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CAS No. : | 403-17-8 | MDL No. : | MFCD00143290 |
Formula : | C7H4ClFO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QPIBHIXKUQKNFP-UHFFFAOYSA-N |
M.W : | 174.56 | Pubchem ID : | 2736536 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 38.37 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.28 cm/s |
Log Po/w (iLOGP) : | 1.42 |
Log Po/w (XLOGP3) : | 2.93 |
Log Po/w (WLOGP) : | 2.6 |
Log Po/w (MLOGP) : | 2.63 |
Log Po/w (SILICOS-IT) : | 2.28 |
Consensus Log Po/w : | 2.37 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.11 |
Solubility : | 0.137 mg/ml ; 0.000784 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.37 |
Solubility : | 0.0736 mg/ml ; 0.000422 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.66 |
Solubility : | 0.379 mg/ml ; 0.00217 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | at 15℃; for 10 h; | Into 9931g of acetic acid, 2.7g of manganese acetate, 105g98percent sulfuric acid to a 20L autoclave, and then put into 99percent 3-fluoro-chlorotoluene 870g (5.96mol), stirred mixture was cooled to 15 , ozone slowly into 215g (total 10H); after completion of the reaction of nitrogen with the ozone photodissociation process; temperature and pressure recovery acetate, layers were separated and the product is recovered 988G, to give 3-fluoro-4-chlorobenzoic acid, 98.2percent pure, a yield of about 94.2 percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 16h; | An aliquot of 28 (0.65 mmol) was stirred with <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (170 mg, 0.98 mmol), EDCI (250mg, 1.3mmol), and diisopropyl- ethylamine (0.57 ml, 3.2mmol) in 5 ml of DMF. After 16 hr, the mixture was diluted with ethyl acetate (50 ml), washed with water and brine, dried over sodium sulfate, concentrated in vacuo, and purified by preparative reverse phase HPLC (Sunfire 19X100mm 5 x C18 column, 8 min gradient: 10%→40% acetonitile/water with 0.1%TFA) to yield 32 (140 mg, 35%). M.S. M+H = 503 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 16h; | Example 11An aliquot of A9 (0.65 mmol) was stirred with <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (170 mg, 0.98 mmol), EDCI (250mg, 1.3mmol), and diisopropyl- ethylamine (0.57 ml, 3.2mmol) in 5 ml DMF for 16 hr. This mixture was diluted with ethyl acetate (50 ml), washed with water and brine, dried over sodium sulfate, concentrated in vacuo, and purified by preparative reverse phase HPLC (Sunfire 19X100mm 5μ C18 column, 8 min gradient: 10%→40% acetonitile/water with 0.1 %TFA) to yield A15 (140 mg, 35%). <n="71"/>M+H = 503 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chlorite; aminosulfonic acid; In water; tert-butyl alcohol; at 0 - 20℃; for 96h; | sodium chlorite (17 g) was added portionwise to a mixture solution composed of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (10 g), amidosulfuric acid (18 g), tert-butyl alcohol (50 ml) and water (50 ml) under ice cooling, and the mixture was stirred for 4 days while the temperature of the system was gradually raised to room temperature.. The reaction mixture was diluted with ethyl acetate and washed with water, 1N hydrochloric acid and saturated aqueous solution of sodium chloride.. After the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the resultant residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g).1H-NMR (DMSO-d6) delta: 7.72(1H,dt,J=8.3,1.5Hz), 7.77(1H,dt,J=8.3,1.6Hz), 7.82(1H,dt,J=9.7,1.5Hz), 13.45(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of the appropriate acid, ZCO2H, (1.5 eq.), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (2 eq.), N-methylmorpholine (5 eq.) and the appropriate amine hydrochloride selected from preparations 2 and 133 (1 eq.) in dichloromethane (8 mLmmol-1) was stirred at room temperature for 24 hours. The reaction was then washed with sodium hydroxide solution and the organic solution was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In tetrahydrofuran; hexane; | REFERENCE EXAMPLE 4 n-Butylithium (2.5M in hexane, 180 ml) was added dropwise to a stirred, cooled solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (37.5 g) in tetrahydrofuran while maintaining the temperature below -40 C. The mixture was stirred at -40 C. for 3 hours. Dimethyl disulphide (60.5 g) in tetrahydrofuran was added dropwise and the mixture was stirred at -40 C. for half an hour and at room temperature overnight. Hydrochloric acid (2M) was added and the layers were separated. The aqueous layer was extracted with ether and the combined organic layers were extracted with aqueous sodium hydroxide (2M). The aqueous extract was acidified to pH1 and extracted with ether. washed with water, dried (Na2 SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 4-chloro-3-fluoro-2-(methylsulphenyl)benzoic acid (32.84 g) as a white solid m.p. 149.5-150.50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | REFERENCE EXAMPLE 15 n-Butyl lithium (2.5M in hexanes, 176 ml) was added to a stirred solution of <strong>[60811-18-9]1-bromo-4-chloro-3-fluorobenzene</strong> (83.38 g) in dry ether. Stirring was maintained for a further 2.5 hours at -78 C., and the mixture poured onto excess solid carbon dioxide pellets, allowed to reach room temperature and water added. The mixture was washed with ether, acidified, extracted (ethyl acetate) and dried (magnesium sulphate). After evaporation the residue was triturated with petroleum ether to give 4-chloro-3-fluorobenzoic acid (66.4 g) as a white solid, m.p. 192-192.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In tetrahydrofuran; hexane; | REFERENCE EXAMPLE 47 n-Butyl lithium (2.5M in hexane; 180 ml) was added with cooling to a solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (37.5 g) in dry tetrahydrofuran while maintaining the temperature below -40 C. The mixture was stirred at -30 to -40 C. for 3 hours. Dimethyl disulphide (60.5 g) was added and the mixture was stirred at -40 C. for 0.5 hours and at room temperature overnight. Hydrochloric acid (2M) was added and the layers were separated. The aqueous layer was extracted with ether and the combined organic layers were extracted with aqueous sodium hydroxide (2M) and water. The aqueous extracts were combined and acidified to pH 1 and extracted with ether, washed with water, dried (Na2 SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 4-chloro-3-fluoro-2-methylsulphenylbenzoic acid (32.84 g) as a yellow solid, m.p. 149.5-150.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In water; | REFERENTIAL EXAMPLE 376 4-Chloro-3-fluorobenzoic acid: Sodium chlorite (17 g) was added portionwise to a mixture solution composed of 4-chloro-3-fluorobenzaldehyde (10 g), amidosulfuric acid (18 g), tert-butyl alcohol (50 ml) and water (50 ml) under ice cooling, and the mixture was stirred for 4 days while the temperature of the system was gradually raised to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water, 1N hydrochloric acid and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the resultant residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g). 1H-NMR (DMSO-d6) δ: 7.72(1H,dt,J=8.3, 1.5 Hz), 7.77(1H,dt,J=8.3, 1.6 Hz), 7.82(1H,dt,J=9.7, 1.5 Hz), 13.45(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 13APreparation of compound 2010Step 1 :To a mixture of 4-chloro-3-fluorobenzoic acid 13a1 (2.0O g, 1 1.5 mmol) in concentrated H2SO4 (15 mL) chilled to O0C is added NaNO2 (1.16 g, 1 1 5 mmol) portion-wise. Once the addition of NaNO2 is complete, the mixture is allowed to warm to RT and stirred overnight. The mixture is chilled to O0C once again and MeOH (20 mL) is added carefully. The ice bath is removed and the mixture is heated to 1000C and stirred for about 4.5 hours. The mixture is carefully diluted into a water/ice mixture. The aqueous mixture is made basic by the addition of NaHCO3 then is partitioned with EtOAc The organic layer is separated then washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Crude nitro-ester 13a2 is utilized without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | (1105) A solution of diisopropylamine (185 mL, 1.32 mol) in THE (200 mL) was placed under an N2 atmosphere and cooled in an ice-water bath. Then n-BuLi (2.5 M in hexanes, 504 mL, 1.26 mol) was added dropwise with stirring. After stirring at 0 C for an additional 5 min, the mixture was cooled to -78 C and stirred for 30 min. Then, a solution of 4-chloro-3- fluorobenzoic acid (100 g, 573 mmol) in THE (400 mL) was added dropwise to the freshly prepared LDA-solution. After 2 h at -78 C, a solution of l,2-dibromotetrachloroethane (375 g, 1.15 mol) in THE (400 mL) was added and the reaction mixture was allowed to stir at room temperature overnight. The mixture was diluted with H20 (500 mL) and extracted with EtOAc (500 mL x 3). The aqueous layer was acidified with 4 N HC1 to pH = 2 and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated in vacuo to give 2-bromo-<strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> as an off-white solid (134 g, yield: 92%). 1H NMR (300 MHz, CDCl3) d: 7.79 (dd / = 8.2 Hz, 1.8 Hz, 1H), 7.55- 7.42 (m, 1H). | |
83.3% | To a cooled (-78 C) solution of DIEA (4.9 mL, 48 mmol) in THF was added dropwise n-BuLi (132 mL, 2.3 eq, 2.5 M solution). The mixture was stirred at -30 C for 30 min. Again the reaction mixture was cooled to -78 C, and a solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (25 g, 143 mmol) in THF was added over 1 h. The reaction was stirred at -78 C overnight. The next day a solution of l,2-dibromo-l, l,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added and the reaction was stirred at -78 C for further 2 h and then RT for 4 h. The reaction mixture was quenched with water, the layers were separated, and the aqueous layer washed with Et20. The aqueous layer was acidified with 1.5N HC1 and then extracted in EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous a2S04, filtered and concentrated to afford Intermediate 18A (30 g, 83.3%).MS (ESI) m/z: 252.6 (M-H)+. | |
83.3% | To a cooled (-78 C) solution of DIEA (4.9 mL, 48 mmol) in THF was added dropwise w-BuLi (132 mL, 2.3 eq, 2.5 M ). The mixture was stirred at -30 C for 30 min. Again the reaction mixture was cooled to -78 C, and a solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (25 g, 143 mmol) in THF was added over 1 h. The reaction was stirred at -78 C overnight. The next day a solution of 1,2-dibromo-1, 1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added and the reaction was stirred at -78 C for further 2 h and then rt for 4 h. The reaction mixture was quenched with ¾0, organic layer was separated and aqueous layer washed with Et2O. Aqueous layer acidified with 1.5 N HCl and extracted in EtOAc (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford Intermediate 12A (30 g, 83.3%). MS (ESI) m/z: 252.6 (M-H)+. |
83.3% | To a cooled (-78 C) solution of DIEA (4.9 mL, 48 mmol) in THF was added drop wise n-BuLi (132 mL, 2.3 eq, 2.5 M solution). The mixture was stirred at -30C for 30 min. Again the reaction mixture was cooled to -78 C, and a solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (25 g, 143 mmol) in THF was added over 1 h. The reaction was stirred at -78 C overnight. The next day a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added and the reaction was stirred at -78 C for further 2 h and then rt for 4 h. The reaction mixture was quenched with H20, organic layer was separated and aqueous layer washed with Et20. Aqueous layer acidified with 1.5N HCl and extracted in EtOAc (2 x 200 mL), dried over anhydrous Na2S04, filtered and concentrated to afford Intermediate 12A (30 g, 83.3% yield). MS (ESI) m/z: 252.6 (M-H)+. | |
83.3% | To a cooled (-78 C) solution of DIEA (4.9 mL, 48 mmol) in THF was added drop wise n-BuLi (132 mL, 2.3 eq, 2.5 M solution). The mixture was stirred at -30C for 30 min. Again the reaction mixture was cooled to -78 C, and a solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (25 g, 143 mmol) in THF was added over 1 h. The reaction was stirred at -78 C overnight. The next day a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added and the reaction was stirred at -78 C for further 2 h and then rt for 4 h. The reaction mixture was quenched with H2O, organic layer was separated and aqueous layer washed with Et2O. Aqueous layer acidified with 1.5N HCl and extracted in EtOAc (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford Intermediate 12A (30 g, 83.3% yield). MS (ESI) m/z: 252.6 (M-H)+. | |
41.3% | Intermediate 4; (E)-2,5-Dioxopyrrolidin- 1 -yl 3-(6-acetyl-3-chloro-2-fluorophenyl)acryIate; [00272] Intermediate 4A. 2-bromo-<strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong>: To a cooled (78C) solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (2.0 g, 11.46 mmol) and TMEDA in THF was added dropwise sec-BuLi (90 mL, 2.2 eq, 1.4 M solution). The mixture was stirred at -78 C for 30 min. Next, a solution of 1,2-dibromo-l,1,2,2- tetrachloroethane (14.92 g, 45.8 mmol) in THF was added. The reaction was stirred at -78 C for awhile and then the reaction was allowed to warm to rt and stir overnight. The reaction was cooled to -78 C and then quenched with 4N HCl in dioxane. Purification by reverse phase chromatography gave Intermediate 4A (1.2Og, 41.3% yield) as a white solid. MS(ESI) m/z: 253/255 (M+H)+. | |
2-Bromo-4-chloro- 1 -(difluoromethyl)-3-fluorobenzene Step 1. 2-Brromo-<strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> A solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (2.0 g, 11.46 mmol) in THF (25 ml) was added by a syringe pump to a solution of LDA (13.18 ml, 26.4 mmol) in THF (50 ml) at -78C over 30 min. followed by stirring at -78C for 3h. Then, a solution of 1 ,2-dibromotetrachloroethane (7.5 g, 23 mmol) in THF (25 ml) was added. The reaction was run at -78C for 30min, then it was slowly warmed up to room temperature and stirred overnight. The reaction mixture was quenched with water, and extracted with Et20. The aqueous was neutralized with 4N HC1 in dioxane (45.8 ml, 45.8 mmol) and extracted with EtOAc. The organic phase was dried over MgS04, filtered and concentrated to give the title compound. MS (ESI) m/z 26Μ (M+H). | ||
Step 1 : 2-bromo-<strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> A solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (2.0 g, 11.46 mmol) in THF (25 ml) was added by syringe pump to a solution of LDA (13.18 ml, 26.4 mmol) in THF (50 ml) at -78C over 30 min followed by stirring at -78C for 3h. Then, to it was added a solution of 1,2-dibromotetrachloroethane (7.46 g, 22.92 mmol) in THF (25 ml). The reaction was run at -78C for 30 min, then slowly warmed up to RT and stirred overnight. The reaction mixture was quenched with water and extracted with Et20. The aqueous was neutralized with 4N HCl in dioxane (45.8 ml, 45.8 mmol) and extracted with EtOAc. The organic phase was dried over MgS04, filtered and concentrated to give the title compound. MS (ESI) m/z 276.04 (M+H). | ||
A solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (2.0 g, 11.46 mmol) in THF (25 ml) was added by a syringe pump to a solution of LDA (13.18 ml, 26.4 mmol) in THF (50 ml) at -78C over 30 min. followed by stirring at -78C for 3h. Then a solution of 1,2-dibromotetrachloroethane (7.5 g, 23 mmol) in THF (25 ml) was added to the reaction mixture. The reaction was run at -78C for 30 min, then slowly warmed up to rt and stirred overnight. The reaction mixture was quenched with water, and extracted with Et2O. The aqueous layer was acidified with 4N HCl in dioxane (45.8 ml, 45.8 mmol) and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated to afford the crude product that was purified on RP-HPLC to give the title compound, which was used in the next step | ||
Lithium diisopropylamide (66 ml, 2.0 M in tetrahydrofuran, 132 mmol, 2.3 eq.) was added to a solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (10.0 g, 57.3 mmol, 1.0 eq.) in tetrahydrofuran (500 ml) dropwise at -78C under nitrogen atmosphere. The resulting mixture was stirred for 8 h at -78C, followed by the addition of a solution of 1,2-dibromo-l, 1,2,2-tetrachloroethane (37.3 g, 114.5 mmol, 2.0 eq.) in tetrahydrofiiran (50 ml) dropwise over a period of 1 h. After stirring for 2 h at -78C and further 15 h at RT, the reaction mixture was worked up by addition of water and extracted with diethyl ether. The aqueous layer was adjusted to pH 3 by addition of aqueous hydrochloric acid (4 N) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was used in the subsequent reaction without further purification. Yield: 13.85 g (90% purity, 86% of theory). Tf-NMR (400 MHz, DMSO-ri6): d [ppm] = 13.79 (br s, 1H), 7.75-7.69 (m, 1H), 7.67-7.60 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h; | Example 2 N-[1-(4-chloro-3-fluorobenzoyl)piperidin-4-yl]-N-phenyl-2-(piperidin-1-yl)acetamide To a solution of <strong>[403-17-8]4-chloro-3-fluorobenzoic acid</strong> (166 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl) (191 mg) and 1-hydroxybenzotriazole (1-HOBt) (134 mg) in dichloromethane (5 ml) was added a solution of N-phenyl-N-(piperidin-4-yl)-2-(piperidin-1-yl)acetamide (200 mg) synthesised in Reference Example 2 (1) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the reaction mixture and the mixture was extracted with chloroform (10 mlx3). The organic layer was washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (elution solvent: hexane/ethyl acetate) to give the object product (230 mg, yield 76%) as an oil. This product and fumaric acid (58.5 mg) were dissolved in isopropanol and concentrated under reduced pressure to give an amorphous form (229 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With thionyl chloride; for 2h;Reflux; | 4-Chloro-3-fluorobenzoic acid (22 g, 126 mmol)Was added to thionyl chloride (200 mL)And refluxed and stirred for 2 hours.After cooling to room temperature,The solid formed by distillation was washed with diethyl ether and dried to give 22.1 g (yield 91%) of Compound A-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; for 24h; | General procedure: To a solution of acid (1.0 eq), HOBt (1.5 eq), EDCI (1.5 eq) and triethylamine (1.5 eq) in DMF, compound a was added and the mixture was stirred for 24h. The mixture was poured into saturated NaHCO3 solution, extracted by ethyl acetate three times and the combined organic layer was washed with water and brine, and dried over with anhydrous Na2SO4. The concentrated residue was purified by recrystallization directly from CHCl3/MeOH or purified by flash column chromatography on silica gel to give the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.9% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 1h; | General procedure: A solution of compound 17 (1 equiv) and various carboxylic acid (1.2 equiv) in dried DCM was treated with EDC.HCl (1.2 equiv) and TEA (1.5 equiv). After 1 h, the resulting mixture was treated with saturated aq. NH4Cl (10 mL). The organic phase was extracted with DCM (3 x 10 mL), and combined organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (CHCl3/MeOH 50:1, v/v) to afford 18a-18m and 19a-19m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;Inert atmosphere; | General procedure: A round-bottom flask was charged with carboxylic acid (1.2-2.0 equiv), compound 2 (1.0 equiv) and EDCI (3.0 equiv). Dichloromethane was added (0.1-0.2M), and the mixture was allowed to stir at room temperature until compound 2 was consumed (determined by TLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With sulfuric acid; manganese(II) acetate; ozone; at 15℃; for 10h; | Into 9931g of acetic acid, 2.7g of manganese acetate, 105g98% sulfuric acid to a 20L autoclave, and then put into 99% 3-fluoro-chlorotoluene 870g (5.96mol), stirred mixture was cooled to 15 , ozone slowly into 215g (total 10H); after completion of the reaction of nitrogen with the ozone photodissociation process; temperature and pressure recovery acetate, layers were separated and the product is recovered 988G, to give 3-fluoro-4-chlorobenzoic acid, 98.2% pure, a yield of about 94.2 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a solution of the corresponding amine (4 or 5, 1.2 equiv), dihalo-substituted benzoic acid (2c, 2d, 2e or 2f, 1.0 equiv), and 1-hydroxybenzotriazole hydrate (HOBt, 1.2 equiv) in DMF (8.0-10.0mL/mmol; extra dry over molecular sieves, 99.8%, Acros) were added EDC-HCl (1.2 eqiv) and DIPEA (2.5 equiv). The mixture was stirred at room temperature until completed conversion (TLC control: CH2Cl2/MeOH 9/1 v/v). Then, the solvent was removed in vacuo and the residue washed with water (20mL/mmol) and dried at 70C. The crude product was purified by column chromatography on silica gel (eluent: CH2Cl2/MeOH 9/1 v/v) following by reversed phase HPLC (for purification methods, see Supporting Information, TableS2) and/or recrystallization as described below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a solution of the corresponding amine (4 or 5, 1.2 equiv), dihalo-substituted benzoic acid (2c, 2d, 2e or 2f, 1.0 equiv), and 1-hydroxybenzotriazole hydrate (HOBt, 1.2 equiv) in DMF (8.0-10.0mL/mmol; extra dry over molecular sieves, 99.8%, Acros) were added EDC-HCl (1.2 eqiv) and DIPEA (2.5 equiv). The mixture was stirred at room temperature until completed conversion (TLC control: CH2Cl2/MeOH 9/1 v/v). Then, the solvent was removed in vacuo and the residue washed with water (20mL/mmol) and dried at 70C. The crude product was purified by column chromatography on silica gel (eluent: CH2Cl2/MeOH 9/1 v/v) following by reversed phase HPLC (for purification methods, see Supporting Information, TableS2) and/or recrystallization as described below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 25℃; for 12h;Inert atmosphere; | To a solution of 4-chloro-3-fluoro-benzoic acid (83 mg, 0.474 mmol) in EtOAc (3 mL) was added Et3N (160 mg, 1.58 mmol), T3P (502 mg, 0.79 mmol, 50% in EtOAc) and 2-(cyclobutoxy)-N- [1-(hydrazinecarbonyl)-3-bicyclo[1.1. ljpentanyllacetamide (100 mg, 0.395 mmol). After addition, the mixture was stirred at 25C for 12 h. The mixture was concentrated under reduced pressure to give the desired product. LC-MS mlz: = 410.2 [M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: Substituted benzoic acid or substituted phenylacetic acid 4(1 mmol) was added to a 50-mL round bottom flask and dissolvedwith DMF (20 mL), HOBt (1.5 mmol), EDCI (1.5 mmol), and TEA(1.5 mmol). Then, the solution was stirred at room temperature for10 min. DMF was added to dissolve 2-phenyl benzoxazole structure3, and then the solution was continuously stirred for 2e4 h. Thereaction was monitored by TLC and then stopped after completionwas indicated. The resultant solution was extracted with ethyl acetate(15 mL), washed twice with dilute hydrochloric acid (50 mL),and the organic phase was dried over anhydrous sodium sulfateand separated by silica gel column chromatography (petroleumether: ethyl acetate 2: 1). A yellow or white solid product 5 wasobtained (yield > 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: Substituted benzoic acid or substituted phenylacetic acid 4(1 mmol) was added to a 50-mL round bottom flask and dissolvedwith DMF (20 mL), HOBt (1.5 mmol), EDCI (1.5 mmol), and TEA(1.5 mmol). Then, the solution was stirred at room temperature for10 min. DMF was added to dissolve 2-phenyl benzoxazole structure3, and then the solution was continuously stirred for 2e4 h. Thereaction was monitored by TLC and then stopped after completionwas indicated. The resultant solution was extracted with ethyl acetate(15 mL), washed twice with dilute hydrochloric acid (50 mL),and the organic phase was dried over anhydrous sodium sulfateand separated by silica gel column chromatography (petroleumether: ethyl acetate 2: 1). A yellow or white solid product 5 wasobtained (yield > 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: Substituted benzoic acid or substituted phenylacetic acid 4(1 mmol) was added to a 50-mL round bottom flask and dissolvedwith DMF (20 mL), HOBt (1.5 mmol), EDCI (1.5 mmol), and TEA(1.5 mmol). Then, the solution was stirred at room temperature for10 min. DMF was added to dissolve 2-phenyl benzoxazole structure3, and then the solution was continuously stirred for 2e4 h. Thereaction was monitored by TLC and then stopped after completionwas indicated. The resultant solution was extracted with ethyl acetate(15 mL), washed twice with dilute hydrochloric acid (50 mL),and the organic phase was dried over anhydrous sodium sulfateand separated by silica gel column chromatography (petroleumether: ethyl acetate 2: 1). A yellow or white solid product 5 wasobtained (yield > 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: Substituted benzoic acid or substituted phenylacetic acid 4(1 mmol) was added to a 50-mL round bottom flask and dissolvedwith DMF (20 mL), HOBt (1.5 mmol), EDCI (1.5 mmol), and TEA(1.5 mmol). Then, the solution was stirred at room temperature for10 min. DMF was added to dissolve 2-phenyl benzoxazole structure3, and then the solution was continuously stirred for 2e4 h. Thereaction was monitored by TLC and then stopped after completionwas indicated. The resultant solution was extracted with ethyl acetate(15 mL), washed twice with dilute hydrochloric acid (50 mL),and the organic phase was dried over anhydrous sodium sulfateand separated by silica gel column chromatography (petroleumether: ethyl acetate 2: 1). A yellow or white solid product 5 wasobtained (yield > 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: Substituted benzoic acid or substituted phenylacetic acid 4(1 mmol) was added to a 50-mL round bottom flask and dissolvedwith DMF (20 mL), HOBt (1.5 mmol), EDCI (1.5 mmol), and TEA(1.5 mmol). Then, the solution was stirred at room temperature for10 min. DMF was added to dissolve 2-phenyl benzoxazole structure3, and then the solution was continuously stirred for 2e4 h. Thereaction was monitored by TLC and then stopped after completionwas indicated. The resultant solution was extracted with ethyl acetate(15 mL), washed twice with dilute hydrochloric acid (50 mL),and the organic phase was dried over anhydrous sodium sulfateand separated by silica gel column chromatography (petroleumether: ethyl acetate 2: 1). A yellow or white solid product 5 wasobtained (yield > 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | General procedure: Substituted benzoic acid or substituted phenylacetic acid 4(1 mmol) was added to a 50-mL round bottom flask and dissolvedwith DMF (20 mL), HOBt (1.5 mmol), EDCI (1.5 mmol), and TEA(1.5 mmol). Then, the solution was stirred at room temperature for10 min. DMF was added to dissolve 2-phenyl benzoxazole structure3, and then the solution was continuously stirred for 2e4 h. Thereaction was monitored by TLC and then stopped after completionwas indicated. The resultant solution was extracted with ethyl acetate(15 mL), washed twice with dilute hydrochloric acid (50 mL),and the organic phase was dried over anhydrous sodium sulfateand separated by silica gel column chromatography (petroleumether: ethyl acetate 2: 1). A yellow or white solid product 5 wasobtained (yield > 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | General procedure: Substituted benzoic acid or substituted phenylacetic acid 4(1 mmol) was added to a 50-mL round bottom flask and dissolvedwith DMF (20 mL), HOBt (1.5 mmol), EDCI (1.5 mmol), and TEA.Then, the solutionwas stirred at room temperature with amagneticstirrer for approximately 10 min. The solution of 2-Arylbenzimidazole structure 8 in DMF was added to the abovesolution, and the mixture was continuously stirred for 2e4 h. Thereaction was monitored by TLC and then stopped after completionwas indicated. The resultant solution was extracted with ethyl acetate(15 mL), washed twice with dilute hydrochloric acid (50 mL),and the organic phase was dried over anhydrous sodium sulfateand separated by silica gel column chromatography (petroleumether: ethyl acetate 2: 1). A yellow or white solid product 9 wasobtained (yield > 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sulfuric acid; nitric acid; In water; at 0 - 20℃; for 1h; | General procedure: To a mixture of 3-fluoro-4-methylbenzoic acid (3.7 g, 24.0 mmol) in 18N aq. H2SO4 (31 mL) cooled down to 0C was added 70% aq. HNO3 (2.14 mL, 48.0 mmol) dropwise. Once the addition of HNO3 was complete, the mixture was allowed to warm to room temperature and stirred for 1 h and LC-MS confirmed the disappearance of the starting material with a new major peak. The mixture was cooled down to 0C once again and EtOH (62 mL) was added carefully. The ice bath was removed and the mixture was heated to 100 C and stirred for about 5 hours. The mixture was carefully diluted into cold water. Solid NaHCO3 was added until pH > 8 and the aqueous layer was extracted with EtOAc (3x 100 mL). The combined organic layers were washed with sat. aq. NaCl (1 × 100 mL), dried over Na2SO4, filtered through a pad of silica and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (1% to 20% EtOAc in hexane, Rf = 0.55 20% EtOAc in hexane) to give ethyl 3-fluoro-4-methyl-5-nitrobenzoate (4.55 g, 83%) of as a yellow liquid.1H NMR (500 MHz, Chloroform-d) d 7.81 (d, J = 6.3 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.38 (d, J = 2.1 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | To a precooled (0 C) solution of <strong>[54012-73-6]3-aminopiperidine</strong> (300. mg, 3.00 mmol) in MeOH (15 mL) under N2 atmosphere was added triethylamine (0.83 mL, 6.0 mmol) then Boc anhydride (0.68 mL, 3.0 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 17 h, then concentrated in vacuo. The resulting residue was taken up in CH2Cl2 and quenched with sat. aq. NaHCO3. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the product as a white solid (573 mg), which was carried forward without additional purification. (0317) [0090] To a precooled (0 C) solution of intermediate (350. mg, 1.75 mmol), 4- chloro-3-fluorobenzoic acid (366 mg, 2.10 mmol) and HATU (731 mg, 1.92 mmol) in DMF (5.8 mL) under N2 atmosphere was added diisopropylethylamine (0.9 mL, 5 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 42 h, then concentrated in vacuo. The resulting residue was taken up in CH2Cl2 and the organic layer was washed with sat. aq. NaHCO3. The aqueous phase was then extracted with CH2Cl2 (1x). The combined organic layers were washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo to afford the product as a white solid (528 mg), which was carried forward without additional purification. (0318) [0091] To a solution of intermediate (526 mg, 1.47 mmol) in CH2Cl2 (7.4 mL) at room temperature under N2 atmosphere was added trifluoroacetic acid (0.34 mL, 4.4 mmol). The resulting mixture was stirred at room temperature for 14 h, followed by addition of trifluoroacetic acid (0.1 mL, 1.3 mmol). The resulting mixture was stirred for an additional 24 h, then concentrated in vacuo. The resulting residue was taken up in CH2Cl2 and diluted with H2O. The layers were separated, and the organic layer was extracted with H2O (3x). The combined aqueous layers were basified with powdered NaHCO3 to pH 8 then diluted with CH2Cl2. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3x). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the product as a white solid (122 mg, 64% yield over 3 steps).1H NMR (500 MHz, Chloroform- d) d 7.71-7.57 (m, 1H), 7.57-7.33 (m, 2H), 7.24-7.00 (m, 1H), 4.44-4.08 (m, 2H), 4.08-3.89 (m, 1H), 3.87-3.66 (m, 1H), 3.62-3.34 (m, 2H), 2.25-2.04 (m, 1H), 1.99-1.83 (m, 1H), 1.83- 1.43 (m, 2H); 13C NMR (126 MHz, CDCl3) d 165.28, 159.24, 159.10, 157.25, 157.10, 131.23, 131.12, 124.03, 123.23, 123.20, 115.90, 115.72, 49.29, 47.55, 42.96, 28.90, 23.28; IR (ATR) vmax 3209, 1674, 1440, 1190, 1133, 801, 724 cm-1; AMM 257.0861 (ESI) m/z [calc for C12H15ClFN2O (M+H)+ 257.0857]. |
Tags: 403-17-8 synthesis path| 403-17-8 SDS| 403-17-8 COA| 403-17-8 purity| 403-17-8 application| 403-17-8 NMR| 403-17-8 COA| 403-17-8 structure
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