(1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one -Drug Synthesis Database

【结构式】

【分子编号】36455

【品名】(1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one

【CA登记号】

【分子式】C₁₃H₁₃NO₅

【分子量】263.24996

【元素组成】C 59.31% H 4.98% N 5.32% O 30.39%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VII)

The condensation of benzaldehyde (I) with malonic ester (II) by means of piperidine and acetic acid in benzene gives the unsaturated malonate (III), which by a selective ester cleavage and a Curtius rearrangement by means of N3-PO(OPh)2 and Et3N in toluene yields the unsaturated aminoester (IV). The reduction of (IV) with a chiral rhodium catalyst affords the chiral protected aminoester (V), which is cyclized to the bridged lactone (VI) by means of BF3 ethearate in dichloromethane. Reductive cleavage of the benzyloxycarbonyl benzyl ether groups of (VI) with H2 over Pd/C affords the free aminophenol (VII). The condensation of (VII) with aldehyde (VIII) (obtained by reduction of ester (IX) with DIBAL in dichloromethane) by means of KCN and AcOH, and after allylation of the aromatic OH group with allyl bromide, the intermediate (X) is obtained. The reduction of the lactone group of (X) with DIBAL, followed by desilylation with KF and cyclization with CH3SO3H affords the polycyclic compound (XI).

参考文献中间体

合成目标

【1】 Gin, D.Y.; Corey, E.J.; Kania, R.S.; Enantioselective total synthesis of Ecteinascidin 743. J Am Chem Soc 1996, 118, 38, 9202-03.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(I)	36449	6-(benzyloxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde		C₁₆H₁₄O₄	详情	详情
(II)	36450	1-(2,2-dimethoxyethyl) 3-isobutyl malonate		C₁₀H₁₆O₆	详情	详情
(III)	36451	1-(2,2-dimethoxyethyl) 3-isobutyl 2-[(E)-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]methylidene]malonate		C₂₆H₂₈O₉	详情	详情
(IV)	36452	2,2-dimethoxyethyl (Z)-2-[[(benzyloxy)carbonyl]amino]-3-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]-2-propenoate		C₃₀H₃₁NO₉	详情	详情
(V)	36453	2,2-dimethoxyethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]propanoate		C₃₀H₃₃NO₉	详情	详情
(VI)	35454	2-phenyl-1H-imidazole-4-carbaldehyde		C₁₀H₈N₂O	详情	详情
(VII)	36455	(1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one		C₁₃H₁₃NO₅	详情	详情
(VIII)	36456	allyl (1S)-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate		C₂₆H₄₅NO₆Si₂	详情	详情
(IX)	36457	methyl (2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate		C₂₇H₄₇NO₇Si₂	详情	详情
(X)	36458	allyl (1S,2R)-2-[(1R,12S)-9-(allyloxy)-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-cyanoethylcarbamate		C₄₃H₆₁N₃O₁₀Si₂	详情	详情
(XI)	36459	allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate		C₃₁H₃₃N₃O₉	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The previously reported synthesis of 139221 (scheme 13922101a) has been investigated in order to find a more efficient, reproducible and economical route to work in the mutikilogram scale. Herein it is reported a new process which is simpler and proceeds with an overall yield of 54% (the original process, 35%). The condensation of intermediate aminolactone (I) (scheme 13922101a, intermediate (VII)) with acid (XLII) (the acid derived from scheme 13922101a, intermediate ester (IX)) by means of 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), and 1-hydroxy-7-azabenzotriazole (HOAt) in THF/dichloromethane gives the coupling product (XLIII), which is allylated with allyl bromide (XLIV) and Cs2CO3 in DMF yielding the allyl ether (XLV). The reduction of the lactone group of (XLV) with LiAlH2(OEt)2 in ethyl ether affords the lactol (XLVI), which is desilylated with KF in methanol to provide the phenolic compound (XLVII). The opening of the lactol ring of (XLVII) with simultaneous cyclization by means of Tf-OH in water/trifluoroethanol gives the hexacyclic intermediate (XLVIII), which is finally reductocondensed with KCN by means of LiAlH2(OEt)2 in THF to furnish the previously reported pentacyclic intermediate (XI) (scheme 13922101a, intermediate (XI)).

参考文献中间体

合成目标

【1】 Martinez, E.J.; Corey, E.J.; A new, more efficient, and effective process for the synthesis of a key pentacyclic intermediate for production of ecteinascidin and phthalascidin antitumor agents. Org Lett 2000, 2, 7, 993.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	36455	(1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one		C₁₃H₁₃NO₅	详情	详情
(XI)	36459	allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate		C₃₁H₃₃N₃O₉	详情	详情
(XLII)	38116	(2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propionic acid		C₂₆H₄₅NO₇Si₂	详情	详情
(XLIII)	38117	allyl (1S)-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-[(1R,12S)-9-hydroxy-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-2-oxoethylcarbamate		C₃₉H₅₆N₂O₁₁Si₂	详情	详情
(XLIV)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XLV)	38118	allyl (1S)-2-[(1R,12S)-9-(allyloxy)-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate		C₄₂H₆₀N₂O₁₁Si₂	详情	详情
(XLVI)	38119	allyl (1S)-2-[(1R,12S,13S)-9-(allyloxy)-13-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate		C₄₂H₆₂N₂O₁₁Si₂	详情	详情
(XLVII)	38120	allyl (1S)-2-[(1R,12S,13S)-9-(allyloxy)-13-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-dihydroxy-4-methoxybenzyl)-2-oxoethylcarbamate		C₃₀H₃₄N₂O₁₁	详情	详情
(XLVIII)	38121	allyl (1R,2S,13R,16S)-5-(allyloxy)-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-15-oxo-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate		C₃₀H₃₂N₂O₁₀	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 reaction of 2,4-dichlorophenyl bromide (I) with 14CO2 (II) by means of BuLi in ethyl ether gives the labeled 2,4-dichlorobenzoic acid (III), which is reduced with LiAlH4 in the same solvent to yield 2,4-dichlorobenzyl alcohol (IV). The oxidation of (IV) with lead tetraacetate affords 2,4-dichlorobenzaldehyde (V), which is condensed with sodium sulfite in water at 160 C in a pressure vessel to provide the disulfonate (VI). Finally, the aldehyde group of (VI) is condensed with N-tert-butylhydroxylamine (VII) in hot acetic acid to give rise to the target imine oxide.

参考文献中间体

合成目标

【1】 Johansson, R.; Werner, R.; Syntheses of two [14C]-labeled disodium 4-[(N-tert-butylimino)methyl]benzene-1,3-disulfonate N-oxides. J Label Compd Radiopharm 2000, 43, 13, 1265.

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)	53307	1-Bromo-2,4-dichlorobenzene	1193-72-2	C₆H₃BrCl₂	详情	详情
(III)	33443	2,4-dichlorobenzoic carboxylic acid; 2,4-dichlorobenzoic acid	50-84-0	C₇H₄Cl₂O₂	详情	详情
(III)	53308	2,4-dichlorobenzoic acid	50-84-0	C₇H₄Cl₂O₂	详情	详情
(IV)	53309	(2,4-dichlorophenyl)methanol	1777-82-8	C₇H₆Cl₂O	详情	详情
(IV)	53310	2,4-Dichlorobenzyl alcohol	1777-82-8	C₇H₆Cl₂O	详情	详情
(V)	22196	2,4-dichlorobenzaldehyde	874-42-0	C₇H₄Cl₂O	详情	详情
(V)	53311	2,4-dichlorobenzaldehyde	874-42-0	C₇H₄Cl₂O	详情	详情
(VI)	37311	Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate	33513-44-9	C₇H₄Na₂O₇S₂	详情	详情
(VI)	53312	disodium 4-formyl-1,3-benzenedisulfonate	119557-95-8	C₇H₄Na₂O₇S₂	详情	详情
(VII)	36455	(1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one		C₁₃H₁₃NO₅	详情	详情

Extended Information