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CAS No. : | 104711-65-1 |
Formula : | C6H4ClN3 |
M.W : | 153.57 |
SMILES Code : | N#CC1=NC(C)=CC(Cl)=C1 |
MDL No. : | MFCD09607719 |
InChI Key : | VLNYLEMSSXHBPF-UHFFFAOYSA-N |
Pubchem ID : | 18505249 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H319 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 38.93 |
TPSA ? Topological Polar Surface Area: Calculated from | 36.68 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.79 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.93 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.92 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 0.73 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 2.4 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.75 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.45 |
Solubility | 0.547 mg/ml ; 0.00358 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.32 |
Solubility | 0.723 mg/ml ; 0.00474 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -3.1 |
Solubility | 0.122 mg/ml ; 0.0008 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) | Yes |
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 | -5.86 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) | 1.67 |
* 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 |
---|---|---|
With ammonium chloride; In diethyl ether; | ii) Production of 1-(4-chloro-6-methyl-2-pyridinyl)ethanone 10 g (66 mmol) of <strong>[104711-65-1]4-chloro-2-cyano-6-methylpyridine</strong> was dissolved in 100 ml of anhydrous diethyl ether. The resultant solution was cooled to maintain the temperature thereof at 5 C., and was then fed dropwise with 262 ml (87 mmol) of diethyl ether solution of 3M-methyl magnesium bromide (manufactured by Aldrich) at the same temperature in a manner of spending 15 min. At that time, the inner temperature of the mixture had elevated to 20 C. due to heat generated by the reaction. The mixture was stirred for 2.5 hours, then cooled down to 5 C. and added with aqueous solution of ammonium chloride to discontinue the reaction. The reacted mixture was extracted with diethyl ether, and the resultant nonaqueous layer was washed with water, then dried with anhydrous magnesium sulfate and condensed under reduced pressure to thereby obtain a crude product. The obtained crude product was purified by means of silica gel column chromatography (elude; hexane:ethyl acetate=4:1 (v/v)) to obtain the target compound in an amount of 3.8 g. 1H-NMR (CDCl3, TMS, delta ppm) data; 2.61 (s, 3H), 2.70 (s, 3H), 7.32 (d, 1H), 7.83 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; | i) Production of 4-chloro-2-cyano-6-methylpyridine 32 g (223 mmol) of 4-chloro-2-methylpyridine-1-oxide was dissolved in 250 ml of methylene chloride. The resultant solution was added with 24. 6 g (248 mmol) of trimethyl silylanilide at a room temperature in a manner of spending 5 min. The mixture was stirred for 10 min. and then added with 23. 5 g (219 mmol) of dimethylcarbamoyl chloride at the same temperature in a manner of spending 5 min. At that time, the inner temperature of the mixture had elevated to the reflux temperature thereof due to heat generated by the reaction. While stirring the mixture, the mixture was naturally cooled until the time that the inner temperature of the mixture falls to reach a room temperature. After stirring the mixture for 4 days, the reacted solution was cooled so as to maintain the temperature thereof at 5 C. and was added with 300 ml of 10% aqueous solution of sodium hydrogen atomcarbonate. The organic layer of the mixture was separated, and the aqueous layer was extracted with chloroform. The obtained chloroform layer was unified with the separated organic layer, and the unified mixture was dried with anhydrous magnesium sulfate and then condensed under reduced pressure to obtain a crude product. The obtained crude product was then purified by means of silica gel column chromatography (elude; hexane:ethyl acetate=4:1 (v/v)) to obtain the target compound in an amount of 10 g. 1H-NMR (CDCl3, TMS, delta ppm) data; 2.60 (s, 3H), 7.40 (d, 1H), 7.53 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<Reference Production Example 30> Into 6 ml of N,N-dimethylformamide was suspended 0.18 g of sodium hydride(60% oily), and 0.44 g of l,l,l-trifluoro-2-propanol was added at 10C. After stirring for 10 minutes, 0.49 g of <strong>[104711-65-1]4-chloro-6-methylpyridine-2-carbonitrile</strong> was added, the mixture was stirred for 1 hour, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert- butyl=methyl=ether. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.72 g of 6-methyl-4-(2,2,2-trifluoro-l-methylethoxy)pyridine-2-carbonitrile. 6-Methyl-4-(2,2,2-trifluoro-l-methylethoxy)pyridine-2-carbonitrile <n="135"/>1H-NMR: 1.56 (d, 3H), 2.57 (s, 3H), 4.76-4.82 (m, IH), 6.91 (d, IH), 7.10 (d, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<Reference Production Example 28>Into 8 ml of N,N-dimethylformamide was suspended 0.22 g of sodium hydride (60% oily), and 0.47 g of trifluoroethyl alcohol was added at 100C. After stirring for 10 minutes, 0.6 g of <strong>[104711-65-1]4-chloro-6-methylpyridine-2-carbonitrile</strong> was added at 0C, the mixture was stirred for 1 hour, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert- butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.79 g of 6-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile. 6-Methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile1H-NMR: 2.59 (s, 3H), 4.43 (q, 2H), 6.91 (d, IH), 7.12 (d, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
c) To a solution of 4-chloro-6-methyl-pyridine-2-carbonitrile (0.460 g, 3.02 mmol) in anhydrous methanol (1 ml) was added sodium methoxide (30% wt, 0.201 ml, 1.055 mmol). The reaction mixture was stirred at RT for 1 h before a solution of anthranilic acid (0.517 g, 3.77 mmol) in dry methanol (6 mL) was added. The resulting yellow solution was stirred at RT for an additional 45 min and then heated under reflux overnight. The reaction mixture was then cooled to 0 C and kept at this temperature for 1 h. The resulting yellow precipitate was filtered to afford 2-(4-chloro-6-methyl-pyridin-2-yl)-3/-/-quinazolin-4-one. The product was used in the next step without further purification.LCMS: 1.87 min; method A; [M+H]+ = 272 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; at 20℃; for 44h;Reflux; | To a solution of intermediate 1A (128.0 g, 889 mmol) and triethylamine (260 ml) in propionitrile (1.5 1) was added trimethylsilyl cyanide (334 ml, 2.67 mol). The mixture was stirred at reflux for26 h then left to stand at room temperature for 18 h. The reaction was quenched by the addition of30% aqueous potassium carbonate solution and the layers were separated. The organic layer was washed with 10% aqueous potassium carbonate solution, brine, dried over magnesium sulfate, filtered and concentrated. The resulting dark solid was recrystallized from hot isopropanol (150 ml) and water (300 ml) to give intermediate 2A (114.3 g, 84%). |
75% | c. PREPARATION OF 4-CHLORO-6-METHYLPICOLINONITRILE.[00398] 4-chloro-2-methylpyridine-N-oxide (8.97g, 62.5 mmol, 1 .00 eq) was dissolved in CH2C12 and dried over MgSO^. The solution was added to a flame-dried round-bottom flask and CH2C12 was added to give a total volume of 188 mL. TMS-cyanide (10 mL, 75 mmol, 1.2 eq) was added and the reaction stirred for 1 5 minutes. Dimethylcarbamyl chloride (6.9 mL, 75 mmol, 1.2 eq) was added dropwise over 20 minutes, and the reaction was stirred for 24 hours. An additional one equivalent each of TMS-cyanide and dimethylcarbamyl chloride were added and the reaction was stirred for another 72 hours. The reaction was made basic with 10% K2C03 and extraxcted with CH2C12 (3 ). The combined organics were dried (MgS04), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 7.2 g (75%) of the title compound as a white solid. NMR (400 MHz, OMSO-d6) delta 8.13 (d, J= 1 .6 Hz, 1), 7.82 (d, J= 1.7 Hz, 1H), 2.52 (s, 3H); ES-MS [M+l ]+: | |
75% | With magnesium sulfate; N,N-Dimethylcarbamoyl chloride; In dichloromethane; for 96.5833h; | b. SYNTHESIS OF 4-CHLORO-6-METHYLPICOLINONITRILE (COMPOUND 2)Compound 1 (8.97 g, 62.5 mmol, 1.00 eq) was dissolved in CH2Cl2 and dried over MgSO4. The solution was added to a flame-dried round-bottom flask and CH2Cl2 was added to give a total volume of 188 mL. TMS-cyanide (10 mL, 75 mmol, 1.2 eq) was added and the reaction stirred for 15 minutes. Dimethylcarbamoyl chloride (6.9 mL, 75 mmol, 1.2 eq) was added dropwise over 20 minutes, and the reaction was stirred for 24 hours. An additional one equivalent each of TMS-cyanide and Dimethylcarbamoyl chloride was added and the reaction was stirred for another 72 hours. The reaction was made basic with 10% K2CO3 and extracted with CH2Cl2 (3x). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 7.2 g (75%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.13 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1 H), 2.52 (s, 3H); ES-MS [M+1]+: 153.2. |
51% | To a solution of 4-chloro-2-methylpyridine-N-oxide(7, 4.3 kg, 29.94 mol) in dichloromethane (64.5 L, 15 V) was added trimethylsilyl cyanide (9.76 L, 77.83 mol) at 25-30 C over a period of 30 min and furtherstirred for 15 min. Reaction mass was cooled to 0-5 C. N,NDimethylcarbamoylchloride (7.17 L, 77.83 mol) was added drop wise over aperiod of 1 h. The reaction mass was slowly warmed to 25-30 C and stirred for36 h. Reaction was monitored by HPLC [7 NMT 1.0%]. The reaction mass wascooled to 0-5 C. The reaction was quenched with 10% aqueous potassiumcarbonate solution until the pH of aqueous layer was about 9-10. Thetemperature of reaction mass was allowed to attain 25-30 C and the layerswere separated. The aqueous layer was extracted with dichloromethane (8.6 L,2 V). The combined organic layer was washed with 0.5 N HCl solution (21.5 L,5 V) followed by brine solution (21.5 L, 5 V), dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was chased twice with nheptane(2 17.2 L). The crude product was diluted with 2% ethyl acetate[Ashok alco-chem limited, Purity (area%) by GC - 100%] in hexanes (43 L, 10 V)and filtered through silica plug (21.5 kg, 5% w/w on SM, 230-400 mesh) andsilica plug was washed with 10% ethyl acetate in hexanes till the product was completely eluted (300 L, 69 V). Combined fractions were concentrated andresidue was chased twice with n-heptane (2 17.2 L). Resulting mass wasstirred in n-heptane (21.5 L, 5 V) at 0-5 C for 1 h and filtered. Solid waswashed with cold n-heptane (4.3 L, 1 V) and dried to get 8 as off white solid(2.32 kg, 51%).. 1H NMR (400 MHz, DMSO-d6) d 8.13 (d, J = 1.6 Hz, 1H), 7.82 (d,J = 1.7 Hz, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, DMSO-d6) d = 161.99, 144.13,133.01, 127.65, 126.40, 116.60, 23.57 ppm; LCMS (Method 1): RT = 0.715 min,m/z = 153.2 [M + H]+; HRMS, calc?d for C7H5ClN2 [M], 152.0141; found152.0139. | |
With triethylamine; In acetonitrile;Reflux; | b) To a solution of 4-chloro-2-methyl-pyridine 1 -oxide (2.250 g, 15.67 mmol) in acetonitrile (50 ml) was added Et3N (6.55 ml, 47.0 mmol,) and TMSCN (1 1.76 ml, 94.03 mmol). The resulting brown solution was heated overnight under reflux and then quenched with 60 mL of sat. aqueous NaHC03. The aqueous phase was extracted with CH2CI2 and the combined organic layers were washed with water and brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography (cyclohexane/AcOEt; 100/0 to 0/100) to afford 4-chloro-6-methyl-pyridine-2-carbonitrile as a light orange powder.LCMS: 1.35 min; method A; [M+H]+ = 153 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.1% | With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 80℃; for 36h;Large scale; | To a solution of 5-hydroxypyrimidine (9, 1.73 kg, 18.08 mol) in DMF (23.0 L,10 V), potassium carbonate (6.25 kg, 45.21 mol) was added followed by <strong>[104711-65-1]4-chloro-6-methylpicolinonitrile</strong> (8, 2.3 kg, 15.07 mol) at 25-30 C. The reactionmass was heated at 75-80 C for 36 h. The reaction was monitored by HPLC 8NMT 2.0% by HPLC). Reaction mass was cooled to 25-30 C. The solid wasfiltered and washed the solid with DMF (4.6 L, 2.0 V). The filtrate was cooled to0-5 C and purified water (27.6 L, 12 V) was added drop wise over a period of1 h. The solid precipitated was filtered and washed with purified water (2.3 L,10 V) to afford 10 as off white solid (2.62 kg, 82.1%). 1H NMR (400 MHz, DMSOd6)d 9.17 (s, 1H), 8.85 (s, 2H), 7.74 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H),2.48 (s, 3H); 13C NMR (100 MHz, DMSO-d6) d = 164.04, 162.28, 155.51, 150.02,148.75, 133.54, 117.05, 115.59, 115.04, 23.82 ppm; LCMS (Method 1):RT = 0.535 min, m/z = 213.2 [M+H]+; HRMS, calc?d for C11H8N4O [M],212.0698; found 212.0697. |
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | d. PREPARATION OF 6-METHYL-4-(PYRIMIDIN-5-YLOXY)PICOLINONITRILE.[00399] <strong>[104711-65-1]4-chloro-6-methylpicolinonitrile</strong> (4.0 g, 26 mmol, 1.0 eq), 5-hydroxypyrimidine (5.56 g, 57.9 mmol, 2.20 eq), K2C03 (7.24 mg, 52.4 mmol, 2.0 eq) and DMF (66 mL) were added to a reaction vessel and heated at 80 C for 16 hours. The reaction was filtered and concentrated on silica gel (25 g). The silica gel was loaded on top of a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude solid was purified by flash chromatography on silica gel to afford 4.31 g (77%) of the title compound as a pale-yellow solid. NMR (400 MHz, DMSO-<¾) delta 9.1 7 (s, 1 H), 8.85 (s, 2H), 7.74 (d, J = 2.4 Hz, 1 H), 7.32 (d, J = 2.3 Hz, 1 H), 2.48 (s, 3H); ES-MS [M+l ]+: 213.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sodium hydride; In N,N-dimethyl-formamide; for 18h; | c. SYNTHESIS OF (R)-6-METHYL-4-((TETRAHYDROFURAN-3- YL)OXY)PICOLINONITRILE (COMPOUND 3)To a solution of (R)-tetrahydrofuran-3-ol (693 mg, 7.86 mmol, 2.0 eq) and sodium hydride (199 mg, 7.86 mmol, 2.0 eq) in DMF (20 mL) was added compound 2 (600 mg, 3.93 mmol, 1.0 eq). After 18 hours, the reaction was diluted with EtOAc and washed with water and brine twice. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 325 mg (40%) of the title compound: 1H NMR (400 MHz, , DMSO-d6) delta 7.52 (d, J = 2.28 Hz, 1H), 7.18 (d, J = 2.28 Hz, 1H), 5.22-5.19 (m, 1H), 3.91-3.33 (m, 4H), 2.46 (s, 3H), 2.34-2.25 (m, 1H), 2.00-1.93 (m, 1H); ES-MS [M+1]+: 205.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | To a solution of intermediate 2A (114 g, 745 mmol) in tetrahydrofuran (1.5 1) was added isopropyl magnesium chloride (2M, 0.48 1, 968 mmol) dropwise, at -78 C. After the addition was complete the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then cooled to 0 C and methanol (0.5 1) was added over a period of 10 mm. The mixture was thenwarmed to room temperature and sodium borohydride (16.9 g, 447 mmol) was added portionwise over a period of 30 mm. The mixture was then stirred at room temperature for 18 h and the reaction was then stopped by the addition of ice. The mixture was concentrated; then, dichloromethane was added followed by celite. The mixture was filtered, washed with dichloromethane and the layers separated. The organic layer was dried and concentrated. The residue was purified by flash chromatography (0-15% methanol in ethyl acetate) to give intermediate 3A (78.5 g, 53%) as a black oil.?H NMR (400 MHz, CDC13) oe [ppm] = 7.07 (d, 1H), 7.00 (d, 1H), 3.64 (d, 1H), 2.47 (s, 3H), 2.02 (sept, 1H), 1.68 (bs, 2H), 0.91 (d, 3H), 0.82 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<strong>[104711-65-1]4-chloro-6-methylpyridine-2-carbonitrile</strong> (CAS 104711-65-1, 45 g, 295 mmol) was dissolved in tetrahydrofuran (700 ml). The mixture was cooled to -60C and isobutyl magnesium chloride solution (25% w/w in THF, 180 g, 384 mmol) was added dropwise. The mixture was stirred fortwo hours at room temperature. The mixture was adjusted to 0 C and methanol (230 ml) was added dropwise. Sodium borohydride (7 g, 177 mmol) was added to the mixture portionwise. The solution was stirred one hour at 0 C. The solution was poured into an ice/water mixture (1.3 1) and the mixture was stirred overnight at room temperature. Dichloromethane (1.5 1) was added and the resulting emulsion was filtered over Celite. The aqueous layer was extracted with dichloromethane.The organic layer was dried over magnesium sulfate, filtered and concentrated to give a black oil (62.2 g). The crude product was purified by column chromatography to give several batches of the expected product as in a combined yield of 50% as a mixture of diastereomers.?H NMR (300 MHz, CDC13) oe [ppm] = 7.28 (s, 1H), 7.03 (s, 1H), 3.85 (isomer 1) and 3.73 (isomer 2) (d, 1H), 2.51 (s., 3H), 1.70 - 1.90 (isomer 1) and 1.11 - 1.29 (isomer 2) (m, 2H), 1.52 - 1.67(isomer 2) and 1.33 - 1.49 (isomer 1) (m, 1 H), 0.80 - 1.01 (m, 3H), 0.74 -0.88 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | 4-Chloro-6-methylpyridine-2-carbonitrile (CAS 104711-65-1, 43.6 g, 286 mmol) was dissolved in tetrahydrofuran (840 ml). The mixture was cooled to -60C and cyclopentyl magnesium chloride solution (2M in diethyl ether, 185 mL, 370 mmol) was added dropwise. The mixture was stirred for two hours at room temperature. The mixture was adjusted to 0C and methanol (284 ml) was addeddropwise. Sodium borohydride (6.5 g, 171 mmol) was added to the mixture portionwise. The solution was stirred two hours at 0C. The solution was poured into an ice/water mixture (1.3 1) and the mixture was stirred overnight at room temperature. Dichloromethane (1.5 1) was added and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a crude product. The productwas mixed with hydrochloric acid solution (400 ml, 2M in ether). The resulting precipitate was filtered and rinsed with tetrahydrofuran. The combined filtrates were concentrated and treated a second time with a hydrochloric acid solution (400 ml, 2M in ether). Diisopropyl ether was added to the resulting suspension and the solid was filtered. The combined solids where re-dissolved into water and the aqueous layer was made basic using a saturated aqueous sodium hydrogen carbonatesolution. The product was extracted three times using dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give an impure product that was purified using column chromatography on silica gel eluting with ethyl acetate, giving the expected product (41.8 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Preparation of the Grignard (carried out in flame dried glassware under argon) - Magnesium turnings 3.00 g (125 mmol) were stirred in tetrahydrofuran 75 mL, one flake of iodine was added. The mixture was stirred for 2 hours until the colour had dissipated. 4-Chlorotetrahydropyran (2.00g) was added and the mixture was heated to 60 C, and one drop of methyl iodide was added. The mixture turned cloudy and an exothermia was observed. A further portion of 4- chlorotetrahydropyran 8.00 g was added and the mixture was stirred at 60 C for 2 hours. To a solution of <strong>[104711-65-1]4-chloro-6-methylpicolinonitrile</strong> (intermediate 2A, 8.50 g, 56.0 mmol) in tetrahydrofuran 400 mL was added the Grignard solution drop-wise, at -78 C, under argon. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was then cooled to 5 C and methanol 150 mL was added drop-wise followed by sodium borohydride 1.50 g (0.40 mmol) which was added portion-wise. After the addition was complete the mixture was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of water and ethyl acetate. The phases were separated and the aqueous phase was extracted again with ethyl acetate. The organic phases were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue waspurified by dry flash chromatography (silica gel, eluent: ethyl acetate/methanol 9:1 to 4:1) to yield5.90 g (44%) of (4-chloro-6-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanamine.?H-NMR (400 MHz, CDC13): oe [ppm] = 1.14-1.45 (m, 4H), 1.83-1.93 (m, 1H), 2.51 (s, 3H), 3.33 (m, 2H), 3.61 (d, 1H), 3.90 (dd, 1H), 4.01 (dd, 1H), 7.02 (s, 1H), 7.04 (s, 1H). |
Tags: 104711-65-1 synthesis path| 104711-65-1 SDS| 104711-65-1 COA| 104711-65-1 purity| 104711-65-1 application| 104711-65-1 NMR| 104711-65-1 COA| 104711-65-1 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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