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CAS No. : | 4021-11-8 | MDL No. : | MFCD00513435 |
Formula : | C7H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PMDHIMMPXRSDML-UHFFFAOYSA-N |
M.W : | 137.14 | Pubchem ID : | 2762821 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.16 |
TPSA : | 50.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.69 cm/s |
Log Po/w (iLOGP) : | 1.06 |
Log Po/w (XLOGP3) : | 0.63 |
Log Po/w (WLOGP) : | 1.09 |
Log Po/w (MLOGP) : | -0.78 |
Log Po/w (SILICOS-IT) : | 1.17 |
Consensus Log Po/w : | 0.63 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.47 |
Solubility : | 4.7 mg/ml ; 0.0343 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.26 |
Solubility : | 7.55 mg/ml ; 0.0551 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.76 |
Solubility : | 2.41 mg/ml ; 0.0175 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.16 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
53% | for 4 h; Reflux | Methyl 2-methylisonicotinate (16.1.B). To a 50 ml flask was added of2-methylisonicotinic acid 16.1A (500 mg, 3.6 mmoles, available from Combiphos), 10 ml of MeOH and 500 ul of concentrated sulfuric acid. The reaction was refluxed for 4 hours at which time the reaction mixture was cooled, diluted with 500 ml of DCM and extracted with 100 ml of saturated sodium bicarbonate. The solvent was removed and the crude purified using a silica gel column (e luting with 5percent MeOH in DCM) to give methyl 2-methylisonicotinate 16.1. B as a clear oil (290 mg, 53percent yield). |
4.5 g | With hydrogenchloride In water at 50℃; for 24 h; | 6.01.25 2-Methyl-isonicotinic acid methyl ester 5 g 2-methyl-isonicotinic acid was stirred 24 h at 50° C. in 150 mL 1.3 mol/L HCl in methanol. The solvent was removed and water was added to the residue. The mixture was basified with saturated sodiumhydrogencarbonate solution and extracted with ethylacetate. The organic layer was dried with magnesiumsulfate and evaporated to give 4.5 g of the desired product. Rt: 0.36 (method S), (M+H)+: 152 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With thionyl chloride In methanol; water | (b) Methyl 2-methylisonicotinate To an ice-cooled suspension of 1.32 g (9.62 mmol) of 2-methylisonicotinic acid in 20 mL of MeOH was added 1.47 mL (20.2 mmol) of thionyl chloride. The ice-bath was removed and the reaction was stirred at rt. After 22 h, the MeOH was evaporated and the residue was taken up in H2 O. The aqueous mixture was neutralized with saturated NaHCO3, then extracted with Et2 O. The organic extracts were washed with saturated NaCl, dried over MgSO4, then filtered through a bed of celite. Evaporation of solvent in vacuo afforded the title compound as a yellow liquid (0.89 g, 61percent): 1 H NMR (CDCl3): d 8.66 (d, 1H); 7.72 (s, 1H); 7.64 (d, 1H); 3.98 (s, 3H); 2.64 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With selenium(IV) oxide In 1,4-dioxane at 110℃; for 24 h; | 2-methyl-4-pyridinecarboxylic acid (5.0 g, 36.5 mmol),Selenium dioxide (10.1 g, 91.3 mmol) was added to 250 ml of dioxane, heated to 110° C., and reacted for 24 hours under magnetic stirring. The reaction was completed by TLC. The reaction solution was filtered while hot, and the solvent was evaporated under reduced pressure. The crude product was recrystallized from absolute ethanol and dried in vacuo to give 2-formyl-4-pyridinecarboxylic acid as a white solid in a yield of 72percent and a purity of 98percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sulfuric acid; for 48h;Reflux; | A few drops of concentrated sulphuric aicd were added to a solution of methylisonicotinic acid in methanol. The mixture was refluxed for 48 hours. The resultant reaction mixture was neutralized with saturated sodium bicarbonate solution followed by extraction with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and solvent evaporated. The crude product was purified using SiO column chromatography and eluted with the solvent system EtOAc: hexanes = 4:1. The pure compound was obtained as colorless oil with 96% yield. 1H-NMR (400 MHz, DMSO-d6): d 8.66 (d, J = 5.08 Hz, 1 H), 7.71 (s, 1H), 7.63 (dd, J = 5.04, 0.32 Hz, 1H), 3.89 (s, 2H), 2.56 (s, 3H) . HRMS (ESI) m/z found 152.07 [M+H]+, Calculated 151.1626 [M]+. |
56% | With sulfuric acid; at 70℃; for 14h;Inert atmosphere; | 2-Methylpyridine-4-carboxylic acid (0.200 g, 1.46 mmol) was added to anoven dried 20 mL vial. The vial was purged with nitrogen for 10 min. before anhydrous methanol (10 mL) was added.Concentrated H2SO4 (0.026 mL, 0.481 mmol) was added to the vial and the reaction was stirred in an oil bath heated to 70C for 14 h. A sample aliquot was taken from the reaction, dissolved in 1 mL HPLC grade MeCN, and analyzed with LCMSto confirm the completion of the reaction. The reaction was diluted with EtOAc (50 mL), and the organic layer waswashed with half sat. aq. sodium bicarbonate solution (10 mL). The aqueous layer was saturated with NaCl and extractedwith EtOAc (4 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate, thencondensed down to yield the title compound as a clear oil (0.122 g, 56%). 1H NMR showed the crude compound to be ofsufficient purity to advance without further purification. This compound has been previously reported and characterized(CAS 16830-24-3).1HNMR (300 MHz, CDCl3) delta = 2.59 (s, 3H), 3.90 (s, 3H), 7.59 (d, J = 5.0 Hz, 1H), 7.67 (s, 1H), 8.60(d, J = 5.0 Hz, 1 H). |
53% | With sulfuric acid; for 4h;Reflux; | Methyl 2-methylisonicotinate (16.1.B). To a 50 ml flask was added of2-methylisonicotinic acid 16.1A (500 mg, 3.6 mmoles, available from Combiphos), 10 ml of MeOH and 500 ul of concentrated sulfuric acid. The reaction was refluxed for 4 hours at which time the reaction mixture was cooled, diluted with 500 ml of DCM and extracted with 100 ml of saturated sodium bicarbonate. The solvent was removed and the crude purified using a silica gel column (e luting with 5% MeOH in DCM) to give methyl 2-methylisonicotinate 16.1. B as a clear oil (290 mg, 53% yield). |
With sulfuric acid; at 70℃; for 18h; | A suspension of 2-methyl-pyridine-4-carboxylic acid (1.0 g, 7.29 mmol) in methanol (50 ml_) and H2SO4 (0.5 ml_) is heated to 700C. The solid material dissolves and stirring is continued at 700C for 18 h. The mixture is cooled to rt, filtered, and the filtrate is evaporated. The remaining solid is washed with diethyl ether and dried to give methyl 2-methyl-pyridine-4-carboxylate; LC-MS: tR = 0.39 min, [IVM]+ = 152.05. This material is dissolved in 7 N NH3 in methanol (25 ml_) and the mixture is stirred in a sealed vial for 20 h at 60C before it is filtered. The filtrate is evaporated to give crude 2-methyl-isonicotinamide (2.12 g) as a brownish solid. To a solution of this material in DCM (25 ml_), pyridine (5.24 g, 54.0 mmol) is added. The mixture is cooled to 00C before trifluoroacetic anhydride (8.10 g, 38.6 mmol) is added portionwise. Stirring is continued at 00C for 2 h before the reaction is quenched with water. The mixture is diluted with DCM and the org. phase is separated and washed with 5% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The washings are extracted back twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 4:1 to give 2-methyl-isonicotinonitrile (330 mg); LC-MS: tR = 0.55 min, [M+1]+ = 119.13. | |
With sulfuric acid; at 70℃; for 18h; | a) A suspension of 2-methyl-pyridine-4-carboxylic acid (1.0 g, 7.29 mmol) in methanol (50 mL) and H2SO4 (0.5 mL) is heated to 70 C. The solid material dissolves and stirring is continued at 70 C. for 18 h. The mixture is cooled to rt, filtered, and the filtrate is evaporated. The remaining solid is washed with diethyl ether and dried to give methyl 2-methyl-pyridine-4-carboxylate; LC-MS: tR=0.39 min, [M+1]+=152.05. This material is dissolved in 7 N NH3 in methanol (25 mL) and the mixture is stirred in a sealed vial for 20 h at 60 C. before it is filtered. The filtrate is evaporated to give crude 2-methyl-isonicotinamide (2.12 g) as a brownish solid. | |
With sulfuric acid; at 70℃; for 18h; | a) A suspension of 2-methyl-pyridine-4-carboxylic acid (1.0 g, 7.29 mmol) in methanol (50 mL) and H2SO4 (0.5 mL) is heated to 70 C. The solid material dissolves and stirring is continued at 70 C. for 18 h. The mixture is cooled to rt, filtered, and the filtrate is evaporated. The remaining solid is washed with diethyl ether and dried to give methyl 2-methyl-pyridine-4-carboxylate; LC-MS: tR=0.39 min, [M+1]+=152.05. | |
2 -Methyl isonicotinate (733 mg) and concentrated H2S04 (70 mg) were dissolved in methanol (30 ml) , and the solution was refluxed for 20 hours. The reaction solution was cooled and concentrated under reduced pressure. To the residue was added saturated sodium bicarbonate aqueous solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 2- methylpyridine-4 -carboxylate (749 mg) . | ||
4.5 g | With hydrogenchloride; In water; at 50℃; for 24h; | 6.01.25 2-Methyl-isonicotinic acid methyl ester 5 g 2-methyl-isonicotinic acid was stirred 24 h at 50 C. in 150 mL 1.3 mol/L HCl in methanol. The solvent was removed and water was added to the residue. The mixture was basified with saturated sodiumhydrogencarbonate solution and extracted with ethylacetate. The organic layer was dried with magnesiumsulfate and evaporated to give 4.5 g of the desired product. Rt: 0.36 (method S), (M+H)+: 152 |
To methanol (1.54 l) at -10 C. was added slowly thionyl chloride (401 g, 3.37 mol) and the solution was stirred 10 minutes at 0 C. Then was added 2-methylisonicotinic acid (154 g, 1.20 mol) and the reaction mixture was stirred at reflux temperature overnight. The mixture was evaporated under vacuo, then diluted in ethyl acetated and finally treated with a 10% sodium hydrogen carbonate aqueous solution until pH 7 was achieved. After separation of the layers the aqueous phase was extracted with ethyl acetate. All collected organic phases were dried over magnesium sulfate, evaporated under dried under vacuo. The crude product was used in the next step without further purification (113.0 g, 48% of theory), 72% purity). LC-MS (Method 1B): Rt=0.43 min, MS (ESIPos): m/z=152 [M+H]+ | ||
To methanol (1.54 1) at -10 C was added slowly thionyl chloride (401 g, 3.37 mol) and the solution was stirred 10 minutes at 0 C. Then was added 2-methylisonicotinic acid (154 g, 1.20 mol) and the reaction mixture was stirred at reflux temperature overnight. The mixture was evaporated under vacuo, then diluted in ethyl acetated and finally treated with a 10% sodium hydrogen carbonate aqueous solution until pH 7 was achieved. After separation of the layers the aqueous phase was extracted with ethyl acetate. All collected organic phases were dried over magnesium sulfate, evaporated under dried under vacuo. The crude product was used in the next step without further purification (113.0 g, 48% of theory), 72% purity). LC-MS (Method IB): Rt = 0.43 min, MS (ESIPos): m/z = 152 [M+H]+ | ||
With sulfuric acid; at 65℃; for 24h; | A suspension of 2-methylpyridine-4-carboxylic acid 7 (5.0 g, 36.5 mmol) in methanol (500 mL) was treated with concentrated sulfuric acid (2.5 mL). The white suspension is refluxed for 24 h to give a clear solution of the corresponding ester. A solution of ammomium persulfate (16.6 g, 72.9 mmol) in water (40 mL) was then added and the reaction mixture was stirred at reflux for 4 h. Another 20 mL of ammomium persulfate aq. solution (8.3 g, 36.5 mmol) were added. After another 6 h at reflux, the reaction mixture was concentrated and partionized between EA (300 mL) and NaHCO3 (6 * 100 mL). The organic phase was dried over MgSO4, filtered and evaporated to give a residue which was purified by prep. HPLC (XBridge Prep C18) to afford 2-hydroxymethyl-6-methyl-isonicotinic acid methyl ester as a white crystalline solid (4.07 g, 62%); | |
To methanol (1.54 1) at -10 C was added slowly thionyl chloride (401 g, 3.37 mol) and the solution was stirred 10 minutes at 0 C. Then was added 2-methylisonicotinic acid (154 g, 1.20 mol) and the reaction mixture was stirred at reflux temperature overnight. The mixture was evaporated under vacuo, then diluted in ethyl acetated and finally treated with a 10% sodium hydrogen carbonate aqueous solution until pH 7 was achieved. After separation of the layers the aqueous phase was extracted with ethyl acetate. All collected organic phases were dried over magnesium sulfate, evaporated under dried under vacuo. The crude product was used in the next step without further purification (113.0 g, 48% of theory, 72% purity). LC-MS (Method IB): Rt = 0.43 min, MS (ESIPos): m z = 152 [M+H]+ | ||
With sulfuric acid; at 70℃; for 18h; | A suspension of 2-methyl-pyridine-4-carboxylic acid (1.0 g, 7.29 mmol) in methanol (50 mL) and H2SO4 (0.5 mL) is heated to 700C. The solid material dissolves and stirring is continued at 700C for 18 h. The mixture is cooled to rt, filtered, and the filtrate is evaporated. The remaining solid is washed with diethyl ether and dried to give methyl 2- methyl-pyridine-4-carboxylate; LC-MS: tR = 0.39 min, [M+1]+ = 152.05. This material is dissolved in 7 N NH3 in methanol (25 mL) and the mixture is stirred in a sealed vial for 20 h at 600C before it is filtered. The filtrate is evaporated to give crude 2-methyl-isonicotinamide (2.12 g) as a brownish solid. To a solution of this material in DCM (25 mL), pyridine (5.24 g, 54.0 mmol) is added. The mixture is cooled to 0C before TFAA (8.10 g, 38.6 mmol) is added portionwise. Stirring is continued at 0C for 2 h before the reaction is quenched with <n="59"/>water. The mixture is diluted with DCM and the org. phase is separated and washed with 5% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The washings are extracted back twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 4:1 to give 2-methyl-isonicotinonitrile (330 mg); LC-MS: tR = 0.55 min, [M+1]+ = 119.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; at 0 - 20℃; for 12h; | First, 90-100 g of 2-methylpyridine-4-carboxylic acid is dissolved in 700 ml of ethanol solvent, stirred uniformly and placed at 0 C.106 g of thionyl chloride was added dropwise, and the mixture was stirred to room temperature for 12 hours, and the reaction was completed by TLC;Next, the ethanol solvent is spin-dried to obtain a hydrochloride solid of 2-methylpyridine-4-carboxylate;Again, the hydrochloride salt of ethyl 2-methylpyridine-4-carboxylate formed in the previous step is added to a saturated aqueous solution of sodium hydrogencarbonate.Stir for 0.5 to 1 h, extract 3 times with 500 ml of ethyl acetate, and combine the extracted organics three times.Drying over anhydrous sodium sulfate and drying the solvent to give ethyl 2-methylpyridine-4-carboxylate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium permanganate; at 80℃; | To a solution of <strong>[108-47-4]2,4-lutidine</strong> (280 g, 2.61 mol) in water (3.0 l) at 80 C. was added potassium permanganate (826 g, 5.23 mol) in small portions over 3 h. The reaction mixture was stirred at 80 C. overnight. The mixture was filtered through silica gel and then the filtrate was evaporated under vacuo until a volume of approximately of 20 ml was achieved. Then the solution was treated with HCl 37% (450 ml) until pH 3-4 was achieved. The solution was kept 1 h at 0 C. and then the resulting solid was filtered, washed with water at 0 C. and finally dried under vacuo overnight over phosphorus pentoxide to yield the title product (130 g, 36% of theory). LC-MS (Method 3B): Rt=0.20 min, MS (ESIPos): m/z=138 [M+H]+ |
36% | With potassium permanganate; In water; at 80℃; | To a solution of <strong>[108-47-4]2,4-lutidine</strong> (280 g, 2.61 mol) in water (3.0 1) at 80 C was added potassium permanganate (826 g, 5.23 mol) in small portions over 3 h. The reaction mixture was stirred at 80 C overnight. The mixture was filtered through silica gel and then the filtrate was evaporated under vacuo until a volume of approximately of 20 ml was achieved. Then the solution was treated with HC1 37% (450 ml) until pH 3-4 was achieved. The solution was kept 1 h at 0 C and then the resulting solid was filtered, washed with water at 0 C and finally dried under vacuo overnight over phosphorus pentoxide to yield the title product (130 g, 36% of theory). LC-MS (Method 3B): Rt = 0.20 min, MS (ESIPos): mlz = 138 [M+H]+ |
36% | With potassium permanganate; In water; at 80℃; | To a solution of <strong>[108-47-4]2,4-lutidine</strong> (280 g, 2.61 mol) in water (3.0 1) at 80 C was added potassium permanganate (826 g, 5.23 mol) in small portions over 3 h. The reaction mixture was stirred at 80 C overnight. The mixture was filtered through silica gel and then the filtrate was evaporated under vacuo until a volume of approximately of 20 ml was achieved. Then the solution was treated with HC1 37% (450 ml) until pH 3-4 was achieved. The solution was kept 1 h at 0 C and then the resulting solid was filtered, washed with water at 0 C and finally dried under vacuo overnight over phosphorus pentoxide to yield the title product (130 g, 36% of theory). LC-MS (Method 3B): Rt = 0.20 min, MS (ESIPos): mlz = 138 [M+H]+ |
30% | Example 47Preparation of 2-methylpyridine-4-carboxylic acid To a mechanically (overhead) stirred solution of <strong>[108-47-4]2,4-lutidine</strong> (140 g, 1.31 mol) in water (1500 mL) was added KMnO4 (412 g, 2.61 mol) portion-wise at 80 C. over a period of 3 h, taking care to allow each portion to react before adding the next. The reaction mixture was then stirred at 80 C. for overnight. The solution was allowed to settle and the aqueous layer separated from the precipitated MnO2. The water was then removed under reduced pressure to produce a volume of approximately 400 mL. Remaining water was chilled in an ice bath and acidified to pH 3.0 with dilute HCl. Solid was allowed to precipitate for an addition hour, then filtered and dried under high vacuum at 50 C. for 48 h to give white solid product (54.9 g, 30% yield). | |
17.42% | With potassium permanganate; In water; at 80℃; for 14h; | To a solution of 2, 4-dimethyl-pyridine (266a) (100 g, 933.245 mmol) in water (1000 mL) was added potassium permanganate (294.97 g, 1866.489 mmol) portion-wise over a period of 2 h. The resulting reaction mixture was heated at 80C for I 2 h. Thereaction mixture was cooled to room temperature, filtered through celite bed and filtrate was concentrated under reduced pressure to a volume of 250 rnL at 50C. The obtained solution was cooled to 0C and pH was adjusted to 3 using I N HCI (temperature between 0C to 5C). The solid obtained was collected by filtration washed with chilled water and dried to afford 2-methylisonicotinic acid (266b) (22.3 g, yield: 17.42%); ?H NMR (D20) 88.52 (s, I H), 7.94-7.90 (m, 2H), 2.69 (s, 3H); MS (+) 138.1 (M+I). |
17.42% | With potassium permanganate; In water; at 80℃; for 14h; | Step-1 : Preparation of 2-methyl-isonicotinic acid (46b) To a solution of 2, 4-dimethyl-pyridine (46a) (100 g, 933.245 mmol) in water (1000 mL) was added potassium permanganate (294.97 g, 1866.489 mmol) portion-wise over a period of 2 h. The resulting reaction mixture was heated at 80C for 12 h. The reaction mixture was cooled to room temperature, filtered through celite bed and filtrate was concentrated under reduced pressure to a volume of 250 mL at 50C. The obtained solution was cooled to 0C and pH was adjusted to 3 using IN HC1 (temperature between 0C to 5C). The solid obtained was collected by filtration washed with chilled water and dried to afford 2-methylisonicotinic acid (46b) (22.3 g, yield: 17.42%); 1H NMR (D20) delta 8.52 (s, 1H), 7.94-7.90 (m, 2H), 2.69 (s, 3H); MS (+) 138.1 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.30 g 5-bromo-2,3-diaminopyridine and 0.212 g 2-methyl-pyridine-4-carboxylic acid were heated in 3 g polyphosphoric acid at 160 C. with stirring for 16 hrs. The mixture was diluted with water and insoluble components removed by filtration. Water was evaporated from the filtrate and the residue dispersed in pyridine. Again, insoluble components were removed by filtration and the filtrate evaporated. The obtained residue was washed thoroughly with water and dried. Yield 130 mg. | ||
Example 3-1 [2-(2-Methyl-pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-6-yl]-carbamic acid isopropyl ester a) 6-Bromo-2-(2-methyl-pyridin-4-yl)-3H-imidazo[4,5-b]pyridine; 0.30 g 5-bromo-2,3-diaminopyridine and 0.212 g 2-methyl-pyridine-4-carboxylic acid were heated in 3 g polyphosphoric acid at 160 C. with stirring for 16 hrs. The mixture was diluted with water and insoluble components removed by filtration. Water was evaporated from the filtrate and the residue dispersed in pyridine. Again, insoluble components were removed by filtration and the filtrate evaporated. The obtained residue was washed thoroughly with water and dried. Yield 130 mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With hydrogen; triethylamine; In ethanol; at 20℃; | Example 1 6-Methylpyridine-4-carboxylic acid A hydrogen filled balloon was attached to a flask containing <strong>[25462-85-5]2-chloro-6-methylpyridine-4-carboxylic acid</strong> (2 g, 12.0 mmol), palladium 10 wt. % on activated carbon (0.5 g), triethyl amine (4.8 ml) and ethanol (24 ml) and then stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with methanol and concentrated. The residue was titurated with dichloromethane and then filtered to afford 6-methylpyridine-4-carboxylic acid as a white solid; 1.05 g (66%). 1H NMR (MeOD) delta (ppm): 8.62 (d, 1H), 7.68 (s, 1H), 7.60 (d, 1H), 2.55 (s, 3H). |
66% | With hydrogen; triethylamine;palladium 10% on activated carbon; In ethanol; at 20℃; | A hydrogen filled balloon was attached to a flask containing [2-CHLORO-6-METHYLPYRIDINE-4-] carboxylic acid (2 g, 12.0 mmol), palladium 10 wt. % on activated carbon (0.5 g), triethyl amine (4.8 ml) and ethanol (24 ml) and then stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with methanol and concentrated. The residue was titurated with dichloromethane and then filtered to afford 6-methylpyridine-4- carboxylic acid as a white solid ; 1.05 g (66%). 1H NMR [(MEOD)] 8 (ppm): 8.62 (d, 1H), 7.68 (s, 1H), 7.60 (d, 1H), 2.55 (s, 3H). |
With hydrogen; triethylamine;palladium 10% on activated carbon; In ethanol; at 20℃; | 2-Methyl-4-pyridinecarboxylic acid (D26) A hydrogen filled balloon was attached to a flask containing 2-chloro-6-methyl-4- pyridinecarboxylic acid (350mg, 2.10mmol), 10% palladium on activated carbon (88.0mg, 0.0deltammol), triethylamine (1 ml) and ethanol (15ml). The mixture was stirred during the afternoon and overnight at room temperature. The reaction mixture was filtered through celite and washed with ethanol. The solvent was evaporated and the residue triturated with dichloromethane and filtered to afford the product (D26); MS (ES+) m/e 138 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | 1.63 g Dimethyl-[2-(2-methyl-pyridin-4-yl)-vinyl]-amine (10 mmol) were dissolved in 19 ml acetic acid containing 1 ml H2O. To the red solution maintained and stirred at ca. 15-20 C. was passed O3 (85 mmol/hour) for 1 hour. The reaction was mildly exothermic, changing in appearance from an orange (10 min) to a yellow solution (15 min) then from a yellow (20 min) to a white suspension (30 min). Excess ozone was purged with argon until a peroxide test was essentially negative. 1.02 ml 30% aqueous H2O2 (10 mmol) was added in one portion, and the resulting yellow suspension was stirred at 50 C. for 2 hours during which time a white suspension was formed. With the aid of toluene, the aqueous acetic acid solvent was removed under reduced pressure (45 C./100-50 mbar). The white residue was briefly digested in 25 ml tert. butyl methyl ether (TBME) at 40 C. then at ambient temperature for 30 min. The product was filtered, washed with TBME and dried for 2 hours at 45 C./25 mbar: 1.17 g (85%) biege crystals (GLC 98 area %, as trimethylsilylester). 1H-NMR: (400 MHz, D6 DMSO): ?=2.54 (s, 3H), 7.59 (dd, 1H), 7.70 (s, 1H), 8.60 (dd, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 20℃; for 1h; | The reaction procedure was performed as according to iii) on a 2 mmol scale. After purging with argon, 1.1 ml 37% aqueous HCl (2 eq.) was added in one portion, and the suspension was stirred at ambient temperature for 1 hour. The solvent was removed with the aid of toluene under reduced pressure (45 C./80-20 mbar). The residue was briefly digested in 5 ml THF at 50 C. then at ambient temperature for 30 min. The product was filtered, washed with THF and dried for 1 hour at 45 C./20 mbar: 0.33 g (94%) pink crystals (HPLC 88 area %, GLC 98 area % as trimethylsilylester). 1H-NMR: (400 MHz, D6 DMSO): delta=2.77 (s, 3H), 8.03 (dd, 1H), 8017 (s, 1H), 8.83 (dd, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; at 20℃; for 1h; | The ozonolysis procedure was performed as according to i) in the presence of 1 eq. 30% aqueous H2O2 on a 2 mmol scale. After purging with argon, 0.12 ml concentrated H2SO4 (2.1 mmol) was added in one portion, and the yellow suspension was stirred at ambient temperature for 1 hour. The solvent was removed with the aid of toluene under reduced pressure (45 C./80-20 mbar). The residue was briefly digested in 5 ml THF at 50 C. then at ambient temperature for 30 min. The product was filtered, washed with THF and dried for 1 hour at 45 C./20 mbar: 0.43 g (92%) pale yellow crystals (HPLC 82 area %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With thionyl chloride; In methanol; water; | (b) Methyl 2-methylisonicotinate To an ice-cooled suspension of 1.32 g (9.62 mmol) of 2-methylisonicotinic acid in 20 mL of MeOH was added 1.47 mL (20.2 mmol) of thionyl chloride. The ice-bath was removed and the reaction was stirred at rt. After 22 h, the MeOH was evaporated and the residue was taken up in H2 O. The aqueous mixture was neutralized with saturated NaHCO3, then extracted with Et2 O. The organic extracts were washed with saturated NaCl, dried over MgSO4, then filtered through a bed of celite. Evaporation of solvent in vacuo afforded the title compound as a yellow liquid (0.89 g, 61%): 1 H NMR (CDCl3): d 8.66 (d, 1H); 7.72 (s, 1H); 7.64 (d, 1H); 3.98 (s, 3H); 2.64 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PPA; In water; | EXAMPLE 4 Preparation of 2-(2-methylpyridin-4-yl)benzimidazole 3.4 g. of o-phenylenediamine, 4.4 g. of <strong>[4021-11-8]2-methylisonicotinic acid</strong> and 30 g. of polyphosphoric acid were heated at 190-200 C. under nitrogen gas current for 4 hours with stirring. The reaction mixture was diluted with 500 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate to give 5.5 g. of colorless needles of the product (82% of theory). M.P. 205-206 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 2-methyl-isonicotinic acid (5.0 g, 36.40 mmol) in methanol (100 ml_), H2SO4 (2 ml_) is added. The mixture is refluxed for 72 h before a solution of ammonium peroxydisulfate (16.64 g, 72.9 mmol) in water (15 ml_) is added. The mixture boils vigorously. Stirring is continued at 65C for 24 h before another portion of ammonium peroxydisulfate is added. Stirring is continued at 65C for 24 h. About 2/3 of the solvent is evaporated, the remaining solution is neutralised with 1 N aq. NaOH and extracted five times with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated to give 2-hydroxymethyl-6-methyl- isonicotinic acid methyl ester (3.71 g) as a yellow solid; LC-MS: tR = 0.44 min, [M+1]+ = 182.05. | ||
A suspension of 2-methyl-isoniconic acid (400 mg, 2.92 mmol) in methanol (50 ml_) and H2SO4 (0.5 ml_) is refluxed for 24 h. To the clear solution a solution of ammonium peroxidilsulfate ((NH4J2S2Os; 1 -33 g, 5.83 mmol) in water (3 ml_) is added and refluxing is continued for 1 h. Another portion of ammonium peroxidilsulfate ((NH4J2S2O8; 1.33 g, 5.83 mmol) in water (3 ml_) is added and refluxing is continued for 3 h before a third portion of ammonium peroxidilsulfate ((NH4)2S2Os; 0.65 g, 2.91 mmol) in water (1.5 ml_) is added. Refluxing is continued for 2 h, the mixture is cooled to rt and the methanol is removed under reduced pressure. The remaining mixture is diluted with sat. aq. NaHCO3-solution (100 ml_), extracted with EA (3x150 ml_) and washed with sat. aq. NaHCO3-solution (100 ml_). The combined org. extracts are dried over MgSO4, filtered, concentrated and briefly dried under HV to give 2-hydroxymethyl-6-methyl-isonicotinic acid methyl ester (400 mg) as a pale yellow solid; LC-MS: tR = 0.44 min, [M+1]+ = 182.01 ; 1H NMR (CDCI3): £2.65 (s, 3 H), 3.69 (t, J = 4.5 Hz, 1 H), 3.97 (s, 3 H), 4.81 (d, J = 4.5 Hz, 2 H), 7.63 (s, 1 H), 7.64 (s, 1 H). | ||
a) To a solution of 2-methyl-isonicotinic acid (5.0 g, 36.40 mmol) in methanol (100 mL), H2SO4 (2 mL) is added. The mixture is refluxed for 72 h before a solution of ammonium peroxydisulfate (16.64 g, 72.9 mmol) in water (15 mL) is added. The mixture boils vigorously. Stirring is continued at 65 C. for 24 h before another portion of ammonium peroxydisulfate is added. Stirring is continued at 65 C. for 24 h. About 2/3 of the solvent is evaporated, the remaining solution is neutralised with 1 N aq. NaOH and extracted five times with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated to give 2-hydroxymethyl-6-methyl-isonicotinic acid methyl ester (3.71 g) as a yellow solid; LC-MS: tR=0.44 min, [M+1]+=182.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Example 48Preparation of allyl 2-methylpyridine-4-carboxylate 2-Methylpyridine-4-carboxylic acid (24 g, 175 mmol), was added to a flask containing 100 mL SOCl2. DMF (0.1 mL) was added and the reaction allowed to stir at room temperature for 1 h. Then the reaction was heated to 80 C. for an additional hour. Excess SOCl2 was removed under vacuum. To ensure complete removal of SOCl2, dry toluene (ca 20 mL) was added (2×) and subsequently removed under high vacuum.The resultant black solid was dissolved in dry CH2Cl2 (300 mL) and chilled to -78 C. Then allyl alcohol (30.5 g, 36 mL, 525 mmol) and Et3N (53 g, 73 mL, 525 mmol) were added. The reaction was then allowed to warm to room temperature over a 2 h period. The reaction was worked up by pouring into aq Na2CO3, separating the layers, washing the organic layer with water. The organic layer was subsequently dried over Na2SO4, concentrated under reduced pressure, and the remaining product distilled under high vacuum (bp=95 C. at 0.2 mm) to produce 22 g product (71% yield).1H-NMR (400 MHz, CDCl3): 2.64 (s, 3H), 4.84 (d, 2H, J=4.47 Hz), 5.31-5.45 (ABq, 2H, J=14.46 Hz, J=8.44 Hz), 6.0-6.07 (m, 1H), 7.66 (dd, 1H, J=4.0 Hz, J=0.5 Hz), 7.73 (s, 1H), 8.65 (d, 1H, J=5.11 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Example 24(4-cyclobutylpiperazin-1-yl)(7-(2-methylisonicotinoyl)-7-azaspiro[3.5]nonan-2-yl)methanone HBTU (152 mg, 0.40 mmol) and Intermediate 7 (117 mg, 0.40 mmol) were added to a solution of <strong>[4021-11-8]2-methylisonicotinic acid</strong> (55.1 mg, 40 mmol) and DIEA (0.210 mL, 1.20 mmol) in DMF (10 mL). The reaction mixture was stirred overnight and the solvent was concentrated. The crude material was purified on preparative HPLC MS using the long high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 15 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 25 min. run) on XBridge Prep C18 OBD, 30×150 mm, 5 mum, Waters reverse phase column to provide title compound (70.9 mg, 43.0%) as a solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.34-1.44 (m, 1H) 1.44-1.52 (m, 1H) 1.53-1.58 (m, 1H) 1.59-1.71 (m, 3H) 1.78 (quintet, J=8.89 Hz, 2H) 1.86-2.06 (m, 6H) 2.17 (br. s., 4H) 2.48-2.51 (m, 3H) 2.60-2.75 (m, 1H) 3.03-3.13 (m, 1H) 3.13-3.21 (m, 1H) 3.23-3.32 (m, 3H) 3.42 (br. s., 2H) 3.46-3.52 (m, 1H) 3.58 (d, J=5.08 Hz, 1H) 7.14 (t, J=5.47 Hz, 1H) 7.21 (d, J=6.64 Hz, 1H) 8.51 (t, J=4.10 Hz, 1H); HRMS (ESI-TOF) m/z calcd for C24H35N4O2 411.27545 [M+H]+, found 411.27426. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.8% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 18h; | Example 34(4-isopropylpiperazin-1-yl)(7-(2-methylisonicotinoyl)-7-azaspiro[3.5]nonan-2-yl)methanone HBTU (204 mg, 0.54 mmol) and Intermediate 9 (100 mg, 0.36 mmol) were added to a solution of <strong>[4021-11-8]2-methylisonicotinic acid</strong> (73.6 mg, 0.54 mmol) and DIEA (0.125 mL, 0.72 mmol) in DMF (10 mL). The reaction mixture was stirred for 18 h and the solvent was concentrated. The product was purified on preparative reverse-phase HPLC using a high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 15 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 25 min. run) on XBridge Prep C18 OBD, 30×150 mm, 5 mum, Waters reverse phase column to provide title compound (49.7 mg, 34.8%) as a solid. 1H NMR (400 MHz, CDCl3) delta ppm 1.04 (d, J=6.64 Hz, 6H) 1.52 (br. s., 1H) 1.59 (br. s., 1H) 1.67 (br. s., 1H) 1.76 (br. s., 1H) 1.97-2.12 (m, 2H) 2.12-2.27 (m, 2H) 2.47 (br. s., 4H) 2.59 (s, 3H) 2.70 (dt, J=12.89, 6.45 Hz, 1H) 3.13-3.31 (m, 3H) 3.35 (br. s., 2H) 3.62 (br. s., 3H) 3.71 (br. s., 1H) 7.04 (br. s., 1H) 7.13 (d, J=5.08 Hz, 1H) 8.55 (d, J=3.91 Hz, 1H); HRMS (ESI-TOF) m/z calcd for C23H35N4O2 399.27545 [M+H]+, found 399.27528. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.56% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Example 43(4-cyclobutyl-1,4-diazepan-1-yl)(7-(2-methylisonicotinoyl)-7-azaspiro[3.5]nonan-2-yl)methanone HBTU (140 mg, 0.37 mmol) and Intermediate 11 (75 mg, 0.25 mmol) were added to a solution of <strong>[4021-11-8]2-methylisonicotinic acid</strong> (50.5 mg, 0.37 mmol) and DIEA (0.086 mL, 0.49 mmol) in DMF (10 mL). The reaction mixture was stirred overnight and the solvent was concentrated. The crude material was purified on preparative HPLC MS using the long high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 15 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 25 min. run) on XBridge Prep C18 OBD, 30×150 mm, 5 mum, Waters reverse phase column to provide title compound (25.6 mg, 24.56%) as a solid. 1H NMR (400 MHz, CDCl3) delta ppm 1.52 (br. s., 1H) 1.55-1.72 (m, 3H) 1.72-1.93 (m, 6H) 1.94-2.11 (m, 4H) 2.11-2.27 (m, 2H) 2.33-2.44 (m, 2H) 2.47 (br. s., 2H) 2.58 (s, 3H) 2.84 (quintet, J=7.62 Hz, 1H) 3.20 (d, J=4.69 Hz, 2H) 3.25 (d, J=8.98 Hz, 1H) 3.41 (d, J=5.47 Hz, 2H) 3.62 (br. s., 3H) 3.71 (br. s., 1H) 7.04 (br. s., 1H) 7.12 (d, J=4.69 Hz, 1H) 8.54 (d, J=4.69 Hz, 1H); HRMS (ESI-TOF) m/z calcd for C25H37N4O2 425.29110 [M+H]+, found 425.29164. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 18h; | Example 53(4-isopropyl-1,4-diazepan-1-yl)(7-(2-methylisonicotinoyl)-7-azaspiro[3.5]nonan-2-yl)methanone HBTU (233 mg, 0.61 mmol) and Intermediate 13 (120 mg, 0.41 mmol) were added to a solution of <strong>[4021-11-8]2-methylisonicotinic acid</strong> (84 mg, 0.61 mmol) and DIEA (0.143 mL, 0.82 mmol) in DMF (10 mL). The reaction mixture was stirred for 18 h and the solvent was concentrated. The product was purified on preparative reverse-phase HPLC using a high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 15 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 25 min. run) on XBridge Prep C18 OBD, 30×150 mm, 5 mum, Waters reverse phase column to provide title compound (95 mg, 56.0%) as a solid. 1H NMR (400 MHz, CDCl3) delta ppm 0.99 (dd, J=6.64, 1.56 Hz, 6H) 1.53 (br. s., 1H) 1.59 (br. s., 1H) 1.68 (br. s., 2H) 1.72-1.86 (m, 3H) 1.97-2.12 (m, 2H) 2.12-2.28 (m, 2H) 2.51-2.61 (m, 4H) 2.61-2.70 (m, 2H) 2.90 (dt, J=12.99, 6.59 Hz, 1H) 3.15-3.24 (m, 2H) 3.24-3.32 (m, 1H) 3.33-3.45 (m, 2H) 3.55-3.67 (m, 3H) 3.67-3.76 (m, 1H) 6.99-7.08 (m, 1H) 7.10-7.16 (m, 1H) 8.55 (d, J=5.08 Hz, 1H); HRMS (ESI-TOF) m/z calcd for C24H37N4O2 413.29110 [M+H]+, found 413.29118. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 4h; | Example 57(4-cyclobutyl-6,6-dimethyl-1,4-diazepan-1-yl)(7-(2-methylisonicotinoyl)-7-azaspiro[3.5]nonan-2-yl)methanone HBTU (200 mg, 0.53 mmol) and Intermediate 16 (100 mg, 0.30 mmol) were added to a solution of <strong>[4021-11-8]2-methylisonicotinic acid</strong> (72.4 mg, 0.53 mmol) and DIEA (0.108 mL, 0.62 mmol) in DMF (15 mL). The reaction mixture was stirred for 4 h and the solvent was concentrated. The product was purified on preparative reverse-phase HPLC using a high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 15 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 25 min. run) on XBridge Prep C18 OBD, 30×150 mm, 5 mum, Waters reverse phase column to provide title compound (57.0 mg, 42.0%) as a solid. 1H NMR (400 MHz, CDCl3) delta ppm 0.92 (br. s., 6H) 1.50-1.62 (m, 3H) 1.62-1.84 (m, 6H) 1.91-2.12 (m, 6H) 2.12-2.28 (m, 2H) 2.45 (br. s., 2H) 2.59 (s, 3H) 2.89 (br. s., 1H) 3.08-3.23 (m, 2H) 3.24-3.30 (m, 1H) 3.30-3.49 (m, 3H) 3.51-3.67 (m, 1H) 3.71 (br. s., 1H) 6.98-7.09 (m, 1H) 7.12 (d, J=5.47 Hz, 1H) 8.55 (d, J=5.08 Hz, 1H); HRMS (ESI-TOF) m/z calcd for C27H41N4O2 453.32240 [M+H]+, found 453.32244. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; | N-(1-Cyanoethyl)isonicotinamide (22B). To a mixture of<strong>[4021-11-8]2-methylisonicotinic acid</strong> (2.00 g, 15 mmol) and 2-aminopropanamide (3.7 g, 29 mmol) in pyridine (15 ml, 15 mmol) was added Nl -((ethylimino)methylene)-N3,N3-dimethylpropane- 1,3-diamine hydrochloride (5.6 g, 29 mmol). The resulting mixture was allowed to stir at rt overnight. The mixture was concentrated, to the residue was added 10% methanol/DCM (80 mL). The white precipitate was collected and the residue was purified by CombiFlash using 0-10% methanol/DCM as the eluent to give 2.14 g of N-(l-cyanoethyl)isonicotinamide 22B. LCMS (ES+) m/z 208. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | Steps 2 and 3 were conducted in close analogy to the method of Gibson et al., J. Org. Chem. 2003, 67, 9354. 1,1'-Carbonyldiimidazole (12.35 g) was added to a solution of 2-methylpyridine-4-carboxylic acid (9.95 g, [CAS Reg. No. 4021-11-8]) in DMF (500 mL). The mixture was stirred for 1.5 hours at 50 C. The reaction mixture was cooled to -10 C. in an ice/methanol bath and (2-chloro-4-methoxy-phenyl)-acetic acid methyl ester (15.57 g) (obtained in Example 93, step 1) was added to the light brown solution followed by addition of sodium hydride (50% in mineral oil, 11.59 g) in small portions over 30 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; N,N-dimethyl-formamide; at 80℃; for 4h; | To a solution of 2-methyl-isonicotinic acid (100 mg) and thionyl chloride (3.0 ml) was added DMF (0.05 ml) and stirring was continued at 80 C for 4 h. The mixture was evaporated, the residue dissolevd in dichloromethane (5 ml), then 3,3-dimethyl-l-oxetan-3-yl-2-oxo-2,3- dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxylic acid hydrazide (180 mg) was added at 22 C followed by triethylamine (0.2 ml) and stirring was continued 12 h. The mixture was partitioned between aqueous sodium hydrogencarbonate and dichloromethane, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, dichloromethane/MeOH 99: 1)) to give the title compound (100 mg, 35%) as a brown solid. MS (ESI, m/z): 396.0 [(M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃; | To a suspension of 2-methyl-isonicotinic acid (45, 2,74 g, 20 mmol) and pcntafluorophenol (46, 3.7 g, 20 mmol) in 100 mL of anhydrous tetrahydrofuran, N,N'-diisopropylcarbodiimide (3, 1 niL, 20 mmol) was added. The mixture was stirred at room temperature overnight, then filtered through a pad of Celite. The filtrate was collected and used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 25℃;Inert atmosphere; | Intermediate 26cis-2-Methyl-pyrimidine-4-carboxylic acid (9,9-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl)-amide Intermediate 26 was prepared via the process of Scheme 13, supra, as follows:Step 1cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(2,4-dimethoxy-benzyl)-9,9-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide To a solution of 2-methylpyridine-4-carboxylic acid (171 mg, 1.24 mmol) in CH2Cl2 (15 mL) was added EDCI (263 mg, 1.69 mmol) and HOBT (152 mg, 1.13 mmol) at 0 C., followed by the addition of cis-9-amino-2-(2,4-dimethoxy-benzyl)-7,7-difluoro-2-aza-spiro[4.5]decan-1-one (400 mg, 1.13 mmol) The reaction mixture was stirred at rt overnight and then diluted with CH2Cl2 (30 mL). The organic layer was washed with saturated aqueous NaHCO3 and brine and concentrated under reduced pressure. The residue was purified by CombiFlash system (12 g silica gel cartridge; gradient: 0 to 2% MeOH (2N NH3) in CH2Cl2 over 10 min) to give 0.4 g (70%) of the title compound, cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(2,4-dimethoxy-benzyl)-9,9-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide. 1H NMR (400 MHz, CDCl3): delta8.89 (d, J=5.0 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.90 (d, J=5.1 Hz, 1 H), 7.10 (d, J=8.7 Hz, 1H), 6.48-6.43 (m, 2H), 4.45 (s, 2H), 4.44-4.34 (m, 1H), 3.82 (s, 3H), 2.81 (s, 3H), 3.25-3.20 (m, 2H), 2.80 (s, 3H), 2.66-2.53 (m, 1H), 2.37-1.72 (m, 7H). ESI-MS m/z: 475 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Example 78cis-N-[2-(3-Fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-2-methyl-isonicotinamide Example 78 was also prepared from intermediate 13 as follows:[2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-carbamic acid tert-butyl ester (0.010 g, 0.028 mmol, intermediate 13) was dissolved in methylene chloride (1.0 mL), 4M of hydrogen chloride in 1,4-dioxane (0.7 mL) was added. The mixture was stirred at rt overnight and then concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride (1.0 mL). Triethylamine (0.015 mL, 0.11 mmol) was added, followed by the addition of <strong>[4021-11-8]2-methylisonicotinic acid</strong> (0.005 g, 0.033 mmol) and BOP (0.015 g, 0.033 mmol). The mixture was stirred at rt for 4 hours and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient: acetonitrile in water, 24-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 28-56% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 48 mM of ammonium formate. Column: Inertsil C18, 30×50 mm, 5 um particle size (GL Sciences)) to afford 0.008 g (80%) of the title compound, cis-N-[2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-2-methyl-isonicotin-amide as a white solid. 1H NMR (400 MHz, CDCl3): delta 8.56 (d, J=5.0 Hz, 1H), 8.20 (bs, 1H), 7.60 (bs, 1H), 7.54-7.59 (m, 1H), 7.49-7.52 (m, 1H), 7.30-7.34 (m, 2H), 6.84-6.90 (m, 1H), 4.28-4.38 (m, 1H), 3.76-3.90 (m, 2H), 2.59 (s, 3H), 2.14-2.23 (m, 1H), 1.82-2.12 (m, 6H), 1.48-1.64 (m, 3H). ESI-MS m/z: 382 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a stirred suspension of <strong>[4021-11-8]2-methylisonicotinic acid</strong> (0.63 g, 4.9 mmol) in dioxane (10 ml) the title compound of Preparation 1 (0.73 g g, 4.9 mmol) was added. To the suspension thus obtained a solution of POCl3 (0.90 ml, 9.9 mmol) in dioxane (3 ml) was added dropwise. The mixture was stirred at 80C for 3.5h. The upper layer of the mixture obtained was poured and water was added to the lower layer. To the aqueos solution thus obtained a solution of potassium carbonate was added to reach pH 7-8 and it was extracted with dichloromethane. The organic phase was washed with brine, dried and concentrated in vacuo. The residue obtained was treated with isopropyl ether, filtered, and dried to yield 0.61g (50%) of the title compound. LRMS: m/z 249 (M+1)+ Retention time: 4.39 min (method B) 1 H NMR (200 MHz, CHLOROFORM-d) delta ppm 0.96 (q, J=6.77 Hz, 3 H) 1.32 - 1.56 (m, 2 H) 1.62 - 1.86 (m, 2 H) 2.62 (s, 3 H) 3.40 (t, J=7.03 Hz, 2 H) 6.18 (s, 1 H) 7.48 (d, J=5.08 Hz, 1 H) 7.49 - 7.59 (m, 1 H) 8.55 (d, J=5.08 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water;pH 1 - 2; | To a stirred suspension of 2-methylisonicotinic acid (a triethylamine salt form) (0.68 g, 4.96 mmol) a 2N aqueous solution of HCl was added to reach acid pH 1-2. The solution obtained was extracted with ethylacetate. The expected compound was not detected in the organic phase. The aqueous phase was concentrated in vacuo. The residue obtained was suspended in ethanol. It was concentrated in vacuo to yield 0.63 g of the acid form of the 2-methylisonicotinic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A mixture of 11 (100 mg, 0.24 mmol), an acid (0.72 mmol), EDCI (125 mg, 0.78 mmol), HOBt (88 mg, 0.78 mmol), TEA (0.167 mL, 1.2 mmol) and DMF (4 mL) was stirred at ambient temperature under N2 protection for 24 h, the reaction was monitored by TLC (CH2Cl2:MeOH = 5:1), upon the completion of the coupling reaction, MeOH (5 mL), and K2CO3 (199 mg, 1.44 mmol) were added to the mixture and stirred at ambient temperature overnight. The mixture was then filtered through celite. The filtrate was concentrated to remove DMF and methanol. The residue was partitioned between CH2Cl2 (50 mL) and H2O (50 mL). The organic layer was separated and washed with H2O (50 mL x 3), dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was then purified by column chromatography (Silica Gel 15 g), eluented with CH2Cl2 (150 mL), CH2Cl2/MeOH (80:1, 160 mL), CH2Cl2/MeOH (60:1, 180 mL), CH2Cl2/MeOH (40:1, 160 mL),CH2Cl2/MeOH (20:1, 160 mL), CH2Cl2/MeOH (10:1, 200 mL) successively to afford the corresponding target compound as free base. Upon confirmation by 1H NMR and 13C NMR, the free base was then transformed into hydrochloride salt by soluting in MeOH (0.1 mL), adding HCl methanol solution (1.25 M, 0.3 mL) and stirred at ambient temperature for 30 min. Diethyl ether (10 mL) was then added and the precipitate formed was collected by filtration, dried in vacuum to give the target compound as hydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.8% | With N-ethyl-N,N-diisopropylamine;2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In tetrahydrofuran; ethyl acetate; at 20℃; for 22h;Reflux; | Example 80 2-Methyl-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)isonicotinamide A mixture of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (156 mg, 0.766 mmol, 1 eq.), <strong>[4021-11-8]2-methylisonicotinic acid</strong> (116 mg, 0.842 mmol, 1.1 eq.), propylphosphonic anhydride in ethyl acetate 50% (1.13 ml, 1.91 mmol, 2.5 eq) and ethyldiisopropylamine (0.535 ml, 3.06 mmol, 4 eq) in tetrahydrofuran (10 ml) is stirred for 18 hours at roomtemperature. The solution is then refluxed for 4 hours. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium bicarbonate, with water, dried over magnesium sulfate and the solvent is removed in vacuo. Purification of the residue by chromatography on a 12 g RediSep silica cartridge using dichloromethane+5% methanol as eluent affords 2-methyl-N-(2-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-isonicotinamide (45 mg, 17.8%) as a yellow solid. MS: m/e=330.2 (M+H+) mp.: 255-7 C. |
A mixture of 2-phenylimidazo[l,2-a]pyrimidin-7-amine (156 mg, 0.766 mmol, 1 eq.), 2- methylisonicotinic acid (116 mg, 0.842 mmol, 1.1 eq.), propylphosphonic anhydride in ethyl acetate 50% (1.13 ml, 1.91 mmol, 2.5 eq) and ethyldiisopropylamine (0.535 ml, 3.06 mmol, 4 eq) in tetrahydrofuran (10 ml) is stirred for 18 hours at roomtemperature. The solution is then refluxed for 4 hours. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium bicarbonate, with water, dried over magnesium sulfate and the solvent is removed in vacuo. Purification of the residue by chromatography on a 12 g RediSep silica cartridge using dichloromethane + 5% methanol as eluent affords 2-methyl-N-(2 -phenyl- imidazo[ 1,2- a]pyrimidin-7-yl)-isonicotinamide (45 mg, 17.8%) as a yellow solid. MS: m/e = 330.2 (M+H+) mp.: 255-7C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a mixture of l-(7H-pyrrolo[2,3-JJpyrirmdm-4^ D2 (100 mg), 2-methyl-4-pyridinecarboxylic acid (63.1 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HO At (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 L, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E12 (72 mg), ¾ NMR (d<5-DMSO) delta 11.70 (1H, brs), 8.55 (2H, m), 8.17 (1H, s), 7.62 (1H, s), 7.53 (1H, d), 7.18 (1H, d), 6.60 (1H, d), 4.70 (2H, dt), 4.15 (1H, m), 3.35 (3H, s), 3.25 (2H, dt), 1.90 (2H, m), 1.53 (2H, m), MS(ES+) 337 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 2-methyl-4-pyridinecarboxylic acid (41 mg, 0.299mmol), EDC (86 mg, 0.448 mmol), HOBt (68.6 mg, 0.448 mmol) and DIPEA (0.130 mL, 0.747 mmol) in DCM (1 mL), prestirred for 10 minutes, was added l-(5-met yl-7H-pyrrolo[2,3-J]pyrimidiri-4-yl)-4- piperidinamine hydrochloride Dll (80 mg) and the mixture stirred at room temperature for 18 hours. The solvent was removed in vacuo and the mixture purified by MDAP to give the title compound E25 (37 mg), ¾ NMR (c¾-DMSO) 5 11.52 (1H, s), 8.59 (1H, d), 8.57 (1H, d), 8.22 (1H, s), 7.65 (1H, d), 7.56 (1H, d), 7.07 (1H, s), 4.11-3.99 (3H, m), 3.06 (2H, t), 2.53 (3H, s), 2.37 (3H, s), 1.94 (2H, d), 1.73 (2H, ddd), MS(ES+) 351 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Example 7: Preparation of benzyl 5-(4-fluorophenyl)sulfanyl-1 -(2- methylpyridine-4-carbonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate To a suspension of <strong>[4021-11-8]2-methylisonicotinic acid</strong> (596 mg, 4.35 mmol) indichloromethane (100 mL) are added Lambda/,/V-diisopropylethylamine (1 .15 mL, 6.72 mmol) and 2-(1 H-7-azabenzotriazol-1-yl)- 1 ,1 ,3, 3-tetramethyl uroniumhexafluorophosphate methanaminium (1.91 g, 5.02 mmol). The mixture was stirred at room temperature for 1 h, after which benzyl 5-(4- fluorophenylthio)spiro[indoline-3,4'-piperidine]-1 '-carboxylate (1 .51 g, 3.37 mmol) is added. The reaction mixture is stirred at room temperature. After 18 h, additional 2-(1 H-7-azabenzotriazol-1 -yl)-1 ,1 ,3, 3-tetramethyl uroniumhexafluorophosphate methanaminium (0.75 equiv) is added. After 2 days reaction time, the mixture is diluted with dichloromethane (300 mL), washed with saturated aqueous sodium hydrogen carbonate (100 mL) and brine (100 mL). The organic layer is dried over sodium sulphate, filtered and is concentrated under reduced pressure to give a brown oil. Purification of the crude by column chromatography on silica gel (heptane / ethyl acetate 40 to 100% as eluent) affords the desired product (1.09 g, 1.92 mmol, 57% yield) (HPLC-MS Method 2: retention time: 2.284 min, m/z 568.1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.4% | To a stirred solution of 2-methylisonicotinic acid (266b) (17.8 g, 129.798 mrnol) in N,N-dimethylformamide (180 mL) was added N,N-diisopropylethylamine (67.105 g, 519.192 mmol) and I -ethyl-3-(3-dirnethylaminopropyl)carbodiimide hydrochloride (EDC I.40.299 g, 259.596 mrnol) and hydroxybenzotriazole (HOBt, 39.753 g, 259.596 mmol) at room temperature. The resulting reaction mixture was stirred for 0.5 h at room temperaturefollowed by the addition of N, 0 dimethyl hydroxyl amine hydrochloride (13.8 g, 141.479 mmol). The reaction mixture was stirred at room temperature for 1 2 Ii, quenched with water (500 mL), extracted with ethyl acetate (5 x 500 rnL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue obtained was purified bycolumn chromatography to afford N -methoxy-N ,2-dimethylisonicotinamide (266c) (23 g,98.4% yield) as a reddish thick solid; ?H NMR (CDC1.) 6 8.29-8.27 (d, I H), 7.08 (s, I H),7.02-7.01 (d, IH), 3.27 (s, 3H), 3.07 (s, 3H), 2.32 (s, 3H); MS (ES+) 181.1 (M+1). | |
98.4% | Step-2: Preparation of N-methoxy-N,2-dimethylisonicotinamide (46c) To a stirred solution of 2-methylisonicotinic acid (46b) (17.8 g, 129.798 mmol) in N,N-dimethylformamide (180 mL) was added N,N-diisopropylethylamine (67.105 gm, 519.192 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 40.299 g, 259.596 mmol) and hydroxybenzotriazole (HOBt, 39.753 g, 259.596 mmol) at room temperature. The resulting reaction mixture was stirred for 0.5 h at room temperature followed by the addition of N, O dimethyl hydroxyl amine hydrochloride (13.8 g, 141,479 mmol). The reaction mixture was stirred at room temperature for 12 h, quenched with water (500 mL), extracted with ethyl acetate (5 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to afford N-methoxy-N,2-dimethylisonicotinamide (46c) (23 g, 98.4% yield) as a reddish thick solid; 1H MR (CDC13) delta 8.29-8.27 (s, 1H), 7.08-7.01 (m, 2H), 3.27 (s, 3H), 3.07 (s, 3H), 2.32 (s, 3H); MS (ES+) 181.1 (M+l). | |
85% | N-((2,4-dimethylphenyl)(phenyl)methyl)-2-(2-(l -hydroxy- l-(2-methylpyridin-4- yl)ethyl)benzofuran-5-ya) N-methoxy-N2-dimethylisonicotinamideA mixture of 2-methylisonicotinic acid (582mg, 4.25mmol), EDCI (1.63g, 8.5mmol), HOBt (1.15g, 8.5mmol) and DIPEA (2.19g, 17mmol) in DMF (20 mL) was stirred at rt for 0.5 h. Then N O-dimethylhydroxylamine hydrochloride (456mg, 4.67mmol) was added. After the addition, the mixture was stirred at rt overnight. Then the reaction solution was washed with water (20 mL* 3) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether/EtOAc=l/l) to obtain title compound (648mg, yield: 85%) as pale yellow oil. LCMS-A024: 181.2 [M+H]+; Rt = 0.729 min. |
85% | (a) AT-rnethoxy-1M 2-dimethylisonicotinatrude: A mixture of 2-methylisonicotinie acid (582mg, 4.2sinmol), EDC1 (L63g, 8.5mmol), f-IOBt (L15g, 8.5mmol) and DIPEA (2.19g,7mmoi) in DMF (20 mL) was stirred at P for 0.5 h. Then ] 0-dimethyihydroxylamine hydrochloride (456mg, 4.67mmol) was added. After the addition, the mixture was stirred at rtovernight. Then the reaction solution was washed with water (20 mLx 3) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel eohirnn chromatography (petroleum ether/EtOAe=1/l) to obtain title compound (648mg, yield: 85%) as pale yellow oil. LCMS-A024: 181.2 [M+H] R = 0.729 mm. | |
79% | General procedure: Oxalyl chloride (1.85 mL, 21.88 mmol) was added to a suspensionof 6-methylpicolinic acid (2.50 g, 18.23 mmol) in DCM (75 mL,anhydrous) and DMF (1.3 mmol) at 20 C. The mixture was stirred at20 C for 1 h to give a colorless solution which was cooled to 0 C. N,ODimethylhydroxylaminehydrochloride (1.95 g, 20.1 mmol) andpyridine (3.25 mL, 40.11 mmol) were added sequentially and themixture was stirred at 20 C for 18 h, then partitioned between EtOAcand sat. aq. NaHCO3. Column chromatography with hexanes:EtOAc 1:1gave N-methoxy-N,6-dimethylpicolinamide as an oil (2.68 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99 mg | b) N-(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indol-6-yl)-2-methyl-isonicotinamide To a suspension of 2-methylisonicotinic acid (175 mg, 1.28 mmol) in dry toluene (12.8 ml) was added SOCl2 (167 mg, 103 mu, 1.4 mmol) and dry DMF (9.33 mg, 9.89 mu, 128 muetaiotaomicron) under an argon atmosphere. The mixture was heated under reflux for 2 hours and the solvent was evaporated under reduced pressure. The residue was suspended in dry dichloromethane (3.51 ml) and a suspension of <strong>[100510-65-4]6-amino-3,3-dimethylindolin-2-one</strong> (0.15 g, 851 muiotaetaomicron) and DIPEA (330 mg, 446 mu, 2.55 mmol) in dry dichloromethane (5ml) was added portionwise. The suspension was stirred under an argon atmosphere at room temperature for 16 hours, then diluted with dichloromethane, water and 1 M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1 M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/ methanol as eluent. The title compound was obtained as brown solid (99 mg). MS ESI (m z): 296.3 [(M+H)+]. 1H NMR (DMSO-D6, 400 MHz): (ppm) = 10.38 (s, 2H), 8.64-8.62 (m, 1H), 7.71 (m, 1H), 7.64-7.62 (m, 1H), 7.49 (m, 1H), 7.31-7.23 (m, 2H), 2.57 (s, 3H), 1.24 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 0.5h; | Into a 50-mL round-bottom flask, was placed a solution of 2-methylpyridine-4-carboxylic acid (548 mg, 4.00 mmol, 1.00 equiv), <strong>[41373-39-1](2S)-piperidin-2-ylmethanol</strong> (460 mg, 3.99 mmol, 1.00 equiv), DIEA (1.29 g, 9.98 mmol, 2.50 equiv) and HATU (1.67 g, 4.39 mmol, 1.10 equiv) in dichloromethane (20 mL). The resulted solution was stirred for 30 min at room temperature. After concentration, the residue was dissolved with 200 mL of EA. Then it was washed with 3 x 20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue. The crude was purified by silica gel column eluted with dichloromethane/methanol (10:1). This resulted in 426 mg (46percent, 97percent ee) of [(2S)-l-[(2-methylpyridin-4-yl)carbonyl]- piperidin-2-yl]methanol as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.69% | 1) To a 100 mL flask was added 0.685 g of 2-methyl-4-picolinic acid,0.675g HOBT,Treated with 20 mL of ethyl acetate,0 C for 0.5 h. 1.03 g of DCC was added,0 C for 2.5 h.1.42 g of dehydroabietylamine was dissolved in 10 mL of ethyl acetate,The solution was added dropwise to the reaction system,Room temperature reaction 8h.At last, Ice bath for half an hour,So that DCU fully precipitated.2) filter to remove DCU,The filtrate was diluted to 200 mL,Respectively, with 20 mL of 5% NaHCO3,20mL 10% citric acid washed 2-3 times,And finally washed with 20 mL of saturated brine.The ethyl acetate layer was dried over anhydrous sodium sulfate for 2 h.3) filter,The filtrate was distilled off ethyl acetate,A white powder of 1.6098 g,The yield was 79.69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With selenium(IV) oxide; In 1,4-dioxane; at 110℃; for 24h; | 2-methyl-4-pyridinecarboxylic acid (5.0 g, 36.5 mmol),Selenium dioxide (10.1 g, 91.3 mmol) was added to 250 ml of dioxane, heated to 110 C., and reacted for 24 hours under magnetic stirring. The reaction was completed by TLC. The reaction solution was filtered while hot, and the solvent was evaporated under reduced pressure. The crude product was recrystallized from absolute ethanol and dried in vacuo to give 2-formyl-4-pyridinecarboxylic acid as a white solid in a yield of 72% and a purity of 98%. |
72% | With iodine; dimethyl sulfoxide; at 150℃; for 1h; | 2-Methylisonicotinic acid (10.0 g, 73.0 mmol), iodine (20.3 g, 80.3 mmol) was added to 120 mL of dimethyl sulfoxide, and the mixture was warmed to 150 C, and the mixture was stirred for 1 hour with magnetic stirring. The reaction was completed by TLC, and the reaction solution was cooled to room temperature and poured to 400 mL.In distilled water, the solid was precipitated, suction filtered, and washed with petroleum ether. The obtained crude product was recrystallized from anhydrous ethanol and dried in vacuo to give 2-formyl isoniconic acid, yield 72%, purity 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a solution of 2-methylpyridine-4-carboxylic acid (1.95 g, 14.2 mmol, 1.00 equiv) in DMF (20 mL) were added DIEA (5.5 g, 42.6 mmol, 3.00 equiv) and HATU (8.1 g, 21.3 mmol, 1.50 equiv). After stirring at r.t. for 15 min, 5-bromo-2,3-dihydro-1H-inden-1- amine (3.0 g, 14.2 mmol, 1.00 equiv) was added and the solution was stirred for 3 h. The resulting solution was diluted with aqueous NH4Cl solution and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (EA/PE = 2/1) to afford 4 g (85%) of N- (5-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpyridine-4-carboxamide as a yellow solid. 3. |
Tags: 4021-11-8 synthesis path| 4021-11-8 SDS| 4021-11-8 COA| 4021-11-8 purity| 4021-11-8 application| 4021-11-8 NMR| 4021-11-8 COA| 4021-11-8 structure
[ 91940-84-0 ]
2-(tert-Butyl)isonicotinic acid
Similarity: 0.91
[ 91940-84-0 ]
2-(tert-Butyl)isonicotinic acid
Similarity: 0.91
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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 |
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