methyl 4-fluoro-3-nitrobenzoate -Drug Synthesis Database

【结构式】

【分子编号】46938

【品名】methyl 4-fluoro-3-nitrobenzoate

【CA登记号】

【分子式】C₈H₆FNO₄

【分子量】199.1383832

【元素组成】C 48.25% H 3.04% F 9.54% N 7.03% O 32.14%

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：(II)

Esterification of 4-fluoro-3-nitrobenzoic acid (I) with MeOH in the presence of SOCl2 provided the methyl ester (II). Subsequent displacement of the fluoro group with the imidazolyl piperidine (III) gave adduct (IV), which was further protected as the N-trityl derivative (V) using triphenylmethyl chloride and N-methylmorpholine. Catalytic hydrogenation of the nitro group of (V) over Raney-Ni produced aniline (VI), which was acylated with cyclopropanecarbonyl chloride (VII) to furnish amide (VIII). After basic hydrolysis of the methyl ester group of (VIII), the resultant carboxylic acid (IX) was coupled with N,N-dimethyl ethanediamine (X) using PyBOP to yield amide (XI). Finally, acidic treatment of (XI) with HOAc removed the N-trityl protecting group.

参考文献中间体

合成目标

【1】 Hoornaert, C.; Rouannet, V.; Dellac, G.; Daumas, M.; Adler, M.-A.; Cremer, G. (Sanofi-Synthelabo); 4-[(1H-Imidazol-4-yl)piperidin-1-yl]anilide derivs., their preparation and application in therapy. EP 0991639; WO 9900379 .

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)	46937	4-fluoro-3-nitrobenzoic acid	453-71-4	C₇H₄FNO₄	详情	详情
(II)	46938	methyl 4-fluoro-3-nitrobenzoate		C₈H₆FNO₄	详情	详情
(III)	46939	4-(5-methyl-1H-imidazol-4-yl)piperidine		C₉H₁₅N₃	详情	详情
(IV)	46940	methyl 4-[4-(5-methyl-1H-imidazol-4-yl)-1-piperidinyl]-3-nitrobenzoate		C₁₇H₂₀N₄O₄	详情	详情
(V)	46945	methyl 4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]-3-nitrobenzoate		C₃₆H₃₄N₄O₄	详情	详情
(VI)	46941	methyl 3-amino-4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]benzoate		C₃₆H₃₆N₄O₂	详情	详情
(VII)	14061	Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride	4023-34-1	C₄H₅ClO	详情	详情
(VIII)	46942	methyl 3-[(cyclopropylcarbonyl)amino]-4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]benzoate		C₄₀H₄₀N₄O₃	详情	详情
(IX)	46943	3-[(cyclopropylcarbonyl)amino]-4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]benzoic acid		C₃₉H₃₈N₄O₃	详情	详情
(X)	14881	N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine	108-00-9	C₄H₁₂N₂	详情	详情
(XI)	46944	3-[(cyclopropylcarbonyl)amino]-N-[2-(dimethylamino)ethyl]-4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]benzamide		C₄₃H₄₈N₆O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Oxidation of 2-fluoro-3-nitrotoluene (I) by means of CrO3 in the presence of H2SO4 in AcOH/H2O yields 2-fluoro-3-nitrobenzoic acid (II), which is converted to the methyl ester (III) by treatment with MeOH and H2SO4. Reduction of the nitro group in compound (III) with N2H4.H2O in the presence of Ra-Ni in THF/MeOH affords amine (IV), which then is coupled with 2,6-difluorobenzenesulfonyl chloride (V) using pyridine in CH2Cl2 to produce the benzenesulfonamide derivative (VI). Condensation of methyl ester (VI) with 2-chloro-4-methylpyrimidine (VII) by means of LiHMDS in THF gives diaryl ethanone (VIII), which by bromination with NBS in DMA or CH2Cl2, followed by cyclization of the crude bromo ketone with 2,2-dimethylpropanethioamide (IX) [prepared by thionation of pivalamide (X) with Lawesson’s reagent in refluxing THF], yields thiazole derivative (XI). Finally, 2-chloropyrimidine derivative (XI) is aminated with NH4OH in H2O/dioxane at 100 °C or with NH3 in MeOH at 90 °C in a sealed vessel, followed by treatment of the resulting free base with MsOH in i-PrOH/acetonitrile .
Alternative synthesis of amine (IV): Esterification of 3-bromo-2-fluorobenzoic acid (XII) with MeOH and H2SO4 provides methyl ester (XIII), which is then condensed with tert-butyl carbamate by means of Pd2(dba)3.CHCl3, xantphos and Cs2CO3, followed by Boc group cleavage with TFA in CH2Cl2 .

参考文献中间体

合成目标

【1】 Adams, J.L. et al. (GlaxoSmithKline Inc.). Benzene sulfonamide thiazole and oxazole compounds. JP 2011519940, KR 2011013456, US 2009298815, US 7994185, US 2011172215, WO 2009137391.

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)	68503	2-fluoro-3-nitrotoluene		C₇H₆FNO₂	详情	详情
(II)	68504	2-fluoro-3-nitrobenzoic acid		C₇H₄FNO₄	详情	详情
(III)	46938	methyl 4-fluoro-3-nitrobenzoate		C₈H₆FNO₄	详情	详情
(IV)	68505	methyl 3-amino-2-fluorobenzoate		C₈H₈FNO₂	详情	详情
(V)	68506	2,6-difluorobenzenesulfonyl chloride;2,6-difluorobenzene-1-sulfonyl chloride		C₆H₃ClF₂O₂S	详情	详情
(VI)	68507	methyl 3-(2,6-difluorophenylsulfonamido)-2-fluorobenzoate		C₁₄H₁₀F₃NO₄S	详情	详情
(VII)	68509	2-chloro-4-methylpyrimidine	13036-57-2	C₅H₅ClN₂	详情	详情
(VIII)	68508	N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide		C₁₈H₁₁ClF₃N₃O₃S	详情	详情
(IX)	68511	2,2-dimethylpropanethioamide;Neopentanethioamide;Thiopivalamide;2,2-dimethylthio-Propionamide;2,2-dimethylPropanethioamide	630-22-8	C₅H₁₁NS	详情	详情
(X)	68512	pivalamide;2,2-Dimethylpropanamide;2,2-Dimethylpropionamide;a,a-Dimethylpropionamide;Neopentanamide;Trimethylacetamide;Pivalic acid amide;	754-10-9	C₅H₁₁NO	详情	详情
(XI)	68510	N-(3-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide		C₂₃H₁₈ClF₃N₄O₂S₂	详情	详情
(XII)	68513	3-bromo-2-fluorobenzoic acid；2-Fluoro-3-bromobenzoicacid;3-Bromo-2-fluorobenzenecarboxylic acid	161957-56-8	C₇H₄BrFO₂	详情	详情
(XIII)	68514	methyl 3-bromo-2-fluorobenzoate；3-Bromo-2-fluorobenzoic acid methyl ester	206551-41-9	C₈H₆BrFO₂	详情	详情

Extended Information