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CAS No. : | 13627-49-1 | MDL No. : | MFCD09834807 |
Formula : | C6H6N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CDBDBWCUGHXFTN-UHFFFAOYSA-N |
M.W : | 138.12 | Pubchem ID : | 18676097 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 33.96 |
TPSA : | 63.08 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.82 cm/s |
Log Po/w (iLOGP) : | 0.87 |
Log Po/w (XLOGP3) : | 0.46 |
Log Po/w (WLOGP) : | 0.48 |
Log Po/w (MLOGP) : | -0.47 |
Log Po/w (SILICOS-IT) : | 0.7 |
Consensus Log Po/w : | 0.41 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.36 |
Solubility : | 5.97 mg/ml ; 0.0432 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.35 |
Solubility : | 6.12 mg/ml ; 0.0443 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.38 |
Solubility : | 5.71 mg/ml ; 0.0413 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.52 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water;pH 1.0; | 2-methyl-4-pyrimidinecarbonitrile (may be prepared as described in Description 30) (62.0mg, 0.52mmol) was dissolved in ethanol (3ml), treated with 10% sodium hydroxide solution (3ml) and heated at reflux for 5 hours. The ethanol was evaporated and the mixture dissolved in water and acidified with 5M HCI solution (pH 1). Extracted with ethyl acetate (3 x 50ml), dried over magnesium sulphate, filtered and evaporated to afford the product (D31); MS (ES+) m/e 139 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With N-ethyl-N,N-diisopropylamine; HATU; In ISOPROPYLAMIDE; at 20 - 80℃; for 1.08333h;Inert atmosphere; | N,N-Diisopropylethylamine (0.163 mL, 0.93 mmol) was added dropwise to a partial solution of <strong>[13627-49-1]2-methylpyrimidine-4-carboxylic acid</strong> (48.4 mg, 0.35 mmol), 9-(8-aminodibenzothiophen-4- yl)-2-morpholin-4-ylpyrido[1 ,2-a]pyrimidin-4-one (B3, 100mg, 0.23 mmol), and O-(7- azabenzotriazol-i-yO-N.N.N'.N'-tetramethyluronium hexafluorophosphate (133 mg, 0.35 mmol) in DMA (1 mL), stirred at room temperature under nitrogen. The mixture was stirred at room temperature for 1 hour and then heated to 8O0C for 5 minutes to ensure dissolution of all of the starting material. LCMS indicated complete reaction so the mixture was quenched into water (1OmL) and the precipitate filtered off, washed with water (5 mL), and dried. The crude product was purified by flash silica chromatography, elution gradient 2 to 5% MeOH in DCM. Pure fractions were evaporated to dryness and the solid produced triturated with acetonitrile (1 mL), filtered and dried to afford 2-methyl-N-[6-(2-morpholin-4-yl- 4-oxopyrido[1 ,2-a]pyrimidin-9-yl)dibenzothiophen-2-yl]pyrimidine-4-carboxamide (47.4 mg, 37%) as a white solid; 1H NMR (400 MHz1 CDCI3) delta 2.89 (3H, s), 3.35 - 3.38 (4H, m), 3.56 - 3.58 (4H, m), 5.63 (1 H, s), 7.02 (1 H, t), 7.55 - 7.59 (2H, m), 7.68 - 7.71 (1H, m), 7.79 (1 H1 d), 7.86 - 7.88 (1 H1 m), 8.06 - 8.07 (1 H, m), 8.25 - 8.29 (1 H, m), 8.86 (1 H1 d), 8.96 (1 H, d), 9.04 - 9.06 (1 H, m), 10.11 (1 H, s); m/z: 549.36 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Example 115cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1,9-dioxo-2-aza-spiro[4.5]dec-7-yl]-amide Example 115 was prepared from intermediate 30 via the process of Scheme 23, supra, as follows:To a solution of cis-13-amino-9-(3,5-difluoro-phenyl)-1,4-dioxa-9-aza-dispiro[4.1.4.3]tetradecan-8-one (300 mg, 0.887 mmol) and <strong>[13627-49-1]2-methylpyrimidine-4-carboxylic acid</strong> (128 mg, 1.05 mmol) in DCM (6 mL) was added PYBOP (508 mg, 0.975 mmol) and triethylamine (0.27 mL, 1.95 mmol). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was chromatographed on silica gel (0 to 70% EtOAc in hexanes) to give an intermediate (300 mg), which was dissolved in THF (5 mL), followed by the addition of 3.0 M HCl in water (5 mL). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was suspended in DCM (20 mL) and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were concentrated. The residue was chromatographed on silica gel (0 to 80% EtOAc in hexanes) to give 190 mg (49% over 2 steps) of the title compound, cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1,9-dioxo-2-aza-spiro[4.5]dec-7-yl]-amide. 1H NMR (400 MHz, CDCl3) delta 8.90 (d, J=5.0 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.33-7.29 (m, 2H), 6.65 (tt, J=8.7, 2.2 Hz, 1H), 4.62-4.50 (m, 1H), 3.88-3.80 (m, 2H), 2.96-2.76 (m, 5H), 2.59 (dd, J=13.6, 11.4 Hz, 1H), 2.44-2.09 (m, 5H). ESI-MS m/z: 415 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 0 - 25℃;Inert atmosphere; | Example 76cis 2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide Example 76 was also prepared from intermediate 33 via the process of Scheme 1, supra, as follows:In a round-bottom flask was charged with cis-7-amino-2-(3,5-difluoro-phenyl)-2-aza-spiro[4.5]decan-1-one. HCl (10.8 g, 34.1 mmol), <strong>[13627-49-1]2-methylpyrimidine-4-carboxylic acid</strong> (4.71 g, 34.1 mmol), and BOP (15.1 g, 34.1 mmol). Methylene chloride (218 mL) was added, and the mixture was cooled at 0 C. Triethylamine (14.2 mL, 102 mmol) was added dropwise. The mixture was warmed up to rt and stirred at rt overnight. The mixture was diluted with methylene chloride (100 mL) and water (50 mL). The aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue obtained was crystallized from ethyl acetate to afford 8.8 g (77%) of the title compound cis 2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide: 1H NMR (400 MHz, CDCl3): delta8.85 (d, J=5.0 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.89 (d, J=5.4 Hz, 1H), 7.28-7.35 (m, 2H), 6.60 (tt, J=8.8, 2.5 Hz, 1H), 4.07-4.18 (m, 1H), 3.74-3.80 (m, 2H), 2.79 (s, 3H), 2.07-2.28 (m, 3H), 1.89-1.97 (m, 2H), 1.55-1.85 (m, 4H), 1.37-1.48 (m, 1H). ESI-MS m/z: 401 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<strong>[13627-49-1]2-methylpyrimidine-4-carboxylic acid</strong> (250 mg, 1.810 mmol) was slurried in N,N,Dimethylformamide (dry) (3 ml). DIPEA (0.378 ml, 2.172 mmol) was added followed by HATU (757 mg, 1.991 mmol). After 15 mins 2-chloroaniline (0.191 ml, 1.810 mmol) was added to the brown suspension and the resulting reaction mixture stirred further at room temperature overnight. The reaction mixture was evaporated (55C to half volume (~4ml). This mixture was added to a cold water/ sat. sodium bicarbonate mixture (2:1, 20 ml). The solvents were filtered and the residue was taken in DCM. The organic layer was dried with Na2SO4, filtered and the filtrate was evaporated to dryness to give the product as a beige solid. Used as such. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | To a solution of 2-methylpyrimidine-5-carboxylic acid (100 mg, 0.724 mmol) and diisopropylethylamine (281 mg, 2.17 mmol) in tetrahydrofuran (4 ml_) at 20 C was added 1 -[b/'s(dimethylamino)methylene]- 1H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (413 mg, 1 .09 mmol). The reaction mixture was stirred for 20 minutes before a solution of 5-(3-fluorobenzyl)pyridin-2-amine (146 mg, 0.724 mmol) in tetrahydrofuran (1 .0 ml_) was added. The reacton solution was heated to 90 C and stirred at 90 C for 1 h. The volatiles were removed under reduced pressure and the residue was added to a mixture of dichloromethane (50 ml_) and water (50 ml_). The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 20/1 ) to offer A/-(5-(3-fluorobenzyl)pyridin-2-yl)-2-methylpyrimidine-5-carboxamide (93.1 mg, 0.29 mmol, 40%) as a white solid. 1 H NMR (400 MHz, Dimethylsulfoxide-c/6) d 1 1 .19 (s, 1 H), 9.18(s, 2H), 8.34 (d, J = 2.0 Hz, 1 H), 8.12 (d, J = 8.8 Hz, 1 H), 7.73-7.76 (m, 1 H), 7.33-7.38 (m, 1 H), 7.02-7.14 (m, 3H), 3.99 (s, 2H), 2.70 (s, 3H); LCMS (ESI) m/z: 323.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | 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℃; for 16h; | In a 40 ml_ reaction vial, combined 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.500 g, 2.27 mmol), dipotassium carbonate (0.375 g, 2.72 mmol) and A2-iron(2+) b/'s((cyclopenta-2,4-diyn-1 -yl)diphenyl-A4-phosphane) palladium dichloride (0.082 g, 0.1 135 mmol). Added 1 ,4-dioxane (6 ml_) and water (2 ml_) and added 1 -(bromomethyl)-3-fluorobenzene (278 mI_, 2.27 mmol). The reaction was degassed by cycling with vacuum and nitrogen gas for 3 cycles. Stirred the reaction at 80 C for 16 h. Cooled to room temperature and diluted with ethyl acetate (15 ml_), then washed with water (10 ml_), then brine (10 ml_). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purified reaction by column chromatography (eluting with 0-100% ethyl acetate/hexanes through 24 g of silica gel) to give 5-[(3-fluorophenyl)methyl]pyridin-2-amine as a brown solid (131 mg, 0.648 mmol, 28%). 1 H NMR (300 MHz, Chloroform-d) d 8.02 - 7.94 (m, 1 H), 7.33 - 7.18 (m, 2H), 7.06 - 6.80 (m, 3H), 6.47 (dd, J = 8.4, 0.9 Hz, 1 H), 4.36 (s, 2H), 3.84 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.133 g | 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℃; for 16h;Inert atmosphere; | To a solution of 5-((6-aminopyridin-3-yl)methyl)-2-fluorobenzonitrile (0.227 mg, 1 .0 mmol), <strong>[13627-49-1]2-methylpyrimidine-4-carboxylic acid</strong> (276 mg, 2.0 mmol) and A/,A/-diisopropylethylamine (388 mg, 3.0 mmol) in A/,A/-dimethylformamide (10 mL) at room temperature was added 1 -[b/s(dimethylamino) methylene]- 7/-/-1 ,2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.570 g, 1 .5 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (100 ml_) and washed with brine (30 ml_ x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude sample was dissolved in minimal A/,A/-dimethylformamide and purified v/'a prep-HPLC (BostonCI 8 21 *250 mm 10 pm column. The mobile phase was acetonitrile/10 mM ammonium acetate aqueous solution) to give A/-(5-(3-cyano-4-fluorobenzyl)pyridin-2-yl)-2-methylpyrimidine-4-carboxamide (0.133 g, 0.38 mmol, 38%) as a white solid. 1 H NMR (400 MHz, Dimethylsulfoxide-c/6) d 1 0.37 (s, 1 H), 9.03 (d, J = 5.2 Hz, 1 H), 8.36 (d, J = 1 .6 Hz, 1 H), 8.17 (d, J = 8.4 Hz, 1 H), 7.94 (d, J = 4.8 Hz, 1 H), 7.88 (dd, J, = 2.0 Hz, J2 = 7.6 Hz, 1 H), 7.79 (dd, Ji = 2.0 Hz, J2 = 8.4 Hz, 1 H), 7.68 - 7.72 (m, 1 H), 7.46 (t, J = 8.8 Hz, 1 H ), 4.02 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z: 348.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.0496 g | 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℃; for 16h;Inert atmosphere; | To a solution of 5-(3-chlorobenzyl)pyridin-2-amine (0.132 g, 0.6 mmol), <strong>[13627-49-1]2-methylpyrimidine-4-carboxylic acid</strong> (0.166 g, 1 .2 mmol) and A/,A/-diisopropylethylamine (0.233 g, 1 .8 mmol) in A/,A/-dimethylformamide (10 ml_) at room temperature was added 1 -[b/s(dimethylamino) methylene]- 7/-/-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.342 g, 0.9 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was, the mixture was diluted with ethyl acetate (100 ml_) and washed with brine (30 ml_ x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude sample was dissolved in minimal A/,A/-dimethylformamide and purified v/'a prep-HPLC (BostonC18 21 *250 mm 10 pm column. The mobile phase was acetonitrile/10 mM ammonium acetate aqueous solution) to give A/-(5-(3-chlorobenzyl)pyridin-2-yl)-2-methylpyrimidine-4-carboxamide (0.0496 g, 0.15 mmol, 24%) as a yellow solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 10.39 (s, 1 H), 9.05 (d, J = 5.0 Hz, 1 H), 8.37 (d, J = 2.0 Hz, 1 H), 8.19 (d, J = 9.0 Hz, 1 H), 7.97 (d, J = 5.0 Hz, 1 H), 7.81 (dd, Ji = 2.5 Hz, J2 = 8.5 Hz, 1 H), 7.33 - 7.37 (m, 2H), 7.25 - 7.29 (m, 2H), 4.00 (s, 2H), 2.79 (s, 3H); LCMS (ESI) m/z: 339.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | A mixture of 3-((6-aminopyridin-3-yl)methyl)-5-fluorobenzonitrile (227 mg, 1 .0 mmol), <strong>[13627-49-1]2-methylpyrimidine-4-carboxylic acid</strong> (138 mg, 1 .0 mmol), 2-(7-azabenzotriazol-1 -yl)-A/,A/,A/',A/'-tetramethyluronium hexafluorophosphate (570 mg, 1 .5 mmol) and diisopropylethylamine (390 mg, 3.0 mmol) in A/,A/-dimethylformamide (4 ml_) was stirred at room temperature for 1 h. The mixture was poured into water. The formed precipitate was collected by filtration and the obtained solid was washed with methanol (15 ml_) to afford A/-(5-(3-cyano-5-fluorobenzyl)pyridin-2-yl)-2-methylpyrimidine-4-carboxamide (0.228 g, 0.66 mmol, 66%) as a grey solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 10.40 (s, 1 H), 9.05 (d, J = 5.0 Hz, 1 H), 8.40 (d, J - 2.0 Hz, 1 H), 8.19 (d, J = 8.5 Hz, 1 H), 7.96 (d, J = 5.5 Hz, 1 H), 7.84 (dd, J = 8.5, 2.5 Hz, 1 H), 7.72-7.70 (m, 2H), 7.60 (d, J = 5.5 Hz, 1 H), 4.06 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z: 348.1 [M+H]+. |
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