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CAS No. : | 915087-25-1 | MDL No. : | MFCD09909322 |
Formula : | C8H9FN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XOKAXPQJUODMSH-UHFFFAOYSA-N |
M.W : | 168.17 | Pubchem ID : | 44139521 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 43.8 |
TPSA : | 55.12 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) : | -6.59 cm/s |
Log Po/w (iLOGP) : | 1.08 |
Log Po/w (XLOGP3) : | 1.04 |
Log Po/w (WLOGP) : | 1.2 |
Log Po/w (MLOGP) : | 1.34 |
Log Po/w (SILICOS-IT) : | 1.08 |
Consensus Log Po/w : | 1.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.78 |
Solubility : | 2.82 mg/ml ; 0.0168 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.79 |
Solubility : | 2.74 mg/ml ; 0.0163 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.7 |
Solubility : | 0.337 mg/ml ; 0.002 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.13 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
100% | With trifluoroacetic acid In dichloromethane at 20℃; | Methyl 4-amino-2-fluoro-benzylamide <n="55"/>[0087] TFA (1 niL) is added dropwise to a solution of methylamide (60 mg, 0.21 mmol) in dry DCM (0.5 mL) under argon. The solution is stirred overnight at room temperature. After completion of the reaction, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (Hexane/EtOac) to afford the desired product quantitatively.[0088] 1H NMR (500 MHz CDC13) δ 2.98 (d, J = 4.8 Hz, 3H), 4.15 (br s, 2H), 6.32(d, J = 14.3 Hz, IH), 6.48 (d, J = 8.2 Hz, IH), 6.61 (br s, IH), 7.90 (dd, J = 8.6 Hz, IH), 13C NMR (500 MHz CDC13) δ 26.63, 100.8 (d, J = 28.8 Hz), 110.3 (d, J = 244.6 Hz), 110.9, 133.3 (d, J = 4.3 Hz), 151.4 (d, J = 12.5 Hz), 162.2 (d, J = 244.6 Hz),164.3 (d, J = 3.5 Hz). |
95% | With trifluoroacetic acid In dichloromethane | A solution of 2,4-difluoro-benzoylchloride D in a solution of methylamine and tetrahydrofuran (THF) is allowed to react to produce 2,4-difluoro-N-methylbenzamide M (quantitative yield). The 2,4-difluoro-N-methylbenzamide M is mixed with in a solution of acetonitrile and 4-methoxy-benzenemethanamine and heated in a microwave for 20 minutes at 190° C. to produce 2-fluoro-4-(4-methoxybenzylamino)-N-methylbenzamide S (yield of 40percent). The 2-fluoro-4-(4-methoxybenzylamino)-N-methylbenzamide S is reacted in a solution of dichloromethane and trifluoroacetic acid to produce 2-fluoro-4-amino-N-methylbenzamide T (yield greater than 95percent). The 2-fluoro-4-amino-N-methylbenzamide T is reacted with a solution of sodium cyanide and cyclobutanone to produce 4-(1-cyanocyclobutylamino)-2-fluoro-N-methylbenzamide B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With acetic acid In ethyl acetateReflux | Synthesis of 4-Amino-2-fluoro-N-methyl-benzamide 4a. [00194] To a solution of 2-fluoro-N-methyl-4-nitro-benzamide 21 (3g, 15.1mmol) in co-solvent of ethyl acetate and acetic acid (12mL+12mL) was added iron dust (8g, 143.mmol). The suspension was heated at reflux until the starting material disappeared in LCMS. Cooled down to 25°C. The solid was filtered off and the filtrate was diluted with ethyl acetate (50mL). The organic phase was washed with brine (3x30mL), dried (MgS04) and concentrated to dryness in vacuo. The title compound 4a was obtained as an orange solid (2.5g, 97percent yield). MS: 169 (M+H)+. 1H NMR (acetone-d6, 500MHz): δ 7.69 (1H, dd, J=8.7, 8.8Hz), 7.15 (1H, s), 6.51 (1H, dd, J=8.6, 2.1Hz), 6.38 (1H, dd, J=14.7, 2.1Hz), 5.70 (1H, br s), 2.88 (3H, d, J=4.3Hz). |
92% | With iron; acetic acid In ethyl acetate for 1 h; Heating / reflux | A mixture of N-methyl-2-fluoro-4-nitrobenzamide (52a) (2.89 g, 14.6 mmol) and iron(5.04 g, 90 mmol) in ethyl acetate (40 ml) and acetic acid (40 ml) was refluxed for 1 hour. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone,95:5) to yield N-methyl-2-fluoro-4-aminobenzamide (52b) (2.3 g, 13.7 mmol, 94percent) as an off-white solid..H ΝMR (acetone-d 400 MHz) δ 2.86 (d, J= 4.3 Hz, 3H), 5.50 (bs, 2H), 6.37 (dd, J&1 = 14.7 Hz, J2 = 2.1Hz, IH), 6.50 (dd, J= 8.5, 2.1 Hz, IH), 7.06 (bs, IH), 7.68 (dd, J= 8.8 8.8 Hz, IH); 13C ΝMR (acetone- d6, 100 MHz) δ 25.8, 99.6 (d, J= 13.8 Hz), 109.2 (d, J= 12.8 Hz), 110.0 (d, J= 1.6 Hz), 132.5 (d, J= 4.8Hz), 153.5 (d, J= 12.6 Hz), 162.2 (d, J= 242.5 Hz), 164.0 (d, J= 3.1 Hz).; A mixture of N-Methyl-2-fluoro-4-nitrobenzamide (Formula 38) (0.18 g, 0.91 mmol) and iron (0.31 g, 5.60 mmol) in ethyl acetate (5 mL) and acetic acid (5 mL) was refluxed for 1 h. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and the residue was purified with SiO2 column chromatography (dichloromethane:acetone, 95:5) to give N-Methyl-2-fluoro-4-aminobenzamide (Formula 39) (0.14 g, 92percent) as an off-white solid. 1H ΝMR (acetone-^) δ 2.86 (d, 3 H, J=4.3), 5.50 (br s, 2 H), 6.37 (dd, 1 H, /=14.7 and 2.1), 6.50 (dd, IH, J=8.6 and 2.1), 7.06 (br s, IH), 7.68 (dd, IH, J=8.8 and 8.8). |
92% | With iron; acetic acid In ethyl acetate for 1 h; Heating / reflux | A mixture of N-Methyl-2-fluoro-4-nitrobenzamide (Formula 38) (0.18 g, 0.91 mmol) and iron (0.31 g, 5.60 mmol) in ethyl acetate (5 mL) and acetic acid (5 mL) was refluxed for 1 h. The solid particles were filtered off. The filtrate washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and the residue was purified with SiO2 column chromatography (dichloromethane:acetone, 95:5) to give N-Methyl-2-fluoro-4-aminobenzamide (Formula 39) (0.14 g, 92percent) as an off-white solid. 1H NMR (acetone-d6) δ 2.86 (d, 3H, J=4.3), 5.50 (br s, 2H), 6.37 (dd, 1H, J=14.7 and 2.1), 6.50 (dd, 1H, J=8.6 and 2.1), 7.06 (br s, 1H), 7.68 (dd, 1H, J=8.8 and 8.8). |
83.3% | With hydrogen; acetic acid In methanol at 20℃; Autoclave | Charge 100g of 2-Fluoro-N-methyl-4-nitrobenzamide and 500ml of methanol into the 1L autoclave at ambient temperature. To this add, 35 ml of Encapsulated Raney Ni (previously washed with water) and 3g of acetic acid. Close the autoclave and flush with nitrogen for 2 times and then pressurized with hydrogen to 5.0 Kg and maintain until completion of the reaction. After completion of the reaction filter the catalyst and wash with 50 ml of methanol. Concentrate the filtrate to remove the methanol under vacuum at 45-50°C to a thick residue and add 300 ml of water, stir slurry for lh and filter, wash with 50 ml of water. Dry the product and dry wt is 70g (83.3percent). |
62% | With iron; acetic acid In ethyl acetate for 16 h; Inert atmosphere; Reflux | To a solution of compound 7 (14.6g, 73.7mmol) in EA (100ml) and AcOH (9.2ml, 0.50mol) was added Fe (39g) portion-wise under N2 at room temperature. The reaction mixture was refluxed for 16h. After cooling to room temperature, the reaction mixture was filter, then, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silics gel (ethyl acetate/ petroleum ether=1/1) to afford 4-amino-2-fluoro-N-methylbenzamide (9) (7.6g, 62percent). 1H NMR (400 MHz, CDCl3) δ 7.92 (t, J=8.8 Hz, 1H)6.60 (s, 1H)6.49 (d, J=8.4 Hz, 1H), 6.32 (d, J=14Hz, 1H), 4.10 (s, 2H), 2.99 (d, J=4.4Hz, 3H). MS (ESI): m/z 169.1 (M+H+, positive mode). |
61.5% | With iron; acetic acid In ethyl acetate for 16 h; Reflux | Synthesis of 2-fluoro-N-methyl-4-amino-benzamide (Compound 5) Compound 4 (14.6 g, 73.7 mmol) was dissolved in a solution of ethyl acetate and acetic acid (50 mL +50 mL). Then 39 g of iron powder was added. The resulting mixture was refluxed overnight (16 h), then cooled to room temperature. The solid was filtered and washed with ethyl acetate for three times (3 * 50 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated to give a yellow solid which was purified by column chromatography (DCM: MeOH = 50:1), to give a pale yellow solid , compound 5 (7.62 g, yield 61.5percent). |
61.5% | With iron; acetic acid In ethyl acetate for 16 h; Reflux | Compound 7 (14.6 g, 73.7 mmol) was dissolved in a solution of ethyl acetate and acetic acid (50 ml: 50 ml). Iron powder (39 g) was added. The resulting mixture was refluxed overnight for 16 h, and then cooled to room temperature. The solid was filtered and washed three times with ethyl acetate (3x50 ml). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated the residue was purified by column chromatography (DCM:MeOH=50:1)to give a pale yellow solid of compound 8 (7.62 g, 61.5percent yield). ‘H NMR (CDC13, 400 MHz): ö 7.92 (1H, m), 6.60 (1H, s), 6.49 (1H, d, J=8.4 Hz), 6.32 (1H, d, J=14 Hz), 4.10 (2H, s), 2.99 (3H, s) ppm. |
10.5 g | With palladium 10% on activated carbon; hydrogen In methanol at 27℃; | N-Methyl 2-flouro-4-nitro benzamide (Formula VI; 13 g) was added to methanol(260 mL) followed by the addition of 10percent (w/w) palladium/carbon (1.3 g) at 27°C andhydrogen gas at 2 Kg/cm2 to 2.5 Kg/cm2 pressure for 2 hours to 4 hours. The reaction mixture was filtered through celite and washed with methanol (40 mL). The solution obtained was concentrated under reduced pressure at 30°C to 35°C for 1 hour to 2 hours to obtain the title compound.Yield: 10.5 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 g | With triethylamine In dichloromethane at 20 - 30℃; for 15 h; Inert atmosphere | In a 500 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, (10 g) 4-amino-2-fluoro-N-methylbenzamide, (16 g) bromo-isobutyric acid and 100 mL dichloromethane were added at room temperature. (25 mL) triethylamine was added and the reaction mixture was stirred for 15 hours at 20-30° C. After completion of reaction, the reaction mixture was concentrated completely UN at 40° C. 100 mL water was added and stirred for 1 hour. 7.5 mL hydrochloric acid was added and stirred for 30 min. The reaction mixture was cooled to 0-5° C. and stirred for 1 hour, filtered, washed with 25 mL water and dried to obtain 15.2 g titled compound with 94.97percent purity by HPLC In a 500 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, (15 g) 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid obtained in example-1 and 120 mL acetone were heated to 55 to 60° C. for 1 hour. The reaction mixture was cooled to 0 to 5° C. and the product thus obtained was filtered and dried under vacuum at 50° C. to obtain 12 g titled compound with 99.54percent purity by HPLC. |