Structure of 402-69-7
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CAS No. : | 402-69-7 |
Formula : | C6H4FNO2 |
M.W : | 141.10 |
SMILES Code : | C1=CC=C(F)N=C1C(=O)O |
MDL No. : | MFCD02181193 |
InChI Key : | DIEMCUFYSOEIDU-UHFFFAOYSA-N |
Pubchem ID : | 226027 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | 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 | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 31.15 |
TPSA ? Topological Polar Surface Area: Calculated from |
50.19 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.89 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.97 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.34 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.69 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.17 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.74 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.7 |
Solubility | 2.79 mg/ml ; 0.0198 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.61 |
Solubility | 3.45 mg/ml ; 0.0244 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.65 |
Solubility | 3.15 mg/ml ; 0.0223 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 |
Yes |
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 |
-6.47 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 |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 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) |
1.5 |
* 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 |
---|---|---|
53% | With potassium permanganate; In water; for 3h;Heating / reflux; | To [A] solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 [MMOL)] in water (170 ml) was added portionwise [KMN04] (2g, 12.65 mmol) and the mixture was heated to reflux. Then [KMN04] (8g, 50.63 [MMOL)] was added portionwise and the mixture was heated under reflux for 3 hours. On cooling, the precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot EtOH, the solid was filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53percent); m. p. [137°C.] |
53% | With potassium permanganate; In water; for 3h;Heating / reflux; | To a solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 [MMOL)] in water (170 ml) was added portion-wise [KMN04] (2g, 12.65 [MMOL)] and the mixture was heated to reflux. [KMN04] [(8G,] 50.63 [MMOL)] was added portion-wise and the mixture was heated under reflux for 3 hours and then cooled. The precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot [ETOH,] the solid filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53percent); m. p. [137°C.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | B. 4-Chloro-2-(difluoromethyl)-1 -[5-(6-fluoro-2-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}-1H-indole-5-carbonitrile; <n="96"/>To a solution of beta-fluoro^-pyridinecarboxylic acid (0.006 g, 0.043 mmol) in MeCN (2 ml_), under N2, was added EDCI (0.0085 g, 0.044 mmol). After 5 min, 2- [4-chloro-5-cyano-2-(difluoromethyl)-1/-/-indol-1-yl]acetohydrazide (0.012 g, 0.040 mmol) was added. After 1 h, additional beta-fluoro^-pyridinecarboxylic acid (0.003 g, 0.02 mmol) and EDCI (0.0077 g, 0.040 mmol) were added. After another 15 min, additional <strong>[402-69-7]6-fluoro-2-pyridinecarboxylic acid</strong> (0.0014 g, 0.01 mmol) and EDCI (0.0046 g, 0.02 mmol) were added. After another 10 min, TsCI (0.009 g, 0.048 mmol) and P-BEMP (loading 2.2 mmol/g, 0.073 g, 0.16 mmol) were added and the mixture was heated at 12O0C for 20 min. Upon cooling, additional TsCI (0.0046 g, 0.024 mmol) and P-BEMP (0.037 g, 0.08 mmol) were added and the mixture was heated at 12O0C for another 20 min. Upon cooling, the resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (0-50percent EtOAc-hexanes gradient) and the product was crystallized from CH2CI2-hexanes to give the title compound as a white solid (0.005 g, 31 percent yield): MS (ES) m/z 404 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium permanganate; at 100℃; for 4h;Heating / reflux; | Add potassium permanganate (12.8 g, 81.0 mmol) to a solution of 2-fluoro-5-methylpyridine (3.0 g, 27.0 mmol) in water (135 ml). Heat the reaction to 100 C for 4hours. While the reaction is hot, filter through Celite Rinse the filter cake with hot water (2 x 50ml) and concentrate the combined aqueous solutions in vacuo to a volume of 50 ml. Acidify with concentrated HCl and concentrate to dryness in vacuo to provide the title compound as a white solid which is used directly in the next step. MS APCI+ m/e 142 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; for 3h;Heating / reflux; | Intermediate 20 (1g, 7.09 [MMOL)] was added portionwise to thionyl chloride (3 ml) and the mixture was heated under reflux for 3 hours and then concentrated under reduced pressure. Isopropanol (3 ml) was added to the residue and the mixture was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was treated with a saturated solution of NaHCO3, extracted with ethyl acetate, the organic phase was dried over [NA2SO4] and concentrated under reduced pressure. The title compound was obtained as an cream oil (1.2g, 93percent); [[APCI] MS] m/z: 184 (MH+). | |
With thionyl chloride; for 5h;Reflux; | 2-fluoro-pyridine-6-carboxylic acid in thionyl chloride (2ml) (86mg, 0.448mmol) was heated under reflux for 5 hours stirred suspension of. Then excess reagent was removed under reduced pressure to give a crude solid. The crude solid, 4- (6-methyl-imidazo [1,2-a] pyridin-2-yl) aniline (100 mg, 0.448 mmol) and dry THF (20 ml) and diisopropylethylamine (94mul, 0.539mmol) in the amide prepared as described in the section amide coupling using, work-up and flash chromatography: the (2 1 EtOAc / hexanes) after to give the title compound 85 mg, 55percent) of a colorless solid . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | EDCI (80 mg) and DMAP (20 mg) are added to a stirred solution of (4,6-diethoxy- PYRIDAZIN-3-YLMETHYL)-3-METHYL-BYTYL)-AMINE (93.5 mg) and fluoropyridinyl acid (59 mg) in DCM (10ML). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (NA2S04), and evaporated. Preparative TLC purification of the residue (2: 1 of hexane: ethyl acetate) provides the title product (Compound 2). HL NMR 6 (CDCI3) 7.80-7. 92 (M, 1H), 7.60-7. 68 (M, 1H), 6.95-7. 02 (M, 1H), 6.22 (s, 2H), 4.98 (s, 2H), 4.56 (q, 2H, J = 7.2 Hz), 4.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a stirred solution of (6-chloro-4-propyl-pyridazin-3-ylmethyl)-isobutyl-amine (940 mg, 3.89 mmol) and <strong>[402-69-7]6-fluoro-pyridine-2-carboxylic acid</strong> (663 mg, 4.7 mmol) in CH2C12 (LOML) is added EDCI (783 mg, 4.7 mmol) and DMAP (244 mg, 2 mmol). The mixture is stirred at room temperature overnight. Water (10 ml) is added and the layers are separated. The organic layer is washed with brine (10 ml), then dried (NA2S04) and evaporated. Flash column purification of the residue (2: 1 of hexane : ethyl acetate) provides the title PRODUCT. 1H NMR (CDCI3) (mixture of rotamers) 7.89 (q, 0.7H), 7.81 (q, 0.3H), 7.69 (dd, 0.3H), 7.53 (dd, 0.7H), 7.34 (s, 0.7H), 7.20 (s, 0. 3H), 6.99 (dd, 0.7H), 6.91 (dd, 0.3H), 5.19 (s, 0.6H), 5.07 (s, 1.4H), 3.41 (d, 0.6H), 3.31 (d, 1.4H), 2.75 (t, 1.4H), 2.48 (t, 0.6H), 2.08-2. 17 (M, 1H), 1.69-1. 75 (M, 1.4H), 1.54-1. 60 (M, 0.6H), 1.02 (t, 2. 1H), 0.99 (d, 1.8 H), 0.97 (t, 0.9H), 0.80 (d, 4.2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a stirred solution of (6-CHLORO-5-PROPYL-PYRIMIDIN-4-YLMETHYL)- (3-METHYL-BUTYL)- amine (0.715 g, 2.8 mmol) and 6-FLUORO-PYRIDINE-2-CARBOXYLIC acid (0.47g, 3.34 mmol) in DCM (LOML) is added EDCI (0.61 g) and DMAP (0.153 g). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (NA2S04) and solvent evaporated. Preparative TLC purification of the residue (2: 1 of hexane : ethyl acetate) provides the title product. HL NMR 6 (CDC13) 8.69 and 8.75 (s, 1H), 7.71- 7.97 (m, LH), 7.58-60 (m, 1H), 4.79 and 5.07 (s, 2H), 3.50-3. 64 (m, 2H), 2.59-2. 87 (m, 2H), 1.45- 1.72 (m, 5H), 0.92-1. 09 (m, 4H), 0.81 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a stirred solution of ISOBUTYL- (8-PROPYL- [1, 2,4] triazolo [1, 5-c] pyrimidin-7-ylmethyl)- amine (2.8 mmol) and <strong>[402-69-7]6-fluoro-pyridine-2-carboxylic acid</strong> (0.47g, 3.34 mmol) in DCM (10ML) is added EDCI (0.61 g) and DMAP (0.153 g). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (NA2S04) and solvent evaporated. Preparative TLC purification of the residue (2: 1 of hexane: ethyl acetate) provides the title product. HL NMR 6 (CDC13) (mixture of rotamers) 9.25 (s, 0. 5H), 9.18 (s, 0. 5H), 8.39 (s, 0. 5H), 8.36 (s, 0. 5H), 7.78-7. 93 (M, 1H), 7.68 (d, 0. 5H), 7.57 (d, 0. 5H), 6.99 (d, 0. 5H), 6.92 (d, 0. 5H), 5.03 (s, 1H), 4.89 (s, 1H), 3.52 (d, 1H), 3.35 (d, 1H), 3.12 (t, 1H), 2.83 (t, 1H), 1.95-2. 20 (M, 1H), 1.59-1. 85 (M, 2H), 0.88-1. 10 (M, 6H), 0.82 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium permanganate; In chloroform; water; | PREPARATION 233 6-Fluoropyridine-2-carboxylic acid To a heterogeneous solution of 2-fluoro-6-methyl-pyridine (9.65 g, 86.8 mmol) in water (400 mL) was added potassium permanganate (31.6 g, 200 mmol), and the reaction was heated to approximately 100° C. After 30 minutes, additional potassium permanganate (16.5 g, 104 mmol) was added, and the reaction heated at 100° C. overnight. The reaction was filtered through celite to remove manganese salts. The mother liquor was washed with ethyl ether (200 mL*3), neutralized to pH 7, and concentrated down to approximately 100 mL total volume. The aqueous solution was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate, followed by 20percent i-PrOH/CHCl3 (*3). The combined organic layers were dried over MgSO4 and concentrated. The solids were suspended in chloroform, sonicated, then filtered to remove remaining side products. The mother liquor was concentrated to give 5.47 g as a white crystalline solid, 45percent yield. 1H NMR: consistent with structure. MS (ion spray) 140 (M-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 24h; | Oxalyl chloride (1.35 g, 10.6 mmol) was added to a stirred solution of <strong>[402-69-7]6-fluoropicolinic acid</strong> (1.0 g, 7.09 mmol) in CH2Cl2 (25 mL) at rt under argon atmosphere. A drop of DMF was added to initiate reaction. After stirring for 24 h at rt, the solvents were removed in vacuo to yield the acid chloride as a colorless solid (1.35 g, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; | General procedure D. 4-(6-Fluoro~pyridine-2-carbonyI)-piperazine-l- carboxylic acid tert-butyl esterTo a stirred solution of 6-fluoro-2-pyridine carboxylic acid (leqv, 2.00 g, 14.2 mmol), N-boc-piperazine (1.15eqv, 3.04 g, 16.3 mmol) and DIPEA (2.5 eqv, 6.12 ml, 35.4 mmol) in DCM (100 ml) at room temperature was added portionwise EDC (1.2eqv, 3.09 g, 17.0 mmol) and HOBt (0.2eqv, 0.383 g, 2.83 mmol). The reaction mixture was stirred at room temperature for 16 hrs then concentrated at reduced pressure. The crude material was purified by chromatography [SiO2, EtOAc / heptane, 1 :1] to give pure product (4.40 g, 84percent, 11.93 mmol) as colourless oil. LC/MS: 95percent MH+, m/z 310, Rt = 0.97 mins. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To <strong>[402-69-7]6-fluoropicolinic acid</strong> (980 mg, 6.95 mmol) was in DCM (50 mL) was added DMF (50 mu., 0.65 mmol), followed by dropwise addition of oxalyl chloride (650 mu, 7.43 mmol). After 1.2 h, N,O-dimethylhydroxyl amine HC1 (1.05 g, 10.8 mmol) was added and the reaction mixture was cooled to 0°C. Pyridine (2.6 mL, 32 mmol) was added and the reaction mixture was allowed to warm to room temperature and stir 72 h. The reaction mixture was quenched by the addition of water and the layers were partitioned. The aqueous phase was extracted with dichlorom ethane and the combined organic layer was washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to afford 6-fluoro-N-methoxy-N-methylpicolinamide (1.09 g, 85.0 percent yield) as a clear pale yellow oil. NMR (500 MHz, CD3C1) delta 7.88 (q, J=7.8 Hz, 1 H), 7.56 (br. s., 1 H), 7.02 (dd, J=8.2, 2.4 Hz, 1 H), 3.79 (br. s., 3 H), 3.37 (br. s., 3 H). LCMS m/z = 185.0 (M+H).+ | |
84% | Step A-6-Fluoro-N-methyl-M-(methyloxy)-2-pyridinecarboxamide 2-Fluoropyridine-6-carboxylic acid (1.00 g, 7.09 mmol) was dissolved in 50 mL of DCM with stirring. DMF (3 drops) was added. Gxalyi chloride (4.3 mL, 2M in DCM, 8.6 mmol) was added dropwise via syringe. The reaction was stirred for 1 h and cooled to 0° C. N,O-Dimethylhydroxylamine hydrochloride (0.761 g, 7.80 mmol) was added in a single portion. Pyridine (1.26 mL, 15.6 mmol) was added via syringe, and the reaction was allowed to warm to room temperature. The reaction was stirred for 16 h and poured into half-saturated NaHCO3 solution and DCM. The layers were separated, and the aqueous layer was washed with EtOAc, The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography provided 1.10 g (84percent) of the title compound. 1H NMR (400 MHz, DMSO-d6) delta 8.11 (m, 1H), 7.56 (m, 1H), 7.32 (dd, J=8.2, 2.4 Hz, 1H), 3.65 (s, 3H), 3.25 (s, 3H). | |
67% | A solution of 6-methoxypicolinic acid (2.018g,13.2 mmol) in DCM (70 mL) was treated with DMF (0.1 mL, 1.3 mmol) and oxalylchloride (1.34 mL, 15.8 mmol), after 1 h the solution was cooled to 0 °C and N,O-dimethylhydroxylamineHCl (1.42 g, 14.6 mmol) and pyridine (2.34 mL, 28.9 mmol) were added. Themixture was stirred at room temperature for 18 h, sat. aq. NaHCO3 (200mL) was added and the mixture was partitioned between DCM and water. Theorganic fractions were dried and evaporated, column chromatography (97.5:2.5DCM:MeOH) gave N,6-dimethoxy-N-methylpicolinamide (2.372 g, 92percent) asan oil. 1H NMR (CD3SOCD3) delta 7.86 (dd, J = 8.3, 7.3 Hz, 1H), 7.66 (dd, J = 7.3, 0.7 Hz, 1H), 7.05 (dd, J = 8.3, 0.7 Hz, 1H), 3.90 (s, 3H), 3.28(bs, 3H). Found: [M+H] = 197.2. |
With triethylamine; HATU; In dichloromethane; at 20℃; for 24h; | A solution of <strong>[402-69-7]6-fluoropicolinic acid</strong> (20.0 g, 142 mmol), Nu,Omicron- dimethylhydroxylamine hydrochloride (16.6 g, 170 mmol), 0-(7-azabenzotriazol-l-yl)- Nu,Nu,Nu,Nu-tetramethyluronium hexafluorophosphate (HATU) (80.8 g, 213 mmol) and triethylamine (59.1 mL, 425 mmol) in dichloromethane (500 mL) was stirred for 24 h at RT and treated with 200 mL of saturated aq. H4CI solution. The resulting solution was extracted with dichloromethane (2 x 500 mL). The organic layers were combined, dried over Na2S04 and concentrated. The residue obtained was purified on silica gel with EtO Ac/petroleum ether (15-50percent) to give the title compound as a yellow oil. LCMS, ESI pos. : Calcd. for C8H9FN2O2: 185.0 (M+H)+; found: 184.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | To a solution of 2-bromo-4-methyl-pyridine (2.58g, 15 [MMOL)] in anhydrous THF (50 [ML) AT-30°C,] was added dropwise [NAHMDS] (solution 2M in THF, 15ml, 30 [MMOL)] and the mixture was stirred [AT-30°C] for 2 hours. A solution of intermediate 20 (2.74g, 15 [MMOL)] in THF (50 ml) was added dropwise and the mixture was stirred at -30°C for 1 hour and then poured into water. After extraction with EtOAc, the organic phase was dried over [NA2SO4] and concentrated under reduced pressure. The residue was purified by chromatography on silica gel [(CH2CI2/MEOH,] 99: 1). The title compound was obtained as a yellow solid (1.6g, 36percent); [[APCI] MS] m/z=295 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Intermediate 4 (1g, 7.09 [MMOL)] was added portion-wise to [THIONYL] chloride (3 [ML)] and the mixture was heated under reflux for 3 hours and then concentrated under reduced pressure. Isopropanol (3 ml) was added to the residue and the mixture was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was treated with a saturated aqueous solution of [NAHCO3] and extracted with ethyl acetate. The combined organic phases were dried over [NA2SO4] and concentrated under reduced pressure. The title compound was obtained as an oil (1. [2G,] 93percent); [[APCI] MS] m/z: 184 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Add N-methylmorpholine (6 ml, 52 mmol) and isobutylchloroformate (3.5 ml, 26.9 mmol) to a solution of <strong>[402-69-7]6-fluoropyridine-2-carboxylic acid</strong> (3.8 g, 26.9 mmol) in methylene chloride at 0 C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (2.6 g, 26.9 mmol) and N-methylmorpholine (3 ml, 26.9 mmol). Stir the reaction at 0 C for 15 minutes and then room temperature for 17 hours. Dilute the reaction with methylene chloride and wash sequentially with water (1 x 50 ml), 10 percent aqueous citric acid (1 x 50 ml), brine (1 x 50 ml), saturated aqueous sodium bicarbonate (1 x 50 ml), and brine (1 x 50 ml). Dry the resulting organic solution with Na2SO4, filter, and purify by flash column chromatography (Silica Gel, 20 percent acetone/hexanes) to provide the title compound 0.97g (18 percent from 2-fiuoro-5-methylpyridine) as a clear, yellow oil. MS APCI+ m/e 185 (M+1). TLC (SiO2): Rf 0.40 (1:3 acetone/hexanes) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; water; | Example 60 N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-6-fluoro-2-pyridinecarboxamide To a solution of 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (0.15 g, 0.68 mmol), DIPEA (0.165 mL, 0.123 g, 0.95 mmol) and 2-fluoro-6-pyridine carboxylic acid (0.115 g, 0.816 mmol) in dichloromethane (5 mL) was added O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 0.26 g, 0.81 mmol) and the mixture was stirred at ambient temperature for 2 h. Water was added and after 10 min, the organic phase was separated and washed with saturated NaHCO3/water, dried (Na2SO4), evaporated, and chromatographed (Silica gel, EtOAc/hexanes, 0-30percent) to provide the title compound as an off-white solid (0.13 g, 61percent yield). 1H-NMR (DMSO-d6): delta 10.92 (s, 1H), 8.8 (d, 1H), 8.2 (quartet, 1H), 8.04 (dd, 1H), 7.43 (m, 2H), 7.28 (d, 1H), 7.0 (dd, 1H), 5.37 (quartet, 1H), 2.62 (m, 2H), 2.0 (m, 3H), 1.8 (m, 1H); MS m/z 365 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
psi-Fluoro^-pyridinecarboxylic acid (available from Asymchem Laboratories, 570mg, 4.0mmol) and O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate(1531 mg, 4.0mmol) were dissolved in DMF (15ml) and treated withDIPEA (2.11 ml). The mixture was stirred at room temperature for 30mins then 6-(1H- indol-4-yl)-1 H-indazol-4-amine (500mg, 2.0mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to approx. 5ml which was added to 2 x 5Og aminopropyl cartridges that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The mixture was concentrated in vacuo to give an orange oil. DCM (5ml) was added and the resultant precipitate was collected by filtration to give the title compound (235mg) as a yellow solid. LCMS (Method B) R1 = 1.04 mins, MH+ = 372 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; N,N-dimethyl-formamide; at 20 - 50℃; for 12.25h; | To each of the reaction test tubes with the appropriate carboxylic acid (1.0 equivalent) in dry l,4-dioxane:DMF:DIEA (2:2: 1, 0.3M) at room temperature was charged with HOBt (1.0 equivalent) and EDCI (1.5 equivalents). After 15 min, the HCl salt (3, 1.0 equivalent) was added and the heterogeneous mixture was heated to 50 0C. After 12 h, the reaction mixture was added to EtOAc:water (1: 1). The organic layer was separated and sequentially washed with water, brine and dried. The residue was purified by mass-directed preparative HPLC. Following the General Procedure 2, 6-fluoro-Nu-(4-(l,l,3,3-tetraoxidobenzo[d][l,3,2]dithiazol-2- yl)phenyl)picolinamide was obtained as an white solid.LCMS: RT = 3.178 min, >;98percent (at) 214 nM, m/z = 434.0 [M + H]+ 1H NMR (400 MHz, (Z6-DMSO): delta 10.90 (br s, IH), 8.61-8.59 (m, 2H), 8.29 (dd, J = 15.6, 8.0 Hz, IH), 8.24-8.22 (m, 2H), 8.20 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 6.4 Hz, IH), 7.60 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 7.6 Hz, IH)HRMS, calc'd for Ci8H13N3O5FS2 (M+H+), 434.0281; found 434.0281. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With pyridine; p-toluenesulfonyl chloride; at 0 - 20℃; for 12h; | Tosyl chloride (915 mg, 4.8 mmol) was added to a solution of 2-fiuoro- picolinic acid (254 mg, 2 mmol) and pyridine (1.08 mL, 13.4 mmol) in 3.6 mL of t-BuOH at 00C. The reaction was then stirred at room temperature for 12 hours. An aqueous solution of NaHCO3 was then added and the mixture was extracted with ethyl acetate (3 times). The combined organic phases were washed with brine and dried over Na2SO4. The crude compound was purified by flash chromatography using SiO2 (Petroleum Ether/EtOAc 100:0 to 90: 10). The product 120A was obtained as a white solid (m = 326 mg, 83percent): 1H NMR (ppm, CDCl3) 1.6 (s, 9H), 7.05-7.11 (m, IH), 7.85-7.93 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6-Fluoro-2-pyridinecarboxylic acid (2.83 g, 20.06 mmol, CAS[402-69-7], commercially available e.g. from Sigma-Aldrich or Apollo Scientific) was dissolved inDichloromethane (DCM) (100 ml.) at 0 0C. Oxalyl chloride (2.107 ml_, 24.07 mmol) and a drop of Lambda/,Lambda/-dimethylformamide (DMF) was added and the mixture was stirred for 2 hours. The solvents were removed in vacuo and azeotroped with toluene (3x20ml). The residue was dissolved in dichloromethane (DCM) (100 ml) whereupon 1 ,1-dimethylethyl hydrazinecarboxylate (2.92 g, 22.06 mmol) and Lambda/,Lambda/-diisopropylethylamine (DIPEA) (7.71 ml_, 44.1 mmol) were added. The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (50 ml). The aqueous phase was extracted with ethyl acetate (3x100ml), the combined organic extracts were washed with brine (50 ml), were dried over anhydrous sodium sulphate and were concentrated in vacuo. The residue was purified by flash chromatography (Biotage SP4, 40+M, 0-100percent ethyl acetate/iso- hexane) to afford 1 ,1-dimethylethyl 2-[(6-fluoro-2- pyridinyl)carbonyl]hydrazinecarboxylate (5.04 g, 19.75 mmol).LC/MS = 156 (M+H-BOC)+, retention time = 0.81 minutes (2 minute method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of 2-(4-amino-2-chlorophenyl)tetrahydroimidazo[ 1 ,5- a]pyridine-l,3(2H,5H)-dione (0.03 g, 0.107 mmol), HATU (0.045 g, 0.119 mmol), DIEA (0.041 mL, 0.236 mmol) in DMF (1 mL) was added 2-fluoro-6-pyridine carboxylic acid (0.017 g, 0.118 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was diluted with water (4 mL) and extracted with ethyl acetate (2 x 3 mL). The organic extracts were combined and concentrated. The residue was purified by reverse phase HPLC to give N-(3- chloro-4-(l,3-dioxotetrahydroimidazo[l,5-a]pyridin-2(lH,3H,5H)-yl)phenyl)-6- fluoropicolinamide (TFA), 1.3.4.LCMS: >98percent (at) 214 nm, RT = 2.85 min., m/z = 403.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; | The compound 1 (the same compound as that described in Reference Example 2) (300 mg) was dissolved in methylene dichloride (5.3 ml), and thereto were added 6-fluoro-2-pyridine carboxylic acid (156 mg), EDCI-HCl (304 mg) and HOBt-H2O (267 mg). After stirring the solution all day and all night, water and potassium carbonate were added thereto, and insoluble materials were filtrated. The organic layer was washed with water, followed by evaporation of the solvent in vacuo, and the residue was purified by the silica gel column chromatography affording the compound 2 (289 mg). |
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