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CAS No. : | 70165-31-0 | MDL No. : | MFCD01318135 |
Formula : | C7H4N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WMHSQCDPPJRWIL-UHFFFAOYSA-N |
M.W : | 148.12 | Pubchem ID : | 2761108 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
20% | Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; |
To a solution of [6-CYANONICOTINIC] acid (12g, 0. [081MOL] ; see step (i) above) in THF at [0°C,] [ET3N] (12.4 mL, 0.0892 mol) was added followed by ethyl chloroformate (8.53 mL, 0.0892 mol). The reaction mixture was stirred for 15 min and [NABH4] (6.14 g, 0.162 mol) was added. Then the mixture was stirred at RT overnight, quenched with water and extracted with methylene chloride. The organic layer was concentrated and purified by column chromatography to yield 4g (20percent) of the alcohol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With chloro-trimethyl-silane; triethylamine In DMF (N,N-dimethyl-formamide) at 110℃; for 10 h; | To a solution of the nicotinic acid N-oxide (51 g, 0.37 mol) in 1.2 L [OF DMF, NACN] (54 g, 1.1 mol) was added, followed by triethylamine (255 mL, 1.83 mol) and TMSCI (185 mL). The reaction mixture was stirred at [110°C] for 10 h, filtered and the filtrate was concentrated. The residue was dissolved in 100 mL of 2N HCI and extracted with methylene chloride. The organic layers were combined, concentrated and recrystallised from water to yield 12 g (22percent) of the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With chloro-trimethyl-silane; triethylamine; In DMF (N,N-dimethyl-formamide); at 110℃; for 10h; | To a solution of the nicotinic acid N-oxide (51 g, 0.37 mol) in 1.2 L [OF DMF, NACN] (54 g, 1.1 mol) was added, followed by triethylamine (255 mL, 1.83 mol) and TMSCI (185 mL). The reaction mixture was stirred at [110C] for 10 h, filtered and the filtrate was concentrated. The residue was dissolved in 100 mL of 2N HCI and extracted with methylene chloride. The organic layers were combined, concentrated and recrystallised from water to yield 12 g (22%) of the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; for 18h; | Example 29a; N-(2-Amino-5-(thiophen-2-yl)phenyl)-4-carbamimidoylbenzamide (253); <n="146"/>Scheme 29; Step 1 : tert-Butyi 2-(6-cyanonicotinamido)-4-(thiophen-2-yl)phenylcarbamate (251); [0880] Following the same procedure as described in Example 1, step 6 (scheme 1), but substituting compound 7 for compound 250, and pyridine for triethyl amine and DMF, title compound 251 was obtained (41% yield).[0881] IH NMR (DMSO-d6) D (ppm): 10.22 (s, IH), 9.25 (d, J = 1.6 Hz, IH), 8.84 (s, IH), 8.53 (dd, J= 8.0, 2.4 Hz, IH), 8.24 (d, J=8.0 Hz, IH), 7.28 (dd, J=3.6, 1.2 Hz, 1 H), 7.75-7.71 (m, 2H), 7.54-7.50 (m, 2H), 7.43 (dd, J= 3.6, 1.2 Hz, IH), 7.11 (dd, J= 5.2, 3.6, IH), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 18 - 25℃; for 16h; | A mixture of N- (2-aminoethyl) -l-phenyl-3- (trifluoromethyl) -lH-pyrazole-4-carboxamide (1.00 g, 3.35 mmol), <strong>[70165-31-0]6-cyanonicotinic acid</strong> (0.55 g, 3.69 mmol), EDACetaC1 (0.84 g, 4.36 mmol), HOBt-H2O (0.67 g, 4.36 mmol) and CH3CN (20 mL) was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic layer was then dried and concentrated. The resulting solid was washed with EtOAc and <n="191"/>dried to give 6-cyano-N- (2- (l-phenyl-3- (trifluoromethyl) -IH- pyrazole-4-carboxamido) ethyl) nicotinamide (1.00 g, 70%) as a beige solid: 1H NMR (400MHz, CDCl3) delta 3.68-3.82 (4H, m) , 6.66 (IH, br) , 7.44 (IH, t, J=7.6 Hz), 7.53 (2H, t, J=7.6 Hz), 7.71 (2H, d, J=7.6 Hz), 7.79 (IH, d, J=8.0 Hz), 7.98 (IH, br) , 8.31 (IH, dd, J=2.4, 8.0 Hz), 8.47 (IH, s) , 9.16 (IH, d, J=2.4 Hz); m/z (APCI pos) 428.9 (25 %) (M+H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; isobutyl chloroformate; In DMF (N,N-dimethyl-formamide); at -20 - 20℃; | To a solution of 444mg (3. 0MMOL) 6-CYANO-NICOTINIC acid and 354mg (3.5mmol) N-methylmorpholine in 7ML DMF at-20C was added 450mg (3. 3MMOL) isobutyl chloroformate. The reaction mixture was warmed to 5C and 625mg (3. 0MMOL) mono-boc-ortho-phenylenediamine were added. The reaction mixture was warmed to rt overnight and then poured into 50ML 5% aqueous citric acid. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with bicarbonate and brine and dried over NA2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (petrol ether/ethyl acetate 2: 1) to yield 795mg (2. 35MMOL) {2-[(6-Cyano-pyridine-3-carbonyl)- AMINO]-PHENYL}-CARBAMIC acid t-butyl ester; mp. 183-184C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With chloroform; hydrogen;palladium on activated charcoal; In ethanol; under 2250.23 Torr; for 5h; | 6-Cyano-nicotinic acid (1 g, 6.7 mmol) is dissolved in ethanol (100 mL) and chloroform (2 ml_) andhydrogenated at 3 bar hydrogen pressure for 5 h using palladium on charcoal as catalyst. AfterNitration of the catalyst the product is isolated by evaporation of the solvent. Yield: 0.54 g (43 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
623 mg (84%) | With pyridine;N,N-dimethyl-formamide; In hexane; dichloromethane; ethyl acetate; tert-butyl alcohol; | A suspension of <strong>[70165-31-0]6-cyanonicotinic acid</strong> (535 mg, 3.6 mmol) in dichloromethane (8 mL) at 0 C. was treated with 2M oxalyl chloride (3.6 mL, 7.2 mmol, dichloromethane) and a catalytic amount of N,N-dimethylformamide. The reaction was then stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue dissolved in dichloromethane (10 mL). The resulting solution was treated with pyridine (2 mL) and tert-butanol (0.8 mL) and the reaction mixture stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (200 mL) and washed sequentially with saturated sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Silica gel chromatography, using a gradient of 5% to 10% ethyl acetate in hexane, afforded 623 mg (84%) of 5-tert-butoxycarbonyl-2-cyano-pyridine, as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 58 6-Cyano-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide The title compound was prepared from <strong>[70165-31-0]6-cyanonicotinic acid</strong> and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.22 (s, 1H), 9.31-9.30 (m, 1H), 8.81 (d, J=9.3, 1H), 8.42-8.38 (m, 1H), 7.90-7.87 (m, 1H), 7.76 (d, J=3.0, 1H), 7.34-7.30 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | EXAMPLE 274A methyl 6-cyanonicotinate A solution of <strong>[70165-31-0]6-cyanonicotinic acid</strong> (5 g) in methanol (100 mL) was titrated to a yellow endpoint with 2M trimethylsilyldiazomethane in hexanes and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3:1/hexanes:ethyl acetate to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; | Example 5 Methyl 6-cyanopyridine-3-carboxylate, a Compound of Formula 1 in which C Comprises 3-methoxycarbonylpyridin-2-yl and R8 is --CN Potassium carbonate (6.1 g, 43.9 mmol) and methyl iodide (21 mL, 338 mmol) were added sequentially to a solution comprising <strong>[70165-31-0]6-cyanopyridine-3-carboxylic acid</strong> (5 g, 33.8 mmol) in acetone (300 mL). The mixture was heated at reflux for 15 hours and concentrated under reduced pressure. The residue was partioned between ether and saturated sodium bicarbonate. The organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to provide methyl 6-cyanopyridine-3-carboxylate (4.4 g, 27.1 mmol) as a tan solid. 1 H-NMR (300 Mhz, DMSO-d6): 3.9 (s, 3H), 8.2 (d, 1H, J=7.5 Hz), 8.5 (d, 1H, J=7.5 Hz), 9.2 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; water; | To a suspension of nicotinic acid N-oxide (0.7 g, 5 mmol) in 10 ml of dichloromethane is added trimethylsilylcyanide (0.55 g, 5,5 mmol), and the solution is stirred for 5 min. Then dimethylcarbamoyl chloride (0.54 g, 5 mmol) is added, and stirring is continued for 5 days under reflux. After cooling, the solution is evaporated to dryness under reduced pressure, and the residue is dissolved in 50 ml of hot water. After standing overnight, the white precipitate is filtered off and is purified by column chromatography (ethyl acetate/ethanol 1:1) to yield 5-carboxy-2-cyano-pyridine, m.p. 194-195 C., Rf =0.54. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In methanol; water; | EXAMPLE 9 5-Carboxy-2-(N-ethylamidino)-pyridine hydrochloride Sodium (12 mmol) is added to a flask containing 30 ml of methanol. After the sodium has dissolved, 5 mmol of <strong>[70165-31-0]5-carboxy-2-cyano-pyridine</strong> is added. The mixture is heated at 50 for 6 h. Then, 10 mmol of a solution of ethylamine hydrochloride in 10 ml of methanol is added dropwise and the temperature raised to 80 for 17 h. After cooling, the solution is evaporated to dryness, the residue dissolved in 30 ml of water and the pH adjusted to 3. The solid is collected and dried and corresponds to the title compound, m.p. >290. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; | EXAMPLE 10 1-(5-Carboxy-2-pyridinyl)-1-butanone To a stirred solution of propyl magnesium bromide (67.5 mmol) in 80 ml of ether, <strong>[70165-31-0]5-carboxy-2-cyano-pyridine</strong> (30.7 mmol), dissolved in 100 ml of tetrahydrofuran, is added dropwise. The mixture is refluxed for 20 h. After cooling, 10 ml of water and 5 ml of 5N H2 SO4 are added. Extraction of the aqueous phase with ether and evaporation of the solvent yield 3.5 g of crude product. Purification by silica gel column chromatography (n-hexane: ethyl acetate: HCOOH 7:3:0.1) yields the title compound, m.p. 128-130. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; In N-methyl-acetamide; water; | EXAMPLE 5 5-Carboxy-2-(5-tetrazolyl)-pyridine Sodium azide (12.0 g, 0.18 mol) and anhydrous ammonium chloride (1.5 g) are added to a stirred solution of 5-carboxy-2-cyanopyridine (22.0 g, 0.15 mol) in dry dimethylformamide (375 ml). The reaction mixture is heated to 80 and held at this temperature for 24 h. After this time, a further portion of sodium azide 6.0 g, 0.09 mol) is added and heating continued for a further 24 h. The reaction mixture is then allowed to cool to ambient temperature and diluted with water (560 ml). This solution is acidified to pH 3 with 5N hydrochloric acid and, while a solid precipitates, stirred at this pH for 30 min. The product is filtered off and stirred in refluxing water (60 ml) for 15 min. It is then refiltered, washed with dichloromethane (5*20 ml) and dried in vacuo at 60 to yield the title compound as a light solid; m.p. 257-259. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; ethylenediamine; In methanol; water; | EXAMPLE 6 5-Carboxy-2-(4,5-dihydro-2-imidazolyl)-pyridine A solution of sodium methoxide is prepared by careful addition of sodium metal (13.6 g, 0.59 mol) to a flask containing methanol (500 ml) which is stirred. A solution of <strong>[70165-31-0]5-carboxy-2-cyano-pyridine</strong> (36.0 g, 0.24 mol) in methanol (200 ml) is added to the sodium methoxide and the mixture heated for 2 h at 50. After this time, freshly distilled ethylenediamine (28.8 g, 0.48 mol) and concentrated hydrochloric acid (64 ml) is added to the solution, which is then heated to 80 for 2.5 h. The reaction mixture is evaporated in vacuo to dryness. The residue is slurried in hot water (75 ml) for 15 min, filtered, washed with cold methanol (2*25 ml) and dried in vacuo at 60 to yield the title compound; m.p. 344-345. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In methanol; | EXAMPLE 8 Methyl 5-carboxy-pyridine-2-carboximidate Sodium (12 mmol) is added to a flask containing 20 ml of methanol. After the sodium has dissolved, 5 mmol of <strong>[70165-31-0]5-carboxy-2-cyano-pyridine</strong> is added. The mixture is heated at 50 for 6 h. After cooling, the reaction mixture is diluted with water and acidified (pH=5)with 2N HCl. The solid is collected and dried, and corresponds to the title compound, m.p. 284-286. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6-Cyano nicotinic acid (18 mg, 0.118 mmol), DIC (18.5 muL, 0.118 mmol), and DMAP (29mg, 0.236 mmol) were dissolved in DCM (ImI). The mixture was stirred for 10 min and then transferred to a solution of 4-[S-(3-bromophenyl)-sulfoxamino]-5- methylsulfanyl-thiophene-2-carbamic acid tert-butyl ester (29 mg, 0.059 mmol, as prepared in Example 24: step j) in THF. After 12 h at RT, another portion of 6-cyano nicotinic acid (37mg, 0.236 mmol) was activated with DIC (37 muL, 0.236 mmol) and DMAP (58 mg, 0.472 mmol) in DCM (2 mL) for 10 min and then transferred to the reaction mixture. The final mixture was stirred for another 48 h at RT. The reaction mixture was evaporated in vacuo and the residue was purified using preparative TLC (2 x 1000 mu, 1:1 EtOAc/Hexanes) to provide 10 mg 4-[S-(3-bromophenyl)-N-(6-cyano~3- rhoyridinecarboxamido)-sulfoxamino]-5-methylsulfanyl-thiophene-2-carbamic acid tert- butyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride; sodium; In ethanol; | EXAMPLE 12 5-Carboxy-pyridine-2-carboxamide oxime Sodium (18 mmol) is added to a flask containing 20 ml of ethanol. After the sodium has dissolved, 3.8 mmol of 5-carboxy-2-cyanopyridine and 18 mmol of hydroxylamine hydrochloride are added, and the solution is refluxed for 5 h. After cooling, the resulting precipitate is filtered off and recrystallized from water; m.p.>300. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In ethanol; chloroform; water; | EXAMPLE 1 5-Carboxy-2-(4,5-dihydro-2-thiazolyl)-pyridine Sodium (11 mmol) is added to a flask containing 75 ml of ethanol. As soon as the sodium has dissolved, 10 mmol of 5-carboxy-2-cyanopyridine and 11 mmol of 2-amino-ethanethiol are added and the solution is refluxed for 24 h. The solution is then diluted with 25 ml of water, made acidic (pH=5) with 2N HCl and evaporated. The residue is dissolved in 100 ml of hot chloroform, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. 234-235 C. The starting material is prepared as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In ethanol; ethyl acetate; | EXAMPLE 3 2-(2-Benzothiazolyl)-5-carboxy-pyridine Sodium (7.7 mmol) is added to a flask containing 70 ml of ethanol. As soon as the sodium has dissolved, 7 mmol of 5-carboxy-2-cyanopyridine and 8.4 mmol of 2-amino-thiophenol are added and the solution is refluxed for 24 h. The solid formed is filtered off, redissolved in ethanol and water, the solution is made acidic (pH=3) with 2N HCl and evaporated. The residue is dissolved in 100 ml of hot ethyl acetate, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. >300. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium; In methanol; ethanol; | EXAMPLE 4 5-Carboxy-2-(4,5-dihydro-2-oxazolyl)-pyridine Under a nitrogen atmosphere, sodium (12 mmol) is added to a flask containing 10 ml of anhydrous methanol. After the sodium has dissolved, a solution of <strong>[70165-31-0]5-carboxy-2-cyano-pyridine</strong> (5 mmol) in 5 ml of methanol is added dropwise. The mixture is heated at 50 for 1.5 h. The mixture is allowed to cool and a solution of ethanolamine (10 mmol) in a mixture of 5 ml methanol and 1.5 of concentrated HCl is added dropwise. After addition is complete, the reaction mixture is refluxed for 2 h. The solvent is evaporated, the residue dissolved in 45 ml of hot ethanol, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. 286-287. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With manganese dioxide; In chloroform; | EXAMPLE 99 In analogy to Example 11, 166 mg of methyl p-(6-amidino nicotinamidoacetyl)phenoxyacetate hydrochloride were obtained from 480 mg of methyl p-(6-cyanonicotinamidoacetyl)phenoxyacetate. The starting material was obtained by reaction of methyl p-[(RS)-2-(6-cyanonicotinamido)-1-hydroxyethyl]phenoxyacetate with manganese dioxide in chloroform, which in turn was produced by reaction of methyl 4-(2-amino-1-hydroxyethyl) phenoxyacetate hydrochloride (melting point 123-125 C.) with <strong>[70165-31-0]6-cyanonicotinic acid</strong> and ethyl chloroformate/4-ethylmorpholine (melting point 131-132 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethanol; water; | Step 1 Synthesis of 6-[imino(pyrrolidin-1-yl)methyl]nicotinic acid dihydrochloride 6-Cyanonicotinic acid (4.15 g, 28.0 mmol) was dissolved in anhydrous ethanol (3.2 ml) and 4N hydrochloric acid/1,4-dioxane (30 ml), and the mixture was stirred in a closed system at room temperature for two nights. The solvent was evaporated under reduced pressure, and the obtained residue was suspended in anhydrous ethanol (90 ml). Pyrrolidine (2.34 ml, 28.0 mmol) was added thereto, and the mixture was stirred at room temperature for 3 days. Pyrrolidine (3.51 ml, 42.0 mmol) was added again, and the mixture was stirred for 2.5 hrs. The solvent was evaporated under reduced pressure, and water and ethanol were added to the obtained residue. The precipitate was filtered off, ethanol was evaporated under reduced pressure, and the obtained aqueous solution was lyophilized to give the title compound without purification operation. yield 10.0 g (34.5 mmol) yield quantitative MS (ESI, m/z) 220 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | In a 50 mL round-bottom flask, FF.1 (0.949 g, 0. 641 mmole), 2-amino-1-phenylethanone (1.10 g, 0.00641 mole), and 1-hydroxybenzotriazole (0.866 g, 0.641 mmole) were dissolved in DMF (20 mL). The mixture was treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.474 g, 0.7691 mmole) and N,N-diisopropylethylamine (1.12 mL, 0.641 mmole). The yellow reaction mixture was allowed to stir at RT for 18 hr and then diluted with 200 mL of EtOAc. The organic layer was washed 2×50 mL of water. FF.2 precipitated as a white solid which was collected by filtration. The filtrate was washed with 50 mL brine, dried over Na2SO4, and concentrated. The combined solids were titurated with Et2O to yield 1.55 g (0.0064 mol, 91%) of FF.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 98% | To a mixture of <strong>[70165-31-0]6-cyanonicotinic acid</strong> (FFD, 1.0Og, 6.75mmol, Sigma-Aldrich) and DMF (4 drops) in CHCl3 (2OmL) at a temperature of about 250C was added thionyl chloride (1.08mL, 14.85mmol). The reaction mixture was reflux ed for 2h, then concentrated under reduced pressure to provide a residue. The residue was dissolved in MeOH (2OmL), stirred at a temperature of about 250C for 2h, then concentrated under reduced pressure to provide 1.34g of the compound of formula FFE, methyl 6-cyanonicotinate hydrochloride, as a pale yellow solid (yield >98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In 1,4-dioxane; for 18.5h;Reflux; | To a solution of tert-butyl 2-(7-(N'-hydroxycarbamimidoyl)-2,3-dihydro-lH- pyrrolo[l,2-a]indol-l-yl)acetate (50 mg, 0.152 mmol) in dioxane (914 mul) and <strong>[70165-31-0]6-cyanonicotinic acid</strong> (45.0 mg, 0.304 mmol) was added TEA (212 muL, 1.518 mmol) followed by addition of 1- propylphosphonic acid cyclic anhydride (49.2 muL, 0.167 mmol). The reaction mixture was stirred for 30 min, heated to reflux for 18 h, and then diluted with water. The resultant precipitate was filtered off and washed with water to provide the title compound as a yellow solid (43 mg). LCMS m/z = 442.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | A mixture of <strong>[70165-31-0]6-cyano-3-pyridine carboxylic acid</strong> (71 mg, 0.48 mmol), 1-hydroxybenzotriazole hydrate (75 mg, 0.48 mmol) and N-cyclohexylcarbodiimide-N'-methyl polystyrene (133 mg, 0.48 mmol, resin loading 1.8mmol/g) in dichloromethane (5ml) was stirred at room temperature for 15 minutes. A solution of 1-(1-methylethyl)-4-[4-(4-piperidinyl)phenyl] oxyjpiperidine (120mg, 0.4mmol) (75 mg, 0.24mmol) (D8) in dichloromethane (3ml) was added and the mixture stirred at room temperature for 24 hours. The mixture was filtered through a SCX column eluting with methanol followed by 10% 0.880 ammonia solution in methanol to elute the product. The residue was purified by silica gel chromatography eluting with a mixture of 0.880 ammonia solution:methanol:dichloromethane (1:9:90) to afford the title compound (28 mg, 27%); MS(ES+) m/e 433 [M+H]+. NMR(CDCI3) 5 1.06 (6H, d), 1.83 (4H, m), 2.00 (4H, m), 2.39 (2H, m), 2.79 (4H, m), 2.91 (H, m), 3.26 (H, m), 3.71 (H, m), 4.27 (H, m), 4.86 (H, m), 6.86 (2H, m), 7.09 (2H, m), 7.77 (H, d), 7.92 (H, d), 8.78 (H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | Example 13 5-[((2S)-2-Methyl-4-[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinyl)carbonyl]-2-pyridinecarbonitrile To a solution of (3S)-3-methyl-1-[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), <strong>[70165-31-0]6-cyano-3-pyridinecarboxylic acid</strong> (48.0 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was reduced in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with NaHCO3 (5 ml), twice. The organic layer was dried with magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo to yield the the title compound (77 mg). m/z (API-ES) 439 [M+H]+, 480 [M+H+41]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
dmap; In dichloromethane; for 2.16667h; | 6-Cyanonicotinic acid (500 mg) was dissolved in dichloromethane (25 ml), water-soluble carbodiimide (776 mg), methanol (0.164 ml) and 4-dimethylaminopyridine (49 mg) were added thereto, and the mixture was stirred for 2 hr 10 min. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified by column chromatography (Yamazen HI-FLASH COLUMN size 2L, elution solvent: hexane/ethyl acetate) to give the title compound. The same reactions were repeated using <strong>[70165-31-0]6-cyanonicotinic acid</strong> (547 mg) to give the title compound (total 951 mg). 1H-NMR(CDCl3)delta:4.01(3H,s), 7.81(1H,dd,J=1.2 Hz,8.1 Hz), 8.45(1H,dd,J=2.4 Hz,8.1 Hz), 9.30(1H,t,J=1.2 Hz). MS:163(M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | To a stirred solution of a carboxylic acid derivative (commercially available or known in the literature) (1 mmol) in 10 mL of CH2Cl2 was added (1.3 mmol) of EDC, (1.3 mmol) of HOBt and Et3N (1.3 mmol). After one hour at RT, was added a corresponding pyrrolidine intermediate. The mixture was stirred at RT over night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. Flash chromatography or preparative HPLC afforded the title compound. Amid Coupling according to General procedure IAmine: (3SR,4RS)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-ylmethyl]-(5-fluoro-pyrimidin-2-yl)-amineAcid: 6-Cyanonicotinic acidES-MS m/e: 471.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6-Cyano-nicotinic acid allyl ester 4 mmol of 6-Cyanonicotinic acid were dissolved in THF. 1.5 eq. of Cs2CO3 were added he reaction stirred for 10 min. 1.5 eq allylbromide and a catalytic amount of KI were added he reaction heated to 100 C. for 4 h. The product was isolated via extraction from cetate/water. MS(ISO): 222.5 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃; | A mixture of l,3-dialkyl-5,6-diaminouracil (1) (20 mmol ), <strong>[70165-31-0]6-cyanonicotinic acid</strong> (2.75g, 18.5 mmol), 4-Dimethylaminopyridine (DMAP) (400 mg) , l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (4.6 g) and dry DCM ( 50 ml) in a flask was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by silica gel column to provide compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 8h; | General procedure: The intermediate (3) (0.5 g, 0.00217 mol), EDCl (0.622 g, 0.00325 mol), DMAP (0.345 g, 0.0028 mol) were stirred in dichloromethane (6 mL) at 0 C, and the substituted acid (0.00217 mol) were dissolved in (4 mL) of dichloromethane and charged to the reaction mixture and stirred at room temperature for 8 h. The reaction completion was monitored by TLC. Reaction was completed. The reaction mixture was diluted with (10 mL) of dichloromethane, and was washed with 10% NaHCO3 (10 mL). Separated the organic layer and was washed with saturated brine solution (10 mL). The organic layer was dried over sodium sulfate and concentrated the organic layer under reduced pressure to afford compounds 4a-t. The spectral data of compounds 4(a-t) are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydroxylamine; In ethanol; water; at 20℃; for 12h; | 6-Cyanonicotinic acid (1.50 g, 10.1 mmol) was dissolved in 60 mL EtOH and treated at rt with an excess of hydroxylamine (3.0 mL, 50 mmol, 50% in water). After stirring the yellow solution for 12 h the white suspension was filtered off and washed with petroleum ether. Yield: 1.75 g (9.66 mmol, 95 %) white solid. 1H NMR (600 MHz, DMSO-cfe) delta ppm 10.08 (br. s, 1 H) 9.01 (d, J=1.13 Hz, 1 H) 8.21 (dd, J=8.28, 2.07 Hz, 1 H) 7.89 (d, J=8.09 Hz, 1 H) 5.91 (br. s, 2 H) MS(APCI) m/e 182 (M+H)+ RT= 0.23 min (Method B) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5. 6-(l,2,4,5-tetrazin-3-yl) nicotinic acid. To a finely divided mixture of <strong>[70165-31-0]6-cyanopyridine-3-carboxylic acid</strong> (2 mmol, 296 mg) and formamidine acetate (10 mmol, 1.04 g) was added hydrazine hydrate (2 mL) via syringe under an atmosphere of nitrogen. The resulting clear solution was then heated in an oil bath under a nitrogen atmosphere at 60 C for 30 min. During this time, the solution turned yellow-orange in color. After cooling, the solution was acidified to pH 3 by addition of 5% aqueous HC1, resulting in formation of a yellow-orange precipitate. The precipitate was filtered and washed with water (3 x 10 mL), and dried to give 185 mg or solid containing the dihydrotetrazine intermediate. This solid was suspended in MeOH (25 mL) with sonication to give a suspension of finely divided particles. To this suspension was added solid tetrachloro- 1.4- benzoquinone (1 mmol, 246 mg) and the suspension was stirred for 15 min. During this time, the tetrachloro-l,4-benzoquinone, and crude dihydrotetrazine intermediate go into solution and a new pink crystalline solid forms. The solution was filtered and washed with MeOH (2 x 5 mL) to give 6-(l,2,4,5-tetrazin-3-yl)nicotinic acid (49 mg). A second crop of product can be obtained by working up the filtrate from the oxidation step. First the filtrate is dried in vacuo, and then washed with dichloromethane (3 x 50 mL), allowing the solids to stir with the dichloromethane for 5 minutes for each wash. The remaining solids were then dried and extracted with ethyl acetate (4 x 20 mL), allowing the solids to stir with the ethyl acetate for 5 minutes for each wash. The last ethyl acetate filtrate only has a light pink color indicating the majority of the tetrazine has been extracted from the solids. The ethyl acetate washes were then combined and dried in vacuo to afford a second batch of product as a pink solid (40 mg), giving a combined yield of 89 mg (22%). HPLC analysis indicates the product is > 90% pure. ESI-MS calc. for C8H4N502+ 202.04; found 202.0. 1H NMR (DMSO-t/6) delta 13.8 (1H, br s), 10.75 (1H, s), 9.35 (1H, s), 8.67 (1H, d, J = 8.0 Hz), 8.59 (1 H, d, J = 8.0). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 6. 5-(l,2,4,5-Tetrazin-3-yl)picolinic acid. To a finely divided mixture of <strong>[70165-31-0]6-cyanopyridine-3-carboxylic acid</strong> (2 mmol, 296 mg) and formamidine acetate (10 mmol, 1.04 g) was added hydrazine hydrate (2 mL) via syringe under an atmosphere of nitrogen. The resulting tan solution was then heated in an oil bath under a nitrogen atmosphere at 60 C for 30 min. During this time, the reaction turned yellow-orange in color. After cooling, the solution was neutralized to pH 7 by addition of 5% aqueous HC1. Then NaN02 (10 mmol, 690 mg) in water (2 mL) was added. To this solution was slowly added 5% aqueous HC1 until the pH of the solution reached 3. After allowing the reaction mixture to stir for approximately 15 min., a pink precipitate forms. The precipitate was isolated by filtration, washed with 0.1 % aqueous HC1 (3 x 10 ml) and dried in vacuo giving product (118 mg, 29%) that is > 90% pure by HPLC without any additional purification. ESI-MS calc. for C8H4N502+ 202.04; found 202.0. 1H NMR (DMSO-t/6) delta 10.71 (1H, s), 9.66 (1H, d, J = 2.0 Hz), 8.93 (1H, dd, J = 8.5, 2.0 Hz), 8.26 (1 H, d, J = 8.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr; for 4h; | Weighed into a 100 ml round-bottomed flask were 500 mg (3.58 mumol) of <strong>[70165-31-0]6-cyanopyridine-3-carboxylic acid</strong> which was dissolved in 50 ml of methanol. Added next were 30 mg of 10% palladium on carbon and hydrogen at one atmosphere for four hours. The reaction is followed by HPLC on a Merck Lichrospher RP 18, 5 mum, 125*4.6 column with a gradient of acetonitrile in water containing 0.2% of trifluoroacetic acid. The product formed was precipitated. 40 ml of demineralized water were added to the reaction mixture, then the palladium was filtered over Celite and the reaction mixture was concentrated under reduced pressure in a 50 ml round-bottomed flask. The round-bottomed flask was placed in an ice/water bath and 4 ml of trifluoroacetic anhydride were slowly added. The reaction mixture was left to return to ambient temperature under stirring for two hours. The reaction was monitored by HPLC. 20 ml of ether were added to the reaction mixture and it was placed in an ice/water bath for 20 min. The precipitate was filtered over a frit and it was dried under vacuum for 48 h. A white solid (450 mg-1.81 mmol-54%) was obtained corresponding to the desired product. | |
750 mg | With 10% palladium hydroxide on charcoal; hydrogen; In methanol; at 20℃; | To a solution of 6-Cyanonicotinic acid (1 g, 6.7 mmol) in MeOH (20 mL) was added Pd(OH)2(10% Pd in carbon, 0.1 g). The mixture was stirred at r.t. under a hydrogen atmosphere overnight. Then the mixture was diluted with H20 (10 mL), the catalyst was filtered, and the filtrate was concentrated in vacuo to give 6-(aminomethyl)nicotinic acid (750 mg), which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfur; hydrazine hydrate; at 100℃; for 2h;Inert atmosphere; | 6-Cyanonicotinic acid (593 mg, 4.00 mmol, 1 equiv), sulfur (90 mg,2.80 mmol, 0.7 equiv), and triethyl orthoacetate (18.3 mL, 100 mmol,25 equiv) were placed in a round-bottomed flask and flushed with N2. Hydrazine monohydrate (15 mL, 300 mmol, 75 equiv) was added andthe reaction mixture was stirred vigorously at 100 C for 2 h. After cooling to r.t., the solution was diluted with EtOAc (200 mL) and washed with 10% (m/m) citric acid solution (2 × 75 mL), sat. aq NaHCO3 (2 × 50 mL) and brine (30 mL), and dried (MgSO4). The solution was filtered and the solvent was evaporated. The crude dihydrotetrazine was suspended in CH2Cl2 (150 mL) and oxidized with in situ generated nitrous gases (NOx) until TLC (eluent: CH2Cl2-MeOH, 10:1v/v) indicated the consumption of all dihydrotetrazine and the solution turned deep red. After evaporation of the solvent, the crude product was purified by column chromatography (SiO2, CH2Cl2-MeOH, 9:1 v/v) to yield 218 mg (25%) of 6 as a purple-red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 12h; | To a solution of <strong>[70165-31-0]6-cyanonicotinic acid</strong> (250 mg, 1.6 mmol) in THF (15mL) were added HBTU (599 mg, 1.5 mmol), HOBt (257 mg, 1.6 mmol),i-Pr2NEt (604 muL, 3.5 mmol), and Et2NH (210 muL, 2.0 mmol). The resulting suspension was stirred at r.t. for 12 h. The volatiles were then evaporated in vacuo. Purification of the product by column chromatography on silica gel with hexanes-EtOAc (3:1 v/v) as eluent afforded 5 as a pale yellow oil in 87% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.7 mg | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | To a solution of (S) - (4- (3-amino-5-chloro-2-methylbenzyl) -2-methylpiperazin-1-yl) (tetrahydro-2H-pyran-4-yl) methanone (D81 112.7 mg) and <strong>[70165-31-0]6-cyanonicotinic acid</strong> (51.7 mg) in anhydrous DMF (5 mL) were added HATU (178.7 mg) and DIPEA (0.161 mL) . The mixture was stirred at RT overnight and purified by MDAP (basic condition ACN/H2O (containing 0.05NH3H2O) ACN 30-80) to afford the title compound (40.7 mg) as an off-white solid.1H NMR (400 MHz MeOD-d4) 9.23 (s 1H) 8.50 (dd J 8.1 Hz 1.7 Hz 1H) 8.04 (d J 8.1 Hz 1H) 7.39 (d J 1.7 Hz 1H) 7.32 (d J 1.7 Hz 1H) 4.72-4.54 (m 1H) 4.37-4.22 (m 1H) 4.01-3.90 (m 2H) 3.84 (d J 13.0 Hz 0.5H) 3.58-3.44 (m 4.5H) 3.44-3.36 (m 0.5H) 3.03-2.82 (m 2.5H) 2.80-2.68 (m 1H) 2.32 (s 3H) 2.28-1.95 (m 2H) 1.93-1.50 (m 4H) 1.42-1.17 (m 3H) . MS (ESI) C26H30ClN5O3requires 495 found 496 [M+H]+. |
40.7 mg | 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 N,N-dimethyl-formamide; at 20℃; | In the containment N-(5-chloro-2-methyl-3-(((S)-3-methyl-4-((R)-tetrahydrofuran-2-carbonyl)piperazine-1-yl)methyl)phenyl)-6-(fluoromethyl)nicotinamide (D81, 112.7 mg) with <strong>[70165-31-0]6-cyanonicotinic acid</strong> (51.7 mg)Of anhydrous DMF (5 mL)Solution was added EtaAlphaTauupsilon (178.7 mg) with DIPEA (0.161 mL).The mixture was stirred overnight at room temperature,Purified by MDAP (base [& ' s condition,ACN / H2O (containing 0.55% NH3H2O), ACN% = 30% -80%) to give the title compound (40.7 mg) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 mg | Description 219 V (S)-tert-butyl 3-((5-chloro-3-(((S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-2-methylphenyl)carbamoyl)pyrrolidine-1-carboxylate (D219) (S)-1 -(Tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (50 mg) was dissolved in DCM (20 mL) and cooled to 0C. Oxalyl chloride (0.024 mL) was added dropwise under a nitrogen atmosphere, followed by a few drops of DMF. The reaction mixture was allowed to warm to 25C and stirredfor 1 h. The mixture was then concentrated to dryness under reduced pressure, and the residue redissolved in DCM (20 mL) was slowly added to the mixture of (S)-(4-(3-amino-5-chloro-2- methylbenzyl)-2-methylpiperazin-1 -yl)(cyclopentyl)methanone (D157, 81 mg) and DIPEA (0.081 mL) at 0C. The reaction mixture was allowed to warm to RT and stirred for 1 hour. The mixture was dulited with water (15 niL), the organic phase was dried over anhydrous sodium sulfate,filtered and concentrated to afford the title compound (80 mg) as yellow oil. MS (ESI):C29H43C1N4O4 requires 546; found 547 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4 mg | To a solution of (S)-(4-(3 -amino-5-chloro-2-methylbenzyl)-2-methylpiperazin-1 - yl)(cyclopentyl)methanone (D157, 115.5 mg) and <strong>[70165-31-0]6-cyanonicotinic acid</strong> (57.2 mg) in anhydrous DMF (5 mL), HATU (255.3 mg) and DIPEA (0.173 mL) were added at RT. The resulting reaction mixture was stirred overnight. Diluted with DCM (15 mL), washed with water (10 mL). The organic layer was separated and solvent was removed under vacuum. The residue was purified withMDAP to afford the title compound (90.4 mg) as white solid. ?H NMR (400 MHz, MeOD-d4): 9.23 (d, J- 1.5 Hz, 1H), 8.52 (dd, J 8.1, 2.2 Hz, 1H), 8.06 (dd, J 8.2, 0.6 Hz, 111), 7.65-7.57 (m, 211), 4.67 (brs, 1H), 4.54-4.38 (m, 2H), 4.21 (d, J 14.4 Hz, 0.511), 3.65-3.40 (m, 2.511), 3.29-2.99 (m, 3.5H), 2.36 (s, 3H), 2.00-1.56 (m, 8H), 1.52-1.21 (m, 311). MS (ESI): C26H30C1N502 requires 479; found 480 {M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100.9 mg | Example 77(S)-N-(5-chloro-3-((4-(2-cyclopropylacetyl)-3-methylpiperazin-1-yl)methyl)-2-methylphenyl)-6-cyanonicotinamide, Trifluoroacetic acid salt (E77)N NHN N?? ?TFA0 -To a solution of (S)-1 -(4-(3-amino-5-chloro-2-methylbenzyl)-2-methylpiperazin-1 -yl)-2- cyclopropylethanone (D169, 122.8 mg) in DCM (5 mL), <strong>[70165-31-0]6-cyanonicotinic acid</strong> (61.9 mg), DMAP (4.9 mg) and EDC (165.5 mg) were added at RT. The resulting reaction mixture was stirred overnight. Diluted with DCM (15 mL), washed with water (10 mL). The organic layer wasseparated and solvent was removed under vacuum. The residue was purified with MDAP to afford the title compound (100.9 mg) as white solid. ?H NMR (400 MHz, MeOD-d4): 9.23 (d, J= 1.5 Hz, 1H), 8.52 (dd, J 8.1, 2.2 Hz, 1H), 8.06 (d, J- 8.1 Hz, 1H), 7.62 (d, J 2.0 Hz, 1H), 7.59 (d, J=2.2 Hz, 1H), 4.66 (brs, 0.5H), 4.57-4.41 (m, 2.5H), 4.07 (brs, 0.5H), 3.76-3.41 (m, 3H), 3.27-2.98 (m, 211), 2.51-2.26 (m, 5H), 1.35 (brs, 3H), 1.07-0.93 (m, 1H), 0.63-0.48 (m, 2H), 0.25-0.11 (m,2H). MS (ESI): C25H28C1N502 requires 465; found 466 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 0 - 20℃; | To a stirred solution of <strong>[70165-31-0]6-cyanopyridine-3-carboxylic acid</strong> (1.0 g, 6.75 mmol) in DMF (3.9 mL), 4-methyl-3-thiosemicarbazide (0.78 g, 7.43 mmol) and DIPEA (2.1 mL, 12.15 mmol) were subsequently added. The mixture was cooled to 0 C then T3P (50% wt / EA) (6.0 mL, 10.13 mmol) was added portion-wise. The ice-bath was removed and the resulting reaction mixture was stirred ON at RT. Aqueous 0.5 M NaOH solution was added (resulting pH8) andthe two resulting phases were separated (the upper organic layer was eliminated) then the mixture was heated to 70 C and stirred for 1.5 h. The solution was cooled to RT and 37% HC1 was slowly added until pH 6. The mixture was stirred for 5 mm then it was filtered. The solid was washed with water and dried under vacuum at 45 C ON affording 1.45 g of title compound (p51, y95%). MS (m/z): 218.1 [IVII{]t |
66% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; | To a stirred solution of <strong>[70165-31-0]6-cyanopyridine-3-carboxylic acid</strong> (230 mg, 1.55 mmol) in DMF (0.9 mL), 4-methyl-3-thiosemicarbazide (180 mg, 1.71 mmol) and DIPEA (0.49 mL, 2.79 mmol) were subsequently added. The mixture was cooled to 0 C then T3P (50% wt / EA) (1.38 mL, 2.33 mmol) was added portion-wise. The ice-bath was removed and the resulting reaction mixture was stirred O/N at RT. Aqueous 0.5 M NaOH solution was added (resulting pH~8) and the two resulting phases were separated (the upper organic layer was eliminated) then the mixture was heated to 75 C and stirred for 1.5 h. The solution was cooled to RT and 37% HCI was slowly added until pH ~ 6. The mixture was extracted with DCM, the organic phase was dried by using a phase separator cartridge and concentrated. The residue was treated with water, the mixture was filtered, the white solid was washed with water and dried under vacuum at 45 C O/N affording 5-(4-methyl-5-sulfanyl-4H-1 ,2,4-triazol-3-yl)pyridine-2- carbonitrile (p128, 224 mg, y=66%). MS (m/z): 218.1 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | To a solution of <strong>[70165-31-0]6-cyanopyridine-3-carboxylic acid</strong> (0.5 g, 3.35 mmol) in DMF (5 mL), 4- methyl-3-thiosemicarbazide (390 mg, 3.71 mmol) was added; DIPEA (1.1 mL, 6.75 mmol) was added dropwise at RT, then the mixture was cooled in an ice bath before adding T3P (50% w/w in EtOAc) (3 mL, 5.05 mmol). The reaction was stirred at RT O/N. NaOH 4M solution was added until the precipitate, formed during the addition, dissolved (resulting pH=8). The reaction was diluted with EtOAc and the two resulting phases were separated (the upper organic layer eliminated). Additional 4M NaOH was added up to pH 1 1 and the mixture heated to 70 C for 2.5 hrs. Then pH was increased to 11 by adding NaOH (pellets) and the reaction was stirred at 70 C for 1 h. The solution was cooled to 0 C, then HCI 6N was slowly added till pH 5. A precipitate formed that was filtered under vacuum to obtain 5- (4-methyl-5-sulfanyl-4H-1 ,2,4-triazol-3-yl)pyridine-2-carboxamide (p130, 585 mg, y= 74%). MS (m/z): 236.1 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: To a solution of acid (0.91 mmol) in dichloromethane (20 mL), HATU (433 mg, 1.14 mmol) and DIPEA (0.4 mL, 2.28 mmol) were added at room temperature and stirred for 20 min. Then, methyl - (4-aminophenyl)-3-methoxythiophene-2-carboxylate 4 (0.76 mmol) was added and stirred at room temperature for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 × 20 mL). The organic layer was washed with H2O (30 mL), brine solution (30 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (ethyl acetate/ hexane) to afford the title compounds (5a-o). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 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 N,N-dimethyl-formamide; at 10 - 35℃; | 6-cyano-N-(1-((3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)carbamoyl)piperidin-3-yl)nicotinamide 6-Cyanonicotinic acid (0.160 mmol) was added to a solution of 3-amino-N-(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)piperidine-1-carboxamide hydrochloride (0.035 g, 0.08 mmol), HATU (0.061 g, 0.160 mmol) and DIEA (0.056 mL, 0.320 mmol) in DMF (1 mL) at room temperature, and the mixture was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate (3 mL) and water (1 mL), and the mixture was stirred for 5 min. The mixture was filtered by Top-Phase Separation Filter Tube, and the filtrate was concentrated by blowing air at 60C. The residue was purified by preparative HPLC (C18, mobile phase: water/acetonitrile (10 mM ammonium carbonate-containing solvent)). The fraction was concentrated by blowing air at 60C to give the title compound (34 mg, 64.2 mumol, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 10 - 35℃; | 6-cyano-N-((3R)-1-((3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)carbamoyl)piperidin-3-yl)nicotinamide T3P (442 muL, 0.75 mmol) was added to a solution of (R)-3-amino-N-(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)piperidine-1-carboxamide (100 mg, 0.25 mmol), <strong>[70165-31-0]6-cyanonicotinic acid</strong> (74.2 mg, 0.50 mmol) and DIEA (219 muL, 1.25 mmol) in ethyl acetate (1669 muL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; ethyl acetate/hexane) and solidified with IPE to give the title compound (100 mg, 0.188 mmol, 75%) as a white solid. 1H NMR (300 MHz, CDCl3):delta 0.39-0.54(m,4H), 1.23-1.38(m,1H), 1.55-2.20(m,10H), 3.35-3.53(m,2H), 3.65-3.79(m,1H), 3.92-4.07(m,3H), 4.23(brs,1H), 5.02(brs,1H), 6.95(s,1H), 7.30(d,J=9.06 Hz,1H), 7.63-7.93(m,4H), 8.29(dd,J=7.93,2.27 Hz,1H), 9.08(d,J=1.51 Hz,1H). |
Tags: 70165-31-0 synthesis path| 70165-31-0 SDS| 70165-31-0 COA| 70165-31-0 purity| 70165-31-0 application| 70165-31-0 NMR| 70165-31-0 COA| 70165-31-0 structure
[ 1970-80-5 ]
(2,2-Bipyridine)-5-carboxylic acid
Similarity: 0.82
[ 887975-97-5 ]
6-(3-Cyanophenyl)nicotinic acid
Similarity: 0.82
[ 89809-65-4 ]
Methyl 6-Cyanopyridine-3-carboxylate
Similarity: 0.93
[ 58553-48-3 ]
5-(Hydroxymethyl)picolinonitrile
Similarity: 0.82
[ 89809-65-4 ]
Methyl 6-Cyanopyridine-3-carboxylate
Similarity: 0.93
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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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