(5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione -Drug Synthesis Database

【结构式】

【分子编号】33100

【品名】(5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione

【CA登记号】

【分子式】C₁₁H₁₃NO₄

【分子量】223.22856

【元素组成】C 59.19% H 5.87% N 6.27% O 28.67%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(VI)

The synthesis of the intermediate oxepinopyridinone (VI) is detailed in Scheme 27517601a: The racemic acid (II), obtained by cleavage of tert-butyl ester (I) with trifluoroacetic acid, was resolved with quinidine to furnish the required (+)-(R)-enantiomer (III). Subsequent debenzylation of (III) by transfer hydrogenation with ammonium formate and Pd/C gave alcohol (IV), which was cyclized to the corresponding lactone (V) employing DCC in hot THF. Dealkylation of the methyl ether group by means of iodotrimethylsilane, generated from Me3SiCl and NaI, produced the intermediate pyridinone (VI).

参考文献中间体

合成目标

【1】 Coulomb, H.; Huchet, M.; Harnett, J.; Rolland, A.; Lanco, C.; Lavergne, O.; Demarquay, D.; Lesueur-Ginot, L.; Bigg, D.C.H.; BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 1999, 9, 17, 2599.
【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	25468	tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate	C₂₃H₃₁NO₅	详情	详情
(II)	33096	3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoic acid	C₁₉H₂₃NO₅	详情	详情
(III)	33097	(3R)-3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoic acid	C₁₉H₂₃NO₅	详情	详情
(IV)	33098	(3R)-3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoic acid	C₁₂H₁₇NO₅	详情	详情
(V)	33099	(5R)-5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one	C₁₂H₁₅NO₄	详情	详情
(VI)	33100	(5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione	C₁₁H₁₃NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Acylation of 3,4-difluoroaniline (VII) with Ac2O and Et3N afforded acetanilide (VIII). Subsequent condensation of (VIII) with the Vilsmeier reagent produced the quinolinecarbaldehyde (IX), which was reduced to alcohol (X) using NaBH4. Coupling of (X) with pyridinone (VI) under Mitsunobu conditions yielded adduct (XI). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound.

参考文献中间体

合成目标

【1】 Demarquay, D.; Lavergne, O.; Bailly, C.; et al.; Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins. J Med Chem 2000, 43, 11, 2285.
【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	33100	(5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione		C₁₁H₁₃NO₄	详情	详情
(VII)	13451	3,4-Difluoroaniline; 3,4-Difluorophenylamine	3863-11-4	C₆H₅F₂N	详情	详情
(VIII)	25472	N-(3,4-difluorophenyl)acetamide	458-11-7	C₈H₇F₂NO	详情	详情
(IX)	25473	2-chloro-6,7-difluoro-3-quinolinecarbaldehyde		C₁₀H₄ClF₂NO	详情	详情
(X)	25474	(2-chloro-6,7-difluoro-3-quinolinyl)methanol		C₁₀H₆ClF₂NO	详情	详情
(XI)	33101	(5R)-8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione		C₂₁H₁₇ClF₂N₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The synthesis of the intermediate oxepinopyridinone (VI) is detailed in Scheme 27517701a: The racemic acid (II), obtained by cleavage of tert-butyl ester (I) with trifluoroacetic acid, was resolved with quinidine to furnish the required (+)-(R)-enantiomer (III). Subsequent debenzylation of (III) by transfer hydrogenation with ammonium formate and Pd/C gave alcohol (IV), which was cyclized to the corresponding lactone (V) employing DCC in hot THF. Dealkylation of the methyl ether group by means of iodotrimethylsilane, generated from Me3SiCl and NaI, produced the intermediate pyridinone (VI).

参考文献中间体

合成目标

【1】 Coulomb, H.; Huchet, M.; Harnett, J.; Rolland, A.; Lanco, C.; Lavergne, O.; Demarquay, D.; Lesueur-Ginot, L.; Bigg, D.C.H.; BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 1999, 9, 17, 2599.
【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	25468	tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate	C₂₃H₃₁NO₅	详情	详情
(II)	33096	3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoic acid	C₁₉H₂₃NO₅	详情	详情
(III)	33097	(3R)-3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoic acid	C₁₉H₂₃NO₅	详情	详情
(IV)	33098	(3R)-3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoic acid	C₁₂H₁₇NO₅	详情	详情
(V)	33099	(5R)-5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one	C₁₂H₁₅NO₄	详情	详情
(VI)	33100	(5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione	C₁₁H₁₃NO₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

Acylation of 3-chloro-4-methylaniline (VII) with chloroacetonitrile in the presence of BCl3 and Et2AlCl produced the chloroacetophenone (VIII). Subsequent condensation of (VIII) with ethylmalonyl chloride gave amide (IX), which was cyclized to the quinolinone (X) upon treatment with ethanolic NaOEt. Reaction of the quinolinone (X) with POCl3 afforded chloroquinoline (XI). The ester group of (XI) was then reduced to alcohol (XII) by means of diisobutylaluminum hydride. Condensation of (XII) with 4-methylpiperidine (XIII) gave adduct (IV), which was further coupled with pyridinone (VI) under Mitsunobu conditions to yield (Xv). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound, which was isolated as the hydrochloride salt.

参考文献中间体

合成目标

【1】 Coulomb, H.; Huchet, M.; Harnett, J.; Rolland, A.; Lanco, C.; Lavergne, O.; Demarquay, D.; Lesueur-Ginot, L.; Bigg, D.C.H.; BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 1999, 9, 17, 2599.
【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	33100	(5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione		C₁₁H₁₃NO₄	详情	详情
(VII)	26794	3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene	95-74-9	C₇H₈ClN	详情	详情
(VIII)	33102	1-(2-amino-4-chloro-5-methylphenyl)-2-chloro-1-ethanone		C₉H₉Cl₂NO	详情	详情
(IX)	33013	O-[tert-butyl(diphenyl)silyl]hydroxylamine; (aminooxy)(tert-butyl)diphenylsilane		C₁₆H₂₁NOSi	详情	详情
(X)	33104	ethyl 7-chloro-4-(chloromethyl)-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate		C₁₄H₁₃Cl₂NO₃	详情	详情
(XI)	33105	ethyl 2,7-dichloro-4-(chloromethyl)-6-methyl-3-quinolinecarboxylate		C₁₄H₁₂Cl₃NO₂	详情	详情
(XII)	33106	[2,7-dichloro-4-(chloromethyl)-6-methyl-3-quinolinyl]methanol		C₁₂H₁₀Cl₃NO	详情	详情
(XIII)	10192	4-Methylpiperidine; gamma-Pipecoline	626-58-4	C₆H₁₃N	详情	详情
(XIV)	33107	[2,7-dichloro-6-methyl-4-[(4-methyl-1-piperidinyl)methyl]-3-quinolinyl]methanol		C₁₈H₂₂Cl₂N₂O	详情	详情
(XV)	33101	(5R)-8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione		C₂₁H₁₇ClF₂N₂O₄	详情	详情

Extended Information