Structure of 874219-34-8
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CAS No. : | 874219-34-8 |
Formula : | C7H7BFNO3 |
M.W : | 182.95 |
SMILES Code : | NC(=O)C1=C(F)C=CC(=C1)B(O)O |
MDL No. : | MFCD08235053 |
InChI Key : | RNNYXSWJFLHIRC-UHFFFAOYSA-N |
Pubchem ID : | 44717530 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
34% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 80.0℃;Inert atmosphere; | A mixture of 3-bromo-6-chloro-2-quinolinamine (3 g, 1 1.65 mmol), [3- (aminocarbonyl)-4-fluorophenyl]boronic acid (2.77 g, 15.14 mmol), potassium acetate (3.43 g, 34.9 mmol ) and PdCI2(dppf)-CH2CI2 adduct (0.953 g, 1.165 mmol) in 1 ,2-Dimethoxyethane (DME) ( 50 mL) and water (12.5 mL) was heated under nitrogen atmosphere at 80 C overnight. Cooled down and loaded the reaction solution to a column and purified by columnchromatography (silica gel, EtOAc/Hexane from 0-50%) to give the desire product. (1.52 g, 34 %). LCMS (ES+) m/z 316. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 110.0℃; for 0.166667h;Microwave irradiation; | To a solution of 55E (50 mg, 0.102 mmol) and 4-fluoro-3carbamoyl phenylboronic acid (21 mg, 0.1 13 mmol) in DME (1 ml) was added 0.4N aq. K2C03 (515 ul) and Pd(PPh3)4 (1 1.9 mg, 0.0010 mmol). The resulting mixture was heated at 110 C for l O in. in a microwave. The reaction mixture was filtered, washed lx with DMF and the solution was purified by RP HPLC using a C18 column with a gradient of 0.1%/H2O, 0.1% TFA-acetonitrile, to provide 37 mg of the title compound. 1H NMR (400 MHz, dmso) δ 10.87 (s, 1H), 8.81 - 8.53 (m, 2H), 7.66 (d, 2H), 7.56 (d, 1H), 7.47 (dd, 1H), 7.39 - 7.32 (m, 1 H), 7.30 - 7.17 (m, 2H), 7.15 - 7.04 (m, 2H), 6.83 (ddd, 2H), 6.51 (d, 2H), 5.12 (dd, 1H), 3.51 - 3.31 (m, 2H), 2.98 (dd, 2H). MS (m/z) 547 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
130 mg | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,2-dimethoxyethane; water; at 65.0℃; for 48h; | To (S)-tert-butyl l -(5-bromopyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate (250 mg, 0.6 mmol) in DME (3 mL) was added 3-carbamoyl-4-fluorophenylboronic acid (110 mg, 0.6 mmol), Xantphos (35 mg), Pd2(dba)3 (28 mg), and aqueous 2M K2C03 (0.45 mL). The reaction was heated to 65 C for 2d at which time it was diluted with aqueous IN HCl and extracted with EtOAc. The organics were separated, washed, dried and removed in vacuo. The crude product was purified by column chromatography on silica to provide 130 mg of the title compound. MS (m/z) 473.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 85.0℃; | A round bottom flask was charged with 50A (3 g, 7.3 mmol), DME (100 ml), 3-carbamoyl-4- fluorophenylboronic acid (1.6 g, 8.7 mmol), Pd(PPh3)4 (419 mg, 0.36 mmol) and K2C03 (2 g, 14.5 mmol) dissolved in water (12 ml). Heat the stirring mixture overnight at 85 C. Allow the reaction to cool then dilute with H20 and extract 2X EtOAc. The combined organic layers were washed with brine then dried over sodium sulfate, concentrated, and purified by flash chromatography to give the title compound (1.8 g, 53%): MS (m/z) 472.6 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In N,N-dimethyl-formamide; at 100.0℃; | General procedure: Example 3: Synthesis of 5-(l-(2-chloro-6-fluorobenzoyl)-l,2,3,4- tetrahydroquinolin-6-yl)-2-fluorobenzamide [00286] To a stirred mixture of intermetidate 1-C (0.1 g, 0.28 mmol), Pd(dppf)Cl2 (0.024 g, 0.03 mmol), and K2C03 (0.082 mg, 0.59 mmol) in 5 mL of DMF was added 3-carbamoyl-4- fluorophenyl boronic acid (0.054 mg, 0.28 mmol). The mixture was heated overnight at 100C. Solvent was removed in vacuo, and the residue was purified by preparative TLC and preparative HPLC to provide the titled compound as a colorless solid (33 mg, 27.7%). 1H NMR (300 MHz, CD3OD): δ 8.06 - 6.92 (m, 9H), 3.97 - 3.48 (m, 2H), 2.89 - 2.80 (m, 2H), 2.08 - 1.93 (m, 2H). HPLC = 98.9% (214 nm), 98.6% (254 nm), tR = 6.49 min. LC-MS: mJz = 427.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 150.0℃; for 0.25h;Microwave irradiation; | A microwave tube was charged with of (S)-tert-butyl l-(3-bromo-5-(l,3- dioxoisoindolin-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (30E, 50 mg, 0.09 mmol), <strong>[874219-34-8](3-carbamoyl-4-fluorophenyl)boronic acid</strong> (25 mg, 0.13 mmol) and PdCl2[P(Cy)3]2 (3.3 mg, 0.004 mmol). To the mixture was added 1.8 mL of 1,4-dioxane and 0.3 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated up in a microwave synthesizer at 150 C for 15 min. The above procedure was repeated 2x more; a total 150 mg of compound 30E was used. After cooling, the combined reactions were partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgS04, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford 30H, MS (m/z) 634.81 [M+H]+ and the title compound 30G. MS (m/z) 616.82 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In Dimethyl ether; water; at 120.0℃; for 0.5h;Microwave irradiation; | A suspension of N-(l-(6-amino-3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2- (5-fluoro-lH-indol-3-yl)acetamide (1G, 30 mg, 0.06 mmol), potassium carbonate (0.06 mL, 2M in water), <strong>[874219-34-8](3-carbamoyl-4-fluorophenyl)boronic acid</strong> (13 mg, 0.072 mmol) and tetrakis(triphenylphosphine) palladium (1.0 mg, 0.0009 mmol) in DME (dimethyl ether)(1.0 mL) was degassed for 30 minutes. The mixture was submitted to microwave heating at 120 C for 30 min. The reaction was cooled and filtered through celite. The filtrate was extracted with EtOAc (2x10 mL). The organic layer was dried over Na2S04, filtered and concentrated. The crude product was purified by reverse phase HPLC to give a mixture of enantiomers. MS (m/z) 562.4 [M+H]+. 1H NMR (400 MHz, CDC13) δ 8.08 (s, 1H), 7.71 (d, J = 1.9 Hz, 2H), 7.62 (s, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.28 - 7.15 (m, 3H), 7.10 (s, 1H), 6.91 (s, 1H), 6.82 (t, J = 8.4 Hz, 2H), 6.58 (d, J = 9.0 Hz, 1H), 6.52 - 6.40 (m, 2H), 6.22 - 6.05 (m, 3H), 5.16 (d, J = 8.1 Hz, 1H), 3.52 (s, 2H), 3.01 - 2.87 (m, 1H), 2.83 - 2.78 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; lithium chloride; In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide; at 150.0℃; for 0.5h;Microwave irradiation; | In a microwave tube were charged with compound 111 (29 mg, 0.1 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid (27 mg, 0.15 mmol), LiCl (13 mg, 0.3 mmol), Na2C03 (17 mg, 0.2 mmol), Pd(PPh3)2Cl2 (3.5 mg, 0.005 mmol). To the mixture was added 2 mL of DME/DMF/ H20 (4/1/1). The mixture was heated up to 150 C for 30 min in a Microwave Synthesizer. After cooled down and filtered through a syringe filter, purified on reverse phase HPLC eluting with acetonitrile and water ( with 0.1% TFA) to afford the title product. 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.48 (dd, J = 6.9, 2.3 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.22 (dd, J = 10.7, 8.5 Hz, 1H), 6.70 (t, J = 9.2 Hz, 1H), 6.45 (d, J = 6.2 Hz, 2H), 5.24 (q, J = 7.5 Hz, 1H), 4.76 (s, 2H), 3.85 - 3.56 (m, 4H), 3.41 (s, 3H), 3.01 (ddd, J = 29.2, 13.3, 7.4 Hz, 2H), 2.63 - 2.34 (m, 4H), 1.88 - 1.60 (m, 4H).MS (m/z) 676.46 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; isopropyl alcohol; toluene; at 120.0℃; for 0.333333h;Microwave irradiation; | In a microwave tube were charged with compound 23C (52 mg, 0.1 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid (27 mg, 0.15 mmol), K2C03 (41mg, 0.3 mmol), Pd(dppf)Cl2 (5 mg). To the mixture was added 2 mL of Toluene/2-propanol/ H20 (3/1/1). The mixture was heated up to 120 C for 20 min in a Microwave Synthesizer. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and concentrated to afford crude product used for next step without further purification.MS (m/z) 582.73 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; lithium chloride; In 1,4-dioxane; methanol; water; at 170.0℃; for 0.25h;Microwave irradiation; | [0416] In a microwave tube was charged with 5F (100 mg, 0.15 mmol), (3-carbamoyl-4- fluorophenyl)boronic acid ( 81 mg, 0.45 mmol), LiC1 (19 mg, 0.45 mmol), Na2CO3 (50 mg, 0.6 mmol) and 5 mg of Pd(PPh3)2C12. To the mixture was added 1.4 mL of 1 ,4-dioxane / methanol / H20 (5/1/1). The mixture was heated up to 170 C for 15 mm in a Microwave Synthesizer. After cooled down and filtered through a syringe filter, purified on reverse phase HPLC eluting with acetonitrile and water ( with 0.1% TFA) to afford the title compound. ‘H NMR (400 MHz, CD3OD) ö 8.90 (d, J= 8.6 Hz, 1H), 8.74 (dd, J= 7.2, 2.4 Hz, 1H), 8.51 - 8.30 (m, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.64 (d, J= 8.1 Hz, 1H), 7.41 (m, 2H), 7.23 (dd, J= 10.7, 8.5 Hz, 1H), 7.02- 6.49 (m, 2H), 6.35 (d, J= 6.2 Hz, 2H), 5.45 (m, 1H), 5.16-5.02 (m, 2H), 3.23-2.97 (m, 2H),2.49 (m, 4H).MS (m/z) 793.19 [M+Hf’. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trans-bis(tricyclohexylphosphine)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; at 150.0℃; for 0.183333h;Inert atmosphere; Microwave irradiation; | General procedure: [0460] Synthesis of (S)-tert-butyl (l-(6-((3,3-difluoro-1-hydroxycyclobutyl)ethynyl)-3-(l- memyl-3-(memylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5- difluorophenyl)e&yi)carbamate (105B): Argon was bubbled through a suspension of 105A(50 mg, 0.09 mmol), the 20B (48 mg, 0.13 mmol), and PdCl2(P(cy)3)2 (3.5 mg, 0.01 mmol) in dioxane (0.6 ml) and 1M NaHC03 (0.2 ml) for 1 min. The mixture was heated at 150 C for 10 minutes in a microwave reactor. The resulting solution was diluted with EtOAc (5 ml) and washed with brine (5 ml). The organic layer was dried with sodium sulfate, filtered, and concentrated under vacuum to give the title compound 105B. The crude product was taken to next step without further purification. MS (m/z) 687.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trans-bis(triphenylphosphine)palladium dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 150.0℃; for 0.333333h;Microwave irradiation; | General procedure: [0295] Synthesis of tert-butyl 3-((6-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)- 3b,4,4a,5-tetrahydro- 1 H-cyclopropa[3 ,4]cyclopenta[ 1 ,2-c]pyrazol-1-yl)acetamido)-2-(3,5- difluorophenyl)ethyl)-5-( 1 -met yl-3 -(methylsulfonamido)- 1 H-indazol-7-yl)pyridin-2- yl)ethynyl)-3-hydroxyazetidine-1-carboxylate (22B): To 22A (30 mg, 0.04 mmol) in dioxane (3 mL) was added N-(l-memyl-7-(4,4,5,5-tetramemyl-l,3,2-dioxaborolan-2-yl)-1H-indazol- 3-yl)methanesulfonamide (20B) (17 mg, 0.05 mmol), PdCl2[P(Ph)3]2(2 mg, 0.003 mmol), and aq 1M NaHCCh (0.11 mL, 0.11 mmol). The reaction mixture sealed and heated in a microwave reactor to 150 C for 20 min. Upon cooling, the reaction mixture was diluted with EtOAc and washed with two portions of brine. The organic layer was dried over Na2SC>4, filtered, concentrated in vacuo, to give the crude title compound 22B. MS (m/z) 772.1[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trans-bis(triphenylphosphine)palladium dichloride; sodium carbonate; lithium chloride; In 1,4-dioxane; water; at 130.0℃; for 0.666667h;Inert atmosphere; Microwave irradiation; | [0282] Synthesis of 5-(2-((S)-1-(2-((3bS,4aR)-5,5-difluorotetrahydro-1H-cyclopropa[3,4]^difluorophenyl)ethyl)-6-(( 1 -hydroxycyclopentyl)ethynyl)pyridin-3-yl)-2-fluorobeiizamide (15B): A microwave tube was charged with compound ISA (20 mg, 0.029 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid ( 8 mg, 0.044mmol), LiCl ( 2.5 mg, 0.058 mmol), Na2C03(9 mg, 0.088 mmol) and PdCl2(PPh3)2 (2 mg, 0.003 mmol). To the mixture was added 0.7 mL of 1 ,4- dioxane and 0.1 mL of H20. The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated in a 130 C bath for 40 min. After cooling to ambient temperature the reaction mixture was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgS04, filtered and concentrated. The residue was purified by reverse phase HPLC to afford the title product. NMR (400 MHz, Methanol-^) δ 7.52 (d), 7.45 (d), 7.39 - 7.25 (m), 7.20 0, 6.71 - 6.58 (m), 6.38 - 6.28 (m), 5.34 (dd), 4.86 (s) , 3.16 - 2.89 (m), 2.55 - 2.39 (m), 2.20 - 1.97 (m), 1.98 - 1.69 (m), 1.58 - 1.23 (m), 1.15 - 1.04 (m). MS {m/z) 744.35 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trans-bis(tricyclohexylphosphine)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 130.0℃; for 0.666667h;Inert atmosphere; Microwave irradiation; | [0286] Syndesis of 5-(4-((S)-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)2-(methylthio)pyrimidin-5-yl)-2-fluorobenzamide(18B): A microwave tube was charged with compound 18A (282 mg, 0.45 mmol), (3-carbamoyl-4- fluorophenyl)boronic acid ( 91 mg, 0.5 mmol) and PdCl2[P(cy)3]2(17 mg, 0.023 mmol). To the mixture was added 10 mL of 1 ,4-dioxane and 1.4 mL of sodium bicarbonate aqueous solution (1 M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated in a 130 C bath for 40 min. After cooled to ambient temperature it was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgS04, filtered and concentrated. The residue was purified by silica gel chromatography to afford title product. MS (m/z) 683.06 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.4 mg | Intermediate 1A (20 mg, 0.055 mmol), <strong>[874219-34-8](3-carbamoyl-4-fluorophenyl)boronic acid</strong> (20.26 mg, 0.111 mmol) and potassium carbonate (30.6 mg, 0.221 mmol) were combined in a vial. DMA (1 mL) and water (0.25 mL) were added and the mixture was degassed by bubbling argon with sonication. Next, tetrakistriphenylphosphine (9.6 mg, 8.3 .imol) was added and the degassing procedure was repeated. The mixture was heated at 90 Cfor 6h. The reaction mixture was diluted with ACN containing 0.1% TFA and purified by reverse phase HPLC eluting with a gradient of 20-90% ACN/Water/0. 1% TFA mixture. Concentration of the appropriate fraction afforded TFA salt of Example 1 (9.4 mg) as a pale yellow solid. LCMS (M+H) = 420.3. HPLC, method E, Rt= 6.48 mm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63 mg | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 120.0℃; for 0.666667h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate 25 Nitrogen was bubbled through a reaction mixture of Intermediate 15 (143 mg, 0.343 mmol), <strong>[874219-34-8](3-carbamoyl-4-fluorophenyl)boronic acid</strong> (69.0 mg, 0.377 mmol) and potassium carbonate (104 mg, 0.754 mmol) in DME (1.5 mL) and water (0.5 mL) for 5 min. Then Pd(Ph3P)4 (39.6 mg, 0.034 mmol) was added, the reaction vessel was sealed and the reaction mixture was heated at 120 C with microwave irradiation for 40 min. The reaction mixture was concentrated and the crude residue was purified using a Biotage Horizon (12g SiC , 30-100% EtOAc/hexanes) to yield the title compound (63 mg). LC- MS retention time = 1.40 min; m/z = 476.4 [M+H]+. (Column: Phenomenex Luna C18 30 x 2.0 mm 3 μιη. Solvent A = 90% Water : 10% Acetonitrile : 0.1% TFA. Solvent B = 10% Water : 90% Acetonitrile : 0.1% TFA. Flow Rate = 1 mL/min. Start % B = 0. Final % B = 100. Gradient Time = 2 minutes, then a 1-minute hold at 100% B. Wavelength = 220 nm). NMR (400 MHZ, CDCh) δ ppm 8.70 (dd, J=4.8, 1.5 Hz, 1H), 7.62 (d, J=6.5 Hz, 1H), 7.42 (dd, J=7.8, 1.5 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.16 (dd, 1=11.3, 8.5 Hz, 1H), 7.03 (br s, 1H), 6.93 (br. s., 1H), 6.63 - 6.54 (m, 1H), 6.14 (d, J=6.3 Hz, 2H), 5.81 (br. s., 1H), 4.70 (td, J=9.2, 5.1 Hz, 1H), 4.47 (d, J=8.8 Hz, 1H), 3.26 - 3.12 (m, 2H), 1.21 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 111A (50 mg, 0.1 mmol) in 1 mL of 4 N of hydrochloride in dioxane and 1 mL of methanol was stirred for 3 hours. The solvent was removed and dried in vacuo. The crude product, 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H- cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (25.8 mg, 0.092 mmol), and (1-Cyano- 2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (39.2 mg, 0.092 mmol) were dissolved in DMF (1 mL) and diisopropylethylamine (0.032 mL, 0.18 mmol) was added. The reaction was stirred at room temperature for 1 hour. The mixture was dissolved in 10 mL of EtOAc, and washed with 5 mL of saturated sodium bicarbonate (aq) and 5 mL of brine. The organic layer was dried with sodium sulfate. The mixture was filtered, and the filtrate was dried and concentrated. The crude product was dissolved in 1 mL of dioxane, <strong>[874219-34-8](3-carbamoyl-4-fluorophenyl)boronic acid</strong> (8.65 mg, 0.047 mmol), 1 N of sodium bicarbonate (0.047 mL), and dichlorobis(tricyclohexylphosphine)palladium(II) (1.16 mg, 0.002 mmol) were added to the mixture. The reaction was heated at 140 C by microwave reactor for 15 minutes. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was dissolved in 1 mL of acetonitrile and 1,1’-carbonyldiimidazole (9.73 mg, 0.06 mmol) was added to the solution, which was stirred for 1 hour. The mixture was filtered, and the reaction mixture was purified on preparatory reverse phase HPLC using 20-80%B over 20 min. (A=0.1%TFA/H2O; B=0.1%TFA/Acetonitrile). The pure fractions as determined by LC/MS were combined and lyophilized to provide the desired compound. MS (m/z) 693 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.88 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.22 - 7.10 (m, 2H), 6.65 (t, J = 9.3 Hz, 1H), 6.37 (d, J = 6.8 Hz, 2H), 5.37 - 5.20 (m, 1H), 4.98 - 4.88 (m, 1H), 3.24 (p, J = 1.7 Hz, 1H), 3.15 - 2.96 (m, 2H), 2.47 (dd, J = 8.1, 4.0 Hz, 1H), 1.39 (d, J = 6.8 Hz, 1H), 1.10 (s, 1H). | ||
A solution of 111A (50 mg, 0.1 mmol) in 1 mL of 4 N of hydrochloride in dioxane and 1 mL of methanol was stirred for 3 hours. The solvent was removed and dried in vacuo. The crude product, 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H- cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (25.8 mg, 0.092 mmol), and (1-Cyano- 2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (39.2 mg, 0.092 mmol) were dissolved in DMF (1 mL) and diisopropylethylamine (0.032 mL, 0.18 mmol) was added. The reaction was stirred at room temperature for 1 hour. The mixture was dissolved in 10 mL of EtOAc, and washed with 5 mL of saturated sodium bicarbonate (aq) and 5 mL of brine. The organic layer was dried with sodium sulfate. The mixture was filtered, and the filtrate was dried and concentrated. The crude product was dissolved in 1 mL of dioxane, <strong>[874219-34-8](3-carbamoyl-4-fluorophenyl)boronic acid</strong> (8.65 mg, 0.047 mmol), 1 N of sodium bicarbonate (0.047 mL), and dichlorobis(tricyclohexylphosphine)palladium(II) (1.16 mg, 0.002 mmol) were added to the mixture. The reaction was heated at 140 C by microwave reactor for 15 minutes. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was dissolved in 1 mL of acetonitrile and 1,1’-carbonyldiimidazole (9.73 mg, 0.06 mmol) was added to the solution, which was stirred for 1 hour. The mixture was filtered, and the reaction mixture was purified on preparatory reverse phase HPLC using 20-80%B over 20 min. (A=0.1%TFA/H2O; B=0.1%TFA/Acetonitrile). The pure fractions as determined by LC/MS were combined and lyophilized to provide the desired compound. MS (m/z) 693 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.88 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.22 - 7.10 (m, 2H), 6.65 (t, J = 9.3 Hz, 1H), 6.37 (d, J = 6.8 Hz, 2H), 5.37 - 5.20 (m, 1H), 4.98 - 4.88 (m, 1H), 3.24 (p, J = 1.7 Hz, 1H), 3.15 - 2.96 (m, 2H), 2.47 (dd, J = 8.1, 4.0 Hz, 1H), 1.39 (d, J = 6.8 Hz, 1H), 1.10 (s, 1H). | ||
A solution of 111A (50 mg, 0.1 mmol) in 1 mL of 4 N of hydrochloride in dioxane and 1 mL of methanol was stirred for 3 hours. The solvent was removed and dried in vacuo. The crude product, 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H- cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (25.8 mg, 0.092 mmol), and (1-Cyano- 2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (39.2 mg, 0.092 mmol) were dissolved in DMF (1 mL) and diisopropylethylamine (0.032 mL, 0.18 mmol) was added. The reaction was stirred at room temperature for 1 hour. The mixture was dissolved in 10 mL of EtOAc, and washed with 5 mL of saturated sodium bicarbonate (aq) and 5 mL of brine. The organic layer was dried with sodium sulfate. The mixture was filtered, and the filtrate was dried and concentrated. The crude product was dissolved in 1 mL of dioxane, <strong>[874219-34-8](3-carbamoyl-4-fluorophenyl)boronic acid</strong> (8.65 mg, 0.047 mmol), 1 N of sodium bicarbonate (0.047 mL), and dichlorobis(tricyclohexylphosphine)palladium(II) (1.16 mg, 0.002 mmol) were added to the mixture. The reaction was heated at 140 C by microwave reactor for 15 minutes. The mixture was filtered, and the filtrate was concentrated to dryness. The mixture was dissolved in 1 mL of acetonitrile and 1,1’-carbonyldiimidazole (9.73 mg, 0.06 mmol) was added to the solution, which was stirred for 1 hour. The mixture was filtered, and the reaction mixture was purified on preparatory reverse phase HPLC using 20-80%B over 20 min. (A=0.1%TFA/H2O; B=0.1%TFA/Acetonitrile). The pure fractions as determined by LC/MS were combined and lyophilized to provide the desired compound. MS (m/z) 693 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.88 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.22 - 7.10 (m, 2H), 6.65 (t, J = 9.3 Hz, 1H), 6.37 (d, J = 6.8 Hz, 2H), 5.37 - 5.20 (m, 1H), 4.98 - 4.88 (m, 1H), 3.24 (p, J = 1.7 Hz, 1H), 3.15 - 2.96 (m, 2H), 2.47 (dd, J = 8.1, 4.0 Hz, 1H), 1.39 (d, J = 6.8 Hz, 1H), 1.10 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; Sodium hydrogenocarbonate; In 1,4-dioxane; at 130.0℃; for 0.166667h;Microwave irradiation; Inert atmosphere; | To a suspension of 111C (10 mg, 0.014 mmol)), (3-carbamoyl-4- fluorophenyl)boronic acid (3.9 mg, 0.021 mmol), 1 N of sodium bicarbonate (0.043 mL) in 1 mL of dioxane, dichlorobis(tricyclohexylphosphine)palladium(II) (1.1 mg, 0.0014 mmol) was added. The reaction was heated at 130 C by microwave reactor for 10 minutes. The mixture was filtered and the filtrate was concentrated to dryness. The mixture was dissolved in 1 mL of DMF and the reaction mixture was purified on preparatory reverse phase HPLC using 20-80%B over 20 min. (A=0.1%TFA/H2O; B=0.1%TFA/Acetonitrile). The pure fractions as determined by LC/MS were combined and lyophilized to provide the desired compound. MS (m/z) 762 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 7.35-7.25 (m,2H), 7.25-7.15 (m, 2H), 6.64 (d, J = 9.8 Hz, 1H), 6.33 (d, J = 7.6 Hz, 2H), 5.24 (d, J = 6.4 Hz, 1H), 4.21 (d, J = 5.1 Hz, 5H), 3.16 - 2.94 (m, 2H), 2.48 (d, J = 8.5 Hz, 2H), 1.57 (s, 4H), 1.39 (d, J = 7.3 Hz, 1H), 1.10 (s, 1H). | |
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; Sodium hydrogenocarbonate; In 1,4-dioxane; at 130.0℃; for 0.166667h;Microwave irradiation; Inert atmosphere; | To a suspension of 111C (10 mg, 0.014 mmol)), (3-carbamoyl-4- fluorophenyl)boronic acid (3.9 mg, 0.021 mmol), 1 N of sodium bicarbonate (0.043 mL) in 1 mL of dioxane, dichlorobis(tricyclohexylphosphine)palladium(II) (1.1 mg, 0.0014 mmol) was added. The reaction was heated at 130 C by microwave reactor for 10 minutes. The mixture was filtered and the filtrate was concentrated to dryness. The mixture was dissolved in 1 mL of DMF and the reaction mixture was purified on preparatory reverse phase HPLC using 20-80%B over 20 min. (A=0.1%TFA/H2O; B=0.1%TFA/Acetonitrile). The pure fractions as determined by LC/MS were combined and lyophilized to provide the desired compound. MS (m/z) 762 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 7.35-7.25 (m,2H), 7.25-7.15 (m, 2H), 6.64 (d, J = 9.8 Hz, 1H), 6.33 (d, J = 7.6 Hz, 2H), 5.24 (d, J = 6.4 Hz, 1H), 4.21 (d, J = 5.1 Hz, 5H), 3.16 - 2.94 (m, 2H), 2.48 (d, J = 8.5 Hz, 2H), 1.57 (s, 4H), 1.39 (d, J = 7.3 Hz, 1H), 1.10 (s, 1H). | |
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; Sodium hydrogenocarbonate; In 1,4-dioxane; at 130.0℃; for 0.166667h;Microwave irradiation; Inert atmosphere; | To a suspension of 111C (10 mg, 0.014 mmol)), (3-carbamoyl-4- fluorophenyl)boronic acid (3.9 mg, 0.021 mmol), 1 N of sodium bicarbonate (0.043 mL) in 1 mL of dioxane, dichlorobis(tricyclohexylphosphine)palladium(II) (1.1 mg, 0.0014 mmol) was added. The reaction was heated at 130 C by microwave reactor for 10 minutes. The mixture was filtered and the filtrate was concentrated to dryness. The mixture was dissolved in 1 mL of DMF and the reaction mixture was purified on preparatory reverse phase HPLC using 20-80%B over 20 min. (A=0.1%TFA/H2O; B=0.1%TFA/Acetonitrile). The pure fractions as determined by LC/MS were combined and lyophilized to provide the desired compound. MS (m/z) 762 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 7.35-7.25 (m,2H), 7.25-7.15 (m, 2H), 6.64 (d, J = 9.8 Hz, 1H), 6.33 (d, J = 7.6 Hz, 2H), 5.24 (d, J = 6.4 Hz, 1H), 4.21 (d, J = 5.1 Hz, 5H), 3.16 - 2.94 (m, 2H), 2.48 (d, J = 8.5 Hz, 2H), 1.57 (s, 4H), 1.39 (d, J = 7.3 Hz, 1H), 1.10 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; In 1,4-dioxane; water monomer; for 0.666667h;Inert atmosphere; Microwave irradiation; Sealed tube; Heating; | A microwave tube was charged with N-(1-(6-bromo-2-(methylthio)thiazolo[4,5-b]pyridin-5-yl)-2- (3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro- 1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (117A, 50 mg, 0.73 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid (20 mg, 0.11 mmol) and PdCl2[P(cy)3]2 (3 mg, 0.004 mmol). To the mixture was added 1.4 mL of 1,4-dioxane and 0.2 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated up to boiling (140 C bath) for 40 min. After being cooled down, the reaction was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford compound 117B and Compound 117. Compound 117B: (MS (m/z) 738.96 [M+H]+). Compound 117: MS (m/z) 829.89 [M+H]+. 1H NMR (400 MHz, Methanol-d4 ) δ 8.63 (m, 1H), 8.39 (m, 1H), 8.30 (s, 1H), 7.48 (m, 3H), 7.36 - 7.16 (m, 1H), 6.65 (m, 1H), 6.38 (m, 2H), 5.49 (m, 1H), 4.88 (s, 2H), 3.14 (m, 2H), 2.46 (m, 2H), 1.39 (m, 1H), 1.11 (m, 1H). | |
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; In 1,4-dioxane; water monomer; for 0.666667h;Inert atmosphere; Microwave irradiation; Sealed tube; Heating; | A microwave tube was charged with N-(1-(6-bromo-2-(methylthio)thiazolo[4,5-b]pyridin-5-yl)-2- (3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro- 1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (117A, 50 mg, 0.73 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid (20 mg, 0.11 mmol) and PdCl2[P(cy)3]2 (3 mg, 0.004 mmol). To the mixture was added 1.4 mL of 1,4-dioxane and 0.2 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated up to boiling (140 C bath) for 40 min. After being cooled down, the reaction was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford compound 117B and Compound 117. Compound 117B: (MS (m/z) 738.96 [M+H]+). Compound 117: MS (m/z) 829.89 [M+H]+. 1H NMR (400 MHz, Methanol-d4 ) δ 8.63 (m, 1H), 8.39 (m, 1H), 8.30 (s, 1H), 7.48 (m, 3H), 7.36 - 7.16 (m, 1H), 6.65 (m, 1H), 6.38 (m, 2H), 5.49 (m, 1H), 4.88 (s, 2H), 3.14 (m, 2H), 2.46 (m, 2H), 1.39 (m, 1H), 1.11 (m, 1H). | |
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; In 1,4-dioxane; water monomer; for 0.666667h;Inert atmosphere; Microwave irradiation; Sealed tube; Heating; | A microwave tube was charged with N-(1-(6-bromo-2-(methylthio)thiazolo[4,5-b]pyridin-5-yl)-2- (3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro- 1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (117A, 50 mg, 0.73 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid (20 mg, 0.11 mmol) and PdCl2[P(cy)3]2 (3 mg, 0.004 mmol). To the mixture was added 1.4 mL of 1,4-dioxane and 0.2 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated up to boiling (140 C bath) for 40 min. After being cooled down, the reaction was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford compound 117B and Compound 117. Compound 117B: (MS (m/z) 738.96 [M+H]+). Compound 117: MS (m/z) 829.89 [M+H]+. 1H NMR (400 MHz, Methanol-d4 ) δ 8.63 (m, 1H), 8.39 (m, 1H), 8.30 (s, 1H), 7.48 (m, 3H), 7.36 - 7.16 (m, 1H), 6.65 (m, 1H), 6.38 (m, 2H), 5.49 (m, 1H), 4.88 (s, 2H), 3.14 (m, 2H), 2.46 (m, 2H), 1.39 (m, 1H), 1.11 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; In 1,4-dioxane; at 150.0℃; for 0.25h;Inert atmosphere; Microwave irradiation; Sealed tube; | A microwave tube was charged with N-(1-(6-bromo-2-cyanothiazolo[4,5-b]pyridin-5-yl)-2-(3,5- difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H- cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (119B, 50 mg, 0.076 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid (21 mg, 0.11 mmol) and PdCl2[P(cy)3]2 (3 mg, 0.004 mmol). To the mixture was added 1.4 mL of 1,4-dioxane and 0.2 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed; and the reaction mixture was heated up at 150 C in microwave for 15 min. After cooled to room temperature, the reaction was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford Compound 119. MS (m/z) 735.88 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J = 7.9 Hz, 1H), 8.38 (s, 1H), 7.46 (m, 2H), 7.25 (m, 1H), 6.65 (m, 1H), 6.37 (m, 2H), 5.48 (m, 1H), 4.85 (s, 2H), 3.23 - 3.09 (m, 2H), 2.46 (m, 2H), 1.38 (m, 1H), 1.09 (m, 1H). | |
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; In 1,4-dioxane; at 150.0℃; for 0.25h;Inert atmosphere; Microwave irradiation; Sealed tube; | A microwave tube was charged with N-(1-(6-bromo-2-cyanothiazolo[4,5-b]pyridin-5-yl)-2-(3,5- difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H- cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (119B, 50 mg, 0.076 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid (21 mg, 0.11 mmol) and PdCl2[P(cy)3]2 (3 mg, 0.004 mmol). To the mixture was added 1.4 mL of 1,4-dioxane and 0.2 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed; and the reaction mixture was heated up at 150 C in microwave for 15 min. After cooled to room temperature, the reaction was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford Compound 119. MS (m/z) 735.88 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J = 7.9 Hz, 1H), 8.38 (s, 1H), 7.46 (m, 2H), 7.25 (m, 1H), 6.65 (m, 1H), 6.37 (m, 2H), 5.48 (m, 1H), 4.85 (s, 2H), 3.23 - 3.09 (m, 2H), 2.46 (m, 2H), 1.38 (m, 1H), 1.09 (m, 1H). | |
With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; In 1,4-dioxane; at 150.0℃; for 0.25h;Inert atmosphere; Microwave irradiation; Sealed tube; | A microwave tube was charged with N-(1-(6-bromo-2-cyanothiazolo[4,5-b]pyridin-5-yl)-2-(3,5- difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H- cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (119B, 50 mg, 0.076 mmol), (3- carbamoyl-4-fluorophenyl)boronic acid (21 mg, 0.11 mmol) and PdCl2[P(cy)3]2 (3 mg, 0.004 mmol). To the mixture was added 1.4 mL of 1,4-dioxane and 0.2 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed; and the reaction mixture was heated up at 150 C in microwave for 15 min. After cooled to room temperature, the reaction was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford Compound 119. MS (m/z) 735.88 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J = 7.9 Hz, 1H), 8.38 (s, 1H), 7.46 (m, 2H), 7.25 (m, 1H), 6.65 (m, 1H), 6.37 (m, 2H), 5.48 (m, 1H), 4.85 (s, 2H), 3.23 - 3.09 (m, 2H), 2.46 (m, 2H), 1.38 (m, 1H), 1.09 (m, 1H). |
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