KF-20444, -Drug Synthesis Database

【结构式】

【药物名称】KF-20444

【化学名称】10-Fluoro-3-(2-fluorophenyl)-6,7-dihydro-5H-benz[6,7]cyclohepta[1,2-b]quinoline-8-carboxylic acid

【CA登记号】154015-73-3

【分子式】C₂₅H₁₇F₂NO₂

【分子量】401.41654

【开发单位】Kyowa Hakko (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants, Dihydroorotate Dehydrogenase Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

Friedel-Crafts condensation of 2-fluorobiphenyl (I) with glutaric anhydride (II) in the presence of AlCl3 gave ketoacid (III). Reduction of the ketonic group of (III) with triethylsilane in trifluoroacetic acid afforded biphenylpentanoic acid (IV), which was cyclized to the benzosuberone derivative (V) using polyphosphoric acid. Ketone reduction of (IV) by means of triethylsilane and trifluoroacetic acid provided the benzocycloheptene (VI), which was further oxidized to the isomeric ketone (VII) with chromic acid. Finally, condensation of (VII) with 5-fluoroisatin (VIII) in the presence of KOH yielded the target tetracyclic system.

参考文献中间体

【1】 Suzuki, F.; Nakasato, Y.; Tsumuki, H.; Ohmori, K.; Nakajima, H.; Tamura, T.; Sato, S. (Kyowa Hakko Kogyo Co., Ltd.); Tetracyclic cpds.. US 5371225; WO 9322286 .

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)	31388	2-fluoro-1,1'-biphenyl	321-60-8	C₁₂H₉F	详情	详情
(II)	15512	Glutaric Anhydride; dihydro-2H-pyran-2,6(3H)-dione	108-55-4	C₅H₆O₃	详情	详情
(III)	31389	5-(2'-fluoro[1,1'-biphenyl]-4-yl)-5-oxopentanoic acid		C₁₇H₁₅FO₃	详情	详情
(IV)	31390	5-(2'-fluoro[1,1'-biphenyl]-4-yl)pentanoic acid		C₁₇H₁₇FO₂	详情	详情
(V)	31391	3-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one		C₁₇H₁₅FO	详情	详情
(VI)	31392	2-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene		C₁₇H₁₇F	详情	详情
(VII)	31393	2-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one		C₁₇H₁₅FO	详情	详情
(VIII)	21552	5-fluoro-1H-indole-2,3-dione	443-69-6	C₈H₄FNO₂	详情	详情

合成路线2

Keto ester (III) was prepared by Friedel-Crafts acylation of 2-fluorobiphenyl (I) with methyl glutaryl chloride (II). Subsequent Pfitzinger condensation of (III) with 5-fluoroisatin (IV) furnished the quinoline derivative (V). Chlorination of diacid (V) with SOCl2, followed by treatment with methanol produced selectively the mono-ester (VI). The remaining carboxyl group of (VI) was activated with SOCl2 in the presence of DMF, and subsequently coupled with n-octyl amine to generate amide (VII). The methyl ester group of (VII) was then hydrolyzed to acid (VIII), which was further subjected to intramolecular ring closure upon heating with triflic acid to afford the tetracyclic system (IX). Keto group reduction in (IX) to give (X) was accomplished by a two-step procedure with NaBH4 and then with HI and Ac2O.

参考文献中间体

【1】 Chujo, I.; et al.; Synthetic study on novel immunosuppressant KF20444. Bioorg Med Chem 2001, 9, 12, 3273.

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)	31388	2-fluoro-1,1'-biphenyl	321-60-8	C₁₂H₉F	详情	详情
(II)	20650	methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate	1501-26-4	C₆H₉ClO₃	详情	详情
(III)	56572	methyl 5-(2'-fluoro[1,1'-biphenyl]-4-yl)-5-oxopentanoate		C₁₈H₁₇FO₃	详情	详情
(IV)	21552	5-fluoro-1H-indole-2,3-dione	443-69-6	C₈H₄FNO₂	详情	详情
(V)	56573	3-(2-carboxyethyl)-6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-quinolinecarboxylic acid		C₂₅H₁₇F₂NO₄	详情	详情
(VI)	56574	6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-(3-methoxy-3-oxopropyl)-4-quinolinecarboxylic acid		C₂₆H₁₉F₂NO₄	详情	详情
(VII)	56575	methyl 3-{6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-[(octylamino)carbonyl]-3-quinolinyl}propanoate		C₃₄H₃₆F₂N₂O₃	详情	详情
(VIII)	56576	3-{6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-[(octylamino)carbonyl]-3-quinolinyl}propanoic acid		C₃₃H₃₄F₂N₂O₃	详情	详情
(IX)	56577	10-fluoro-3-(2-fluorophenyl)-N-octyl-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide		C₃₃H₃₂F₂N₂O₂	详情	详情
(X)	56578	10-fluoro-3-(2-fluorophenyl)-N-octyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide		C₃₃H₃₄F₂N₂O	详情	详情

合成路线3

The title carboxylic acid was obtained by nitrosation of amide (X) with sodium nitrite and Ac2O, followed by treatment with KOH.

参考文献中间体

【1】 Chujo, I.; et al.; Synthetic study on novel immunosuppressant KF20444. Bioorg Med Chem 2001, 9, 12, 3273.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	56578	10-fluoro-3-(2-fluorophenyl)-N-octyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide		C₃₃H₃₄F₂N₂O	详情	详情

合成路线4

In a different strategy for protecting the quinoline carboxyl group, acid (VI) was reduced to alcohol (XI) via chlorination with SOCl2, followed by treatment with NaBH4. Alcohol (XI) was then converted to the alkyl chloride (XII) with SOCl2 in dichloroethane. Subsequent ester group hydrolysis in (XII) under acidic conditions furnished the carboxylic acid (XIII). The tetracyclic compound (XIV) was obtained by cyclization of acid (XIII) in hot triflic acid. Displacement of the chloride group of (XIV) with sodium acetate in HOAc yielded acetate ester (XV), which was subsequently hydrolyzed to alcohol (XVI). Oxidation of (XVI) with DMSO and Ac2O provided aldehyde (XVII).

参考文献中间体

【1】 Chujo, I.; et al.; Synthetic study on novel immunosuppressant KF20444. Bioorg Med Chem 2001, 9, 12, 3273.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	56574	6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-(3-methoxy-3-oxopropyl)-4-quinolinecarboxylic acid	C₂₆H₁₉F₂NO₄	详情	详情
(XI)	56579	methyl 3-[6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-(hydroxymethyl)-3-quinolinyl]propanoate	C₂₆H₂₁F₂NO₃	详情	详情
(XII)	56580	methyl 3-[4-(chloromethyl)-6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-quinolinyl]propanoate	C₂₆H₂₀ClF₂NO₂	详情	详情
(XIII)	56581	3-[4-(chloromethyl)-6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-quinolinyl]propanoic acid	C₂₅H₁₈ClF₂NO₂	详情	详情
(XIV)	56582	8-(chloromethyl)-10-fluoro-3-(2-fluorophenyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinolin-5-one	C₂₅H₁₆ClF₂NO	详情	详情
(XV)	56583	[10-fluoro-3-(2-fluorophenyl)-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinolin-8-yl]methyl acetate	C₂₇H₁₉F₂NO₃	详情	详情
(XVI)	56584	10-fluoro-3-(2-fluorophenyl)-8-(hydroxymethyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinolin-5-one	C₂₅H₁₇F₂NO₂	详情	详情
(XVII)	56585	10-fluoro-3-(2-fluorophenyl)-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carbaldehyde	C₂₅H₁₅F₂NO₂	详情	详情

合成路线5

Aldehyde (XVII) was further oxidized to carboxylic acid (XVIII) using sodium chlorite. Conversion of acid (XVIII) into the methyl ester (XIX) was effected by treatment with iodomethane and K2CO3. Finally, the two-step reduction of the carbonyl group of (XIX) with NaBH4 followed by HI/Ac2O, proceeded with concomitant ester hydrolysis, yielding the title compound.

参考文献中间体

【1】 Chujo, I.; et al.; Synthetic study on novel immunosuppressant KF20444. Bioorg Med Chem 2001, 9, 12, 3273.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVII)	56585	10-fluoro-3-(2-fluorophenyl)-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carbaldehyde	C₂₅H₁₅F₂NO₂	详情	详情
(XVIII)	56586	10-fluoro-3-(2-fluorophenyl)-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxylic acid	C₂₅H₁₅F₂NO₃	详情	详情
(XIX)	56587	methyl 10-fluoro-3-(2-fluorophenyl)-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxylate	C₂₆H₁₇F₂NO₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)