* 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.
Reference：
[1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
2
[ 403-33-8 ]
[ 459-56-3 ]
[ 391-92-4 ]
[ 392-04-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
3
[ 67-56-1 ]
[ 345-29-9 ]
[ 392-04-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 80℃; for 12 h;
A solution of 4-fluoro-2-hydroxybenzoic acid (5.0 g, 32 mmol) and H2SO4 (4 mL) in MeOH (26 mL) was stirred at 80 °C for 12 h. After this time the mixture was concentrated under reduced pressure and water (10 mL) was added. The pH was adjusted to 8 by addition of an aqueous solution of NaOH (6 N) and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2S04, filtered and concentrated under vacuum to give the title compound (4.6 g, 87percent) as a yellow oil.
87%
at 0 - 70℃; for 16 h;
To a solution of 100 g (0.64 mol, 1.0 eq.) of 1,4-fluoro-2-hydroxybenzoic acid (XLIa) in 1 L of MeOH at 0 °C was slowly added 100 mL of concentrated sulfuric acid at 0 °C. The mixture was allowed to warm to room temperature and then heated at 70 °C for 16 h. The mixture was then allowed to cool to room temperature and concentrated under reducedpressure. The residue was redissolved in 1 L of ethyl acetate and washed with 500 mL of sat. NaHCO3 followed by 500 mL of brine. The organic phase was dried (Na2SO4), filtered and the solvent was removed in vacuo to provide 95 g (0.56 mol, 87percent) of methyl 4-fluoro-2- hydroxybenzoate (XLIIa).
74.9%
at 60℃; for 5 h;
Methanol (4L) was added to a dry 10L four-necked flask,4-Fluorosalicylic acid (500 g, 3.20 mol) was added with stirring,Then SOCl2 (761 g, 6.40 mol) was added slowly,During the reaction temperature, so that it does not exceed 60 , Canada completed,Insulation reaction for about 5h, TLC test until the reaction is completed, the reaction mixture was concentrated under reduced pressure to a volume of 1.5L,Cool to -5-0 ,Stirring crystallization 2h after filtration, the filter cake with an appropriate amount of ice methanol until neutral,A white solid was obtained and dried under reduced pressure at 30 ° C for 12h,432 g of methyl 4-fluorosalicylic acid was obtained in a yield of 74.9percent.mp 39.4 ~ 40.2 ° C.
22.8 g
Reflux
B. Methyl-2-hydroxy-4-fluorobenzoate (3) Crude (2) was suspended in absolute methanol (500 mL), and concentrated sulfuric acid (100 mL) was added slowly. The suspension was heated at reflux overnight. To the suspension was added water (300 mL) and the methanol was mostly removed under vacuum, but without heating, to avoid sublimation of the product. The precipitate was collected, and dissolved in organic solvent (such as dichloromethane), dried with Na2SC>4, and the solvent was evaporated, again without heat, to yield (3) (22.8 g, 134 mmol).
17 g
at 0 - 60℃; for 48 h;
To a solution of 4-fluoro-2-hydroxybenzoic acid (20 g) in MeOH (300 mL) at 0 °C was added sulfuric acid (20.49 mL) dropwise. The reaction mixture was heated to 60 °C and was stirred for 2 days. The reaction mixture was concentrated under reduced pressure and the residue poured into water and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (17 g). GSMS m/z 170.1 (M+). Alternatively, the title compound can be prepared by the following method. A mixture of 4- fluoro-2-hydroxybenzoic acid (0.800 g) in thionyl chloride (3.0 mL) was stirred at room temperature for 10 min and then heated at 70 °C for 30 min. The reaction mixture was then concentrated in vacuo to yield a light yellow semi-solid (857 mg). The solid was cooled to 0 °C and MeOH (6.0 mL) was carefully added (gas evolution observed). The reaction mixture was warmed to room temperature and then concentrated in vacuo to afford the crude title product as a white solid (754 mg). LCMS m/z 171 .1 (M+H)+.
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 2, p. 223 - 234
[2] Patent: WO2018/148204, 2018, A1, . Location in patent: Page/Page column 176
[3] Patent: WO2018/172852, 2018, A1, . Location in patent: Page/Page column 214; 222-223
[4] Patent: CN107501260, 2017, A, . Location in patent: Paragraph 0030; 0031; 0032; 0035; 0036
[5] Acta Chemica Scandinavica, 1997, vol. 51, # 8, p. 881 - 888
[6] Patent: US2004/176325, 2004, A1, . Location in patent: Page/Page column 25; sheet 26
[7] Patent: WO2013/148857, 2013, A1, . Location in patent: Paragraph 00394; 00408; 00418
[8] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5301 - 5303
[9] Patent: WO2017/153952, 2017, A1, . Location in patent: Page/Page column 91
4
[ 403-33-8 ]
[ 392-04-1 ]
Yield
Reaction Conditions
Operation in experiment
78%
With oxone; Ru(MesCO2)(4,4'-dibromobipyridine)(p-cymene); trifluoroacetic acid; trifluoroacetic anhydride In 1,2-dichloro-ethane at 110℃; for 8 h; Sealed tube; Green chemistry
General procedure: The Ru(MesCO2)(L) (p-cymene) [L- 2,2’-bypyridine or 4,4’-dibromobipyridine] (2.5 molpercent), oxidant (2.0 eq) and ester (1.0 eq) were added to a sealed tube. Following that, trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) in the ratio of 0.6 ml: 0.4 were added. The reaction mixture was kept on a pre-heated bath at 110°C and stirred until its completion. It was continuously monitored by TLC. Ice water was added to quench the reaction mixture and it was extracted with dichloromethane. The organic layer was dried over Na2SO4 and rota-evaporated. Finally the residue was purified by silica gel column chromatography to give corresponding products.
Example 33: Intermediate 87--Methyl 4-fluoro-2-hydroxybenzoate [0418] To 4-fluoro-2-hydroxybenzoic acid (5.33g, 0. 034MOL) in anhydrous methanol (26mL), under nitrogen at room temperature, was added sulfuric acid (1. 5ML). The reaction mixture was brought to reflux and kept under reflux overnight. More sulfuric acid (2. 5mL) was added and the reaction mixture kept under reflux overnight. Half the solvent was removed in vacuo and the remaining solution poured over ice-H2O. The product was then extracted with ET20 (2X). The combined ether extracts were washed with a cold solution of saturated sodium bicarbonate, treated with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. 5.49g (95percent) of methyl 4-fluoro-2-hydroxybenzoate were isolated as a white solid. Its identity was confirmed BY#x0;HNMR.
92%
Stage #1: With sulfuric acid In methanol for 48 h; Heating / reflux
Reference Example 48 methyl 2-[[(dimethylamino)carbothioyl]oxy]-4-fluorobenzoate 4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300 ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto.. The reaction mixture was refluxed for 48 hrs.. The solvent was evaporated, and the residue was neutralized with 2 N aqueous sodium hydroxide solution.. ethyl acetate was added to the mixture.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated to give methyl 4-fluorosalicylate (10.0 g, 92 percent) as white crystals..
A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100mL) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of (trimethylsilyl) diazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the (trimethylsilyl) diazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give the title compound (10.4 g, 98percent) as a solid. 1NMR FD-MS, m/e 170 (m+) Analysis forCgH7FO3 :Calcd: C, 56.48 ; H, 4.15 ;Found: C, 56.17 ; H, 4.28.
To an acetone (10 mL) solution of 4-fluoro-2-hydroxy benzoic acid methyl ester (1.0 g), potassium carbonate (1.2 g) and iodomethane (732 muL) were added one by one, and the reaction solution was concentrated under reduced pressure, after refluxing for 4 hours. Potassium carbonate (1.20 g) and imidazole (479 mg) were added to a DMF (10 mL) solution of the obtained residue (1.08 g) one by one, and the reaction solution was agitated at 80 C. overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:hexane:ethyl acetate=3:1?ethyl acetate:methanol=10:1), and 370 mg of the title compound was obtained. The physical properties of the compound are as follows. 1H-NMR (CDCl3) delta (ppm): 7.92-7.96 (m, 2H), 7.34 (s, 1H), 7.23 (s, 1H), 6.97-7.04 (m, 2H), 3.98 (s, 3H), 3.91 (s, 3H)
N-cyclopropyl-4-fluoro-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 20℃;
A suspension of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (510 mg, 3.0 mmol) in cyclopropylamine (5 mL) was stirred at room temperature overnight when it became a clear solution. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum ether) to give the subtitled compound (493 mg). 1H-NMR (CD3OD, 400 MHz): delta 12.65 (s, 1H) ; 7.28 (m, 1H) ; 6.69 (dd, J = 2.6, 10.4 Hz, 1H) ; 6. 56 (ddd, J = 2.6, 8.0, 10.4 Hz, 1H) ; 6.30 (br. s, 1H) ; 2.88 (m, 1H) ; 0.98 (m, 2H); 0.66 (m, 2H). APCI-MS: m/z 196 (MH+).
With 1,4-diaza-bicyclo[2.2.2]octane; In DMF (N,N-dimethyl-formamide); at 20℃; for 7h;
<strong>[392-04-1]methyl 4-fluorosalicylate</strong> (10.0 g, 58 mmol) and N,N-dimethylthiocarbamoyl chloride (9.6 g, 77 mmol) were dissolved in DMF (100 ml), and 1,4-diazabicyclo[2.2.2]octane (8.5 g, 75 mmol) was added thereto.. The reaction mixture was stirred at room temperature for 7 hrs.. The reaction mixture was combined with ethyl acetate and water.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated.. The residue was subjected to a silica gel column chromatography.. The fractions eluted with ethyl acetate-hexane (1:5, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (12.1 g, 80 %) as white crystals. mp. 106.8-107.2 C1H-NMR (CDCl3) delta: 3.39 (3H, s), 3.46 (3H, s), 3.83 (3H, s), 6.87 (1H, m), 7.02 (1H, m), 8.03 (1H, m). IR(KBr): 2949, 1728, 1606, 1539, 1496, 1396, 1286, 1257, 1151, 1113, 1086 cm-1
Example 33: Intermediate 87--Methyl 4-fluoro-2-hydroxybenzoate [0418] To 4-fluoro-2-hydroxybenzoic acid (5.33g, 0. 034MOL) in anhydrous methanol (26mL), under nitrogen at room temperature, was added sulfuric acid (1. 5ML). The reaction mixture was brought to reflux and kept under reflux overnight. More sulfuric acid (2. 5mL) was added and the reaction mixture kept under reflux overnight. Half the solvent was removed in vacuo and the remaining solution poured over ice-H2O. The product was then extracted with ET20 (2X). The combined ether extracts were washed with a cold solution of saturated sodium bicarbonate, treated with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. 5.49g (95%) of methyl 4-fluoro-2-hydroxybenzoate were isolated as a white solid. Its identity was confirmed BY HNMR.
92%
Reference Example 48 methyl 2-[[(dimethylamino)carbothioyl]oxy]-4-fluorobenzoate 4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300 ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto.. The reaction mixture was refluxed for 48 hrs.. The solvent was evaporated, and the residue was neutralized with 2 N aqueous sodium hydroxide solution.. ethyl acetate was added to the mixture.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated to give methyl 4-fluorosalicylate (10.0 g, 92 %) as white crystals..
With potassium carbonate; In acetone; toluene; at 20℃;
Example 34: Intermediate 88--Methyl 4-FLUORO-2- (PROP-2-YN-1-YLOXY) benzoate [0419] To <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (5.49g, 0. 032MOL) in anhydrous acetone (120ML), under nitrogen at room temperature, was added propargyl bromide (7.2mL, 80% w/toluene, 0. 048MOL) and powdered potassium carbonate (8.8g, 0. 064MOL). The reaction mixture was stirred at room temperature overnight. Same work-up as for example 7.6. 45g (97/O) of methyl 4-FLUORO-2- (PROP-2-YN-1-YLOXY) benzoate was isolated as a pale orange oil. Its identity was confirmed by IHNMR
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 95℃; for 18h;
Step B: A solution of compound 2e, K2CO3, and benzyl chloride in DMF (200 mL) was heated at 95 C. for 18 hours. The mixture was filtered and the filtrate was concentrated in vacuum to a yellow oil. The oil was purified on a Biotage column, eluting with 7:2 hexane/EtOAc to provide 19.4 g of compound 3e as a clear oil.
A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100mL) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of (trimethylsilyl) diazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the (trimethylsilyl) diazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give the title compound (10.4 g, 98%) as a solid. 1NMR FD-MS, m/e 170 (m+) Analysis forCgH7FO3 :Calcd: C, 56.48 ; H, 4.15 ;Found: C, 56.17 ; H, 4.28.
With methanol; In hexane; benzene; at 20℃;
A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100 mL ) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of trimethylsilyldiazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the trimethylsilyldiazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give 10.4 g of an oil which crystallized.1NMRFD-MS, m/e 170 (m+) Analysis for C8H7FO3:Calcd: C, 56.48; H, 4.15; Found: C, 56.17; H, 4.28.
With triphenylphosphine; diethylazodicarboxylate; In benzene; at 0℃; for 1h;
A mixture of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (5.1 g, 30 mmol), triphenylphosphine (9.5 g, 36 mmol),1-tert- butoxycarbonyl-4-hydroxypiperidine (6 g, 30 mmol), and benzene (10 mL) was heated until all solids dissolved. The solution was cooled to0 C, then sonicated while adding <Desc/Clms Page number 41>diethyl azodicarboxylate (6.3 g, 36 mmol) dropwise. After the addition was complete, the reaction mixture was sonicated for an additional 60 min, diluted withCH2Cl2 (25 mL), and purified by flash chromatography, eluting with 10% EtOAc in hexanes to yield the title compound (6.45 g, 61%) as a white solid. 1NMR IS-MS, m/e 354(mol) Analysisfor ClgH24FNO5 :Calcd :C, 61. 18 ; H, 6.85 ; N, 3.98 ;Found: C, 60.98 ;H, 6.86 ; N, 4.04.
EXAMPLE 1 1.1 50 ml of DMF are added under argon to 6.0 g of 4-fluoro-2-hydroxybenzoic acid and 4.52 g of potassium hydrogencarbonate, and the mixture is stirred for 10 minutes. 3.05 ml of iodomethane are added dropwise, and the mixture is stirred at 40 for 3 hours. The mixture is poured into 150 ml of water and subjected to conventional work-up, giving 6.48 g of methyl 4-fluoro-2-hydroxybenzoate ("1a").
1.2 5 ml of dichloromethane are added under argon to 1.06 g of aluminium chloride, and the mixture is cooled to 0 with stirring. 940 mul of phenylacetyl chloride are added dropwise, followed by a solution of 695 mg of "11a" in 5 ml of dichloromethane. The mixture is stirred at 0 for 10 minutes, then at RT for 16 hours. The mixture is cooled to 0, hydrolyzed using 1 N HCl and subjected to conventional work-up. For purification, the residue is chromatographed over a 40 g silica-gel column, giving 323 mg of methyl 4-fluoro-2-hydroxy-5-phenylacetylbenzoate ("11b")
With caesium carbonate; In N,N-dimethyl-formamide; for 24h;
EXAMPLE 3A methyl 2-(benzyloxy)-4-fluorobenzoate; Methyl 4-fluoro-2-hydroxybenzoate (2.00 g), benzyl bromide (1.54 mL), and cesium carbonate (4.60 g) in N,N-dimethylformamide (50 mL) were stirred for 24 hours. The reaction was taken up in ether and washed with 3x IM NaOH solution, and brine, then concentrated to give the pure product.
With caesium carbonate; In N,N-dimethyl-formamide; for 24h;
Example 7C methyl 2-(benzyloxy)-4-fluorobenzoate Methyl 4-fluoro-2-hydroxybenzoate (2.00 g), benzyl bromide (1.54 mL), and cesium carbonate (4.60 g) in N,N-dimethylformamide (50 mL) were stirred in for 24 hours. The reaction was taken up in ether and washed 3* with 1M NaOH solution and with brine, then concentrated to give the title compound.
With potassium carbonate; In N,N-dimethyl-formamide;Heating;
Methyl 4-fluoro-2-hydroxybenzoate (0.3 g, 1.8 mmol), K2CO3 (0.15 g, 3.0 mmol) and benzylbromide (0.34 g, 2.0 mmol) were mixed in 2 mL dry DMF. The reaction-64-SDI-10975vl Attorney Docket No. 12560-046-228mixture was heated for several hours and thereafter concentrated and extracted with CH2Cl2 after addition of water. The combined organic phases were dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2, CH2Cl2) to afford 400 mg of pure (NMR) methyl 2-benzyloxy-4-fluorobenzoate.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 24h;
EXAMPLE 4A methyl 4-fluoro-2-phenethoxybenzoate; Methyl 4-fluoro-2-hydroxybenzoate (1.00 g) and phenethyl alcohol (0.64 niL) were added to triphenylphosphine (1.54 g) and diisopropylazodicarboxylate (1.04 rnL) in tetrahydrofuran (20 rnL) at O0C, and the reaction was stirred at room temperature for 24 hours. The mixture was chromatographed on silica gel with 5% ethyl acetate/hexanes.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h;
Example 8A methyl 4-fluoro-2-phenethoxybenzoate Methyl 4-fluoro-2-hydroxybenzoate (1.00 g) and phenethyl alcohol (0.64 mL) were added to triphenylphosphine (1.54 g) and diisopropylazodicarboxylate (1.04 mL) in tetrahydrofuran (20 mL) at 0 C., and the mixture was stirred at room temperature for 24 hours. The reaction was chromatographed on silica gel with 5% ethyl acetate/hexanes.
Methyl 4-fluoro-2-hydroxybenzoate (1661 mg) was added to N,N-dimethylformamide (50 mL). Sodium hydride (60% in mineral oil, 430 mg) was added, the solution stirred for 15 minutes at room temperature, and 1-(bromomethyl)-4-methoxybenzene (2061 mg) was added. The solution was stirred at room temperature for three days, added to 0.01M aqueous HCl, and extracted with ethyl acetate. The organic phase was washed with water twice, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum.
methyl 4-fluoro-2-((6-nitropyridin-3-yl)oxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.3 g
With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 1h;
A mixture of 5-chloro-2-nitropyridine (2.5 g, 15.75 mmol), <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (2.44 g, 14.38 mmol), K 2CO 3 (3.96 g, 28.65 mmol) in DMSO (30 mL) was stirred at 110 C for 1 hour. TLC showed the reactant was consumed completely. The reaction mixture was cooled to room temperature and was poured into water and was then extracted with EA (40 mL 3). The combined organic layers were washed with brine (50 mL 2), dried over Na 2SO 4, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluent: PE/EA = 50/1 to 1/1) to obtain methyl 4-fluoro-2- ((6-nitropyridin-3-yl) oxy) benzoate (1.3 g). MS (ESI, m/e) [M+1] + 293.5.
Example 44A methy 4-fluoro-2-(3-fluoro-2-nitrophenoxy)benzoate To a solution of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (3.0 g) in tetrahydrofuran (65 ml) was added potassium t-butoxide (1.979 g) portionwise. The resulting solution was stirred at ambient temperature for 30 minutes and a solution of 1,3-difluoro-2-nitrobenzene (2.338 g) in tetrahydrofuran (15 ml) was added dropwise. After 1 hour the reaction was heated at reflux for 18 hours. The reaction was quenched with water (10 ml), diluted with brine (75 ml) and extracted with twice methylene chloride (75 ml). The crude product was isolated by concentration and purified on silica gel, and eluted with a 10, 20, 50% ethyl acetate in hexane step gradient.
With hydrazine hydrate; In methanol; at 80℃; for 18h;Reflux;
To a solution of <strong>[392-04-1]methyl 4-fluorosalicylate</strong> (500 mg, 2.94 mmol, commercially available from e.g. Apollo, Alfa Aesar or ABCR ) in methanol (15 ml) stirred under argon at room temp was added neat hydrazine monohydrate (0.722 ml, 14.69 mmol). The reaction mixture was stirred at 80 0C for 18 hr. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (~ 50 ml) and water (~ 25 ml). The aqueous phase was extracted with ethyl acetate (2 x 25 ml) and the combined organic extracts washed with brine (25 ml), dried over sodium sulphate, evaporated in vacuo and dried (vacuum oven, 40 0C, 24 hr) to afford the crude product as an off-white solid in 385 mg.LCMS: 2 minute run in MeOH. [M+H]+ m/z = 171.16 Da, retention time = 0.50-0.51 min.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -20 - 20℃; for 2h;Inert atmosphere;
Example 24: Methyl 2-(5-(tert-butoxycarbonylamino)pentyloxy)-4-fluorobenzoate (I- 25} The reaction was carried out under N2 atmosphere. Triphenyl phosphine (0.52 mol) was added to a solution of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (0.47 mol), tert-butyl 5-hydroxypentylcarbamate (0.47 mol) and diisopropyl azodicarboxylate (DIAD;0.94 mol) in THF (1 1) drop wise at -20C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. The resulting mixture was used directly in the next step without further purification.
With potassium carbonate; potassium iodide; In acetone; for 6h;Inert atmosphere; Reflux;
Example 39: Methyl 2-(allyloxy)-4-fluorobenzoate (1-40) Methyl 4-fluoro-2-hydroxybenzoate (0.27 mol), K2C03 (0.41 mol), and KI (27 mmol) were charged in a 1-1 reactor under N2. Acetone (500 ml) was added, followed by 3-bromo-propene (0.33 mol). The mixture was refluxed for 6 h under N2. The mixture was cooled to room temperature and filtered to remove the solid. The solvent was removed under vacuum, and the residue dissolved in water (200 ml) and CH2C12 (300 ml). The organic and aqueous layers were separated and the aqueous phase extracted with CH2C12. The organic layers were combined and dried with Na2S04. The solvent was removed under vacuum to give Intermediate 1-40 as a white solid.
With potassium carbonate; In acetonitrile; for 12h;Reflux;
Example 37: Methyl 4-fluoro-2-(4-methoxybenzyloxy)benzoate (1-38) Methyl 4-fluoro-2-hydroxybenzoate (0.88 mol) was dissolved in CH3CN (1.5 1). Para methoxy benzylchloride (1.3 mol) and K2C03 (2.2 mol) were added. The mixture was refluxed for 12 h. The mixture was filtered to remove the solid. The solvent was removed under vacuum. The resulting residue was purified by flash columnchromatography (eluent: CH2C12). Yield 270 g (90% purity, 95% yield).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -10 - 20℃;Inert atmosphere;
Example 27: Methyl 2-(4-(tert-butoxycarbonylamino)butoxy)-4-fluorobenzoate (1-28)Methyl 4-fluoro-2-hydroxybenzoate (21 mmol), tert-butyl 4-hydroxybutylcarbamate (21 mmol) and triphenyl phosphine (24 mmol) in THF (70 ml) was cooled to -10C. Then, DIAD (43 mmol) was added. The mixture was stirred for 30 min at -10C under N2. The ice-bath was removed and the mixture was stirred overnight at 20C. The solvent was removed under vacuum. The residue was washed with petroleum and diethyl ether. The white solid was filtered and it was confirmed to betriphenylphosphine oxide (RhoRho1¾=0). The filtrate was evaporated to dryness. The residue was purified with flash column (petroleum/ethyl acetate 100:0 to 5: 1). Yield: 8.18 g (purity 90%, yield 98%).
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 20℃; for 6.33333h;Cooling with ice;
To a solution of 2 g of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> in 60 mL of tetrahydrofuran were added 1.83 g of hydroxyethyl 2-acetate and 3.56 g of tributylphosphine, and then 5.93 g of 1,1'-(azodicarbonyl)dipiperidine was slowly added thereto under ice-cooling, followed by stirring for 20 minutes. The mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was poured into a mixed liquid of water and ethyl acetate. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 2.4 g of methyl 2-(2-acetoxyethoxy)-4-fluorobenzoate.
With potassium carbonate; In acetone; at 60℃; for 12h;
Preparation Example 17 To a mixture of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (29.55 g), potassium carbonate (31.00 g), and acetone (280 mL) was added 3-bromodihydrofuran-2(3H)-one (25 mL). The reaction mixture was warmed to 60 C. and stirred for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-fluoro-2-[(2-oxotetrahydrofuran-3-yl)oxy]benzoate (31.90 g) as a white solid.
With caesium carbonate; In dimethyl sulfoxide; at 60℃; for 18h;
A mixture of <strong>[392-04-1]4-fluoro-2-hydroxy-benzoic acid methyl ester</strong> (1.00 g, 5.88 mmol), 1 ,2- dibromo-1 ,1 ,2,2-tetrafluoro-ethane (3.05 g, 11.76 mmol) and cesium carbonate (2.87 g, 8.82 mmol) was prepared in DMSO (6 mL) and heated at 60C for 18 hours. The reaction mixture was diluted with MTBE (100 mL) and washed with water (2x50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (100 ml). The organic layers were combined, dried (Na2S04) and concentrated under vacuum to give 1.85 g of a yellow oil. The oil was taken up with A(731C8EB7-9285-4FBA-891A- 47644E86CDBD)cOH (6 mL) and heated at 60C, then zinc powder(606F2DFB- D1 E8-432B-8EFC-22C7EA414249 (1.15 g, 17.6 mmol) was added in four portions over 1 hour. After 1 hour of stirring at 60C, the reaction mixture was diluted with DCM (50 mL) and the suspension was removed by filtration. The filtrate was washed with water (25 mL) and a 1 N aqueous solution of NaOH (25 mL + 5N aqueous solution of NaOH to adjust pH=14). The aqueous layers were extracted with DCM (25 mL). The organic layers were combined, dried (Na2S04) and concentrated under vacuum. After purification by flash chromatography (silica, heptane/DCM), the title compound was obtained as a colorless oil (917 mg, 58%).
With 1,1'-(azodicarbonyl)dipiperazine; tributylphosphine; In tetrahydrofuran;
Preparation Example 16 [0119] To a solution of 3 g of 111 <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> in 60 mL of 95 tetrahydrofuran were added 1.98 g of 112 tetrahydrofuran-3-ylmethanol and 4.28 g of 113 tributylphosphine, followed by ice-cooling. To a mixture was gradually added 6.67 g of 114 1,1'-(azodicarbonyl)dipiperazine, followed by stirring for 20 minutes. The mixture was warmed to room temperature, stirred for 16 hours, and then poured into a mixed liquid of water and ethyl acetate. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 3.14 g of 115 methyl 4-fluoro-2-(tetrahydrofuran-3-ylmethoxy)benzoate.
C. 4-Fluoro-2-hydroxy-5-propionyl-benzoic acid methyl ester (4) A flask was charged with aluminum chloride (40 mmol), and dichloromethane (100 mL). To the stirred suspension was added propionyl chloride (40 mmol), and after five minutes, a solution of (3) (2.0 g, 12 mmol) in dichloromethane (20 mL), was added. The reaction was heated at reflux overnight. An aliquot was analyzed, and if the reaction was not complete, an additional equivalent of aluminum chloride and propionyl chloride was added, and the reaction was then allowed to continue stirring at reflux. Once the reaction was found to be complete, then the reaction was quenched by the addition (very slowly at first) of IN HC1 (100 mL). Sufficient DCM and IN HC1 was added until there was no precipitate. The organic layer was isolated, dried with Na2S04, and evaporated to give (4) as an oil.
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