(2-aminophenyl)(4-fluorophenyl)methanone -Drug Synthesis Database

【结构式】

【分子编号】17467

【品名】(2-aminophenyl)(4-fluorophenyl)methanone

【CA登记号】

【分子式】C₁₃H₁₀FNO

【分子量】215.2269432

【元素组成】C 72.55% H 4.68% F 8.83% N 6.51% O 7.43%

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：(LIV)

6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII), which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV). The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII), which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI). 7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX), which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).

参考文献中间体

合成目标

【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859.
【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4.
【3】 Iwasaki, H.; Miyachi, N.; Yanagawa, Y.; Ohara, Y.; Hiyama, T.; A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence. Tetrahedron Lett 1993, 34, 51, 8267-70.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXI)	17435	2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline		C₁₈H₁₃FIN	详情	详情
(XXXVII)	17451	[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline		C₂₅H₂₀FNS	详情	详情
(LI)	11661	2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid	118-92-3	C₇H₇NO₂	详情	详情
(LII)	17465	2-aminobenzoyl chloride		C₇H₆ClNO	详情	详情
(LIII)	17466	Fluorobenzene	462-06-6	C₆H₅F	详情	详情
(LIV)	17467	(2-aminophenyl)(4-fluorophenyl)methanone		C₁₃H₁₀FNO	详情	详情
(LV)	15949	3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate	24922-02-9	C₈H₁₂O₃	详情	详情
(LVI)	12435	Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone	765-43-5	C₅H₈O	详情	详情
(LVII)	17470	diethyl carbonate; diethylcarbonate	105-58-8	C₅H₁₀O₃	详情	详情
(LVIII)	17471	ethyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate		C₂₁H₁₈FNO₂	详情	详情
(LIX)	17472	[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol		C₁₉H₁₆FNO	详情	详情
(LX)	17473	diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide	882-33-7	C₁₂H₁₀S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

A synthesis of pitavastatin has been reported: Cyclization of 2-amino-4'-fluorobenzophenone (I) with 3-cyclopropyl-3-oxopropionic acid methyl ester (II) by means of H2SO4 in refluxing acetic acid or methanesulfonic acid in refluxing benzene gives 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylic acid methyl ester (III), which is reduced with DIBAL in toluene to yield the carbinol (IV). Oxidation of compound (IV) with PCC and AcONa in dichloromethane affords carbaldehyde (V), which is condensed with tributylstannane (VI) by means of BuLi in THF to provide the enol ether (VII). Hydrolysis of (VII) by means of TsOH in THF/water gives the unsaturated carbaldehyde (VIII), which is condensed with acetoacetic ester (IX) by means of NaH and BuLi in THF to yield the 5-hydroxy-3-oxoheptenoic ester derivative (X). Stereoselective reduction of the oxo group of (X) by means of diethylmethoxyborane and NaBH4 in THF/methanol gives the racemic syn-dihydroxy compound (XI) in a syn/anti ratio of 98:2. Finally, compound (XI) is hydrolyzed with NaOH in aqueous ethanol to yield racemic pitavastatin sodium. Alternatively, the unsaturated carbaldehyde (VIII) can also be obtained by reaction of carbaldehyde (V) with phosphonate (XII) by means of NaOH in toluene/water to give the unsaturated nitrile (XIII), which is finally reduced with DIBAL in toluene to afford the target carbaldehyde (VIII).

参考文献中间体

合成目标

【1】 Fujikawa, Y.; Suzuki, M.; Iwasaki, H.; Kitahara, M.; Sakashita, M.; Sakoda, R.; Synthesis and biological evaluations of quinolone-based HMG-CoA reductase inhibitors. Bioorg Med Chem 2001, 9, 10, 2727.

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)	17467	(2-aminophenyl)(4-fluorophenyl)methanone		C₁₃H₁₀FNO	详情	详情
(II)	51482	Methyl 3-cyclopropyl-3-oxopropanoate	32249-35-7	C₇H₁₀O₃	详情	详情
(III)	51483	methyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate		C₂₀H₁₆FNO₂	详情	详情
(IV)	17472	[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol		C₁₉H₁₆FNO	详情	详情
(V)	17425	2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde	121660-37-5	C₁₉H₁₄FNO	详情	详情
(VI)	51484	ethyl (E)-2-(tributylstannyl)ethenyl ether; tributyl[(E)-2-ethoxyethenyl]stannane		C₁₆H₃₄OSn	详情	详情
(VII)	51485	(E)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3-ethoxy-2-propen-1-ol		C₂₃H₂₂FNO₂	详情	详情
(VIII)	39666	(E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenal		C₂₁H₁₆FNO	详情	详情
(IX)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(X)	39667	ethyl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-3-oxo-6-heptenoate		C₂₇H₂₆FNO₄	详情	详情
(XI)	51486	ethyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate		C₂₇H₂₈FNO₄	详情	详情
(XII)	10045	Diethyl cyanomethylphosphonate	2537-48-6	C₆H₁₂NO₃P	详情	详情
(XIII)	39665	(E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenenitrile		C₂₁H₁₅FN₂	详情	详情

Extended Information