* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With silver fluoride In toluene at 130℃; for 18 h; Sealed tube
Methyl 4-fluoro-3-methylbenzoate. Methyl 4-bromo-3-methylbenzoate (27.5 mg, 0.12 mmol), BrettPhos (6.4 mg, 0.012 mmol, 10 mol percent), (COD)Pd(CH2TMS)2 (2.3 mg, 0.006 mmol, 5 mol percent), AgF (22.8 mg, 0.18 mmol, 1.5 equivalents) and toluene (2 mL) were added to an oven dried resealable screw-top test tube equipped with a stir bar. The tube was then sealed with a cap and taken out of the glove box, wrapped in aluminum foil and placed into a preheated 130° C. oil bath with adequate stirring. After 18 h, the tube was removed from the oil bath and allowed to cool to room temperature. p-Fluorotoluene (6.5 μL, 0.06 mmol, 0.5 equivalent) and dodecane (27.3 μL, 0.12 mmol, 1 equivalent) were added as standard. The reaction mixture was filtered through a glass filter and a plug of Celite.(R). to remove all solids. The clear yellow solution was then analyzed by 19F NMR (282 MHz) for yield and GC for conversion as well as reduction product. The yield is determined by comparing integration of the 19F NMR resonance of p-Fluorotoluene (-118 ppm) and that of methyl 4-fluoro-3-methylbenzoate (-106 ppm, 0.100 mmol, 83percent yield). GC/MS analysis of the sample confirmed that the only compound in solution is methyl 4-fluoro-3-methylbenzoate
To a 100 mL round bottom flask with 40 mL of methanol was added 4-fluoro-3- methyl benzoic acid (4.0 g, 25.96 mmol) followed by concentrated H2SO4 (1.0 mL). The reaction vessel was equipped with a condenser and refluxed overnight at 65°C. Cooled down reaction and diluted with ether and NaHC03.The organic layer was washed with brine (3x), dried over MgS04, and concentrated at room temperature under reduced pressure to give methyl 4-fluoro-3- methylbenzoate (7) as a clear liquid (98percent yield, 4.38g). 1H NMR (400 MHz, DMSO-J6) δ 7.90 (dd, J = 1.5, 2.2 Hz, 1H), 7.83 (ddd, J = 7.9, 5.0, 2.3 Hz, 1H), 7.27 (t, J = 9.1 Hz, 1H), 3.83 (s, 3H), 2.28 (s, 3H). HPLC purity: 100percent.
83.7%
With hydrogenchloride In water for 4 h; Reflux
3-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-4-fluoro-benzoic acid To a solution of 4-fluoro-3-methylbenzoic acid (5.0 g, 32.4 mmol) in methanol (150 mL) was added concentrated hydrochloric acid (2 mL). The mixture was refluxed for 4 hrs and then concentrated. The residue was treated with ether (200 mL) and washed with water, 10percent sodium hydroxide solution, water and finally brine. The organic layer was dried over sodium sulfate and solvents were removed to give 4-fluoro-3-methylbenzoic acid methyl ester (4.56 g, 83.7percent) as an off-white solid.
83.7%
With hydrogenchloride In water for 4 h; Reflux
To a solution of 4-fluoro-3-methylbenzoic acid (5.0 g, 32.4 mmol) in methanol (150 mL) was added concentrated hydrochloric acid (2 mL). The mixture was refluxed for 4 hrs and then concentrated. The residue was treated with ether (200 mL) and washed with water, 10percent sodium hydroxide solution, water and finally brine. The organic layer was dried over sodium sulfate and solvents were removed to give 4-fluoro-3-methylbenzoic acid methyl ester (4.56 g, 83.7percent) as an off white solid.
Reference：
[1] Patent: WO2016/23028, 2016, A2, . Location in patent: Paragraph 00103
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 8, p. 3793 - 3807
[3] Patent: US2011/118322, 2011, A1, . Location in patent: Page/Page column 10
[4] Patent: US2011/136792, 2011, A1, . Location in patent: Page/Page column 18
[5] European Journal of Medicinal Chemistry, 2007, vol. 42, # 11-12, p. 1334 - 1357
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6707 - 6713
[7] Patent: WO2009/67081, 2009, A1, . Location in patent: Page/Page column 116
[8] Patent: EP2080761, 2009, A1, . Location in patent: Page/Page column 40
[9] Patent: WO2010/133885, 2010, A1, . Location in patent: Page/Page column 48
EXAMPLE 11 3-Methyl-4-(4-(1-methylpiperazin-4-yl-sulfonyl)phenoxy)benzoylguanidine STR28 a) Methyl 3-methyl-4-phenoxybenzoate 3.4 g of <strong>[180636-50-4]methyl 4-fluoro-3-methylbenzoate</strong>, 2.4 g of phenol and 19.5 g of Cs2 CO3 were stirred at 160 C. for 20 minutes in 100 ml of NMP. The mixture was poured into 400 ml of a saturated aqueous solution of NaHCO3 and the whole was diluted with 400 ml of water and extracted 3 times with 200 ml of MTB on each occasion. The organic phases were dried over Na2 SO4 and the solvent was removed in vacuo. Chromatographing the residue on silica gel using EA/HEP 1:4 yields 2.0 g of a colorless oil. The title compound of Example 12 was synthesised in analogy with Example 9:
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 15h;
To a stirring solution of <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> (5.0 g, 0.032 mol) and K2CO3 (9.0 g 0.064 mol) in 80 ml DMF was added iodomethane (2.4 ml, 0.038 mol). The reaction mixture was allowed to stir at 25 0C for 15 h. The DMF was removed under reduced pressure and the resulting residue was washed with EtOAc and H2O. The organic layer was dried and the solvent was removed under reduced pressure, m/z 169.
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 15h;
Method 5; Methyl 4-fluoro-3-methylbenzoate; To a stirring solution of <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> (5.0 g, 0.032 mol) and potassium carbonate (9.0 g 0.064 mol) in DMF (80 ml) was added iodomethane .(2.4 ml, 0.038 mol). The reaction mixture was allowed to stir at 25 C for 15 h. The DMF was removed under reduced pressure and the resulting residue was washed with EtOAc and H2O.The organic layer was dried and the solvent was removed under reduced pressure; m/z 169.
With sulfuric acid; In methanol; for 4h;Heating / reflux;
Preparation 63A mixture of <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> (15.2g) andH2SO4 (4.5ml) in methanol (150ml) was refluxed for 4h. After cooling to room temperature, the mixture was poured into a mixture of diisopropyl ether (200ml) and cold water (400ml) with stirring. The separated aqueous layer was extratedwith diisopropylether. The combined organic layer was washedwith saturatedNaHCO3 andbrine, dried over Na2SO4 and concentrated in vacuo to afford methyl4-fluoro-3-methylbenzoate (17.Ig) as a pale yellow oil. 1HNMR (200MHz, DMSO-d6) d2.29(3H, d) , 3.84(3H, s) , 7.28(1H, t, J=9.3 Hz), 7.79-7.97(2H, m) .
To a 100 mL round bottom flask with 40 mL of methanol was added 4-fluoro-3- methyl benzoic acid (4.0 g, 25.96 mmol) followed by concentrated H2SO4 (1.0 mL). The reaction vessel was equipped with a condenser and refluxed overnight at 65C. Cooled down reaction and diluted with ether and NaHC03.The organic layer was washed with brine (3x), dried over MgS04, and concentrated at room temperature under reduced pressure to give methyl 4-fluoro-3- methylbenzoate (7) as a clear liquid (98% yield, 4.38g). 1H NMR (400 MHz, DMSO-J6) delta 7.90 (dd, J = 1.5, 2.2 Hz, 1H), 7.83 (ddd, J = 7.9, 5.0, 2.3 Hz, 1H), 7.27 (t, J = 9.1 Hz, 1H), 3.83 (s, 3H), 2.28 (s, 3H). HPLC purity: 100%.
83.7%
With hydrogenchloride; In water; for 4h;Reflux;
3-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-4-fluoro-benzoic acid To a solution of <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> (5.0 g, 32.4 mmol) in methanol (150 mL) was added concentrated hydrochloric acid (2 mL). The mixture was refluxed for 4 hrs and then concentrated. The residue was treated with ether (200 mL) and washed with water, 10% sodium hydroxide solution, water and finally brine. The organic layer was dried over sodium sulfate and solvents were removed to give <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> methyl ester (4.56 g, 83.7%) as an off-white solid.
83.7%
With hydrogenchloride; In water; for 4h;Reflux;
To a solution of <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> (5.0 g, 32.4 mmol) in methanol (150 mL) was added concentrated hydrochloric acid (2 mL). The mixture was refluxed for 4 hrs and then concentrated. The residue was treated with ether (200 mL) and washed with water, 10% sodium hydroxide solution, water and finally brine. The organic layer was dried over sodium sulfate and solvents were removed to give <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> methyl ester (4.56 g, 83.7%) as an off white solid.
With thionyl chloride; at 0 - 20℃; for 24.1667h;
(i) Methyl 4-fluoro-3-methylbenzoateThionyl chloride (5.68 ml) was added dropwise to a solution of <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> (10 g) in MeOH (150 mL) at O0C over a period of 10 minutes under nitrogen. The resulting mixture was stirred at rt for 24h. The solvent was removed and the residue diluted with EtOAc, washed with sat. NaHCO3 , brine, dried, filtered and evaporated to afford the subtitle compound, 9.85 g. LC-MS m/z 169 ESI
With thionyl chloride; at 20℃;
To a suspension of <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> (300 mg) in MeOH (4.5 ml) was added dropwise thionyl chloride (142 mul). The solution was stirred at room temperature overnight and concentrated in vacuo to give 297 mg of the title compound. 1H-NMR (delta, ppm, CDCl3): 7.92-7.84 (m, 2H), 7.05 (t, 1 H), 3.91 (s, 3H), 2.32 (d, 3H).
With thionyl chloride; at 0 - 20℃;Inert atmosphere of N2;
SOCl2 (5.68 niL) was added dropwise to a solution of <strong>[403-15-6]4-fluoro-3-methylbenzoic acid</strong> (10 g) in MeOH (150 niL) at O0C over a period of 10 mins. under N2. The resulting mixture was stirred at r.t. for 24 h and then the solvent was removed by evaporation. The residue was dissolved in EtOAc, washed with sat. NaHCO3, sat. brine, dried and then concentrated by evaporation to afford the subtitle compound (9.85 g); 1H NMR: 7.93-7.83 (m, 2H), 7.04(dd, IH), 3.90 (s, 3H), 2.31 (s, 3H).
With sulfuric acid;Reflux;
General procedure: (1) Take 0.20 muM different substituted benzoic acid in 250 ml round bottom flask, added 20 times equivalent methanol and 4 ml 98% concentrated sulfuric acid, then carried out reflux reaction for 4 - 6h. Distilled under reduced pressure to remove the methanol then stirred and mixed with silica gel, through the column chromatography purification to obtain compound 1, yield 96-99%.
To a mixture of 19.2 g (155 mmol) dimethyl methylphosphonate in 150 mL THF at -70 C. was added 97 mL (155 mmol) 1.6M n-BuLi in hexane. The mixture was stirred for 45 min and a solution of 11.8 g (70 mmol) <strong>[180636-50-4]4-fluoro-3-methyl-benzoic acid methyl ester</strong> in 15 mL THF was added. After 15 min at -70 C. the mixture was allowed to warm to 0 C. and neutralized with 4N HCl in dioxane. The mixture was diluted with 500 mL THF to obtain [2-(4-fluoro-3-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester. 6 mmol [2-(4-fluoro-3-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester in THF was stirred together with 0.5 g (4.6 mmol) pyrimidine-5-carboxaldehyde and 1.65 g Cs2CO3 for 16 h at room temperature. The mixture was diluted with NH4Cl aq. and ethyl acetate. The organic layer was separated, dried with MgSO4 and evaporated to dryness. The residue was used crude in the consecutive step.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Heating;
To a 250 mL closed pressure vessel was added <strong>[180636-50-4]methyl 4-fluoro-3-methylbenzoate</strong> (4.02g, 23.91 mmol) dissolved in anhydrous carbon tetrachloride (40 mL). N-bromosuccinimide (3.83g, 21.50 mmol) was then added followed by benzoyl peroxide (0.290g, 1.20 mmol). The reaction stirred for 1 hour at 65C then cooled and filtered through celite with dichloromethane and concentrated. Purified using 0%-l% EtOAc/Hexanes using flash chromatography to give methyl 3-(bromomethyl)-4-fluorobenzoate (8) as a clear oil (82% yield, 4.3 lg). 1H NMR (400 MHz, DMSO- ) delta 8.19 (dd, J = 1.4, 2.3 Hz, 1H), 8.00 (ddd, J = 8.7, 5.0, 2.3 Hz, 1H), 7.41 (dd, J = 9.8, 8.7 Hz, 1H), 4.79 (d, J = 1.1 Hz, 2H), 3.87 (s, 3H).
45%
With dibenzoyl peroxide; In tetrachloromethane; for 6h;Reflux;
4-Fluoro-3-methylbenzoic acid methyl ester (4.56 g, 2.71 mmol) was suspended in carbon tetrachloride (80 mL) and benzoyl peroxide (1.0 g, 75% by weight, 3.0 mmol) was added. The mixture was refluxed for 6 hrs and the solid was filtered. The filtrate was concentrated and purified through flash column chromatography (200 g silica gel, 0% to 15% ethyl acetate in hexanes over 50 minutes) to give 3-bromomethyl-4-fluorobenzoic acid methyl ester as a white solid (3.0 g, 45%).
45%
With dibenzoyl peroxide; In tetrachloromethane; for 6h;Reflux;
4-Fluoro-3-methylbenzoic acid methyl ester (4.56 g, 2.71 mmol) was suspended in carbon tetrachloride (80 mL) and benzoyl peroxide (1.0 g, 75% by weight, 3.0 mmol) was added. The mixture was refluxed for 6 hrs and the solid was filtered. The filtrate was concentrated and purified through flash column chromatography (200 g silica gel, 0% to 15% ethyl acetate in hexanes over 50 minutes) to give 3-bromomethyl-4-fluorobenzoic acid methyl ester as a white solid (3.0 g, 45%).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In ethyl acetate; at 80℃; for 20h;
(ii) Methyl 3-(bromomethyl)-4-fluorobenzoate NBS (14.60 g) and AIBN (2.89 g) were added to a solution of the product from step (i) (9.85 g) in EtOAc (200 mL). The resulting mixture was stirred at 8O0C for 2Oh. After cooling the mixture was washed with sat. sodium thiosulphate, brine, dried, filtered and the solvent removed. The crude product was purified using chromatography, to give the subtitle compound, 5.30 g. LC-MS m/z 248 ESI
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 20℃; for 18h;Reflux;
Synthesis of Aryl Ethyl and Aryl Methyl Amines,Represenative Bromination Procedure, Scheme 1, Step i;3-Bromomethyl-4-fluoro-benzoic acid methyl ester: To a solution of <strong>[180636-50-4]methyl 4-fluoro-3-methyl-benzoate</strong> (3 g, 17.84 mmol) in CCl4 (40 mL) was added N-bromo succinimide (3.8 g, 21.41 mmol) followed by AIBN (0.29 g, 1.78 mmol) at room temperature. The mixture was then heated at reflux temperature for 18 h, cooled and filtered. The filtrate was concentrated, recovered in Et2O (75 mL) and washed with H2O (3×20 mL), saturated NaCl solution (2×20 mL), and then dried over MgSO4. Filtration and removal of solvent under reduced pressure gave 3.55 g of colorless oil that was used without further purification.
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h;
General procedure: A mixture of methyl 3-bromo-2-methylbenzoate (500 mg, 3.3 mmol), NBS (770.4 mg, 4.3 mmol), and di-benzoyl peroxide (BPO, 80.7 mg, 0.3 mmol) in 1,2-dichloroethane (10 mL) was heated at 80 C for 12 h. The reaction mixture was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over NaSO4, filtered and concentrated to give a crude product (683.2 mg, 89.6%), which was used in the next step reaction without further purification.
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h;
General procedure: A mixture of methyl 2-fluoro-3-methylbenzoate (1g, 6.0mmol), NBS (1.3g, 7.1mmol) and di-benzoyl peroxide (BPO) (144.0mg, 84.4mmol) in 1,2-dichloroethane (5mL) was heated to 80C, and stirred for 12h. After cooling to r.t., the precipitated solid was separated by filtration. The filtrate was evaporated in vacuo and the residue was dissolved in ethers (15mL) and washed with NaHCO3 (2N, 15mL). The organic layer dried over Na2SO4, filtered and concentrated to give a crude product (1.2g, 82%), which was used in the next step reaction without further purification.
With silver fluoride;bis[(trimethylsilyl)methyl](1,5-cyclooctadiene)palladium(II); dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; In toluene; at 130℃; for 18h;Sealed tube;
Methyl 4-fluoro-3-methylbenzoate. Methyl 4-bromo-3-methylbenzoate (27.5 mg, 0.12 mmol), BrettPhos (6.4 mg, 0.012 mmol, 10 mol %), (COD)Pd(CH2TMS)2 (2.3 mg, 0.006 mmol, 5 mol %), AgF (22.8 mg, 0.18 mmol, 1.5 equivalents) and toluene (2 mL) were added to an oven dried resealable screw-top test tube equipped with a stir bar. The tube was then sealed with a cap and taken out of the glove box, wrapped in aluminum foil and placed into a preheated 130 C. oil bath with adequate stirring. After 18 h, the tube was removed from the oil bath and allowed to cool to room temperature. p-Fluorotoluene (6.5 muL, 0.06 mmol, 0.5 equivalent) and dodecane (27.3 muL, 0.12 mmol, 1 equivalent) were added as standard. The reaction mixture was filtered through a glass filter and a plug of Celite to remove all solids. The clear yellow solution was then analyzed by 19F NMR (282 MHz) for yield and GC for conversion as well as reduction product. The yield is determined by comparing integration of the 19F NMR resonance of p-Fluorotoluene (-118 ppm) and that of methyl 4-fluoro-3-methylbenzoate (-106 ppm, 0.100 mmol, 83% yield). GC/MS analysis of the sample confirmed that the only compound in solution is methyl 4-fluoro-3-methylbenzoate
1-(4-fluoro-3-mehyl-phenyl)-3-phenyl- 1 , 3-propanedione17.3 g KOtBu was dissolved in 500 mL THF and 9 mL acetophenone was added. After 15 min at RT 25.9 g 4-fluoro-3-mehyl-benzoic acid methyl ester was added and stirred for 3 h at RT. The solvent was removed and the residue was purified by chromatography on silica gel(cyclohexane/EE: 98:2) to yieled 19.3 g of the desired compound.
19.3 g
6.02.01.09 1-(4-fluoro-3-methyl-phenyl)-3-phenyl-1,3-propanedione 17.3 g KOtBu was dissolved in 500 mL THF and 9 mL acetophenone was added. After 15 min at RT 25.9 g <strong>[180636-50-4]4-fluoro-3-methyl-benzoic acid methyl ester</strong> was added and stirred for 3 h at RT. The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). After combination of the desired fractions and removal of the solvent 19.3 g of the desired compound was obtained. (M+H)+: 257
19.3 mg
6.02.01.01 1-(4-fluoro-3-methyl-phenyl)-3-phenyl-1,3-propanedione 17.3 g KOtBu was dissolved in 500 mL THF and 9 mL acetophenone was added. After 15 min at RT 25.9 g <strong>[180636-50-4]4-fluoro-3-methyl-benzoic acid methyl ester</strong> was added and stirred for 3 h at RT. The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2) to yielded 19.3 g of the desired compound.
methyl 4-(2-bromo-3-ethylphenoxy)-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 3h;
Methyl 4-(2-bromo-3-ethylphenoxy)-3-methylbenzoate. To a solution of methyl 4- fluoro-3-methylbenzoate (1.7 g, 10 mmol) and 2-bromo-3-ethylphenol (2.0 g, 10 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (2.8 g, 20 mmol). The reaction mixture was stirred at 130C for 3 hours. After the reaction, the mixture was poured into water (50 mL) and the solution was extracted with ethyl acetate (50 mL), washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure to give the pure product methyl 4-(2-bromo-3- ethylphenoxy)-3-methylbenzoate as colorless oil (2.10 g, 60%).
60%
With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 3h;
To a solution of <strong>[180636-50-4]methyl 4-fluoro-3-methylbenzoate</strong> (1.7 g, 10 mmol) and 2-bromo-3-ethylphenol (2.0 g, 10 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (2.8 g, 20 mmol). The reaction mixture was stirred at 130 C. for 3 hours. After the reaction, the mixture was poured into water (50 mL) and the solution was extracted with ethyl acetate (50 mL), washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure to give the pure product methyl 4-(2-bromo-3-ethylphenoxy)-3-methylbenzoate as colorless oil (2.10 g, 60%).
methyl 4-fluoro-3-methyl-5-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; nitric acid; at 0 - 20℃; for 1.5h;
Step A: Concentrated H2S04 (17.5 mL) was slowly added to methyl 4-fluoro-3- methylbenzoate (12.8 g, 76 mmol) and the mixture was cooled to 0 C. A solution of fuming HNO3 (69.5%, 11.6 mL) in concentrated H2S04 (17.5 mL) was then added drop- wise over 10 mm. The mixture was stirred for 80 mm while slowly warming up to room temperature (reaction completion monitored by TLC). The mixture was slowly pouredinto ice, the aqueous layer was extracted with CH2C12 (3 x 200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography to afford methyl 4-fluoro-3-methyl-5-nitrobenzoate (I-35a) as a white solid. MS calculated for C9H9FNO4 (M+H) 214.04, found 214.0.
In N,N-dimethyl-formamide; at 55℃; for 16h;Green chemistry;
<strong>[180636-50-4]methyl 4-fluoro-3-methyl-benzoate</strong> (8.0 g, 47.57 mmol), DMF (64.00 mL),and sodium ethanethiolate (10.00 g, 118.9 mmol) and the reaction was heated for16h at 55 C. The reaction was found to be complete by lcms analysis. Thereaction was removed from the oil bath and was allowed to cool to rt. Thereaction was quenched with brine and allowed to stir for 20 minutes. Thereaction mixture was then extracted with EtOAc 3 times and the aqueous layerwas collected in a 1 L erlenmeyer flask. The aqueous layer was then treatedwith 150 mL of commercial bleach and the reaction mixture immediately turnedcolorless and transparent. The reaction mixture was then allowed to stir for 10minutes. The reaction was then treated with 1N HCl until the reaction was pH 1.The reaction was then extracted with EtOAc 3 times and the organic layers werethen washed with brine 3 times to remove any trace DMF. The organic layer wasthen dried over sodium sulfate and the solvent was removed to provide4-ethylsulfonyl-3-methyl-benzoic acid (9.37 g, 41.05 mmol, 86.3%) as a whitesolid 1H NMR (400 MHz, CDCl3)delta 8.13 (dd, J = 13.8, 8.3 Hz, 3H), 3.22 (q, J = 7.4 Hz, 2H), 2.79 (s, 3H), 1.31(t, J = 7.4 Hz, 3H).
In N,N-dimethyl-formamide; at 55℃; for 16h;Green chemistry;
To a 250 mL rbf was added <strong>[180636-50-4]methyl 4-fluoro-3-methyl-benzoate</strong> (6.8 g,40.44 mmol), DMF (54.40 mL), and sodium propane-2-thiolate(9.922 g, 101.1 mmol) and the reaction was heated for 16h at 55 C. Thereaction was found to be complete by lcms analysis. The reaction was removedfrom the oil bath and was allowed to cool to rt. The reaction was quenched withbrine and allowed to stir for 20 minutes. The reaction mixture was thenextracted with EtOAc 3 times and the aqueous layer was collected in a 1 L erlenmeyerflask. The aqueous layer was then treated with 150 mL of commercial bleach andthe reaction mixture immediately turned colorless and transparent. The reactionmixture was then allowed to stir for 10 minutes. The reaction was then treatedwith 1N HCl until the reaction was pH 1. The reaction was then extracted withEtOAc 3 times and the organic layers were then washed with brine 3 times toremove any trace DMF. The organic layer was then dried over sodium sulfate andthe solvent was removed to provide 4-isopropylsulfonyl-3-methyl-benzoic acid(7.93 g, 32.73 mmol, 80.93%) as a white solid 1H NMR (400 MHz, CDCl3)delta 8.21 - 8.03 (m, 3H), 3.43 - 3.21 (m, 1H), 2.77 (s, 3H), 1.32 (d, J = 6.8 Hz,6H).
4-(3-(2-((2,6-dimethylbenzyl)amino)-2-oxoethyl)-4-fluorophenyl)-N-(1H-indazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide[ No CAS ]
4-(3-(2-((2,6-bis(trifluoromethyl)benzyl)amino)-2-oxoethyl)-4-fluorophenyl)-N-(1H-indazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide[ No CAS ]
4-(3-(2-((2,6-dimethoxybenzyl)amino)-2-oxoethyl)-4-fluorophenyl)-N-(1H-indazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide[ No CAS ]
4-(3-(2,6-dichlorophenoxy)-1H-indazol-1-yl)-3-methylbenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: 3-(2,6-Dichlorophenoxy)-1H-indazole (75.0 mg; 0.27 mmol; 1.00 eq.) and tetrahydrofuran (3.00 mL) were stirred at room temperature in a round bottom flask under nitrogen atmosphere. Sodium hydride 60% in mineral oil (21.5 mg; 0.54 mmol; 2.00 eq.) was added portion wise. After 15 minutes, methyl-6-chloro-nicotinic acid (92.2 mg; 0.54 mmol; 2.00 eq.) was added and the reaction mixture was stirred at 80 C for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate (50 mL). The organic layer was washed with a saturated solution of NH4Cl (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue, methanol (5.00 mL) were stirred in a round bottom flask. A 10 M solution of sodium hydroxyde (1.00 mL; 10.0 mmol; 37.2 eq.) was added and the reaction mixture was stirred at 50 C for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate (20 mL) and water (10 mL). The pH of the aqueous layer was adjusted to 1 using a 3 M solution of hydrochloric acid. The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were dried over MgSO4, filtered and concentrated. The residue was purified using preparative LCMS.6-(3-(2,6-Dichlorophenoxy)-1H-indazol-1-yl)nicotinic acid was isolated as a beige solid (41.0 mg; 36.6%).1
(cis)-3-methyl-5-carboxylic acid methyl ester-2-(2-(trimethylsilyl)vinyl)phenyltrimethylsilane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 100℃; for 12h;Inert atmosphere;
0.2 mmol of potassium carbonate and 0.01 mmol of palladium acetate.Triphenylphosphine 0.02mmol,Methyl 2,3-dicarboxylate-7-oxanorbornadiene 0.2 mmol,2-fluoro-4-carboxylic acid methyl ester iodobenzene 0.1 mmol,Hexamethyldisiloxane 0.15mmol,1 mL of N,N-dimethylformamide was added to a 15 mL reaction tube.Nitrogen was repeatedly filled 3 times, placed in an oil bath at 100 C, and reacted for 12 h;After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with water three times.The organic phase was dried over anhydrous Na2SO4, filtered and concentrated.Purified by column chromatography22.4 mg of target product,The yield was 70%.
General procedure: (2) Take 0.15 muM compound 1 in 100 ml round bottom flask, added 2.5 times equivalent of 80% hydrazine hydrate, reflux reaction for 2 h. After the system was cooled, a white solid precipitated, which was washed and dried to obtain the compound 2, yield 77-91%.
methyl (R)-2-((8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-1-yl)methyl)benzoate hydrochloride[ No CAS ]
Chemistry
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Material Science
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110K+ Compounds
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