanophenylcarbamate | 143090-18-0 | C12H14N2O2 | 详情 | 详情 |
| (X) | 35108 | tert-butyl 5-ethyl-5-hydroxy-3,15-dioxo-12-(trimethylsilyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino[1,2-b]quinolin-10-ylcarbamate | C29H35N3O6Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：The known enol ether (I) was dihydroxylated with OsO4 and then oxidatively cleaved to the keto formate (II) by means of Pb(OAc)4. Reformatskii reaction of (II) with (tert-butoxycarbonyl)methylzinc bromide gave hydroxyester (III). Further cyclization of (III) using trifluroacetic acid produced lactone (IV). Halogenation with iodine monochloride afforded iodopyridine (V). Then, cleavage of the methyl ether of (V) employing trimethylsilyl iodide generated the pyridone lactone (VI), which was N-alkylated with 3-(tert-butyldimethylsilyl)propargyl bromide (VII), yielding (VIII). Finally, radical annulation of (VIII) with phenyl isonitrile (IX) in the presence hexamethylditin furnished the title pentacyclic compound.
| 【1】 Bom, D.; et al.; Novel A,B,E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities. J Med Chem 1999, 42, 16, 3018. |
| 【2】 Burke, T.G.; Curran, D.P.; Bom, D. (University of Kentucky; University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. WO 0061146 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | ||
| (I) | 35096 | 4-ethyl-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridine | C14H21NO2Si | 详情 | 详情 | |
| (II) | 35097 | [2-methoxy-4-propionyl-6-(trimethylsilyl)-3-pyridinyl]methyl formate | C14H21NO4Si | 详情 | 详情 | |
| (III) | 35098 | tert-butyl 3-[3-[(formyloxy)methyl]-2-methoxy-6-(trimethylsilyl)-4-pyridinyl]-3-hydroxypentanoate | C20H33NO6Si | 详情 | 详情 | |
| (IV) | 35099 | 5-ethyl-5-hydroxy-9-methoxy-7-(trimethylsilyl)-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C15H23NO4Si | 详情 | 详情 | |
| (V) | 35100 | 5-ethyl-5-hydroxy-7-iodo-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H14INO4 | 详情 | 详情 | |
| (VI) | 35101 | 5-ethyl-5-hydroxy-7-iodo-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H12INO4 | 详情 | 详情 | |
| (VII) | 35102 | (3-bromo-1-propynyl)(tert-butyl)dimethylsilane | C9H17BrSi | 详情 | 详情 | |
| (VIII) | 35103 | 8-[3-[tert-butyl(dimethyl)silyl]-2-propynyl]-5-ethyl-5-hydroxy-7-iodo-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C20H28INO4Si | 详情 | 详情 | |
| (IX) | 35104 | Benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)3,5-Dichlorosalicylaldehyde (I) was protected by treatment with methoxyethoxymethyl chloride (II) in the presence of K2CO3 in DMF. The protected aldehyde (III) was then condensed with (S)-phenylglycinol (IV) to give the chiral imine (V). Addition of the Reformatskii reagent (VI) to the imine function gave rise to aminoester (VII) as a single diastereoisomer. Dealkylation of (VII) with lead tetraacetate furnished the chiral primary amine (VIII). Subsequent acidic treatment of (VIII) cleaved the methoxyethoxy protecting group and the tert-butyl ester to afford (IX). Amine (IX) was then coupled with N-Boc-glycine N-hydroxysuccinimidyl ester (X), producing amide (XI). Acid cleavage of the N-Boc group of (XI) then yielded the intermediate (XII).
| 【2】 Ruminski, P.G.; Rogers, T.E. (Pharmacia Corp.); Meta-azacyclic amino benzoic acid cpds. and derivs. thereof being integrin antagonists. EP 1060164; WO 9944994 . |
| 【3】 Gordon, G.B.; Ruminski, P.G.; Nickols, G.A.; Westlin, W.F.; Rogers, T.E.; Cunningham, J. (Pharmacia Corp.); Use of integrin antagonist and a chemotherapeutic agent in the treatment of neoplasia. WO 0051686 . |
| 【1】 Ruminski, P.G.; Clare, M.; Collins, P.W.; Desai, B.N.; Lindmark, R.J.; Rico, J.G.; Rogers, T.E.; Russell, M.A. (Pharmacia Corp.); Meta-guanidine, urea, thiourea or azacyclic amino benzoic acid derivs. as integrin antagonists. EP 0850221; JP 1999510814; US 6013651; WO 9708145 . |
| 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) | 21323 | 3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde | 90-60-8 | C7H4Cl2O2 | 详情 | 详情 |
| (II) | 40670 | 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride | 3970-21-6 | C4H9ClO2 | 详情 | 详情 |
| (III) | 47968 | 3,5-dichloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H12Cl2O4 | 详情 | 详情 | |
| (IV) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (V) | 47969 | (2R)-2-[((E)-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]methylidene)amino]-2-phenyl-1-ethanol | C19H21Cl2NO4 | 详情 | 详情 | |
| (VI) | 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | |
| (VII) | 47970 | tert-butyl (3S)-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]propanoate | C25H33Cl2NO6 | 详情 | 详情 | |
| (VIII) | 47971 | tert-butyl (3S)-3-amino-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]propanoate | C17H25Cl2NO5 | 详情 | 详情 | |
| (IX) | 47972 | ethyl (3S)-3-amino-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C11H13Cl2NO3 | 详情 | 详情 | |
| (X) | 16364 | tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester | 3392-07-2 | C11H16N2O6 | 详情 | 详情 |
| (XI) | 47973 | ethyl (3S)-3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C18H24Cl2N2O6 | 详情 | 详情 | |
| (XII) | 47974 | ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C13H16Cl2N2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The hydroxyl group of 3,5-dichlorosalicylaldehyde (I) is protected as the methoxyethoxymethyl (MEM) ether (II) with MEM chloride in DMF. Condensation of the protected salicylaldehyde (II) with (S)-phenylglycinol (III) yields the chiral aldimine (IV). This is then reacted with the Reformatski reagent (VI), prepared from t-butyl bromoacetate (V), to provide adduct (VII). Oxidative removal of the chiral auxiliary group of (VII) with lead tetraacetate, followed by acidic cleavage of the t-butyl and MEM groups, leads to amino ester (VIII). Coupling of (VIII) with the succinimidyl ester of N-Boc-glycine (IX) furnishes amide (X). The N-Boc protecting group of (X) is then removed under acidic conditions to yield amine (XI) (1).
| 【1】 Miyashiro, J.M.; Gasiecki, A.F.; Khanna, I.K.; Chandrakumar, N.S.; Desai, B.N.; Russell, M.A.; Devadas, B.; Rico, J.G.; Rogers, T.E.; Rao, S.N.; Malecha, J.W.; Ruminski, P.G.; Yu, Y.; Huff, R. (Pfizer Inc.); Heterocyclic glycyl beta-alanine derivs. as vitronectin antagonists. EP 1070060; JP 2002511462; WO 9952896 . |
| 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) | 21323 | 3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde | 90-60-8 | C7H4Cl2O2 | 详情 | 详情 |
| (II) | 47968 | 3,5-dichloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H12Cl2O4 | 详情 | 详情 | |
| (III) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (IV) | 47969 | (2R)-2-[((E)-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]methylidene)amino]-2-phenyl-1-ethanol | C19H21Cl2NO4 | 详情 | 详情 | |
| (V) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | |
| (VII) | 47970 | tert-butyl (3S)-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]propanoate | C25H33Cl2NO6 | 详情 | 详情 | |
| (VIII) | 47972 | ethyl (3S)-3-amino-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C11H13Cl2NO3 | 详情 | 详情 | |
| (IX) | 16364 | tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester | 3392-07-2 | C11H16N2O6 | 详情 | 详情 |
| (X) | 47973 | ethyl (3S)-3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C18H24Cl2N2O6 | 详情 | 详情 | |
| (XI) | 47974 | ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C13H16Cl2N2O4 | 详情 | 详情 |