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CAS No. : | 73781-91-6 | MDL No. : | MFCD00023420 |
Formula : | C7H6ClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RMEDXVIWDFLGES-UHFFFAOYSA-N |
M.W : | 171.58 | Pubchem ID : | 254249 |
Synonyms : |
|
Num. heavy atoms : | 11 |
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 : | 40.53 |
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) : | -6.16 cm/s |
Log Po/w (iLOGP) : | 1.91 |
Log Po/w (XLOGP3) : | 1.67 |
Log Po/w (WLOGP) : | 1.52 |
Log Po/w (MLOGP) : | 0.93 |
Log Po/w (SILICOS-IT) : | 1.83 |
Consensus Log Po/w : | 1.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.23 |
Solubility : | 1.02 mg/ml ; 0.00592 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.11 |
Solubility : | 1.34 mg/ml ; 0.00781 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.71 |
Solubility : | 0.333 mg/ml ; 0.00194 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.57 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H317-H319 | 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 |
---|---|---|
94% | With phosphorus(V) oxybromide In toluene at 90℃; for 3 h; | Dissolve 6-chloropyridine-3-carboxylic acid methyl ester (6.86 g, 40 mmol) in toluene (100 mL) and heat to 90°C. Add phosphorous oxybromide (25 g, 87 mmol) in several portions and continue heating for 3 hours. Cool the reaction to room temperature and pour onto ice water. Extract the reaction with ethyl acetate and wash organics again with water then NAHC03. COMBINE organics, dry over MGS04, filter, and evaporate to orange solid (8.1 g, 94percent) which is an 8: 1 mixture OF 6-BROMOPYRIDINE-3-CARBOXYLIC acid methyl ester : 6-CHLOROMOPYRIDINE-3-CARBOXYLIC acid methyl ester BY LH NMR. Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd (OAC) 2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80°C for 18 hours. Cool reaction to room temperature. Add a solution of 1-BROM-2, 6- difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd (OAC) 2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80°C for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (silica, 10percent ethyl acetate in hexane) to give 50 mg (20percent yield) OF 6- (2, 6-difluorophenyl) pyridine-3-carboxylic acid ethyl ester. Hydrolyze the ester with IN sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the RESIDUE with IN hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63percent yield) of the title compound. MS (ES): m/z 235.9 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.1% | With methylamine In methanol at 0 - 20℃; for 4 h; | A mixture of 6-chloronicotinic acid methyl ester(10.0 g, 58.3 mmol) was dissolved in 10 mL of methanol and stirred to form a pale yellow solution. A 40percent aqueous solution of methylamine (2.7 g, 87.5 mmol) was added dropwise at 0 ° C, and the reaction was carried out at room temperature for 4 h The The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, crystallized, filtered and dried to give 9.4 g of pale yellow crystals, and the residue was washed with water, Yield 99.1percent. Μρ: 140-142 ° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.1% | at 0 - 20℃; for 4 h; | 6-chloronicotinic acid methyl ester (10.0g, 58.3mmol) was dissolved in 10mL 52 methanol to get light yellow solution, the 14 methylamine (2.7g, 87.5mmol) in 53 water solution was added dropwise at 0–5°C under stirring. The mixture was stirred at room temperature for 4h, and then concentrated in vacuum. Finally, 54 ethyl acetate (100mL) was added, and the resulting mixture was stirred at room temperature. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give light yellow crystalline (2) 9.4g, yield: 99.1percent, mp: 145–146°C. 1H NMR (DMSO‑d6, 400MHz): δ 2.75 (d, J=4.5Hz, 3H), 6.89 (d, J=8.8Hz, 1H), 8.16 (dd, J=8.7, 2.4Hz, 1H), 8.46 (br d, J=4.4Hz, 1H), 8.57 (d, J=2.3Hz, 1H). ESI-MS m/z 171.1 [M+H]+; Anal. Calcd for (C7H7ClN2O FW: 170.5); C, 49.28; H, 4.14; Cl, 20.78; N, 16.42. Found: C, 49.24; H, 4.16; Cl, 20.79; N, 16.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; toluene at -78 - 20℃; for 1 h; Stage #2: With rochelle salt In tetrahydrofuran; dichloromethane; water; toluene |
To a solution of methyl 6-chloronicotinate (0.60 g, 3.50 mmol) in THF (10 niL) at - 78 °C was added a solution of DIBAL-H (1 M in toluene, 10.5 m-L, 10.5 mmol) and the reaction stirred from -78 0C to room temperature for 1 h. The reaction was diluted with a saturated aqueous solution of sodium potassium tartrate (25 mL) and CH2Cl2 (30 mL) and stirred vigorously overnight. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were dried (Na2SO4) and concentrated to afford the desired alcohol (0.48 g, 95percent) as a white solid. |
70% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 3 h; Inert atmosphere | a) (6-chloropyridin-3-yl)methanol To a suspension of LiAIH4(1.5 g, 40 mmol) in THF(80 mL) was added methyl 6-chloronicotinate (1.56 g, 10 mmol) slowly at 0-5 Π under N2atmosphere. The reaction mixture was stirred at rt for 3h before it was quenched with 15percent NaOH and water. The mixture was filtered through Celite® and the cake was washed with EtOAc (100 ml_x3). Thefiltrate was washed with brine (200 mL), dried and concentrated to give the desired product as yellow oil (1 g, 70percent). [LCMS: RtA = 0.88 min, m/z 144.2 [M+H]+]. |
70% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 3 h; Inert atmosphere | a) (6-chloropyridin-3-yl)methanol To a suspension of LiAlH4 (1.5 g, 40 mmol) in THF (80 mL) was added methyl 6-chloronicotinate (1.56 g, 10 mmol) slowly at 0-5□ under N2 atmosphere. The reaction mixture was stirred at rt for 3 h before it was quenched with 15percent NaOH and water. The mixture was filtered through Celite and the cake was washed with EtOAc (100 mL*3). The filtrate was washed with brine (200 mL), dried and concentrated to give the desired product as yellow oil (1 g, 70percent). [LCMS: RtA=0.88 min, m/z 144.2 [M+H]+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: With sodium hydride In dimethyl sulfoxide at 0 - 20℃; for 1 h; Stage #2: at 20℃; for 6 h; |
Example 7. Preparation of 0-(6-pyrazol-l-yl-pyridin-3-almethel)-hadroxylamine (Compound of formula (Xl)); Step 7a. Preparation of 6-Pyrazol-1-vl-nicotinic acid methyl ester (Compound of formula (XI-a)); To a solution of pyrazole (19.4g, 0. 28mol) in 100 mL anhydrous DMSO, which was at a temperature of 0°C, was added NaH (7. 5g, 0. 3mol) gradually over a period of 30 min. The resulting reaction mixture was allowed to warm to room temperature, at which the mixture continued to agitate for an additional 30 min. Methyl 6- chloronicotinate (35g, 0. 2mol) was added to the stirring reaction mixture and agitated vigorously for a period of 6 hr. The reaction mixture was subsequently cooled to a temperature of about 0°C and poured into a saturated aqueous, 0°C NH4C1 solution. The resulting precipitate was filtered, washed with water, and dried to give a compound of formula (XI-a) (38.3g, 93percent yield) as an off-white solid. |
40% | Stage #1: With sodium hydride In N,N-dimethyl acetamide for 0.166667 h; Stage #2: at 95℃; Stage #3: With sodium hydroxide In water |
Pyrazole (2.4 g, 35.4 mmol) was added to DMA (100 ml) and to this was slowly added NaH (1.85 g, 38.6 mmol). The reaction mixture was stirred for 10 mins under a nitrogen atmosphere. To the resulting anion was added methyl 6-chloropyridine-3-carboxylate (5.5 g, 32.2 mmol) and the reaction was heated at 95° C. overnight. The reaction mixture was evaporated to dryness, quenched with 2.0 N NaOH (100 ml), extracted with DCM (3.x.100 ml), dried (MgSO4) and the solvent removed in vacuo to yield a brown solid. This solid was purified via silica column chromatography, eluting with 0-40percent diethyl ether in iso-hexane. A white solid was obtained, which was dissolved in hot iso-hexane. On cooling a white solid was obtained which was filtered and dried (2.6 g, 40percent); 1H NMR (400.132 MHz, CDCl3) δ 3.96 (s, 3H), 6.50 (s, 1H), 7.77 (s, 1H), 8.05 (d, 1H), 8.40 (dd, 1H), 8.62 (d, 1H), 9.02 (d, 1H); MH+203. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With NH-pyrazole; NaH In dimethyl sulfoxide | Step 7a. Preparation of 6-Pyrazol-1-yl-nicotinic acid methyl ester (Compound of formula (XI-a)) To a solution of pyrazole (19.4 g, 0.28 mol) in 100 mL anhydrous DMSO, which was at a temperature of 0° C., was added NaH (7.5 g, 0.3 mol) gradually over a period of 30 min. The resulting reaction mixture was allowed to warm to room temperature, at which the mixture continued to agitate for an additional 30 min. Methyl 6-chloronicotinate (35 g, 0.2 mol) was added to the stirring reaction mixture and agitated vigorously for a period of 6 hr. The reaction mixture was subsequently cooled to a temperature of about 0° C. and poured into a saturated aqueous, 0° C. NH4Cl solution. The resulting precipitate was filtered, washed with water, and dried to give a compound of formula (XI-a) (38.3 g, 93percent yield) as an off-white solid. |
64% | Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) for 5 h; Stage #2: for 27 h; |
Reference Example 54; Methyl 6-(1H-pyrazol-1-yl)nicotinate; To a suspension of pyrrole (0.356 g, 5.23 mmol) in DMF (20 ml) was added sodium hydride (60percent in oil, 0.233' g, 5.81 mmol). After stirring for 5 hrs. , methyl 6- chloronicotinate (1.00 g, 5.81 mmol) was added, and the mixture was further stirred for 27 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgS04). After concentration under reduced pressure, the precipitated solid was collected by filtration and washed with hexane to give the title compound (0.683 g, 64percent) as a colorless powder. 1H-NMR (CDCl3) No.: 3.97 (3H, s), 6.51 (lH, dd, J=4.2,2.4 Hz), 7.75-7.81 (lH, m), 8.05 (lH, dd, J=12.6,0.9 Hz), 8.40 (lH, dd, J=12.6,3.3 Hz), 8.62 (lH, dd, J=4.2,1.2 Hz), 9.03 (lH, dd, J=3.3,0.9Hz). |
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