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CAS No. : | 2457-47-8 | MDL No. : | MFCD00006376 |
Formula : | C5H3Cl2N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WPGHPGAUFIJVJF-UHFFFAOYSA-N |
M.W : | 147.99 | Pubchem ID : | 17153 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 34.26 |
TPSA : | 12.89 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) : | -5.39 cm/s |
Log Po/w (iLOGP) : | 1.77 |
Log Po/w (XLOGP3) : | 2.56 |
Log Po/w (WLOGP) : | 2.39 |
Log Po/w (MLOGP) : | 1.68 |
Log Po/w (SILICOS-IT) : | 2.73 |
Consensus Log Po/w : | 2.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.93 |
Solubility : | 0.176 mg/ml ; 0.00119 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.48 |
Solubility : | 0.492 mg/ml ; 0.00332 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.24 |
Solubility : | 0.0859 mg/ml ; 0.000581 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.34 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P280-P305+P351+P338-P309+P311-P302+P352 | UN#: | 2811 |
Hazard Statements: | H311-H302-H315-H319-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
22% | Stage #1: at 210℃; for 3 h; Stage #2: With ammonium hydroxide In 1-methyl-pyrrolidin-2-one; water at 0℃; for 0.0833333 h; |
A mixture of 3,5-dichloropyridine (4.23 g, 28.6 mmol), CuCN (3.07 g, 34.3 mmol), and argon-bubbled NMP (8 mL) was placed in a 40 mL scintillation vial, flushed with argon for 1 min, and then quickly capped and stirred under argon at 210° C. for 3 h. The dark brown easily stirred solution was allowed to cool somewhat, and was then poured into concentrated NH4OH (50 mL) on an ice bath, and stirred vigorously for 5 min. DCM (50 mL) was added, the bilayer was stirred for an additional 5 min, and then filtered. The lower dark amber organic layer was saved, and the dark blue aqueous layer was extracted with DCM (2.x.50 mL). The organic layers were combined and washed with NH4OH (1.x.30 mL), 4 M NaCl (1.x.30 mL), dried (Na2SO4), and concentrated to give an amber oil heavily contaminated with NMP. Silica flash chromatography of this residue (90 mm.x.6 column; 6:1 hex/EtOAc eluent; 100 mL fractions; fractions 15-19 combined) afforded, after rotary evaporation at 40° C., the title compound as brilliant white microcrystals (891 mg, 22percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -20 - -10℃; for 1 h; Stage #2: at -70℃; |
EXAMPLE 6 (Scheme 1) Preparation of 3,5-dichloro-4-methylpyridine (4); Diisopropylamine (70 mL, 500 mmol) is dissolved in dry tetrahydrofuran (500 mL), the solution is cooled to -10°C and butyl lithium (2.5 N in hexane, 210 mL, 525 mmol) is added dropwise under stirring. After 30 minutes the solution is cooled to -20°C and 3,5-dichloropyridine (66.6 g, 450 mmol) in tetrahydrofuran (200 mL) is added dropwise. The solution is stirred at -10°C for 30 minutes, then cooled to -70°C and iodomethane (50 mL, 1.6 mol) in tetrahydrofuran (100 mL) is added dropwise. The reaction mixture is allowed to warm to room temperature, quenched with water (100 mL) and extracted with diethyl ether (3 x 100 mL); the combined organic layers are dried over sodium sulphate (5 g) and evaporated to dryness. The crude product is crystallized twice from aqueous ethanol, then from hexane to afford 3,5-dichloro-4-methylpyridine (49.9 g, 306 mmol, 68percent yield) as a white solid. |
68% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -20 - -10℃; for 1 h; Stage #2: at -70 - 20℃; |
Diisopropylamine (70 mL, 500 mmol) was dissolved in dry tetrahydrofuran (THF) (500 mL), the solution was cooled to -10°C and buthyl lithium (2.5 N in hexane, 210 mL, 525 mmol) was added dropwise under stirring. After 30 minutes the solution was cooled to -20°C and 3,5-dicholopyridine (66.6 g, 450 mmol) in tetrahydrofuran (200 mL) was added dropwise. The solution was stirred at -10°C for 30 minutes, cooled to -70°C and added dropwise with iodomethane (50 mL, 1.6 mol) in tetrahydrofuran (100 mL). The reaction mixture was allowed to warm to room temperature, quenched with water (100 mL) and extracted with diethyl ether (3 x 100 mL); the combined organic layers were dried over sodium sulphate (5 g) and evaporated to dryness. The crude product was crystallized twice from aqueous ethanol than from hexane to afford 3,5-dichloro-4-methylpyridine (49.9 g, 306 mmol, 68 percent yield) as a white solid. MS/ESI+ 162-164-166 m/z [MH] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With lithium diisopropyl amide In tetrahydrofuran at -78 - 20℃; for 2 h; | Intermediate 1 3.5-Dichloropyridine-4-carboxylic acid A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25 ml) was added to a solution of LDA [generated from NBuLi (2.5M solution hexanes, 14.9 ml, 37.2 mmol) and diisopropylamine (4.10 g, 5.7 ml, 40.6 mmol)] in THF (25 ml) at -78° then CO2 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2 h, then quenched with water (20 ml) and partitioned between diethylether (100 ml) and 1M NaOH (100 ml).. The aqueous layer was separated and acidified to PH1 with concentrated hydrochloric acid and then extracted with 10percent MeOH in DCM (100 ml*3).. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give a brown solid that was recrystallized from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63 g, 41percent): δH (DMSO d6) 8.72 (2H, s). |
41% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2 h; |
A solution of 3, [5-DICHLOROPYRIDINE] (5. [00G,] 33. [8MMOL)] in THF [(25ML)] was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14. [9MI,] 37. [2MMOL)] and diisopropylamine (4. 10g, 5. [7MOI,] 40. 6mmol)] in THF [(25MOI)] [AT-78 . ? UNDER] nitrogen, to give a yellow/brown slurry. The reaction was stirred for 30min [AT-78XB0;] then C02 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2h, then quenched with water [(20MI)] and partitioned between [ET2O] [(100MOI)] and [1 M NAOH] [(100ML).] The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid and then extracted with 10percent [MEOH] in DCM [(100MIX3).] The combined organic layers were dried [(MGS04)] and the solvent removed under vacuum to give a brown solid that was [RECRYSTALLISED] from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63g, [41percent). 8H] (DMSO-d6) 8.74 (2H, s). |
41% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2 h; |
A solution of 3, [5-DICHLOROPYRIDINE (5. 00G,] 33. [8MMOL)] in THF [(25ML)] was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14. [9MOI,] 37. [2MMOL)] and diisopropylamine (4. [1 OU,] 5. [7MI,] 40. 6mmol)] in THF [(25ML)] at- [78-UNDER] nitrogen, to give a [YELLOW/BROWN SLURRY.] The reaction was stirred for 30min [AT-78G] then COs gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to RT over 2h, then quenched with water [(20MI)] and partitioned between [ET20] [(100ML)] and [1 M NAOH] [(100MI).] The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid and then extracted with 10percent [MEOH] in DCM [(1 00MIX3).] The combined organic layers were dried [(MGS04)] and the solvent removed under vacuum to give a brown solid that was recrystallised from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63g, [41percent). 5H] (DMSO-d6) 8.74 (2H, s). 8C (DMSO-d6) 163.5, 147.7, 141.0, 126.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With n-butyllithium; diisopropylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide | Preparation Example 7 Synthesis of 3,5-dichloro-4-pyridinecarbaldehyde Under an argon atmosphere, to a solution of diisopropylamine (33.6 ml, 0.24 mol) in tetrahydrofuran (400 ml) at -65° C. was added a 1.6 M solution of n-butyl lithium in hexanes (156 ml). After 20 minutes later, a solution of 3,5-dichloropyridine (29.6 g, 0.20 mol) in tetrahydrofuran (150 ml) was added dropwise, and the mixture was stirred for 30 minutes. Subsequently, the mixture was treated with dimethylformamide (23.2 ml, 0.30 mol) in tetrahydrofuran (50 ml), and then stirred for one hour under the same conditions. The reaction mixture was poured into a 5percent aqueous ammonium chloride solution (1,000 ml) and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried, and then concentrated under reduced pressure. The residue was chromatographed on silica gel, to thereby obtain the title compound (27.2 g, yield 77percent). 1 H-NMR(CDCl3) δ: 8.63(2H, s), 10.44(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium fluoride In sulfolane at 205℃; for 48 h; | Example 1; Preparation of 3,5-difluoropyridine; 1000 g of dichloropyridine and 1580 g of dry potassium fluoride were initially charged in 1700 ml of sulpholane in an autoclave. Subsequently, 84 g of CNC catalyst (compound (III-1)) were added, nitrogen was injected to 3 bar and the mixture was heated to 205° C. with stirring for 48 h. During the reaction, a maximum total pressure of 12.4 bar arose. Subsequently, the mixture was cooled to 10° C. and the product was distilled off at standard pressure. After redistillation, 473 g of dichloropyridine (60percent of theory) were obtained as a colourless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexanes at -78℃; Stage #2: at -78℃; for 3 h; Stage #3: With water; ammonium chloride In tetrahydrofuran; hexanes at -78℃; |
To a 3 -neck 12 L round bottom flask add tetrahydrofuran (THF, 3 L) and diisopropylamine (DIPA, 315 mL, 2.24 mol) and cool to -78 0C. Add slowly n- butyllithium (1.6 M in hexanes, 1400 mL, 2.24 mol). After the addition is complete and the temperature has settled at -78 0C slowly add a solution of 3,5-dichloropyridine (296.7 g, 2.00 mol) which immediately forms a yellow solution that changes to a rust colored suspension. After the addition is complete and the temperature has settled at -78 0C slowly add acetaldehyde (230 mL, 4.05 mol) in THF (600 mL). Continue -A-stirring at -78 0C. After 3 hours, remove the dry ice bath and begin quenching the reaction by the dropwise addition of saturated aqueous ammonium chloride (1 L). Allow the reaction to warm to room temperature (RT) overnight with stirring. Dilute the mixture with methyl-tert-butylether (MTBE, 2 L), saturated aqueous ammonium chloride (1 L) and water (2 L). Partition and wash organics with saturated aqueous sodium chloride (brine). Extract the aqueous phase with MTBE (1.5 L). Combine the organic layers, dry over sodium sulfate, filter and concentrate in vacuo. Purify the residue by silica gel chromatography [25percent ethylacetate (EA) in hexanes] to give the title compound as a red oil. Yield: 352 g (90percent). MS (ES) m/z 192 [M+l]+. |
90% | Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 3 h; Stage #2: With ammonium chloride In tetrahydrofuran; hexane; water at -78 - 20℃; |
To a 3-neck 12 L round bottom flask add tetrahydrofuran (THF, 3 L) and diisopropylamine (DIPA, 315 mL, 2.24 mol) and cool to -78° C. Add slowly n-butyllithium (1.6 M in hexanes, 1400 mL, 2.24 mol). After the addition is complete and the temperature has settled at -78° C. slowly add a solution of 3,5-dichloropyridine (296.7 g, 2.00 mol) which immediately forms a yellow solution that changes to a rust colored suspension. After the addition is complete and the temperature has settled at -78° C. slowly add acetaldehyde (230 mL, 4.05 mol) in THF (600 mL). Continue stirring at -78° C. After 3 hours, remove the dry ice bath and begin quenching the reaction by the dropwise addition of saturated aqueous ammonium chloride (1 L). Allow the reaction to warm to room temperature (RT) overnight with stirring. Dilute the mixture with methyl-tert-butylether (MTBE, 2 L), saturated aqueous ammonium chloride (1 L) and water (2 L). Partition and wash organics with saturated aqueous sodium chloride (brine). Extract the aqueous phase with MTBE (1.5 L). Combine the organic layers, dry over sodium sulfate, filter and concentrate in vacuo. Purify the residue by silica gel chromatography [25percent ethylacetate (EA) in hexanes] to give the title compound as a red oil. Yield: 352 g (90percent). MS (ES) m/z 192 [M+1]+. |
66% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 2 h; |
LDA (242mL, 484mmol, 2.0mol/L) was added dropwise to a solution of 3,5-dichloropyridine (58.8g, 404mmol)in tetrahydrofuran (600mL) under the protection of nitrogen at -78 °C. After the addition, the reaction was further stirredfor an hour under the atmosphere of nitrogen at -78 °C. And then, anhydrous acetaldehyde (35.5g, 808mmol) was addedto the reaction solution in batches. After the addition, the reaction solution was heated to room temperature 20 °C andstirred for another 2 hours. The reaction was quenched by the addition of saturated ammonium chloride (200mL) andthen extracted with ethyl acetate (400 mL 3 3). The organic phases were combined and dried over anhydrous sodiumsulfate, filtered and the filtrate was concentrated to give a residue that was purified by flash silica gel column chromatographyto give the title compound (51g, yield 66percent). 1H NMR (400MHz, METHANOL-d4) ppm: 8.43 (s, 2H), 5.53 (t,J=6 Hz, 1H), 3.12 (d, J=6 Hz, 1H), 1.64 (d, J=6.8 Hz, 3H). |
65% | With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 3 h; | Diisopropylamine (DIPA, 13.2 ml, 94.60 mmol) was dissolved in anhydrous tetrahydrofuran (THF, 50 ml), cooled at -78 ° C, n-butyllithium (1.6M hexane solution, 50 ml, 81.08 (10 g, 67.57 mmol) in THF (30 ml) was added dropwise over 20 min, and the reaction solution was yellowish turbid. The reaction mixture was cooled to a solution of 3,5-dichloropyridine (I) (10 g, 67.57 mmol) in THF (30 ml)After completion of the dropwise addition, the solution was cooled to a solution of the pre-cooled solution of acetaldehyde (8.93 g, 11.4 ml, 135.14 mmol) in THF (20 ml), and the reaction solution became clear.After reacting for 3 h at -78 ° C, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and stirred at room temperature overnight.The reaction mixture was diluted with methyl tert-butyl ether (MTBE, 200 ml) and saturated ammonium chloride solution (500 ml). The organic phase was separated and the aqueous layer was washed three times with MTBE. The combined organic phases were washed with saturated brine, dried over sodium sulfate , Concentrated in red oil.Purification by Evaporative Column Chromatography (petroleum ether: ethyl acetate = 20: 1) gave 8.50 g as a white solid in 65percent yield. |