2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】10801

【品名】2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid

【CA登记号】2252-51-9

【分子式】C₇H₄ClFO₂

【分子量】174.5586632

【元素组成】C 48.17% H 2.31% Cl 20.31% F 10.88% O 18.33%

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：(I)

Flosequinan has been synthesized by two new related ways: 1) The reaction of 2-chloro-4-fluorobenzoic acid (I) with refluxing aqueous methylamine Cu powder and CuCl2 gives 4-fluoro-2-(methylamino)benzoic acid (II), which is cyclized with phosgene to yield 7-fluoro-1-methyl-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (III). The reaction of (III) with dimethyl sulfoxide and NaH in toluene affords 4-fluoro-2-(methylamino)-alpha-(methylsulfinyl)acetophenone (IV), which is finally cyclized with refluxing triethyl orthoformate. 2) The reaction of 2-amino-4-fluorobenzoic acid (V) with phosgene as before gives the corresponding benzoxazine (VI), which is treated with dimethyl sulfoxide and NaH in refluxing toluene to afford 2-amino-4-fluoro-alpha-(methylsulfinyl)acetophenone (VII). The cyclization of (VII) with refluxing trimethyl orthoformate gives 7-fluoro-3-(methylsulfinyl)quinolin-4(1H)-one (VIII), which is finally methylated with dimethyl sulfate and KOH in water.

参考文献中间体

合成目标

【1】 Birch, A.M.; Maclean, L.; Robinson, K.; Davies, R.V.; Syntheses of flosequinan: A novel 4-quinolone shown to be useful in congestive heart failureSyntheses of flosequinan: A novel 4-quinolone shown to be useful in congestive heart failure. J Chem Soc - Perkins Trans I 1994, 4, 387.

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)	10801	2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid	2252-51-9	C₇H₄ClFO₂	详情	详情
(II)	10802	4-Fluoro-2-(methylamino)benzoic acid		C₈H₈FNO₂	详情	详情
(III)	10803	7-Fluoro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione		C₉H₆FNO₃	详情	详情
(IV)	10804	1-[4-Fluoro-2-(methylamino)phenyl]-2-(methylsulfinyl)-1-ethanone		C₁₀H₁₂FNO₂S	详情	详情
(V)	10805	2-Amino-4-fluorobenzoic acid	446-32-2	C₇H₆FNO₂	详情	详情
(VI)	10806	7-Fluoro-2H-3,1-benzoxazine-2,4(1H)-dione		C₈H₄FNO₃	详情	详情
(VII)	10807	1-(2-Amino-4-fluorophenyl)-2-(methylsulfinyl)-1-ethanone		C₉H₁₀FNO₂S	详情	详情
(VIII)	10808	7-Fluoro-3-(methylsulfinyl)-4(1H)-quinolinone		C₁₀H₈FNO₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

ARI-509 can be obtained by four related synthetic routes (a-d), scheme 16434601a: A key advanced intermediate (VI) was used for the preparation of ARI-509. This intermediate (VI) was prepared by two synthetic routes a and b: In route a, commercially available homophthalic acid diester (I) or homophthalic anhydride (II) was reacted with 4-bromo-2-fluorobenzyl amine to give homophthalimide (IV). Treatment of (IV) with Mander's reagent yielded the key intermediate (VI). In route b, 2-chloro-4-fluorobenzoic acid (III) was converted to diester (V) by the Hurtley reaction. Treatment of (V) with thionyl chloride and further reaction of the generated acid chloride with 4-bromo-2-fluorobenzyl amine gave the key intermediate (VI). Conversion of (VI) to the final product was accomplished by routes c and d: In route c, alkylation of (VI) with tert-butyl bromoacetate, followed by acidic hydrolysis gave acid (VII). Generation of the acid chloride of (VII) with thionyl chloride and treatment with ammonia yielded amide (VIII). In route d, amide (VIII) was obtained in a more direct way, by formation of nitrile (IX) from (VI) with bromoacetonitrile and subsequent acidic hydrolysis. Amide (VIII) was cyclized to the final product (ARI-509), upon treatment with a variety of bases including sodium hydride, sodium methoxide or lithium bis(trimethylsilyl)amide.

参考文献中间体

合成目标

【1】 Bruggin, K.A.; McKillop, A.; A study of the copper-catalyzed direct arylation of beta-dicarbonyl compounds with 2-bromobenzoic acid. Tetrahedron 1975, 31, 2607-19.
【2】 Sethi, P.; Mander, L.N.; Regioselective synthesis of beta-ketoesters from lithium enolates and methyl cyanoformate. Tetrahedron Lett 1983, 24, 5425.
【3】 Malamas, M.S.; Hohman, T.C.; ARI-509. Drugs Fut 1994, 19, 5, 442.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	19560	(4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine	112734-22-2	C₇H₇BrFN	详情	详情
(I)	14105	methyl 4-fluoro-2-(2-methoxy-2-oxoethyl)benzoate		C₁₁H₁₁FO₄	详情	详情
(II)	14106	6-Fluoro-1H-isochromene-1,3(4H)-dione		C₉H₅FO₃	详情	详情
(III)	10801	2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid	2252-51-9	C₇H₄ClFO₂	详情	详情
(IV)	14108	2-(4-Bromo-2-fluorobenzyl)-6-fluoro-1,3(2H,4H)-isoquinolinedione		C₁₆H₁₀BrF₂NO₂	详情	详情
(V)	14109	4-Fluoro-2-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]benzoic acid		C₁₂H₁₁FO₆	详情	详情
(VI)	14110	methyl 2-(4-bromo-2-fluorobenzyl)-6-fluoro-1,3-dioxo-1,2,3,4-tetrahydro-4-isoquinolinecarboxylate		C₁₈H₁₂BrF₂NO₄	详情	详情
(VII)	14111	2-[2-(4-Bromo-2-fluorobenzyl)-6-fluoro-4-(methoxycarbonyl)-1,3-dioxo-1,2,3,4-tetrahydro-4-isoquinolinyl]acetic acid		C₂₀H₁₄BrF₂NO₆	详情	详情
(VIII)	14112	methyl 4-(2-amino-2-oxoethyl)-2-(4-bromo-2-fluorobenzyl)-6-fluoro-1,3-dioxo-1,2,3,4-tetrahydro-4-isoquinolinecarboxylate		C₂₀H₁₅BrF₂N₂O₅	详情	详情
(IX)	14113	methyl 2-(4-bromo-2-fluorobenzyl)-4-(cyanomethyl)-6-fluoro-1,3-dioxo-1,2,3,4-tetrahydro-4-isoquinolinecarboxylate		C₂₀H₁₃BrF₂N₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

2-Chloro-4-fluorobenzoic acid (I) was converted to acid chloride (II) upon treatment with oxalyl chloride and a catalytic amount of DMF. Subsequent coupling of (II) with pyrrolobenzodiazepine (III) yielded the corresponding amide (IV). Then, displacement of the fluorine atom of (IV) by the sodium salt of 3-methylpyrazole (V) produced a mixture of the required compound and its regioisomer (VI), which were separated by column chromatography.

参考文献中间体

合成目标

【1】 Dusza, J.P.; Ashwell, M.A.; Caggiano, T.J.; et al.; VNA-932: First orally active, nonpeptide, vasopressin V2 receptor selective agonist. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 203.
【2】 Trybulski, E.J.; Ashwell, M.A.; Molinari, A.J.; Bagli, J.F.; Chan, P.S.; Failli, A.A.; Dusza, J.P.; Albright, J.D.; Caggiano, T.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000062; WO 9906409 .

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)	10801	2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid	2252-51-9	C₇H₄ClFO₂	详情	详情
(II)	37996	2-chloro-4-fluorobenzoyl chloride	21900-54-9	C₇H₃Cl₂FO	详情	详情
(III)	21084	10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine	22162-53-4	C₁₂H₁₂N₂	详情	详情
(IV)	37997	(2-chloro-4-fluorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₁₉H₁₄ClFN₂O	详情	详情
(V)	37998	3-methyl-1H-pyrazole	1453-58-3	C₄H₆N₂	详情	详情
(VI)	37999	[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)phenyl][5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₂₃H₁₉ClN₄O	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 the pyrrolobenzodiazepine (I) with 2-chloro-4-fluorobenzoyl chloride (V) prepared from the acid (VI) and oxalyl chloride and catalytic DMF with Hünig's base in dichloromethane gives the acylated pyrrolobenzodiazepine (VII). Treatment of (VII) with a solution of the sodium salt of 3-methylpyrazole (VIII) in DMF yields a 85:15 mixture of WAY-VNA-932 and its 5-methyl isomer (IX) which can be separated by column chromatography using an ethyl acetate/hexane mixture over silica gel.

参考文献中间体

合成目标

【1】 Caggiano, T.J.; WAY-VNA-932. Drugs Fut 2002, 27, 3, 248.
【2】 Trybulski, E.J.; Ashwell, M.A.; Molinari, A.J.; Bagli, J.F.; Chan, P.S.; Failli, A.A.; Dusza, J.P.; Albright, J.D.; Caggiano, T.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000062; WO 9906409 .

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)	21084	10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine	22162-53-4	C₁₂H₁₂N₂	详情	详情
(V)	37996	2-chloro-4-fluorobenzoyl chloride	21900-54-9	C₇H₃Cl₂FO	详情	详情
(VI)	10801	2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid	2252-51-9	C₇H₄ClFO₂	详情	详情
(VII)	37997	(2-chloro-4-fluorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₁₉H₁₄ClFN₂O	详情	详情
(VIII)	37998	3-methyl-1H-pyrazole	1453-58-3	C₄H₆N₂	详情	详情
(IX)	52180	[2-chloro-4-(5-methyl-1H-pyrazol-1-yl)phenyl][5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₂₃H₁₉ClN₄O	详情	详情

Extended Information