Structure of 100137-47-1
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CAS No. : | 100137-47-1 |
Formula : | C6H7N3O |
M.W : | 137.14 |
SMILES Code : | O=C(N)C1=NC=CC(N)=C1 |
MDL No. : | MFCD08062892 |
InChI Key : | QKNCZYUYGMWQPB-UHFFFAOYSA-N |
Pubchem ID : | 23131262 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 36.74 |
TPSA ? Topological Polar Surface Area: Calculated from |
82.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.75 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.62 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.23 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.01 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.21 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.26 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.68 |
Solubility | 28.8 mg/ml ; 0.21 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.63 |
Solubility | 32.2 mg/ml ; 0.235 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.23 |
Solubility | 8.15 mg/ml ; 0.0594 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.58 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.29 |
* 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 |
---|---|---|
87% | With hydrogen;palladium 10% on activated carbon; In methanol; for 8h; | 99A was hydrogenated in MeOH with 10% Pd/C (40 mg) with a hydrogen balloon for 8 h. The Pd/C was removed by filtration. The filtrate was condensed to give 99B (80 mg, 87% yield). 1H NMR (400 MHz, Methanol-d4) delta ppm 6.65 (dd, J=5.71, 2.64 Hz, 1H) 7.27 (d, J=2.20 Hz, 1H) 8.03 (d, J=5.71 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | 4-Aminopyridine-2-carboxamide (102 mg, 0.744 mmol) was dissolved in dichloromethane (2.5 mL) and DIEA (260 mu, 1.49 mmol) and cooled to -10 C. A solution of cold (-10 C) racemic fr 5-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carbonyl chloride (240 mg, 0.597 mmol) in dichloromethane (2.5 mL) was added dropwise to the stirring amine solution. The resulting suspension was slowly allowed to warm to room temperature over 1 hour. DMF (0.5 mL) was added and the reaction was stirred for 1 additional hour. The reaction was diluted with ethyl acetate and washed with 50% saturated sodium carbonate, water, and brine. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (40 g silica, 0-10%methanol/dichloromethane). Additional silica gel chromatography (40 g silica, 0-40% ethylacetate/dichloromethane) provided racemic fras-N-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4- (trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxamide (85 mg, 27%). ESI-MS m/z calc. 502.15, found 503.4 (M+l)+; retention time (Method B): 1.41 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 10.82 (s, 1H), 8.56 (s, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.65 (d, J = 3.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 7.07 (ddd, J = 8.8, 2.7, 1.3 Hz, 1H), 6.58 (s, 1H), 3.79 (s, 3H), 1.83 (dt, J = 8.4, 4.4 Hz, 1H), 1.39 - 1.28 (m, 1H), 1.16 - 1.12 (m, 1H), 1.10 (d, J = 5.9 Hz, 3H), 0.80 - 0.70 (m, 1H) ppm. SFC purification (36% methanol/64% CO2, ChiralPak IG (250 x 21.2 mm) 5mupiiota column, flow =70 mL/min) provided separated enantiomers re/-N-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4- (trifluoromethoxy)phenoxy]-6-(( 1 S,2S)-2-methylcyclopropyl)pyridine-3-carboxamide (111) and re/-N-(2- carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-((lR,2R)-2- methylcyclopropyl)pyridine-3-carboxamide (112). The absolute stereochemistry of enantiomers 111 and 112 was not determined. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 16h; | To a solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (37 mg, 0.27 mmol) and DIEA (94 mu, 0.54 mmol) in THF (1 mL) at 0 C was added a solution of 3-chloro-2-fluoro-6-[4- (trifluoromethoxy)phenoxy]benzoyl chloride (100 mg, 0.271 mmol) in THF (1.0 mL) anddichloromethane (1.0 mL) at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over MgSO/t, filtered and concentrated in vacuo. Silica gel columnchromatography (0-60% ethyl acetate/hexanes) provided 4-[[3-chloro-2-fluoro-6-[4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (15 mg, 11%). ESI-MS m/z calc. 469.05, found 470.1 (M+l)+; retention time (Method B): 1.74 minutes (3 minute run).lNMR (400 MHz, DMSO-d6) delta 11.39 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.10 (s, 1H), 7.77 (dd, J = 5.7, 2.3 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 2.8 Hz, 1H), 7.41 (dq, J = 7.8, 1.0 Hz, 2H), 7.28 - 7.21 (m, 2H), 6.93 (dd, J = 9.0, 1.4 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 4h; | To a solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (19 mg, 0.14 mmol) in THF ( 1 mL) and DIEA (72 nL, 0.41 mmol) at 0 C was added a slurry of 5-(l, l,2,2,2-pentafluoroethyl)-2-[4- (trifluoromethoxy)phenoxy]benzoyl chloride (60 mg, 0.14 mmol) in THF (1 mL) dropwise. The reaction was allowed to come to room temperature and stirred for 4 hours. The solvent was evaporated under a stream of N2. HPLC purification (1-99% acetonitrile/5 mM HC1) provided 4-[[5-( l, 1,2,2,2- pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (10 mg, 13%). ESI-MS m/z calc. 535.08, found 535.9 (M+l)+; retention time (Method B): 1.95 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 1 1.12 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.96 - 7.76 (m, 2H), 7.65 (d, J = 2.8 Hz, 1H), 7.56 - 7.39 (m, 2H), 7.39 - 7.24 (m, 2H), 7.14 (d, J = 8.8 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (58 mg, 0.43 mmol) and DIEA (222 mu, 1.28 mmol) in dichloromethane (1 mL) at 0 C was added a slurry of 2,3-difluoro-6-[4- (trifluoromethoxy)phenoxy]benzoyl chloride (150 mg, 0.425 mmol) in dichloromethane (1 mL) slowly and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated under a stream of N2. HPLC purification (1-99% acetonitrile/5 mM HC1) provided 4-[[2,3-difluoro-6-[4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (33 mg, 17%). ESI-MS m/z calc. 453.08, found 454.1 (M+l)+; retention time (Method B): 1.55 minutes (3 minute run). 1H NMR (400 MHz, DMSO-d6) delta 11.39 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.76 (dd, J = 5.5, 2.2 Hz, 1H), 7.70 - 7.59 (m, 2H), 7.42 - 7.35 (m, 2H), 7.21 - 7.13 (m, 2H), 7.02 - 6.92 (m, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 0 - 20℃; for 16h; | To a solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (2.90 g, 21.2 mmol) and DIEA (7.19 g, 55.7 mmol) in NMP (27 mL) at 0 C was added dropwise a solution of 2-fluoro-4-(trifluoromethoxy)benzoyl chloride (5.40 g, 22.3 mmol) in dichloromethane (27 mL). The reaction mixture was removed from the ice bath and stirred at room temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The crude material was triturated with a mixture of hexanes/dichloromethane and the solid was collected by vacuum filtration to obtain 4-[[2-fluoro-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide (650 mg, 9%). ESI-MS m/z calc. 343.05, found 344.1 (M+l)+; retention time (Method B): 1.65 minutes(3 minute run). NMR (400 MHz, DMSO-d6) delta 1 1.09 (s, 1H), 8.56 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.1 1 (d, J = 2.7 Hz, 1H), 7.95 - 7.80 (m, 2H), 7.74 - 7.54 (m, 2H), 7.50 - 7.32 (m, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | To <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (2.559 g, 18.66 mmol) and diisopropylethylamine (6.03 g, 46.65 mmol) in dichloromethane (28.5 mL) cooled at 0C was added dropwise a solution of 6-bromo- 2- fluoro-3-(trifluoromethyl)benzoyl chloride (5.7 g, 18.66 mmol) in dichloromethane (28.5 mL). The mixture was stirred at room temperature overnight. Ethyl acetate (150ml) was added to the mixture was washed with water. The organic layer was dried over sodium sulfate and concentrated. Purification by silica gel chromatography (dichloromethane/methanol gradient) gave 4-[[6-bromo-2-fluoro-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (800 mg, 11%). ESI-MS m/z calc. 406.97, found 408.2 (M+l)+; retention time (Method A): 0.58 minutes (1.2 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 0 - 20℃; for 16h; | 4-Aminopyridine-2-carboxamide (32 mg, 0.23 mmol) was dissolved in NMP (1 mL) and DIEA (100 mu, 0.57 mmol) and then cooled to 0 C. To this was added dropwise a cold solution of freshly prepared 2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4- (trifluoromethyl)benzoyl chloride (100 mg, 0.23 mmol) in dichloromethane (3 mL). The reaction was allowed to warm to room temperature and stirred for 16 hours. Reverse phase HPLC purification provided 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (30.3 mg, 25%). ESI-MS m/z calc. 536.101, found 537.2 (M+l)+; retention time (Method B): 1.75 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 11.41 (s, 1H), 8.55 (d, J = 5.4 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 2.7, 0.8 Hz, 1H), 7.01 (ddd, J = 8.8, 2.8, 1.3 Hz, 1H), 6.86 (s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | To an ice cold solution of 2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]- 3-(trifluoromethyl)benzoic acid (prepared as described in Example 1, 5 g, 11.98 mmol) and DMF (46 mu, 0.5941 mmol) in anhydrous dichloromethane (50 mL) under nitrogen was added oxalyl chloride (1.7 mL, 19.49 mmol) dropwise. Five minutes after the addition the ice bath was removed and the mixture was stirred at room temperature for 1 hour and at 35 C for 15min. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (12.5 mL) and the resulting solution was added dropwise to a cold solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (1.97 g, 14.36 mmol) and DIEA (5.2 mL, 29.85 mmol) in NMP (50 mL) keeping the internal temperature between 1 and 5 C. The mixture was stirred for 10 minutes, and then the ice bath was removed and the mixture was stirred at room temperature for 2 hours. The reaction was partitioned between water (250 mL) and dichloromethane (50 mL) and the dichloromethane phase was washed with water (250 mL) and brine (100 mL) and the combined aqueous phases were back extracted with dichloromethane (25 mL). The combined organic phases were dried, filtered and evaporated. The residue was purified by silica gel chromatography (dichloromethane/methanol gradient) to give 5.75 g of an oil which was dissolved in ethyl acetate (50 mL), washed three times with water (3x50 mL) and once with brine (50 mL). The aqueous phases were back extracted once with ethyl acetate (25 mL) and the combined organic phases were dried, filtered, and concentrated under reduced pressure to give 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide (3.7 g, 57%) as a cream colored foam. ESI-MS m/z calc. 536.10, found 537.0 (M+l)+; retention time (Method B): 1.81(3 minute run). i NMR ^OO MHz, DMSO-d6) delta 11.43 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.88 - 7.77 (m, 2H), 7.66 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.68 (d, J = 8.9 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 18h; | To <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (98 mg, 0.71 mmol), DMAP (17 mg, 0.14 mmol) and N- ethyl-N-isopropyl-propan-2 -amine (276 mg, 373 mu, 2.14 mmol) in DCM (3 mL), cooled to 0 C and was added dropwise a solution of 2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl chloride (300 mg, 0.71 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 18 hours. Mixture was concentrated in vacuo and purified by silica gel chromatography (0-40% ethyl acetate/hexanes) to afford 4-[[2-fluoro-6-[3-fluoro-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (28 mg, 7%). ESI-MS m/z calc. 521.06, found 522.1 (M+l)+; Retention time (Method B): 1.81 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 1 1.46 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.94 (t, J = 8.6 Hz, 1H), 7.79 (dd, J = 5.5, 2.2 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.51 (dd, J = 1 1.1, 2.8 Hz, 1H), 7.17 (ddd, J = 9.1, 2.9, 1.6 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With copper(l) iodide; In 2-methyltetrahydrofuran; at 75℃; for 24h;Molecular sieve; | A flask equipped with a reflux condenser was charged with <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (1.12 g, 8.17 mmol), benzenesulfonylsulfanylbenzene (1.85 g, 7.39 mmol), 2-isocyano-2-methyl-propane (3.0 mL, 27 mmol), copper (I) iodide (60 mg, 0.32 mmol) and molecular sieves (2.2 g) in 2- methyltetrahydrofuran (10 mL), and the mixture was heated at 75 C for 24 hours. The reaction mixture was filtered through Celite and the cake was rinsed with ethyl acetate. The filtrate was concentrated and dried under vacuum. The residue was purified by silica gel chromatography (0-60% ethyl acetate/hexanes) to obtain 4-[(Z)-[(feri-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2- carboxamide (1.25 g, 51%). ESI-MS m/z calc. 328.14, found 329.2 (M+l)+; retention time (Method B): 1.07 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 8.17 (dd, J = 5.3, 0.6 Hz, 1H), 7.94 (d, J = 3.0 Hz, 1H), 7.49 (s, 1H), 7.28 (dd, J = 2.2, 0.6 Hz, 1H), 7.25 - 7.17 (m, 5H), 6.74 (dd, J = 5.3, 2.2 Hz, 1H), 6.66 (s, 1H), 1.35 (s, 9H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
316 mg | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 20℃; for 1.16667h;Cooling with ice; | A solution of 2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethoxy)benzoic acid (prepared as described in Example 3, 600 mg, 1.39 mmol) in dichloromethane (12 mL) was cooled using an ice-bath. To this was added DMF (20 mu, 0.26 mmol) followed by careful addition of oxalyl chloride (275 mu, 3.15 mmol). The solution was stirred for 10 minutes then removed from the ice bath and allowed to warm to room temperature over lh. The reaction was concentrated under reduced pressure and azeotroped with dichloromethane to afford 2,5-difluoro-4- (trifluoromethyl)benzoyl chloride, which was used without purification. An ice cold solution of this material in dichloromethane (6 mL) was added to an ice cold solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (190 mg, 1.39 mmol), dichloromethane (6 mL), NMP (2 mL) and DIEA (725 mu, 4.16 mmol). The reaction was stirred for 10 minutes then removed from the ice bath and allowed to come to room temperature over lhour. The reaction was concentrated and purified by reverse phase HPLC to provide 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide (316 mg, 41%). ESI-MS m/z calc. 552.10, found 553.2 (M+l)+; retention time (Method B): 1.77 minutes (3 minute run). 'H NMR (400 MHz, DMSO-d6) delta 11.41 (s, 1H), 8.55 (d, J = 5.4 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.69 - 7.58 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 2.8, 0.8 Hz, 1H), 7.02 (ddd, J = 8.8, 2.7, 1.2 Hz, 1H), 6.65 (dd, J = 9.2, 1.6 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 50℃; for 0.666667h;Inert atmosphere; | To a solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (0.73 g, 5.3 mmol), DMAP (0.13 g, 1.1 mmol) and DIEA (2.1 g, 2.8 mL, 16 mmol) in dichloromethane ( 13 mL) at 0 C was added a solution of 2,5-difluoro-4-(trifluoromethyl)benzoyl chloride (1.3 g, 5.3 mmol) in THF (13 mL) dropwise. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate and washed with aqueous NaHCC , water and brine. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. Silica gel chromatography (0-40% ethyl acetate/hexanes) provided 4-[[2,5- difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (1.7 g, 85%). ESI-MS m/z calc. 345.05, found 346.2 (M+l)+; retention time (Method A): 0.53 minutes (1 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | To a solution of 2,6-difluoro-3-(trifluoromethyl)benzoic acid (250 mg, 1.11 mmol) in dichloromethane (4 mL) at 0 C was added DMF (10 mu, 0.13 mmol) followed by the dropwise addition of oxalyl chloride (0.250 mL, 2.87 mmol). The reaction mixture was stirred at 0 C for 40 minutes. The solvent was removed in vacuo to afford a gummy solid. The solid was dissolved in dichloromethane and added dropwise to a solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (152 mg, 1.11 mmol) and DIEA (0.40 mL, 2.3 mmol) in NMP (3 mL) at 0 C. The reaction mixture was allowed to warm to room temperature slowly with ice-bath in place and stirred for 16 hours. The reaction mixture was poured onto ice, diluted with dichloromethane and stirred for 30 minutes. The organic layer was separated, concentrated in vacuo, and the resulting brown oil was partitioned between ethyl acetate and water. The layers were separated and the organic layer was further washed with water. The organic layer was dried (by passing through a phase separation cartridge) and concentrated in vacuo. Purification by silica gel chromatography (0- 100% ethyl acetate/petroleum ether) provided 4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (77 mg, 20%). ESI-MS m/z calc. 345.05, found 346.0 (M+l)+;344.0 (M-l)-; retention time (Method F): 0.76 minutes (1.5 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 0 - 20℃; for 16h; | To 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1.20 g, 4.08 mmol) and DIEA (1.8 mL, 10 mmol) in 1 -methyl -pyrrolidin-2-one (12 mL) at 0 C was added a solution of 4-aminopyridine-2- carboxamide (560 mg, 4.08 mmol) in dichloromethane (6 mL) dropwise. The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water. Organic layer was concentrated to dryness. Silica gel chromatography (1-5%methanol/dichloromethane) provided 4-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide (400 mg, 11%). ESI-MS m/z calc. 395.05, found 396.6 (M+l)+; retention time (Method A): 0.55 minutes (1 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h; | To a suspension of 6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3- (trifluoromethyl)benzoic acid (600 mg, 1.641 mmol, prepared as described in Example 128) and DMF (5 mu, 0.06457 mmol) in dichloromethane (9 mL) at 0 C was added oxalyl chloride (700 mu, 8.024 mmol) dropwise. The reaction was allowed to come to room temperature and stirred for -30 min. The reaction mixture was concentrated, and the residue was taken up in dichloromethane and concentrated (3 x 5 mL). A cold solution of the crude 6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoyl chloride in dichloromethane (ImL) was then added to 5-aminopyridine-3-carboxamide (35 mg, 0.26 mmol) suspended in dichloromethane (ImL) and diisopropylethylamine (136 mu, 0.78 mmol) at 0 C. The reaction was then allowed to warm to room temperature and stirred for 16 hours. The reaction was concentrated, dissolved in DMSO and purified by HPLC to afford 4-(6-((6-chloro-2-methoxypyridin-3- yl)oxy)-2-fluoro-3-(trifluoromethyl)benzamido)picolinamide (1.5 mg, 2%). ESI-MS m/z calc. 484.79, found 485.0 (M+l)+; Retention time (Method B): 1.45 minutes (3 minutes run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 0 - 20℃; for 16h; | To a solution of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (565 mg, 4.12 mmol) and DIEA (1.33 g, 10.3 mmol) in NMP (10 mL) at 0 C was added a solution of 2-fluoro-5-(trifluoromethoxy)benzoyl chloride (1.00 g, 4.123 mmol) in dichloromethane (5 mL) dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, and the layers separated. The organic layer was dried over Na2SC>4, filtered and concentrated in vacuo to obtain 4-[[2-fluoro-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide (850 mg, 60%). ESI-MS m/z calc. 343.05, found 344.1 (M+l)+; retention time (Method B): 0.51 minutes (3 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | To an ice-cooled solution of 2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]- 3-(trifluoromethyl)benzoic acid (60 mg, 0.14 mmol) in dichloromethane (10 mL) and DMF (6 mu, 0.077 mmol) was carefully added oxalyl chloride (25 mu, 0.29 mmol) and the mixture was warmed to room temperature over 30 minutes and stirred for a further hour. The reaction mixture was concentrated under reduced pressure to afford a yellow solid. The residue was dissolved in dichloromethane (10 mL) followed by the addition of <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (25 mg, 0.18 mmol) and triethylamine (60 mu, 0.43 mmol). The resulting mixture was stirred at RT for 45 minutes and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether gradient) to yield 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (4 mg, 4%) as a white solid. ESI-MS m/z calc. 551.07, found 552.0 (M+l)+; retention time (Method E): 3.36 minutes (4.45 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; dichloromethane; at 0 - 20℃; for 16h; | To <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (1.51 g, 11.0 mmol) and DIEA (4.8 mL, 27.5 mmol) in 1 -methyl -pyrrolidin-2 -one (25 mL) cooled at 0 C was added a solution of 2,4-dichloro-6-fluoro-benzoyl chloride (2.5 g, 11 mmol) in dichloromethane (12.5 mL) dropwise. The reaction was stirred at room temperature for 16 hours. Water was added to the reaction mixture and the resulting precipitate was filtered and dried to obtain 4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (1.05 g, 29%). ESI-MS m/z calc. 327.00, found 328.1 (M+l)+; retention time (Method B): 1.16 minutes (3 minute run). NMR (400 MHz, DMSO-d6) delta 11.42 (s, 1H), 8.58 (d, J = 5.4 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.88 - 7.51 (m, 4H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | A solution of 4-fert-butyl-2-[[6-(trifluoromethyl)-3-pyridyl]oxy]benzoic acid (34 mg, 0.1 mmol), <strong>[100137-47-1]4-aminopyridine-2-carboxamide</strong> (15 mg, 0.11 mmol) and HATU (46 mg, 0.12 mmol) in DMF (0.5 mL) with N-methylmorpholine (33 mu, 0.3 mmol) was stirred at room temperature for 16 hours. After 16 hours, 4-dimethylaminopyridine (12 mg, 0.1 mmol) was added and the reaction mixture stirred at 60 C for 2h. Purification by HPLC (1-99% acetonitrile in water (HCl modifier)) afforded 4-(4-(fert- butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamido)picolinamide (3.11 mg, 7%). ESI-MS m/z calc. 458.16, found 459.5 (M+l)+; retention time (Method B): 1.70 minutes (3 minute run). |