2,4-difluorobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】35123

【品名】2,4-difluorobenzoic acid

【CA登记号】1583-58-0

【分子式】C₇H₄F₂O₂

【分子量】158.1043664

【元素组成】C 53.18% H 2.55% F 24.03% O 20.24%

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：(I)

Treatment of 2,4-difluorophenylacetic acid (I) with NaOH in dimethylimidazolinone at 135 C afforded 4-fluorosalicylic acid (II). After activation of (II) with SOCl2, coupling with 3-nitrobenzylamine (III) gave amide (IV). Subsequent O-alkylation of (IV) by means of ethyl bromoacetate (A) and K2CO3 yielded ether (V). Conversion of the amide function of (V) to the corresponding thioamide (VI) was accomplished using phosphorus pentasulfide (P4S10) in pyridine. Finally, the ester group of (VI) was hydrolyzed with NaOH to the title carboxylic acid.

参考文献中间体

合成目标

【1】 Van Zandt, M.C.; Sibley, E.O.; Combs, K.J.; et al.; Design and synthesis of novel inhibitors of aldose reductase for the treatment of diabetic complications. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 137.

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)	35123	2,4-difluorobenzoic acid	1583-58-0	C₇H₄F₂O₂	详情	详情
(II)	35124	4-fluoro-2-hydroxybenzoic acid	345-29-9	C₇H₅FO₃	详情	详情
(III)	35125	(3-nitrophenyl)methanamine; 3-nitrobenzylamine		C₇H₈N₂O₂	详情	详情
(IV)	35126	4-fluoro-2-hydroxy-N-(3-nitrobenzyl)benzamide		C₁₄H₁₁FN₂O₄	详情	详情
(V)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(VI)	35127	ethyl 2-(5-fluoro-2-[[(3-nitrobenzyl)amino]carbonyl]phenoxy)acetate		C₁₈H₁₇FN₂O₆	详情	详情
(VII)	35128	ethyl 2-(5-fluoro-2-[[(3-nitrobenzyl)amino]carbothioyl]phenoxy)acetate		C₁₈H₁₇FN₂O₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Paclitaxel (I) was sequentially protected at the 2'-O with tert-butyldimethylsilyl chloride and imidazole and then at the 7-O with triethylsilyl chloride to afford the bis-silyl derivative (II). Selective hydrolysis of the benzoate ester group of (II) using Triton B provided (III). The vicinal 1,2-diol group of (III) was protected as the cyclic carbonate (IV) by treatment with either triphosgene or carbonyldiimidazole. The remaining free hydroxyl group of (IV) at position 4 was then acylated with cyclopropanecarbonyl chloride (V) in the presence of lithium hexamethyldisilazide to furnish the corresponding ester (VI). Subsequent deprotection of the cyclic carbonate ester of (VI) was achieved by selective hydrolysis with LiOH to afford diol (VII). Regioselective acylation of (VII) on the 2-hydroxyl with 2,4-difluorobenzoic acid (VIII) and DCC produced ester (IX). The final desilylation step was performed by treatment with HF-pyridine.

参考文献中间体

合成目标

【1】 Johnston, K.A.; Kingston, D.G.I.; Chordia, M.D.; Fairchild, C.R.; Kadow, J.F.; Long, B.H.; Yuan, H.; Jagtap, P.G.; Synthesis and bioactivity of 2,4-diacyl analogues of paclitaxel. Bioorg Med Chem 2001, 9, 1, 171.

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)	48197	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,4,9-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₄₅H₄₉NO₁₃	详情	详情
(II)	48198	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-15-[((2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoyl)oxy]-1,4-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₅₇H₇₇NO₁₃Si₂	详情	详情
(III)	48199	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-1,2,4-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoate		C₅₀H₇₃NO₁₂Si₂	详情	详情
(IV)	48200	(1S,5S,6R,7S,10R,12S,13S,15R,18S)-15-(acetoxy)-7-hydroxy-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-18-yl (2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoate		C₅₁H₇₁NO₁₃Si₂	详情	详情
(V)	14061	Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride	4023-34-1	C₄H₅ClO	详情	详情
(VI)	48201	(1S,5S,6R,10R,12S,13S,15R,18S)-15-(acetoxy)-18-[((2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoyl)oxy]-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-7-yl cyclopropanecarboxylate		C₅₅H₇₅NO₁₄Si₂	详情	详情
(VII)	48202	(1S,2S,3R,7R,9S,10S,12R,15S)-12-(acetoxy)-15-[((2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoyl)oxy]-1,2-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-4-yl cyclopropanecarboxylate		C₅₄H₇₇NO₁₃Si₂	详情	详情
(VIII)	35123	2,4-difluorobenzoic acid	1583-58-0	C₇H₄F₂O₂	详情	详情
(IX)	48203	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-15-[((2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoyl)oxy]-4-[(cyclopropylcarbonyl)oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 2,4-difluorobenzoate		C₆₁H₇₉F₂NO₁₄Si₂	详情	详情

Extended Information