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CAS No. : | 3177-20-6 | MDL No. : | MFCD09910342 |
Formula : | C6H4Cl2N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FNNAWVXVOHNOFF-UHFFFAOYSA-N |
M.W : | 207.01 | Pubchem ID : | 23156323 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 43.33 |
TPSA : | 52.08 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.16 cm/s |
Log Po/w (iLOGP) : | 2.0 |
Log Po/w (XLOGP3) : | 1.98 |
Log Po/w (WLOGP) : | 1.57 |
Log Po/w (MLOGP) : | 0.75 |
Log Po/w (SILICOS-IT) : | 2.05 |
Consensus Log Po/w : | 1.67 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.61 |
Solubility : | 0.509 mg/ml ; 0.00246 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.7 |
Solubility : | 0.413 mg/ml ; 0.002 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.97 |
Solubility : | 0.223 mg/ml ; 0.00108 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.75 |
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 |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1 h; | To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IPA (20 mL) and followed by the addition of traw-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((trans-4-hydroxycyclohexyl)amino)pyrimidine-5- carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1 , 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+. |
94% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1 h; | To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropyeihylamine (369 mg, 2,86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461rng, 94percent) was dissolved in IPA (20 ml,) and followed by the addition of trans-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwiseiy. The resulting mixture was stirred at 0 °C for 90 min. After which buiyiamine (208,8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg., 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4, filtered and concentrated. The residue was purified on ISCO to give methyl 2-(butylamino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), S.77 (s, 1H), 6.29 (s, 1H), 4.81 - 4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35 - 2.25 (m, 2H), 2.23 - 2.00 (m, 6H), 1 ,67 (t, J- 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.9, 162,5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41. L 33.8, 31 ,7, 30.3, 20.1, 13,8; MS m/z 323.20 [M+H]+ |
94% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1 h; | Methyl 2-(butYlaminoV4-(((tra^^ (0734) (0735) To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IP A (20 mL) and followed by the addition of tra5'-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((traj,-4-hydroxycyclohexyl)amino)pyrimidine-5 - carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDC13) δ 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.11 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J = 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDC13) δ 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1, 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; acetone; | EXAMPLE II 2-chloro-4-methylamino-5-methoxycarbonyl-pyrimidine 19.1 g of potassium carbonate in 50 ml water are added dropwise to 13 g of <strong>[3177-20-6]2,4-dichloro-5-methoxycarbonyl-pyrimidine</strong> and 4.7 g of methylamine-hydrochloride in 500 ml acetone at 0 to 5° C. within one hour. Then the mixture is stirred for one hour in an ice bath. The acetone is largely removed in vacuo and the residue is distributed between water and ethyl acetate. Then the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are dried and evaporated down. The residue is separated by chromatography through a silica gel column with cyclohexane/ethyl acetate (2:1). Yield: 8,8 g (69percent of theory), melting point: 121° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h; | To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IPA (20 mL) and followed by the addition of traw-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((trans-4-hydroxycyclohexyl)amino)pyrimidine-5- carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) delta 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1 , 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+. |
94% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h; | To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropyeihylamine (369 mg, 2,86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461rng, 94percent) was dissolved in IPA (20 ml,) and followed by the addition of trans-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwiseiy. The resulting mixture was stirred at 0 °C for 90 min. After which buiyiamine (208,8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg., 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4, filtered and concentrated. The residue was purified on ISCO to give methyl 2-(butylamino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) delta 9.21 (s, 1H), S.77 (s, 1H), 6.29 (s, 1H), 4.81 - 4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35 - 2.25 (m, 2H), 2.23 - 2.00 (m, 6H), 1 ,67 (t, J- 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 167.9, 162,5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41. L 33.8, 31 ,7, 30.3, 20.1, 13,8; MS m/z 323.20 [M+H]+ |
94% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h; | Methyl 2-(butYlaminoV4-(((tra^^ (0734) (0735) To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IP A (20 mL) and followed by the addition of tra5'-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((traj,-4-hydroxycyclohexyl)amino)pyrimidine-5 - carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDC13) delta 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.11 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J = 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDC13) delta 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1, 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 120℃; for 2h; | Example 16 9-[2-Chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-cyano-7,9-dihydro-8H-purin-8-one A mixture of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (0.41 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline hydrochloride (0.81 g) and N,N-diisopropylethylamine (0.73 mL) in acetonitrile (9 mL) was stirred at 120°C in a reaction vessel equipped with a reflux condenser for 2 hours. The reaction mixture was cooled to room temperature. To the mixture was added water (9 mL), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give methyl 2-chloro-4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-pyrimidine-5-carboxylate (0.88 g). To the suspension of the obtained methyl 2-chloro-4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-pyrimidine-5-carboxylate (0.35 g) in dimethyl sulfoxide (6 mL) were added a solution of potassium cyanide (0.13 g) in water (1 mL) and 1,4-diazabicyclo[2,2,2]octane (25 mg), and the mixture was stirred at 30°C for 10 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water twice and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate = 1/1), and collected by filtration. The collected solids were washed with the same solvent, and dried under reduced pressure to give methyl 4-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenylamino]-2-cyanopyrimidine-5-carboxylate (0.22 g). To the obtained methyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl-amino]-2-cyanopyrimidine-5-carboxylate (0.12 g) were added tetrahydrofuran (3 mL), water (1.5 mL) and lithium hydroxide monohydrate (30 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate = 1/1), and collected by filtration. The collected solids were washed with the same solvent, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-cyanopyrimidine-5-carboxylic acid (75 mg). To this material were added 1,4-dioxane (2 mL), triethylamine (0.066 mL) and diphenylphosphoryl azide (0.034 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1/1 - 1/3) to give the title compound (46 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Alternatively, instead of the hydrazone linkage describe above, the compounds may have an amide linkage (see Scheme I below). The synthesis consists of 3 steps. First, to a stirred solution of 4-(2-hydroxyethyl)morpholine (B) (2.8 g, 21.3 mmol) in anhydrous THF (45 mL) at 0 0C, sodium hydride, 60percent dispersion in mineral oil, (0.9 g, 22.5 mmol) is added in three portions under nitrogen purge. Ice-bath was removed and a mixture is stirred at room temperature for 20-30 minutes. The mixture is cooled to 0 0C and added drop-wise (using syringe or dropping funnel) under nitrogen purge to a solution of methyl 2,4-dichloropyrirnidine carboxylate (A) (4.03 g, 19.4 mmol) in anhydrous THF (35 mL) at 0 0C. The resultant solution is stirred for 30 minutes at 0 0C, followed by 30 minutes at room temperature. It is then quenched carefully with ice-water (115mL) and diluted with ethyl acetate (115 mL). Organic layer is separated, water layer extracted once with ethyl acetate, combined ethyl acetate extracts are washed with brine and dried over anhydrous sodium sulfate. Concentration, followed by column chromatography with gradient eluation (hexane : ethyl acetate, 1:1; hexane : ethyl acetate,l:2; ethyl acetate; dichloromethane-acetone-methanol, 3:1:01) affords 3 fractions: first (0.56 g, 9.5percent ) - mostly isomer C, second (1.28 g, 21.8percent)- a mixture of C and D, and byproduct (E), third (0.7 g, 11.9percent) - mostly isomer (D). EPO <DP n="99"/>In the second step, a solution of compound C (0.6 g, 2 mmol), 5-amino-2,3- dimethylindole (F) (0.32 g, 2 mmol) and DIPEA (0.28 g, 2.2 mmol)in dioxane is heated at reflux for two hours. Ethyl acetate and water are added to the concentrated reaction mixture, water layer extracted with ethyl acetate, combined ethyl acetate extracts washed with brine and dried over anhydrous sodium sulfate. Product G (0.64 g, 75percent) is isolated by column chromatography with gradient eluation (ethyl acetate; dichloromethane- acetone-methanol, 3:1:01).In the same manner compound D is converted into product H.Compounds H is then converted into their corresponding amides (I) using appropriate amines following general procedure for amide formation.To a stirred mixture of ester (1 mmol) and amine (1.05 mmol) in toluene (3.2 mL)., 2 M solution of trimethylaluminum in toluene (1.6 eq) is added drop-wise under nitrogen purge. The reaction mixture is stirred until gas evolution halted, and then mixture is micro waved at 120 0C for 5-7 minutes (Emrys Optimizer). To the reaction mixture were added IN NaOH solution and dichloromethane, organic layer separated, washed with water, brine and dried over anhydrous sodium sulfate. Flash column chromatography purification affords about 65-75percent of a desired amide (I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (27 mg, 0.13 mmol) in dichloroethane / i-butanol (1: 1, 2mL) was cooled to 0°C. ZnCl2 solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. After stirring for lh, a solution of (R)-methyl 1- isopropyl-7-(methylsulfonyl)-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyrazine-8- carboxylate (30 mg, 0.09 mmol) in dichloroethane / i-butanol (1: 1, 2 mL) was added slowly at 0°C. The mixture was stirred at rt overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL X 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-l- isopropyl-7-(methylsulfonyl)-l,2,3,4-tetrahydrobenzo[4,5]irnidazo[l,2-a]pyrazine-8- carboxylate (34 mg, 77.3percent yield) as a solid. | |
77.3% | A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (27 mg, 0.13 mmol) in dichloroethane / i-butanol (1: 1, 2mL) was cooled to 0°C. ZnCl2 solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. After stirring for lh, a solution of (R)-methyl 1- isopropyl-7-(methylsulfonyl)-l,2,3,4-tetrahydrobenzo[4,5]irnidazo[l,2-a]pyrazine-8- carboxylate (30 mg, 0.09 mmol) in dichloroethane / i-butanol (1: 1, 2 mL) was added slowly at 0°C. The mixture was stirred at rt overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL X 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-l- isopropyl-7-(methylsulfonyl)-l,2,3,4-tetrahydrobenzo[4,5]irnidazo[l,2-a]pyrazine-8- carboxylate (34 mg, 77.3percent yield) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In tetrahydrofuran; for 4h;Inert atmosphere; Reflux; | To a solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL X 3). The organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26percent yield) as a white solid. |
26% | In tetrahydrofuran; water; | (S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2 (1H)-yl)pyrimidin-5-yl)methanol To a solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1 g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26percent yield) as a white solid. |
26% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; at 20℃; for 4h;Inert atmosphere; Reflux; | To a solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL X 3). The organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26percent yield) as a white solid. |
26% | In tetrahydrofuran; water; | Example 20 (R)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol and (S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol To a solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1 g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26percent yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0℃; for 1.5h; | To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IPA (20 mL) and followed by the addition of traw-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((trans-4-hydroxycyclohexyl)amino)pyrimidine-5- carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) delta 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1 , 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+. | |
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0℃; for 1.5h; | To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropyeihylamine (369 mg, 2,86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461rng, 94percent) was dissolved in IPA (20 ml,) and followed by the addition of trans-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwiseiy. The resulting mixture was stirred at 0 °C for 90 min. After which buiyiamine (208,8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg., 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4, filtered and concentrated. The residue was purified on ISCO to give methyl 2-(butylamino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) delta 9.21 (s, 1H), S.77 (s, 1H), 6.29 (s, 1H), 4.81 - 4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35 - 2.25 (m, 2H), 2.23 - 2.00 (m, 6H), 1 ,67 (t, J- 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 167.9, 162,5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41. L 33.8, 31 ,7, 30.3, 20.1, 13,8; MS m/z 323.20 [M+H]+ | |
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0℃; for 1.5h; | Methyl 2-(butYlaminoV4-(((tra^^ (0734) (0735) To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IP A (20 mL) and followed by the addition of tra5'-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((traj,-4-hydroxycyclohexyl)amino)pyrimidine-5 - carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDC13) delta 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.11 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J = 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDC13) delta 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1, 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -78 - 20℃; | To a solution of the dichloropyrimidine (93.5 mg, 0.423 mmol) in dry THF (2 mL) at -78°C was added dropwise a solution of the aminoindole from Step (1) (1 19 mg, 0.423 mmol) in dry THF (2mL) followed by DIPEA (81 uL, 0.465 mmol). The mixture was warmed to room temperature overnight. Water (20 mL) was added to the mixture. The mixture was extracted twice with EtOAc (10 mL). The EtOAc layers were combined, washed with brine and dried through a phase separating cartridge. The residue was dissolved in THF (2 mL) and a 1 M aqueous sodium hydroxide solution (0.592 mL, 0.592 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was treated with a 1 M solution of hydrochloric acid (600 uL). The mixture was filtered and washed with water. The solid was dried in vacuo at 45°C overnight. LCMS: m/z 437 M35CIH+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; for 1h; | Step 1 [00144] To vial containing <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (1.30 g, 6.28 mmol) was added acetonitrile (10 mL), diisopropylethyl amine (2.19 mL, 12.56 mmol) and 2-aminobezamide (855 mg, 6.28 mmol). The reaction was heated to 70 °C for 60 minutes and then cooled to room temperature resulting in the product crashing out as a solid. The solid was filtered off, rinsing with acetonitrile, collected and dried yielding Int4 as a crude solid (2.3 g, 90percent pure). An analytically pure sample was obtained using automated silica gel chromatography (40-85percent EtOAc/hexanes). 1H NMR (400MHz, MeOD/chloroform-d) delta 8.85 - 8.77 (m, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.58 - 7.48 (m, 1H), 7.25 (t, J=7.6 Hz, 1H), 4.04 - 3.98 (m, 3H). LC retention time 0.76 min [J]. MS(E+) m/z: 307 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; for 1.5h; | Step 1 [00140] To vial containing <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (140 mg, 0.68 mmol) was added acetonitrile (1 mL), diisopropylethyl amine (0.24 mL, 1.4 mmol) and 2- (methylthio)aniline (94 mg, 0.68 mmol). The reaction was heated to 70 °C for 90 minutes and then cooled to room temperature and the solvent removed in vacuo. The residual solid was re-dissolved in dichloromethane (DCM) and then precipitated out via the addition of hexanes. The product was collected via filtration, rinsing with hexanes and used without further purification. Collected material (220 mg) was c. 50percent pure. LC retention time 1.08 min [J]. Mass Spectrometry ("MS") (E+) m/z: 310 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0℃; for 1.5h; | A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (252 mg, 1.22 mmol) in i-PrOH (6 mL) was added 2-(2-aminoethoxy)ethanol (122 mu,, 1.22 mmol) and IEA (319 pL, 1.83 mmol) at 0 °C. After 1 ,5 h the volatiies were removed imder a reduced pressure and the residue was purified by ISCO silica gel column to provide the title compound (243 mg, 72 percent) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.67 (s, 1H), 3.90 (s, 3H), 3.82-3.74 (m, 4H), 3.70 (t, J - 5.2 Hz, 2H), 3.67-3.61 (m} 2H), 2.17 (t, J - 6.3 Hz, 1H). |
72% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0℃; for 1.5h; | Methyl 2-chloTo-4-{i2-(2-hYdroxyethoxy)ethyl amino}pyrimidine-5-carboxylate (1254) (1255) A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (252 mg, 1.22 mmol) in i- PrOH (6 mL) was added 2-(2-aminoethoxy)ethanol (122 iL, 1.22 mmol) and DIEA (319 mu,, 1.83 mmol) at 0 °C. After 1.5 h the volatiles were removed under a reduced pressure and the residue was purified by ISCO silica gel column to provide the title compound (243 mg, 72 percent) as a white solid. 1H N R (400 MHz, CDCI3) delta 8.67 (s, 1H), 3.90 (s, 3H), 3.82-3.74 (m, 4H), 3.70 (t, J = 5.2 Hz, 2H), 3.67-3.61 (m, 2H), 2.17 (t, J = 6.3 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | In water; tert-butyl alcohol; | Example 19a (R)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-methylpyrimidin-5-yl)methanol A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (27 mg, 0.13 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was cooled to 0° C. ZnCl2 solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. After stirring for 1 h, a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (30 mg, 0.09 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was added slowly at 0° C. The mixture was stirred at rt overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (34 mg, 77.3percent yield) as a solid. |
77.3% | In water; tert-butyl alcohol; | Example 19 (R)-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-methylpyrimidin-5-yl)methanol A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (27 mg, 0.13 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was cooled to 0° C. ZnCl2 solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. After stirring for 1 h, a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (30 mg, 0.09 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was added slowly at 0° C. The mixture was stirred at rt overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (34 mg, 77.3percent yield) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; isopropyl alcohol; at 0 - 20℃; | To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for at 0 °C 1 h. Then the solvent was removed. The residue (412mg, 2.0 mmol) was dissolved in IPA (20 mL) followed by the addition of Z-Ormthine (465 mg, 2.0 mmol) and N,N- diisopropylethylamine (388 mg, 3.0 mmol). The resulting mixture was stirred at 0 °C for 90 min, then dichloromethane (5.0 mL) was added. The resulting mixture was stirred at 0 °C for 1.0 h and at room temperature overnight. Solvent was removed and the residue (MS m/z 403.30 [M+H]+) was dissolved in DMF (5.0 mL) and was added dropwise into a solution of 1,4-diaminobutane (1.68g, 19.1 mmol) in DMF (1.0 mL) at room temperature. The resulting mixture was heated to 45 °C for l . The solvent was removed and the residue was dissolved in ethyl acetate (35 mL) and washed with water (3x). The organic layer was dried ( a2S04), filtered and concentrated. The residue was purified on HPLC to provide (S)-5-((2-((4- aminobutyl)amino)-5-(methoxycarbonyl)pyrimidin-4-yl)amino)-2-((tert-butoxycarbonyl) amino)pentanoic acid as a semisolid (MS m/z 455.30 [M+H]+). The semisolid (595 mg, 1.31 mmol) was dissolved in DMF (150 mL), then TBTU (546.4 mg, 1.70 mmol) and DIEA (508 mg, 3.93 mmol) were added sequentially. The resulting mixture was stirred at room temperature overnight. The solvent was removed. The residue was dissolved in ethyl acetate and washed with water (3x). The organic layer was dried (Na2S04), filtered and concentrated. The residue was purified on HPLC to provide the totle compound (UNC2343A). 1H NM (400 MHz, CD3OD) S 8.42 (s, 1H), 4.08-3.99 (m, 1H), 3.90-3.84 (m, 3H), 3.59-3.47 (m, 2H), 3.46-3.31 (m, 2H), 3.28-3.21 (m, 1H), 3.09-2.95 (m, 1H), 1.90-1.52 (m, 8H), 1.51- 1.32 (m, 9H); MS m/z 437.30 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (2.07 g, 10 mmol) in DCE (15 mL) was cooled to 0 °C before aluminum chloride (2.7 g, 20 mmol) was added. The resulting mixture was warmed to rt and stirred for 15 min before adding 1-methyl-indole (1.32 g, 10 mmol). The resulting mixture was stirred at 55°C for 1.5 h, then cooled to 0 °C. MeOH (5 mL) and water (10 mL) were added, and the resulting mixture was stirred at rt for 30 min. Additional water (20 mL) was added and the layers were separated. The aqueous phase was extracted with DCM (4 x 30 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (0percent? 20percent EtOAc/DCM) to afford methyl 2-chloro-4-(1 -methyl-1 H-indol-3-yl)pyrimidine-5-carboxylate (G1) as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | With potassium carbonate; In N,N-dimethyl-formamide; acetone; at -40℃; for 6h; | Following the preparation protocol of Section5.1.2.1, the reaction mixture of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (8e) (228 mg, 1.10 mmol), K2CO3 (276 mg,2.0 mmol) and 4-hydroxyl benzo[d]oxazole (3) (135 mg, 1.0 mmol)in DMF (1 mL) and acetone (9 mL) was stirred at 40 C for 6 h togive compound 9g as a white solid (268 mg, 87.7percent); mp 131?133C; 1H NMR (400 MHz, DMSO d6) d (ppm) 9.13 (s, 1H), 8.76 (s, 1H),7.80 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz,1H), 3.93 (s, 3H); HRMS (ESI): m/z, Calcd. for C13H9O4N3Cl[M+H]+: 306.0276, Found 306.0273 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; | <strong>[3177-20-6]methyl 2,4,-dichloropyrimidine-5-carboxylate</strong> (20.70 g, 100 mmol), N,N-dimethylformamide (104 mL) was added to a three-necked flask, stirred and dissolved, and sodium carbonate (26.50 g, 250 mmol) was added. stir evenly and add 2-cyclopentylamino-N,N-dimethylformamide (17.03 g, 100 mmol) was reacted at room temperature for 6-8 hours. At the end of the reaction, water (207 mL), ethyl acetate (207 mL),The extract was extracted once more with ethyl acetate (104 mL), and the organic phase brine (110 mL) was washed once, dried over anhydrous sodium sulfate, filtered, concentrated with ethyl acetate and petroleum ether, and the solid was separated by filtration. drying in vacuo to gave methyl 2-chloro-4-(cyclopentyl(2-(dimethylamino)-2-oxoethyl)amino)pyrimidine-5-carboxylate (30.33 g, 89percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; | <strong>[3177-20-6]methyl 2,4,-dichloropyrimidine-5-carboxylate</strong> (20.70 g, 100 mmol), N,N-dimethylformamide (104 mL) was added to a three-necked flask, stirred and dissolved, and sodium carbonate (26.50 g, 250 mmol) was added. stir evenly and add ethyl 2-cyclopentylaminoacetate (17.12 g, 100 mmol) was reacted at room temperature for 6-8 hours. At the end of the reaction, water (207 mL) was added, and the mixture was separated, and the aqueous phase was extracted twice with dichloromethane (104 mL), and the organic phase brine (104 mL) was washed once, dried over anhydrous sodium sulfate, filtered, concentrated, The mixture is pulverized with isopropanol and petroleum ether. The solid is separated by filtration and dried in vacuo to give methyl 2-chloro-4-(cyclopentyl(2-ethoxy-2-oxoethyl)amino)pyrimidine-5-carboxylate (30.76g, 90percent). |
Tags: 3177-20-6 synthesis path| 3177-20-6 SDS| 3177-20-6 COA| 3177-20-6 purity| 3177-20-6 application| 3177-20-6 NMR| 3177-20-6 COA| 3177-20-6 structure
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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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