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【结 构 式】 
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【分子编号】48806 【品名】 【CA登记号】 |
【 分 子 式 】C14H22N2O3 【 分 子 量 】266.34036 【元素组成】C 63.14% H 8.33% N 10.52% O 18.02% |
合成路线1
该中间体在本合成路线中的序号：(XV)The reaction of L-tyrosine (I) with methyl chloroformate (II) by means of NaOH in water gives the carbamate (III), which is methylated at the remaining phenol and carboxylic groups with dimethyl sulfate and K2CO3 in refluxing acetone to yield the 4-O-methyl tyrosine derivative (IV). The hydrolysis of the methyl ester of (IV) with NaOH in dioxane/water, followed by reaction with O-methylhydroxylamine by means of DCC and HOBT, affords the methyl hydroxamate (V). The cyclization of (V) by means of bis(trifluoroacetoxy)iodobenzene in dichloromethane/methanol provides the spirodienone (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the saturated ketone (VII). The protection of the ketonic group of (VII) with ethyleneglycol and PPTS yields the cyclic ketal (VIII), which is reduced with LiAlH4 in THF to afford the methoxyamine (IX). The protection of the N-methylamine of (IX) with benzyl chloroformate and TEA provides the carbamate (X), which is treated with Zn in acetic acid in order to cleave the N-methoxyamine group and yield the spiropyrrolidine (XI). The alkylation of the pyrrolidine NH with benzyl chloroformate (XII) and K2CO3 in warm acetonitrile affords the adduct (XIII), which is treated with H2 over Pd/C in methanol in order to remove the benzyl and benzyloxycarbonyl protecting groups, providing the amino acid (XIV). The cyclization of (XIV) by means of DPPA and NaHCO3 in DMF/dichloromethane gives the tetracyclic compound (XV), which is condensed with 4-(prenyloxy)benzaldehyde (XVI) by means of LDA in THF yielding the aldol condensation product (XVII).
| 【1】 Basak, A.; Wardrop, D.J.; N-methoxy-N-acylnitrenium ions: Application to the formal synthesis of (-)-TAN1251A. Org Lett 2001, 3, 7, 1053. |
| 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) | 48794 | (S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine | 60-18-4 | C9H11NO3 | 详情 | 详情 |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 48795 | (2S)-3-(4-hydroxyphenyl)-2-[(methoxycarbonyl)amino]propionic acid | C11H13NO5 | 详情 | 详情 | |
| (IV) | 48796 | methyl (2S)-2-[(methoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C13H17NO5 | 详情 | 详情 | |
| (V) | 48797 | methyl (1S)-2-(methoxyamino)-1-(4-methoxybenzyl)-2-oxoethylcarbamate | C13H18N2O5 | 详情 | 详情 | |
| (VI) | 48798 | methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]deca-6,9-dien-3-ylcarbamate | C12H14N2O5 | 详情 | 详情 | |
| (VII) | 48799 | methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]dec-3-ylcarbamate | C12H18N2O5 | 详情 | 详情 | |
| (VIII) | 48800 | methyl (11S)-9-methoxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-ylcarbamate | C14H22N2O6 | 详情 | 详情 | |
| (IX) | 48801 | (11S)-9-methoxy-N-methyl-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecan-11-amine; N-[(11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl]-N-methylamine | C13H24N2O3 | 详情 | 详情 | |
| (X) | 48802 | benzyl (11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate | C21H30N2O5 | 详情 | 详情 | |
| (XI) | 48803 | benzyl (11S)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate | C20H28N2O4 | 详情 | 详情 | |
| (XII) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XIII) | 48804 | benzyl 2-[(11S)-11-[[(benzyloxy)carbonyl](methyl)amino]-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetate | C29H36N2O6 | 详情 | 详情 | |
| (XIV) | 48805 | 2-[(11S)-11-(methylamino)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetic acid | C14H24N2O4 | 详情 | 详情 | |
| (XV) | 48806 | C14H22N2O3 | 详情 | 详情 | ||
| (XVI) | 19019 | 4-[(3-methyl-2-butenyl)oxy]benzaldehyde | C12H14O2 | 详情 | 详情 | |
| (XVII) | 19020 | (1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C26H36N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The reaction of L-tyrosine methyl ester (I) with ethyl chloroformate and K2CO3 in water gives the carbamate (II), which is protected with Bn-Br and K2CO3 in DMF, yielding the benzyl ether (III). The reduction of (III) by means of LiAlH4 in refluxing THF affords the chiral 2-methylaminopropanol (IV), which is protected as its Boc derivative (V) by means of Boc2O. The oxidation of (V) by means of DMP provides the carbaldehyde (VI), which is reductocondensed with glycine methyl ester (VII) by means of NaBH3CN in methanol to give the adduct (VIII). Elimination of the Boc protecting group of (VIII) by means of TFA yields the diamine (IX), which is cyclized by means of NH4OH in ethanol to afford the piperazinone (X). Elimination of the benzyl protecting group of (X) by hydrogenation with H2 over Pd/C provides the phenol (XIa)-(XIb), which is cyclized by means of bis(acetoxy)iodobenzene in hexafluoroisopropanol to give the spiranic cyclohexadienone (XII). The hydrogenation of (XII) by means of Tes-H and CuI in dichloromethane yields the spiranic cyclohexanone (XIII), which is finally ketalized by means of ethyleneglycol (XIV) and PPTS in refluxing benzene to provide the target ethyleneketal intermediate (XV) (See scheme no. 18599903a, intermediate (XV)).
| 【1】 Mizutani, H.; et al.; Facile synthesis of enantiopure (-)-TAN1251A. Tetrahedron Lett 2002, 43, 13, 2411. |
| 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) | 21431 | methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 1080-06-4 | C10H13NO3 | 详情 | 详情 |
| (II) | 57099 | methyl (2S)-2-[(ethoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | C13H17NO5 | 详情 | 详情 | |
| (III) | 57100 | methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[(ethoxycarbonyl)amino]propanoate | C20H23NO5 | 详情 | 详情 | |
| (IV) | 57101 | (2S)-3-[4-(benzyloxy)phenyl]-2-(methylamino)-1-propanol | C17H21NO2 | 详情 | 详情 | |
| (V) | 57102 | tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-hydroxyethyl(methyl)carbamate | C22H29NO4 | 详情 | 详情 | |
| (VI) | 57103 | tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-oxoethyl(methyl)carbamate | C22H27NO4 | 详情 | 详情 | |
| (VII) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (VIII) | 57104 | methyl 2-({(2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)(methyl)amino]propyl}amino)acetate | C25H34N2O5 | 详情 | 详情 | |
| (IX) | 57105 | methyl 2-{[(2S)-3-[4-(benzyloxy)phenyl]-2-(methylamino)propyl]amino}acetate | C20H26N2O3 | 详情 | 详情 | |
| (X) | 57106 | (6S)-6-[4-(benzyloxy)benzyl]-1-methyl-2-piperazinone | C19H22N2O2 | 详情 | 详情 | |
| (XI) | 57107 | (6S)-6-(4-hydroxybenzyl)-1-methyl-2-piperazinone | C12H16N2O2 | 详情 | 详情 | |
| (XII) | 57108 | C12H14N2O2 | 详情 | 详情 | ||
| (XIII) | 57109 | C12H18N2O2 | 详情 | 详情 | ||
| (XIV) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XV) | 48806 | C14H22N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XX)The alkylation of the protected hydroxyproline (I) with 4-iodo-1-butene (II) by means of LDA in THF gives the 2-alkylproline (III), which is reduced with DIBAL in toluene to yield the carbinol (IV). The oxidation of (IV) by means of TPAP and NMO in dichloromethane affords the carbaldehyde (V), which is oxidated at its terminal vinyl group by means of PdCl2, CuCl2 and O2 in aqueous DMF to provide the methyl ketone (VI). The cyclization of (VI) by means of KOH in ethanol furnishes the cyclic aldol (VII), which is treated with Ms-Cl and TEA to give the mesylate (VIII). The elimination reaction of (VIII) over chromatographic silicagel yields enone (IX), which is hydrogenated with H2 over Pd/C in benzene to afford the spiranic ketone (X). The reaction of (X) with ethyleneglycol and Ts-OH in refluxing benzene provides the ethylene ketal (XI), which is desilylated by means of TBAF in THF to gives the alcohol (XII). The reaction of (XII) with DPPA, DEAD and PPh3 in THF yields the azide (XIII), which is subjected to removal of the Boc protecting group by means of TFA affording unprotected spiro pyrrolidine derivative (XIV). Alkylation of (XIV) with ethyl bromoacetate (XV) by means of K2CO3 in acetonitrile provides the ester (XVI), which is reduced at the azido group by means of H2 over Pd/C in methanol to give the aminoester (XVII). The hydrolysis of the ester group of (XVII) with LiOH in water yields the spiranic aminoacid (XVIII), which is cyclized by means of DPPA and TEA in DMF to afford the tetracyclic amide (XIX). Finally this compound is methylated by means of methyl iodide and NaH in THF to provide the target tetracyclic intermediate (XX) (see scheme no.18599903a, intermediate (XV)).
| 【1】 Nagumo, S.; et al.; Synthesis of (-)-TAN1251A using 4-hydroxy-L-proline as a chiral source. Tetrahedron 2002, 58, 49, 9871. |
| 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) | 60484 | 1-(tert-butyl) 2-methyl (2S,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-1,2-pyrrolidinedicarboxylate | C27H37NO5Si | 详情 | 详情 | |
| (II) | 60485 | 4-iodo-1-butene | C4H7I | 详情 | 详情 | |
| (III) | 60486 | 1-(tert-butyl) 2-methyl (4R)-2-(3-butenyl)-4-{[tert-butyl(diphenyl)silyl]oxy}-1,2-pyrrolidinedicarboxylate | C31H43NO5Si | 详情 | 详情 | |
| (IV) | 60487 | tert-butyl (4R)-2-(3-butenyl)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C30H43NO4Si | 详情 | 详情 | |
| (V) | 60488 | tert-butyl (4R)-2-(3-butenyl)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-formyl-1-pyrrolidinecarboxylate | C30H41NO4Si | 详情 | 详情 | |
| (VI) | 60489 | tert-butyl (4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-formyl-2-(3-oxobutyl)-1-pyrrolidinecarboxylate | C30H41NO5Si | 详情 | 详情 | |
| (VII) | 60490 | tert-butyl (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-6-hydroxy-8-oxo-1-azaspiro[4.5]decane-1-carboxylate | C30H41NO5Si | 详情 | 详情 | |
| (VIII) | 60491 | tert-butyl (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-6-[(methylsulfonyl)oxy]-8-oxo-1-azaspiro[4.5]decane-1-carboxylate | C31H43NO7SSi | 详情 | 详情 | |
| (IX) | 60492 | tert-butyl (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-8-oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylate | C30H39NO4Si | 详情 | 详情 | |
| (X) | 60493 | tert-butyl (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-8-oxo-1-azaspiro[4.5]decane-1-carboxylate | C30H41NO4Si | 详情 | 详情 | |
| (XI) | 60494 | tert-butyl (11R)-11-{[tert-butyl(diphenyl)silyl]oxy}-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane-9-carboxylate | C32H45NO5Si | 详情 | 详情 | |
| (XII) | 60495 | tert-butyl (11R)-11-hydroxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane-9-carboxylate | C16H27NO5 | 详情 | 详情 | |
| (XIII) | 60496 | tert-butyl (11S)-11-azido-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane-9-carboxylate | C16H26N4O4 | 详情 | 详情 | |
| (XIV) | 60497 | (11S)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl azide; (11S)-11-azido-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane | C11H18N4O2 | 详情 | 详情 | |
| (XV) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (XVI) | 60498 | C14H22N4O4 | 详情 | 详情 | ||
| (XVII) | 60499 | C14H24N2O4 | 详情 | 详情 | ||
| (XVIII) | 60648 | 2-[(11S)-11-amino-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetic acid | C13H22N2O4 | 详情 | 详情 | |
| (XIX) | 60649 | C13H20N2O3 | 详情 | 详情 | ||
| (XX) | 48806 | C14H22N2O3 | 详情 | 详情 |