* 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] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
[2] Journal of the Chemical Society, 1954, p. 2556,2557, 2561
[3] Molecular Crystals and Liquid Crystals, 2009, vol. 502, p. 258 - 271
5
[ 321-28-8 ]
[ 350-29-8 ]
Reference：
[1] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
[2] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
6
[ 405-04-9 ]
[ 350-29-8 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
7
[ 99-96-7 ]
[ 350-29-8 ]
[ 74799-63-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
13
[ 367-12-4 ]
[ 350-29-8 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24
14
[ 351-54-2 ]
[ 350-29-8 ]
Reference：
[1] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
15
[ 351-52-0 ]
[ 350-29-8 ]
Reference：
[1] Monatshefte fuer Chemie, 1955, vol. 86, p. 511,515
16
[ 331-62-4 ]
[ 350-29-8 ]
Reference：
[1] Journal of Materials Chemistry, 2002, vol. 12, # 8, p. 2214 - 2220
17
[ 67-56-1 ]
[ 350-29-8 ]
[ 403-01-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 80℃; Cold solution
Methyl 3-fluoro-4-hydroxybenzoate (T10.1). To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (commercially available from Sigma- Aldrich, St. Louis, MO, USA) (5.03 g, 32.22 mmol) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80°C and monitored with TLC. After 20.5 hours, the solvent was removed and the resulting mixture was diluted with diethyl ether. The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to afford TlO.1 as a white solid (4.79 g, 87percent yield). 1H NMR (400 MHz, CDCl3) 7.81 (2 H, m), 7.06 (1 H, t, J=8.4 Hz), 5.62 (1 H, d, J=4.3 Hz), 3.91 (3 H, s).
87%
at 80℃; for 20.5 h;
Methyl 3-fluoro-4-hydroxybenzoate (T25.1). To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (5.03 g, 32.22 mmol)(comrnercially available from Aldrich) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80°C and monitored with TLC. After 20.5 hours, the solvent was removed and the mixture was diluted with diethyl ether. The organic phase was washed carefully twice with saturated aqueous NaHCO3 and once with brine. The organic phase was then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to afford T25.1 as a white solid (4.79 g, 87percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (2 H, m), 7.06 (1 H, t, J=8.4 Hz), 5.62 (1 H, d, J=4.3 Hz), 3.91 (3 H, s).
85%
Heating / reflux
Hydroxy -aryl- or hydroxy-heteroaryl-carboxylic acid to methyl ester- General procedure4-hydroxy-benzoic acid (usually 24.0 mmol) was dissolved in MeOH (50 mL) and sulfuric acid (1 mL/g substrate) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification. The yields were between 80 and 90percent.; a) 3-Fluoro-4-hydroxy-ben.sum.oic acid methyl ester3-Fluoro-4-hydroxy-benzoic acid (5 g, 32.0 mmol) was dissolved in-MeOH (50 niL) and catalytic quantity of sulfuric acid (1 mL) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; <n="121"/>the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the residue was used without further purification (yield 85percent).C8H7FO31H-NMR (dmso-d6): 3.78 (3H, s); 7.00-7.02 (IH, m); 7.61-7.64 (2H5 m); 10.89 (l , br s).
85%
Reflux
Hydroxy-aryl- or hydroxy-heteroaryl-carboxylic acid to methyl ester - General procedure; [0157] 4-hydroxy-benzoic acid (usually 24.0 mmol) was dissolved in MeOH (50 mL) and sulfuric acid (1 mL/g substrate) was added. The mixture was re fluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification. The yields were between 80 and 90percent.
82%
for 48 h; Heating / reflux
A solution of 3-fluoro-4-hydroxybenzoic acid (5.00 g, 32.0 mmol) in 15percent methanolic sulfuric acid solution (50 mL) was heated at reflux over 48 h, then poured upon ice and extracted with ethyl acetate. The organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated to afford 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester (4.48 g, 82percent). Off-white solid, MS (ISP)=169.1 (M-H)-.
21 g
at 0 - 65℃; for 18 h;
Intermediate 26: methyl 3-fluoro-4-hydroxybenzoate To a stirred solution of 3-fluoro-4-hydroxybenzoic acid (25 g, 160 mmol, Combiblocks) in methanol (250 mL), was added SOCI2 (25 ml, 343 mmol) at 0 °C and the mixture stirred at 65 °C for 18 h. The solvent was removed under reduced pressure and the residue diluted with diethyl ether (500 ml). The mixture was washed with cold saturated NaHC03 solution (3 x 500 ml), brine solution (2 x 500 ml), dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give the title compound as a brown solid (21 g) which was used in the next step without further purification. (0324) LCMS Method B: m/z [M-H]" 169, tR 0.73 min
With sulfuric acid; sodium hydrogencarbonate In methanol; hexane
Step i) Production of methyl 3-fluoro-4-hydroxybenzoate 10.0 g (64.1 mM) of 3-fluoro-4-hydroxybenzoic acid, 150 ml of 1,2-dichloroethane, 80 ml of methanol and 10 ml of concentrated sulfuric acid were mixed, followed by refluxing for 5.5 hours under stirring and further stirring for 12 hours at room temperature. After the reaction, a solution of salt was added to the reaction mixture, followed by sufficient shaking to separate the reaction mixture. The organic layer was recovered from the reaction mixture and the water layer was subjected to extraction with methylene chloride to be added thereto. The resultant organic layer was washed with a 5percent-aqueous solution of sodium hydrogencarbonate in a solution of salt and further washed with a solution of salt, followed by drying with anhydrous sodium sulfate. The sodium sulfate was recovered by filtration and the filtrate was condensed into a solid. Hexane was added to the solid and subjected to filtration to obtain 9.98 g of methyl 3-fluoro-4-hydroxybenzoate (Yield: 91.6percent).
2,3-Difluoro-4-tetradecyloxy-benzoic acid 4-{4'-[4-(10-benzyloxycarbonyl-decyloxy)-3-fluoro-benzoyloxy]-biphenyl-3-yloxycarbonyl}-phenyl ester[ No CAS ]
PART A -- Preparation of (S)-2-methyl-1-butyl 3-fluoro-4-hydroxybenzoate . In a 250-ml, round-bottomed flask equipped with a heating mantle, magnetic stirrer, condenser and Dean Stark trap, were placed 2.5 g (16.0 mmol) of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong>, ten g (113.4 mmol) of (S)-2-methyl-1-butanol, 0.347 g of p-toluenesulfonic acid monohydrate and 100 ml of benzene. The reaction mixture was stirred overnight under reflux. The reaction mixture was extracted using saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered through cotton and evaporated to an oil. The product was purified by flash chromatography on silica gel with 3percent diethyl ether in dichloromethane. Fractions containing the desired product were combined and evaporated to a pale-yellow oil. Analysis by NMR showed that considerable starting alcohol remained. The oil was placed under vacuum (at 70°C) for two days. No alcohol was shown by gas chromatography to be present. The desired product was obtained in the amount of 2.39 g (66percent yield) and had the following structure.
With potassium carbonate; In tetrahydrofuran; water;
a 3-Fluoro-4-(4-fluoro-benzyloxy)-benzoic Acid 4-Fluoro-benzyl Ester A mixture of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (4.68 g, 30 mmol), 4-fluorobenzyl bromide (17.0 g, 90 mmol) and potassium carbonate (8.3 g, 60 mmol) in THF: water (1:1, 100 mL) was heated at 65° C. for 48 h. After cooling to room temperature the mixture was extracted with ethyl acetate (2*100 mL) and the combined extracts washed with brine (100 mL) and dried over sodium sulfate. Filtration and evaporation gave a residue which was crystallized from ether:heptane to afford the title compound (8.4 g, 75percent) as a white solid. MS: m/e=372.0 (M+).
75%
With potassium carbonate; In tetrahydrofuran; water; at 65℃; for 48h;
Example 18; (S)-N-(1-carbamoyl-ethyl)-3-fluoro-4-(4-fluoro-benzyloxy)-benzamide; a) 3-fluoro-4-(4-fluoro-benzyloxy)-benzoic acid 4-fluoro-benzyl ester; A mixture of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (4.68 g, 30 mmol), 4-fluorobenzyl bromide (17.0 g, 90 mmol) and potassium carbonate (8.3 g, 60 mmol) in THF: water (1: 1, 100 mL) was heated at 65 °C for 48 h. After cooling to room temperature the mixture was extracted with ethyl acetate (2 x 100 mL) and the combined extracts washed with brine (100 mL) and dried over sodium sulfate. Filtration and evaporation gave a residue which was crystallised from ether: heptane to afford the title compound (8.4 g, 75percent) as a white solid. MS: m/e = 372.0 (M+).
With HOAt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 15h;
To the solution of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (5 g, 32 MMOL) and propylamine (3.1 ML, 38 ML) in DMF (250 ML), HOAt (5.2 g, 38 MMOL) and WSCI. HCI (7.2 g, 38 MMOL) are added at 0C. THE REACTION mixture is stirred at rt for 15 h and quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts are washed with H20, brine and dried over magnesium sulfate. Chromatography on silica gel (eluent ; dichloromethane and 3 percent MeOH in DICHLOROMETHANE) gives 4.8 g of desired product; RF=0. 76 (DICHLOROMETHANE : MeOH = 8: 2)
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;
A solution of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (5.0 g, 32 mmol), piperidine (5 mL, 51 mmol), and EDCl (9.3 g, 49 mmol) in CH2Cl2 (100 mL) was stirred at room temperature for 20 h. The reaction mixture was added to CH2Cl2 (200 mL) and was washed with 1 M HCl (2.x.100 mL). The organic layers were combined, dried (MgSO4), and concentrated under reduced pressure to yield a clear golden oil. The oil was purified on SiO2 (120 g; 0-10percent acetone/CH2Cl2) to give a white solid (2.4 g, 34percent yield). TLC (SiO2, 15percent acetone/CH2Cl2): Rf=0.35. MS (ESI): mass calculated for C12H14FNO2, 223.1; m/z found, 224.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 10.26 (s, 1H), 7.18 (d, J=11.6, 1H), 7.00 (d, J=8.3, 1H), 6.98 (t, J=8.5, 1H), 3.42 (br s, 4H), 1.65-1.45 (m, 6H).
34%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;
EXAMPLE 252; 2- (2-FLUORO-4-PIPERIDIN-1-YLMETHYL-PHENOXY)-BENZOTHIAZOLE; A. (3-FLUORO-4-HVDROXV-PHENVL)-PIPERIDIN-1-VL-METHANONE; A solution of 3- fluoro-4-hydroxybenzoic acid (5.0 g, 32 MMOL), piperidine (5 mL, 51 MMOL), and EDCI (9.3 g, 49 MMOL) in CH2CI2 (100 mL) was stirred at room temperature for 20 h. The reaction mixture was added to CH2CI2 (200 mL) and was washed with 1 M HCI (2 x 100 mL). The organic layers were combined, dried (MGS04), and concentrated under reduced pressure to yield a clear golden oil. The oil was purified on Si02 (120 g; 0-10percent ACETONE/CH2CI2) to give a white solid (2.4 g, 34percent yield). TLC (SIO2, 15percent ACETONE/CH2CI2) : Rf= 0.35. MS (ESI) : mass calculated for C12H14FNO2, 223.1 ; m/z found, 224.3 [M+H] +. H NMR (400 MHz, DMSO-d6) : 10.26 (s, 1H), 718 (d, J=11. 6, 1 H), 7. 00 (d, J= 8.3, 1H), 6.98 (t, J = 8.5, 1 H), 3.42 (br s, 4H), 1.65-1. 45 (m, 6H)
To a solution of 3-fiuoro-4-hydroxybenzoic acid (Aldrich, 4.0 mmol, 624 mg) in ethanol (10 mL), was added thionyl chloride (2 mL, Aldrich). The reaction mixture was heated at 800C for 4 h, and concentrated in vacuo to remove the solvent and excess thionyl chloride to afford the desired product (736 mg, 100percent yield) as a white solid. MS(ESI+) m/z 185.33 (M + H)+.
85%
With sulfuric acid; for 96h;Heating / reflux;
A solution of <strong>[350-29-8]3-fluoro-4-hydroxy-benzoic acid</strong> (5.16g, 33.1mmol) in ethanol (100ml) was treated with cone, sulphuric acid (5ml), and the mixture heated at reflux for 4 days. The volatiles were removed in vacuo, and the aqueous residue was basified with saturated NaHC03 and extracted twice with diethyl ether. The combined organic extracts were dried and concentrated in vacuo to yield the title compound (5.16g, 85percent).
With sulfuric acid; for 24h;Heating / reflux;
A mixture of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (5.0 g), ethanol (100 ml) and concentrated sulfuric acid (1ml) was refluxed for 1 day. The reaction mixture was poured into ice water, the crystal that was precipitated was filtered, then dried to provide the title compound (24.3 g).1H-NMR (400MHz, CDCl3); delta (ppm): 1.38 (m, 3H), 4.34 (q, 2H), 5.75 (brs, 1H), 7.01 (t, 1H), 7.75-7.80 (m, 2H).
With sulfuric acid; for 5h;Heating / reflux;
Example 238 Step 1 3-FLUORO-4-HYDROXYBENZOIC acid ethyl ester To a solution of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (300 mg) in ethanol (3 ml) was added a several drop of concentrated sulfuric acid under an argon atmosphere, and the mixture was refluxed under heating for 5 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (337 mg) as a white solid. H-NMR (8PPM, DMSO-d6) 1.29 (3H, t, J=7. 0HZ), 4.26 (2H, q, J=7. 0HZ), 7.04 (1H, t, J=8.6Hz), 7.61-7. 64 (1H, m), 7.66 (1H, s), 10.83 (1H, brs).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h;
Preparation 112; 4-Ethoxv-3-fluoro-benzoic acid ethyl ester; Ethyl iodide (10.5mL, 128mmol) and potassium carbonate (44g, 320mmol) were added to a solution of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (5g, 32mmol) in N, N- dimethylformamide (50mL) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound in 80percent yield, 5.42g. rH NMR (400MHz, CDC13) d : 1.39 (t, 3H), 1.44 (t, 3H), 4.18 (q, 2H), 4.37 (q, 2H), 6.97 (m, 1 H), 7.77 (dd, 1H), 7.80 (d, 1 H) ; LRMS ESI m/z 235 [M+Na] +
cis-N-[4-(4-chlorophenoxy)cyclohexyl]methyl}-3-fluoro-4-hydroxybenzamide[ No CAS ]
trans-N-[4-(4-chlorophenoxy)cyclohexyl]methyl}-3-fluoro-4-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of 4- (azidomethyl) cyclohexyl 4-chlorophenyl ether (3.0 g, 11 mmol) and 10 percent Pd/C (0.3 g) in MeOH (50 mL) was stirred under H2 atmosphere at rt. After 14 h, the mixture was filtered through a pad of celite and washed with MeOH (50 mL) and concentrated in vacuo. The residue (0.76 g out of 2.5 g,-3. 4 mmol) was dissolved in DMF (20 mL) and to this were added <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (0.5 g, 3.2 mmol), WSC (0.73 g, 3.8 mmol), HOBt (0.58 g, 3. 8 mmol) and Et3N (0.90 mL, 6.4 mmol) at rt. After 18 h, the reaction mixture was quenched by addition of sat. aq. NaHC03 (50 mL) and diluted with AcOEt (50 mL). The aqueous layer was extracted with AcOEt (50 mL x 2) and the combined organic layer was washed with H2O (50 mL x 2) and brine (50 mL), dried over MgS04, filtered and concentrated. The residue was dissolved in MeOH (15 mL) and to this solution was added 2N NaOH (10 mL) and the mixture was stirred at rt. After 2 h, to this was added sat. aq. NaHC03 (50 mL) and extracted with AcOEt (100 mL). The aqueous layer was extracted with AcOEt (50 mL) and the combined organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: AcOEt = 2: 1-1. 5: 1) and HPLC saparation to give 3-fluoro-4-hydroxy-N [ (4-phenoxycyclohexyl) methyl] benxamide (94.7 mg, 8percent over 2 steps) and N-[4-(4-chlorophenoxy) cyclohexyl] methyl}-3-fluoro-4- hydroxybenzamide (80.7 mg, 6percent over 2 steps). The cisltrans separation of N-[4-(4-chlorophenoxy)cyclohexyl]methyl}-3-fluoro-4- hydroxybenzamide was carried out by chiral column (Chiralcel OJ, 20 mm I. D. x 250 mm (No. 53-03-20910), DAICEL) using n-hexane: EtOH: Et2NH = 79: 21: 0.1 as an eluent (Flow rate = 7 mL/min) at 40 °C. Example 52 white solid. , 99percent de, trans isomer, retention time 24 min. IH NMR (300 MHz, CDCI3) 8 : 7.59 (dd, J = 11. 1, 2.1 Hz, 1H), 7.46-7. 42 (m, 1H), 7.24- 7. 18 (m, 2H), 7.04 (t, J = 8.4 Hz, 1H), 6.84-6. 79 (m, 2H), 6.08 (bs, 1H), 4.11 (tt, J = 10.8, 4.2 Hz, 1H), 3.34 (t, J = 6.3 Hz, 2H), 2.19-2. 15 (m, 2H), 1.94-1. 90 (m, 2H), 1.71-1. 59 (m, 1H), 1.50-1. 36 (m, 2H), 1.29-1. 07 (m, 2H) ppm. (OH was not observed.) MS (ESI) : 378.07 (M+H) +, 376.08 (M-H)- Example 53 white solid, 98percent de, cis isomer, retention time 28 min. IH NMR (300 MHz, CDC13) 8 : 7.57 (dd, J = 11. 1, 2.1 Hz, 1H), 7.44-7. 41 (m, 1H), 7.24- 7.19 (m, 2H), 7.02 (t, J = 8.4 Hz, 1H), 6. 85-6. 80 (m, 2H), 6.12 (bs, 1H), 4.49 (bs, 1H), 3.35 (t, J = 7.5 Hz, 2H), 2.06-2. 02 (m, 2H), 1.72-1. 28 (m, 7H) ppm. (OH was not observed.) MS (ESI) : 378.10 (M+H) +, 376.07 (M-H)-
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 66h;
Step B. 3- (3-Fluoro-4-hydroxy-benzoylamino)-propionic ethyl ester; Combine 3-Fluoro-4-hydroxy-benzoic acid (l.Og, 6.4mmol), PyBOP (4.0g, 7.69mmol), 3-amino-propionic acid ethyl ester hydrochloride (1.47g, 9.6mmol) and ethyl- diisopropyl-amine (4.55mL, 25.6mmol) in N, N-dimethyl-formamide (20mL). Stir for sixty-six hours at room temperature. Dilute reaction with ethyl acetate and water. Wash organic layer with saturated solution of ammonium chloride and water. Extract combined aqueous fraction with ethyl acetate. Wash combined organic fractions with saturated sodium chloride solution. Dry organic fraction with Na2S04, filter and concentrate under reduced pressure. Purify on silica gel chromatography (20-80percent Ethyl acetate/ hexanes gradient) to provide 1.24g of title compound (76percent).
With sulfuric acid; acetic anhydride; In methanol; water;
Step i) Production of 4-acetoxy-3-fluorobenzoic acid 6.40 ml of acetic anhydride was added to 5.00 g (32.00 mM) of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong>. Under stirring at room temperature, two drops of concentrated sulfuric acid was added thereto (the mixture solidified as soon as the concentrated sulfuric acid was added), followed by heat-stirring for 10 minutes at 107°-111° C. on an oil bath (the mixture became transparent and melted by heating). After the reaction, the reaction mixture was poured into 150 ml of iced water to precipitate a crystal. The crystal was recovered by filtration and recrystallized from 20 ml of methanol to obtain 5.04 g of 4-acetoxy-3-fluorobenzoic acid (Yield: 79.4percent).
With sulfuric acid; acetic acid; In water;
2) Production of 4-acetoxy-3-fluorobenzoic acid (2) STR14 3-Fluoro-4-hydroxybenzoic acid (4.3 g) and 8.4 g of anhydrous acetic acid were charged into a two-necked flask and mixed. Five drops of sulfuric acid were added under ice cooling. After heat generation stopped, the mixture was heated at 80° C. for 30 minutes. Subsequently, the reaction mixture was charged in cold water, and precipitated crystals were filtered. The crystals were vacuum-dried and then used in the next step. The yielded amount was 4.8 g.
With sulfuric acid; In hexane; dichloromethane; water;
(a) allyl 3-fluoro-4-hydroxybenzoate Into a round bottom flask, there are introduced 5.35 g (35 mmoles) of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> and 50 ml of allyl alcohol. 1 5 ml of concentrated sulfuric acid are added and the mixture is heated to 100° C. for 12 hours. The reaction medium is evaporated to dryness and 200 ml of water are added. The reaction medium is neutralized with sodium bicarbonate and extracted with dichloromethane. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column by eluding with an 80:20 mixture of dichloromethane and hexane. 3.7 g (55percent yield) of the expected ester having a melting point of 42°-43° C. are recovered.
4-methoxycarbonyloxy-3-fluorobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With sodium hydroxide; In water;
4-methoxycarbonyloxy-3-fluorobenzoic acid (VI) was synthesised from <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (V) by reaction of the latter with methyl chloroformate. NaOH (90 mmol) and <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (30 mmol) were dissolved in water (80 ml) and cooled to -20° C. Methyl chloroformate (45 mmol) was added dropwise to the mixture. The mixture was then stirred with a magnetic stir bar at 5° C. for four hours and left overnight in the refrigerator. The mixture was then acidified to pH 5 to precipitate 4-methoxycarbonyloxy-3-fluorobenzoic acid. The precipitates were filtered and crystallized from acetonitrile to afford the clean product, 4-methoxycarbonyloxy -3-fluorobenzoic acid (VI), in a 77percent yield.
77%
With sodium hydroxide; In water;
4-methoxycarbonyloxy-3-fluorobenzoic acid (VI) was synthesised from <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (V) by reaction of the latter with methyl chloroformate. NaOH (90 mmol) and <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (30 mmol) were dissolved in water (80 ml) and cooled to -20° C. Methyl chloroformate (45 mmol) was added dropwise to the mixture. The mixture was then stirred with a magnetic stir bar at 5° C. for four hours and left overnight in the refrigerator. The mixture was then acidified to pH 5 to precipitate 4-methoxycarbonyloxy-3-fluorobenzoic acid. The precipitates were filtered and crystallized from acetonitrile to afford the clean product, 4-methoxycarbonyloxy-3-fluorobenzoic acid (VI), in a 77percent yield.
Synthesis of 3-fluoro-4-pentyloxy benzoic acid A solution of 2.26 g of potassium hydroxide in 10 ml of water was added 80 ml of ethanol, 3.13 g of <strong>[350-29-8]3-fluoro-4-hydroxy benzoic acid</strong> and 5.94 g of 1-iodopentane, which were heated under reflux for 8 hours. Then, 20 ml of 10percent potassium hydroxide was added and heated under reflux for 2 hours, and ethanol was distilled off. The reaction product was poured into 100 ml of water in a flask and added with a concentrated hydrochloric acid to adjust pH to less than 1. The precipitated crystal was filtered and recrystallized with ethanol and further with toluene two times to obtain 2.88 g (yield: 64percent) of a white crystal having the following properties: Melting point: 138.1°-138.9° C. IR (KBr, cm-1): 2920, 2550, 1680, 1610, 1280, 760
(1) A mixture of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (1.2 g), ethanol (20 ml) and concentrated sulfuric acid (1 ml) was refluxed for 13 hours, then concentrated and extracted with chloroform. The extract was washed with aqueous sodium hydrogen carbonate solution, dried and the solvent was distilled off, whereby crystals of ethyl 3-fluoro-4-hydroxybenzoate (1.3 g) was obtained. m.p. 79°-80° C.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h;
Reference Production Example 3; To 50 ml of DMF were added 5.5 g of 4-hydroxy-3- fluorobenzoic acid, 9.4 g of propargyl bromide and 11 g of potassium carbonate and the mixture was stirred at room temperature for 8 hours. Then, ethyl acetate was added to the reaction mixture and then, the mixture was filtered through Celite. Water and dilute hydrochloric acid were added to the filtrate in order and it was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 10.8 g of 2-propynyl 4- (2-propynyloxy) -3- fluorobenzoate represented by the formula: <n="163"/>2-Propynyl 4- (2-propynyloxy) -3-fluorobenzoate :1H-NMR (CDCl3) delta: 2.50 (IH, t, J = 2.5 Hz), 2.56 (IH, t, J = 2.4 Hz), 4.82 (2H, d, J = 2.4 Hz), 4.89 (2H, d, J = 2.4 Hz), 7.13 (IH, t, J = 8.3 Hz), 7.78 (IH, dd, J = 11.5, 2.1 Hz) ,' 7.82-7.86 (IH, m) .
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h;
Reference Production Example 3; To 50 ml of DMF were added 5.5 g of 4-hydroxy-3- fluorobenzoic acid, 9.4 g of propargyl bromide and 11 g of <n="106"/>potassium carbonate, and the mixture was stirred at room temperature for 8 hours. Then, ethyl acetate was added to the reaction mixture and then, the mixture was filtered through Celite. Water and dilute hydrochloric acid were added to the filtrate in order and it was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 10.8 g of 2-propynyl 4- (2-propynyloxy) -3- fluorobenzoate represented by the formula:2-Propynyl 4- (2-propynyloxy) -3-fluorobenzoate :1H-NMR (CDCl3) delta: 2.50 (IH, t, J = 2.5 Hz), 2.56 (IH, t, J= 2.4 Hz), 4.82 (2H, d, J = 2.4 Hz), 4.89 (2H, d, J = 2.4 Hz), 7.13 (IH, t, J = 8.3 Hz), 7.78 (IH, dd, J = 11.5, 2.1 Hz) , 7.82-7.86 (IH, m) .
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h;
To 50 ml of DMF were added 5.5 g of <strong>[350-29-8]4-hydroxy-3-fluorobenzoic acid</strong>, 9.4 g of propargyl bromide and 11 g of potassium carbonate, and the resulting mixture was stirred at room temperature for 8 hours. Thereafter, ethyl acetate was added to the reaction mixture, and this was filtered through Celite (registered trade mark). Water and dilute hydrochloric acid were successively added to the filtrate, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 10.8 g of 2-propynyl 4-(2-propynyloxy)-3-fluorobenzoate was obtained.2-Propynyl 4-(2-propynyloxy)-3-fluorobenzoate [Show Image] 1H-NMR (CDCl3) delta: 2.50 (1H, t, J = 2.5 Hz), 2.56 (1H, t, J = 2.4 Hz), 4.82 (2H, d, J = 2.4 Hz), 4.89 (2H, d, J = 2.4 Hz), 7.13 (1H, t, J = 8.3 Hz), 7.78 (1H, dd, J = 11.5, 2.1 Hz), 7.82-7.86 (1H, m).
a 3-Fluoro-4-(4-trifluoromethyl-benzyloxy)-benzoic Acid 4-Trifluoromethyl-benzyl Ester As described for example 18a, <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (2.5 g, 16 mmol) [using 4-(trifluoromethyl)-benzyl bromide instead of 4-fluorobenzyl bromide] was converted to the title compound (5.3 g, 69percent) which was obtained as a white solid. MS: m/e=472.1 (M+).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;
STEP 1 : A mixture of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (500 mg, 3.2 mmol), cesium carbonate (3.1 g, 9.6 mmol) and iodomethane (440 mul, 7.0 mmol) in dimethylformamide (7 mL) was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with 5percent aqueous lithium chloride, IN aqueous sodium hydroxide, brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded 534 mg, 2.9 mmol (92percent ) of methyl 3-fluoro-4- (methyloxy)benzoate. MS (EI) for C9H9FO3: 185 (MH+).
A) 3-Fluoro-4-propoxybenzoic acid A mixture of 2 g of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> and 5.31 g of K2CO3 in 50 ml of acetonitrile is refluxed for 24 hours, 0.5 ml of 1-iodopropane is added and the refluxing is continued for 7 hours. After cooling to AT, the reaction mixture is concentrated under vacuum, the residue is taken up with water, the mixture is extracted with EtOAc and the solvent is evaporated off under vacuum. The residue is taken up in 30 ml of EtOH, 5 ml of a concentrated NaOH solution are added, and the mixture is left to stir at 60° C. for 1 hour. The mixture is concentrated under vacuum, the residue is taken up with a 10percent HCl solution, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. 0.8 g of the expected compound is obtained.
With sulfuric acid; nitric acid; In water; at -5 - 20℃;
3-Fluoro-4-hydroxy-5-nitrobenzoic acid was obtained by allowing <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> and fuming nitric acid to undergo the reaction in concentrated sulfuric acid at -5°C to room temperature.
biphenyl-2-yl-carbamic acid 1-(9-methylamino-nonyl)-piperidin-4-yl ester dihydrochloride salt[ No CAS ]
[ 350-29-8 ]
[ 1205552-69-7 ]
Yield
Reaction Conditions
Operation in experiment
52%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20 - 60℃; for 36.25h;
Example 69 Biphenyl-2-yl-carbamic acid 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl}-piperidin-4-yl ester To a solution of biphenyl-2-yl-carbamic acid 1-(9-methylamino-nonyl)-piperidin-4-yl ester dihydrochloride salt (Preparation 7, 4.47 g, 9.90 mmol) in tetrahydrofuran (150 ml), was added <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (1.85 g, 11.9 mmol), triethylamine (2.07 ml, 14.8 mmol), N,N-dimethylaminopyridine (484 mg, 3.96 mmol) and (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (2.66 g, 13.9 mmol). The mixture was stirred at room temperature for 15 minutes and then at 60° C. for 18 hours. Further <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (308 mg, 2.0 mmol) was added and the reaction heated at 60° C. for a further 18 hours. The solvent was removed in vacuo and residue partitioned between ethyl acetate (200 ml) and water (150 ml). The aqueous layer was further extracted with ethyl acetate (200 ml) and the combined organic layers dried over magnesium sulphate and concentrated in vacuo. The residue was dissolved in methanol/water (115 ml/23 ml), treated with potassium carbonate (12.9 g, 93.2 mmol) and heated at 50° C. for 18 hours. The solvent was removed in vacuo and residue partitioned between dichloromethane (200 ml) and water (200 ml). The organic layer was washed with brine (100 ml) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluding with dichloromethane:methanol:880 ammonia (100:0:0 to 95:5:0.5, by volume), to furnish the title compound as an oily foam, in 52percent yield, 3.01 g. LCMS: APCI ESI m/z 590 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) delta=1.12-1.40 (m, 10H), 1.45-1.54 (m, 2H), 1.56-1.68 (m, 4H), 1.81-1.91 (m, 2H), 2.29-2.40 (m, 4H), 2.64-2.75 (m, 2H), 3.01 (s, 3H), 3.34-3.53 (m, 2H), 4.58-4.65 (m, 1H), 6.92-6.96 (m, 1H), 7.05 (d, 1H), 7.12 (d, 1H), 7.23-7.44 (m, 8H), 7.55 (d, 1H) ppm.
52%
To a solution of biphenyl-2-yl-carbamic acid 1 -(9-methylamino-nonyl)-piperidin-4-yl ester dihydrochloride salt (Preparation 5, 4.47g, 9.90mmol) in tetrahydrofuran (150ml), was added <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (1 .85g, 1 1 .9mmol), triethylamine (2.07ml, 1 4.8 m m o l ) , N , N-dimethylaminopyridine (484mg, 3.96mmol) and (3- (dimethylamino)propyl)ethyl carbodiimide hydrochloride (2.66g, 13.9mmol). The mixture was stirred at room temperature for 15 minutes and then at 60°C for 18 hours. Further <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (308mg, 2.0mmol) was added and the reaction heated at 60°C for a further 18 hours. The solvent was removed in vacuo and residue partitioned between ethyl acetate (200ml) and water (150ml). The aqueous layer was further extracted with ethyl acetate (200ml) and the combined organic layers dried over magnesium sulphate and concentrated in vacuo. The residue was dissolved in methanol/water (1 15ml/23ml), treated with potassium carbonate (12.9g, 93.2mmol) and heated at 50°C for 18 hours. The solvent was removed in vacuo and residue partitioned between dichloromethane (200ml) and water (200ml). The organic layer was washed with brine (100ml) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (100:0:0 to 95:5:0.5, by volume), to furnish the title compound as an oily foam, in 52percent yield, 3.01 g.LCMS: APCI ESI m/z 590 [M+H]+ 1H NMR (400 MHz, Methanol-d4) delta = 1 .12-1 .40 (m, 10H), 1 .45-1 .54 (m, 2H), 1 .56-1 .68 (m, 4H), 1 .81 -1 .91 (m, 2H), 2.29-2.40 (m, 4H), 2.64-2.75 (m, 2H), 3.01 (s, 3H), 3.34- 3.53 (m, 2H), 4.58-4.65 (m, 1 H), 6.92-6.96 (m, 1 H), 7.05 (d, 1 H), 7.12 (d, 1 H), 7.23- 7.44 (m, 8H), 7.55 (d, 1 H) ppm.
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 60℃; for 75h;Cooling with ice;
Example 115; Preparation of 5-[4-(1-methylethoxy)-3-fluorophenyl]-3-(3-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)benzyl)-5-methylimidazolidine-2,4-dione; 115-a) Preparation of 5-(3-fluoro-4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione; 115-a-1) Preparation of isopropyl 3-fluoro-4-(1-methylethoxy)benzoate; 3-Fluoro-4-hydroxybenzoic acid (500 mg, 3.20 mmol) was dissolved in N,N-dimethylformamide (16 mL). The resultant mixture was sequentially added with sodium hydride (purity 50percent) (384 mg, 8.01 mmol) and 1-methylethyl iodide (959 muL, 9.61 mmol) under ice-cold conditions, and stirred at 60° C. for 3 hours and then at room temperature for 3 days. The reaction solution was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate) and isopropyl 3-fluoro-4-(1-methylethoxy)benzoate (618 mg, yield 80percent) was obtained as a colorless oil.1H-NMR (CDCl3) delta: 1.35 (6H, d, J=6.4 Hz), 1.39 (6H, d, J=6.0 Hz), 4.61-4.70 (1H, m), 5.17-5.26 (1H, m), 6.97 (1H, dd, J=8.3, 8.6 Hz), 7.73 (1H, dd, J=2.2, 11.5 Hz), 7.78 (1H, ddd, J=1.2, 2.2, 8.6 Hz).
Example 4Biphenyl-2-yl-carbamic acid 1-(2-{4-[2-(3-fluoro-4-hvdroxy-benzoylamino)-ethyl1-phenyl)-ethyl)-piperidin- 4-yl esterBiphenyl-2-yl-carbamic acid 1-{2-[4-(2-amino-ethyl)-phenyl}-ethyl}-piperidin-4-yl ester (Preparation 5, 168mg, 0.379mmol), (3-(dimethylamino)propyl)ethylcarbodimide hydrochloride (87.2mg, 0.455mmol) and <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (59.2 mg, 0.379 mmol) were added to the reaction flask. A mixture of 1- methyl-2-pyrrolidinone (2ml) and 2-methyltetrahydrofuran (4ml) was added, followed by N, N- diisopropylethylamine (0.165ml, 0.948mmol) and the reaction stirred for 24 hours at room temperature under nitrogen. 1-Hydroxybenzotriazole monohydrate (70mg, 0.455mmol) was added and stirring continued for a further 24 hours. The solvent was removed in vacuo an d the residue was partitioned between dichloromethane (50ml) and water (30ml). The layers were separated and the organic layer washed with further water (30ml), dried (magnesium sulphate) and the solvent removed in vacuo. The crude residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia, 99:1 :0.1 to 90:10:1 (by volume), to furnish the title compound as an off-white solid, 31 percent yield, 67 mg.1H NMR (400 MHz, METHANOL-c/4) delta = 1.57-1.69 (m, 2H), 1.81-1.90 (m, 2H), 2.29-2.39 (m, 2H), 2.48- 2.55 (m, 2H), 2.67-2.78 (m, 4H), 2.86 (t, J=7.22 Hz, 2H), 3.54 (t, J=7.22 Hz, 2H), 4.57-4.65 (m, 1 H), 6.91 (t, J=8.58 Hz, 1 H), 7.05 (t, J=8.78 Hz, 2H), 7.09 (s, 1 H), 7.18-7.57 (m, 12H) ppm. LCMS: APCI ESI m/z 582 [M+H]+
With sulfuryl dichloride; In acetic acid; at 50 - 60℃; for 3.5h;
Sulfuryl chloride (4.7 ml.) is added to a solution of <strong>[350-29-8]3-fluoro-4-hydroxy-benzoic acid</strong> (2.97 g) in acetic acid (20 ml.) stirred at 50 0C. in N,N-dimethylformamide (3 ml.) at room temperature. The resulting solution is stirred for 2 h, prior to the addition of another portion of sulfuryl chloride (1.0 ml_). The solution is stirred at 60 0C for another 1.5 h and then cooled to ambient temperature. The solution is poured into ice-cold water and the precipitate formed is separated by filtration, washed with ice-cold water, and dried at 50 0C to afford the title compound as a beige solid. Yield: 2.15 g (57percent of theory) LC (method 1 ): tR = 2.1 1 min; Mass spectrum (ESI"): m/z = 189 [M-H]"
Carbamate 50-c (71 mg, 0.15 mmol) was dissolved in a solution of methanol: acetyl chloride 9:1 (1.5 mL) at 0 0C. The solution was stirred at room temperature for 16 hrs, then concentrated and co-evaporated twice with DCM. The crude product was dissolved in dry DMF (1 mL) at 0 0C and then added to a cold solution of <strong>[350-29-8]4-hydroxy-3-fluorobenzoic acid</strong> (25 mg, 0.165 mmol) and HATU (63 mg, 0.165 mmol) in dry DMF (2 mL). DIEA (130 muL, 0.75 mmol) was added and the reaction mixture was stirred at 0 0C for 30 minutes, then at RT for 2h. The solution was concentrated under vacuum and the residue was dissolved in DCM (3 mL) and purified by flash chromatography on a silica column (10 g) eluted with (DCM:MeOH 100:0-92:8) and then by prep (20-70percent gradient, mobile phase: acetonitrile- water, 1percent NH4OH), which gave the title compound (4.2 mg, 6percent). MS m/z 514.1 494 (M-HF)+. Purity 91percent as assessed by analytical LCMS.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
To a solution of 3-fluoro-4-hydroxybenzole acid (1.00 g), dimethylamine hydrochloride (1.57 g), triethylamine (2.68 mL) and N-hydroxybenzotriazole monohydrate (1.47 g) in methylene chloride (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.83 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added diluted hydrochloric acid water, and then the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (solvent; chloroform/methanol = 100/0 to 89/11) to give the titled compound (515 mg) as a colorless solid (yield: 44percent). MS(APCI)m/z; 184[M+H]+.
9%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;
3-Fluoro-4-hydroxybenzoic acid (2.00 g, 12.8 mmol), dimethylamine hydrochloride (4.28 g, 20.5 mmol), 1 -hydroxy benzotriazole monohydrate (1 .96 g, 12.8 mmol), and diisopropylethyl amine (4.5 ml_, 26 mmol) were combined in dichloromethane. 1 -Ethyl- 3-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.93 g, 20.5 mmol) was added, and the reaction vessel was flushed with nitrogen, capped, and stirred overnight at room temperature. The reaction was diluted with dichloromethane and Lambda Mu phosphoric acid. The precipitate that formed was filtered off and the dichloromethane layer was washed with dilute aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 65percent ethyl acetate in heptanes to give the desired product (218 mg, 9percent). LC/MS (ES+): 184.1 (M+1 )
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