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CAS No. : | 78686-79-0 | MDL No. : | MFCD03844848 |
Formula : | C7H5BrClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MOMQDEDQGJAKII-UHFFFAOYSA-N |
M.W : | 250.48 | Pubchem ID : | 2763343 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 48.23 |
TPSA : | 39.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.15 cm/s |
Log Po/w (iLOGP) : | 2.19 |
Log Po/w (XLOGP3) : | 2.36 |
Log Po/w (WLOGP) : | 2.28 |
Log Po/w (MLOGP) : | 1.67 |
Log Po/w (SILICOS-IT) : | 2.53 |
Consensus Log Po/w : | 2.21 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.12 |
Solubility : | 0.191 mg/ml ; 0.000763 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.82 |
Solubility : | 0.376 mg/ml ; 0.0015 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.58 |
Solubility : | 0.0666 mg/ml ; 0.000266 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.82 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
87% | With potassium phosphate In water; toluene at 100℃; | INTERMEDIATE 31Methyl 2-chloro-5-methylnicotinate; To a solution of methyl 5-bromo-2-chloronicotinate (1.05g, 4.19mmol), K3PO4 (2.95g, 13.90mmol), methylboronic acid (0.32g, 5.26mmol) and tricyclohexylphosphine (0.11g, 0.39mmol) in toluene/water (16ml/0.8ml) under nitrogen atmosphere was added Pd(OAc)2 (0.04g, 0.18mmol). The mixture was heated at 1000C overnight under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated in vacuum. Ethyl acetate was added to the residue and this organic layer was washed with water, brine, dried over MgSO4, filtered and the solvent evaporated under vacuum to yield the desired product as a yellow oil. Yield=87percent LRMS: m/z 186 (M+1 )+ Retention time: 4.84min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: at 60℃; for 36 h; Stage #2: With sodium hydrogencarbonate In water |
To 0.5 L flask charged with 5-Bromo-2-chloronicotinic acid (25.0 g, 106.4 mmol) in MeOH (250 mL) was added H2SO4 (5 mL). The mixture was heated to 60° C., stirred for 1.5 day. LC-MS indicated full conversion of starting material at this time. The reaction was cooled to RT and the volatile components removed in vacuo. The crude residue was dissolved in EtOAc (300 mL), quenched with sat. aqueous Na(HCO3)2 (200 mL). The organic layer was separated, washed with brine, dried over MgSO4 and concentrated to afford the compound, methyl-5-bromo-2-chloronicotinate, as a while solid (quantitative yield). LC-MS (M+H)=250.1. |
89% | for 15 h; Reflux | Sulfuric acid (2 mL, 52.1 mmol) was added to the suspension of 5-bromo-2-chloronicotinic acid (1) (12.3 g, 52 mmol) was in methanol (100 mL). The mixture was stirred and refluxed for 15 hours. The solvent was evaporated and the residue was neutralized with saturated aqueous NaHC03(aq.). The result suspension was filtered and the solid was washed by water and dried by pump. Methyl 5-bromo-2-chloronicotinate (2) (11.6 g, 89 percent yield) was afforded. NMR (400 MHz, CDCL) δ 8.53 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H). 13C NMR (101 MHz, CDCL) δ 163.58, 152.75, 148.61, 142.49, 127.64, 118.57, 53.10. ESI-MS m/z: 251.9 (M+H+). |
85% | at 90℃; for 12 h; | To a solution of 5-bromo-2-chloronicotinic acid (50 g, 211 mmol) in MeOH (200 mL) was added H2SO4 (20.7 g, 211.46 mmol) at 25 °C. The mixture heated to 90 °C and stirred for 12 hours. LCMS showed that the reaction was complete. The reaction was neutralized with Na2CO3 to pH = 7-8 and concentrated under reduced pressure to remove MeOH. The residue was extracted with EtOAc (300 mL x 3). The combined organic layer was concentrated under reduced pressure to give methyl 5-bromo-2-chloronicotinate (45 g, 180 mmol, 85percent yield) as a brown solid. ESI-MS (m/z): 249.9 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: at 80℃; for 2 h; Stage #2: for 1 h; |
Example 18; 2-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-5-bromo-N-(2,4-difluorophenyl)nicotinamide, dihydrochloride salt; A) Methyl 5-bromo-2-chloronicotinate; To a suspension of 5-bromo-2-hydroxynicotinic acid (4.34 g, 20 mmol) in 20 mL of SOCl2 at room temperature was added 1 mL of DMF slowly. The solution was then heated at 80° C. for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL of DCM. To the mixture was added 10 mL of MeOH and the stirring continued for 1 h. The solution was concentrated in vacuo and the residue was dissolved in 200 mL of EtOAc. The mixture was then washed with brine and dried over MgSO4. After filtration and concentration in vacuo, the desired product (5.0 g, >95percent yield) was obtained. MS (ESI) m/z 250.04, 252.05, 254.05 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: at 95℃; for 16 h; Cooling with ice Stage #2: at 20℃; for 2 h; Cooling |
POCl3 (50 mL) was added slowly through an addition funnel to ice-cooled 5-bromo- 2-hydroxynicotinic acid (10 g, 45.9 mmol). The reaction mixture was heated to 95°C and stirred at the same temperature for 16 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove POCh. To the residue was added toluene (100ml), and the mixture evaporated under reduced pressure to remove residual POCb . The obtained residue was diluted with DCM (100 mL) and cooled. MeOH (50 mL) was added slowly through an addition funnel to the mixture under nitrogen. The resulting mixture was then stirred at room temperature for 2 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was diluted with water, neutralized by using saturated aq.Na2C03 solution, and extracted with EtOAc (50ml x3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified via Combiflash column chromatography using a 40g silica gel column with 7percent EtOAc in pet. ether as an eluent to afford methyl 5-bromo-2-chloronicotinate as a white solid. Yield: 8.5 g, (74 percent). 1H MR (400 MHz, CDCh) δ ppm = 8.57 (d, J= 2.4 Hz, 1 H), 8.29 (d, J= 2.4 Hz, 1 H), 3.91 (s, 3H). LCMS: (ES+) m/z observed = 252.1 (M+H)+, Column- Acquity BEH CI 8 (2.1 x 50 mm) 1.7 urn, Buffer : lOmM AmmoniumAcetate pH-5 adjusted with HCOOH, Mobile phase A: Buffer : MeCN (95:5), Mobile phase B: Buffer : MeCN (5:95), Flow: 0.8 ml/min. Rt: 0.86 min, wavelength: 220nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.15% | at 0 - 80℃; for 12.5 h; Inert atmosphere | Example 30 - Preparation of Intermediate 7 [ 00261] The synthesis of Intermediate 7 followed General Procedure 8 following. General Procedure 8 Intermediate 5 Intermediate 7 [ 00262 ] To a round-bottomed flask charged with methyl 5-bromo-2-oxo- l,2-dihydropyridine-3-carboxylate (Intermediate 5, 50.0 g, 0.2154 mol, 1.0 eq) at 0 C under N2 atmosphere was added POCl3 (100 mL) dropwise. After 30 minutes the reaction mixture was warmed to 80 C and stirred for 12-15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured slowly into ice cold water. It was stirred for 30 min, at which point the product precipitated out as a white solid. The solid product was filtered and vacuum dried to give desired Intermediate 7 (40.0 g, yield-94.15percent). m/z 252.12 [M+2]+ 1H NMR (DMSO-de, 400 MHz) δ 8.78 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.5 Hz, 1H), 3.89 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | at 0℃; for 1 h; | Example 24; A. Methyl 5-bromo-2-chloropyridine-3-carboxylate; To a solution of S-bromo-l-chloropyridine-S-carboxylic acid (1.0 g, 4.2 mmol) in methanol :benzene (1 :1, 50 mL) was added trimethylsilyldiazomethane (3.2 mL, 6.5 mmol) at 0 0C. The reaction mixture was then stirred at 0 0C for 60 min. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (40 mL), washed with water (10 mL x 2). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous MgSO4 and evaporated under reduced pressure to provide the crude product. The crude product was purified through a filter column (Silica gel, 100-200 mesh) to provide methyl 5-bromo-2-chloropyridine-3-carboxylate as an off- white solid (0.72 g, 69percent). LC-MS: [M+H] + 251 1H NMR (400 MHz, CDCl3) δ: ppm 8.59 (s, IH) 8.35 (s, IH), 3.99 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With diisobutylaluminium hydride In dichloromethane at -78℃; for 2 h; | To a (-78eC) cooled and stirred solution of methyl 5-bromo-2-chloronicotinate (10.0 g, 39.9 mmol) in DCM (100 mL) was added diBAL-H (43.9 mL, 43.9 mmol, 1.6 M in hexane) dropwise and then stirred for 2h at the same temperature. Reaction was quenched with 2M aqueous HCI (50 mL) and stirred for 30 min at room temperature. Reaction mixture was filtered through the celite. The layers were separated and the aqueous layer was extracted with ethyl acetate (2/1,100 mL). The combined organic layer was washed with brine (100 mL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, 20-30percent EtOAc in hexane system as eluent) to afford 6.50 g (74percent) of the titled compound. 1HNMR (400 MHz, DMSO- d6) U10.19 (s, 1H), 8.86 (brs, 1H), 8.40 (brs, 1H); GCMS (m/z) 218.94(M)\ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With cesium fluoride In dimethyl sulfoxide at 20 - 60℃; for 52 h; | B) Methyl 5-bromo-2-fluoronicotinate; To a solution of methyl 5-bromo-2-chloronicotinate (170 mg, 0.68 mmol) in 3 mL of DMSO was added CsF (152 mg, 1.0 mmol). The solution was stirred at room temperature for 2 d and then heated at 60° C. for 4 h. After cooling, the mixture was diluted with 30 mL of H2O. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by silica gel flash chromatography to give the desired product (90 mg, 57percent yield). MS (ESI+) m/z 234.06, 236.09 (M+H)+. |
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