N-(3,4-difluorophenyl)acetamide -Drug Synthesis Database

【结构式】

【分子编号】25472

【品名】N-(3,4-difluorophenyl)acetamide

【CA登记号】458-11-7

【分子式】C₈H₇F₂NO

【分子量】171.1465264

【元素组成】C 56.14% H 4.12% F 22.2% N 8.18% O 9.35%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XII)

2-Chloro-4-propionylpyridine (I) was protected as the cyclic ketal (II) with 1,3-propanediol and p-toluenesulfonic acid in refluxing toluene with azeotropical removal of water. Subsequent halogen displacement in (II) with sodium methoxide in boiling acetonitrile gave methoxypyridine (III). Lithiation of (III) with mesityllithium, followed by condensation with dimethylformamide provided formylpyridine (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. The hydroxyl group of (V) was protected as the benzyl ether (VI), and the ketal group was then hydrolyzed to ketone (VII) with aqueous trifluoroacetic acid. Reformatskii reaction of (VII) with tert-butyl bromoacetate and zinc afforded the beta-hydroxyester (VIII). Further hydrogenolysis of benzyl ether of (VIII) over Pd/C gave alcohol (IX). Then, treatment of (IX) with trifluoroacetic acid produced lactone (X), and hydrolysis of the methoxy group of (X) with aqueous HCl furnished pyridone (XI). Condensation of 3,4-difluoroacetanilide (XII) with Vilsmeier reagent yielded quinolinecarboxaldehyde (XIII), which was reduced to alcohol (XIV) with NaBH4. This was then coupled with pyridone (XI) under Mitsunobu conditions to give (XV). Finally, Heck reaction of (XV) with palladium acetate and triphenyl phosphine generated the target pentacyclic compound.

参考文献中间体

合成目标

【1】 Lavergne, O.; Lesuer-Ginot, L.; Pla Rodas, F.; Kasprzyk, P.G.; Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D.C.; Homocamptothecins: Synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem 1998, 41, 27, 5410.
【2】 Bigg, D.; Lavergne, O.; Pla Rodas, F.; Pommier, J.; Ulibarri, G. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Novel camptothecin analogues, preparation methods therefor, use thereof as drugs, and pharmaceutical compsns. containing said analogues. EP 0835258; JP 1999508249; US 5981542; WO 9700876 .
【3】 Lanco, C.; Rolland, A.; Bigg, D.; Lavergne, O.; Harnett, J.; Liberatore, A.-M. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Pro-drugs and counterparts of camptothecin, their application as medicines . EP 0946566; WO 9828304 .

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
	14685	1,3-propanediol; Trimethylene Glycol	504-63-2	C₃H₈O₂	详情	详情
	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(I)	25461	1-(2-chloro-4-pyridinyl)-1-propanone		C₈H₈ClNO	详情	详情
(II)	25462	2-chloro-4-(2-ethyl-1,3-dioxan-2-yl)pyridine		C₁₁H₁₄ClNO₂	详情	详情
(III)	25463	4-(2-ethyl-1,3-dioxan-2-yl)-2-pyridinyl methyl ether; 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine		C₁₂H₁₇NO₃	详情	详情
(IV)	25464	4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxynicotinaldehyde		C₁₃H₁₇NO₄	详情	详情
(V)	25465	[4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methanol		C₁₃H₁₉NO₄	详情	详情
(VI)	25466	3-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine; benzyl [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methyl ether		C₂₀H₂₅NO₄	详情	详情
(VII)	25467	1-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-1-propanone		C₁₇H₁₉NO₃	详情	详情
(VIII)	25468	tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate		C₂₃H₃₁NO₅	详情	详情
(IX)	25469	tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate		C₁₆H₂₅NO₅	详情	详情
(X)	25470	5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one		C₁₂H₁₅NO₄	详情	详情
(XI)	25471	5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione		C₁₁H₁₃NO₄	详情	详情
(XII)	25472	N-(3,4-difluorophenyl)acetamide	458-11-7	C₈H₇F₂NO	详情	详情
(XIII)	25473	2-chloro-6,7-difluoro-3-quinolinecarbaldehyde		C₁₀H₄ClF₂NO	详情	详情
(XIV)	25474	(2-chloro-6,7-difluoro-3-quinolinyl)methanol		C₁₀H₆ClF₂NO	详情	详情
(XV)	25475	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2

该中间体在本合成路线中的序号：(VIII)

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

Extended Information