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CAS No. : | 4595-61-3 | MDL No. : | MFCD00856162 |
Formula : | C5H4N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IIVUJUOJERNGQX-UHFFFAOYSA-N |
M.W : | 124.10 | Pubchem ID : | 78346 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 28.99 |
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) : | -7.25 cm/s |
Log Po/w (iLOGP) : | 0.62 |
Log Po/w (XLOGP3) : | -0.27 |
Log Po/w (WLOGP) : | 0.17 |
Log Po/w (MLOGP) : | -0.85 |
Log Po/w (SILICOS-IT) : | 0.32 |
Consensus Log Po/w : | 0.0 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.87 |
Solubility : | 16.9 mg/ml ; 0.136 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.6 |
Solubility : | 31.5 mg/ml ; 0.254 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.98 |
Solubility : | 12.9 mg/ml ; 0.104 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: at 20℃; for 0.1 h; Stage #2: With hydrogenchloride In water |
Pyrimidine-5-carboxylic acid 19.50 ml (149 mmol) ethyl pyrimidine-5-carboxylate are shaken in 40 ml of 4 molar sodium hydroxide solution for 0.1 hours at ambient temperature, then 40 ml of 4 molar hydrochloric acid solution are added. The precipitate formed is suction filtered, washed with petroleum ether and dried. Yield: 14.80 g (80percent of theoretical) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; at 110℃; for 1h; | <strong>[4595-61-3]5-Pyrimidinecarboxylic acid</strong> (500mg) in thionyl chloride (5mL) was stirred at 110°C5 under nitrogen for 1h. The solvent was evaporated under vacuum to give 5-pyrimidinecarbonyl chloride as a brown oil (505mg). (4-Bromo-2-fluorophenyl)(iodo)zinc intetrahydrofuran (0.5M, 7.0ml_) was added slowly to a stirred mixture of the acid chloride(500mg) and tetrakis(triphenylphosphine)palladium(0) (203mg) in tetrahydrofuran (3mL) atroom temperature under nitrogen then stirred at room temperature for 1h. Aqueous10 ammonium chloride (1M, 5mL) was added and the mixture was absorbed onto silica andpurified by chromatography on a silica column eluting with a cyclohexane/ethyl acetategradient to give the title compound (712mg).LC-MS: Rt 2.65min. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; | (+)-*ralphan.s-2-Methyl- 1 -(pyrimidine-5-carbonyl)- 1,2,3 ,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting pyrimidine-5-carbonyl chloride for 4-trifluoromethyl-benzoyl chloride. Pyrimidine-5-carbonyl chloride was prepared by reaction of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> with oxalyl chloride and dimethylformamide in methylene chloride. The crude 2-methyl-l-(pyrimidine-5-carbonyl)-l,2,3,4- tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (2percent methanol / methylene chloride) EPO <DP n="76"/>yielded (+)-Zrapii-2-niethyl-l-(pyrimidine-5-carbonyl)-l,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (44percent). 1H-NMR (CDCl3) delta: 1.02 - 1.18 (m, 6H), 1.65 - 1.75 (m, IH), 2.50 - 2.60 (m, IH), 3.60 - 3.70 (m, IH), 3.80 (q, 2H), 4.98 - 5.10 (m, IH), 6.40 (d, IH), 6.70 (d, IH), 6.90 - 7.00 (m, 2H), 7.20 (d, 2H), 7.50 (d, 2H), 8.85 (s, 2H), 9.15 (s, IH). MS m/z: 435/437 (M+l). | |
With thionyl chloride; for 2h;Heating / reflux; | Pyrimidine-5-carboxylic acid 43 (20 mmol, Peakdale Mol. Int., 20044809) and thionyl chloride (20 mL) is refluxed for 2 hours. Excess thionyl chloride is removed via rotary evaporation followed by a protocol of treatment with benzene followed by rotary evaporation. Compound 44 is used without further purification. |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; | The titled compound was prepared according to the procedure of Method D using 3,4-difluoro-N'-hydroxybenzimidamide (Tyger) and pyrimidine-5-carbonyl chloride. The <n="80"/>pyrimidine-5-carbonyl chloride was prepared by the reaction of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (Maybridge, 138 mg, 1.0 mmol) with oxalyl chloride (Aldrich, 2 M, in CH2Cl2, 1.0 mL, 2.0 mmol) and a drop of dimethylformamide at room temperature over 1 hour with subsequent removal of volatiles under reduced pressure. 1H NMR (300 MHz, DMSO-J6) delta 7.72 (dt, J=10.5, 8.5 Hz, 1 H), 7.94 - 8.05 (m, 1 H), 8.11 (ddd, J=10.9, 7.7, 2.0 Hz, 1 H), 8.12 (none, 1 H), 9.51 (s, 1 H), 9.54 (s, 2 H) ppm; MS (DCIZNH3) m/z 261 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Pyrimidine-5-carboxylic acid 19.50 ml (149 mmol) ethyl pyrimidine-5-carboxylate are shaken in 40 ml of 4 molar sodium hydroxide solution for 0.1 hours at ambient temperature, then 40 ml of 4 molar hydrochloric acid solution are added. The precipitate formed is suction filtered, washed with petroleum ether and dried. Yield: 14.80 g (80percent of theoretical) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With thionyl chloride; In N,N-dimethyl-formamide; at 70℃; for 4h; | Pyrimidine-5-carbonyl chloride hydrochloride 7.50 g (60 mmol) <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> are stirred in 50 ml of thionyl chloride and 0.5 ml dimethylformamide for 4 hours at 70° C. The reaction mixture is evaporated to dryness and re-evaporated several times with toluene. Yield: 7.80 g (72percent of theoretical) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | Example 29 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyrimidine-5-carbonyl)-piperidin-4-yl]-nicotinamide 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110 mg, 0.276 mmol), 1-hydroxybenzotriazole (46 mg, 0.304 mmol) and N-methylmorpholine (67.box.l, 0.611 mmol) were added to a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (52 mg, 0.42 mmol) in dichloromethane (2.5 ml) under nitrogen at room temperature and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89 mg, 0.468 mmol) was added. The reaction was stirred at room temperature for 18 h and quenched with sat. ammonium chloride (0.5 ml) and diluted with water (3 ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluding with a solvent gradient of dichloromethane: methanol:concentrated aqueous ammonia (99.5:0.5:0.05 changing to 95:5:0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyrimidine-5-carbonyl)-piperidin-4-yl]-nicotinamide (40 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): delta=9.21 (1H, s), 8.82 (2H, s), 8.11-8.13 (1H, d), 7.98-8.02 (1H, m), 7.30-7.35 (1H, t), 7.11-7.15 (1H, d), 7.04 (1H, s), 6.84-6.88 (1H, d), 4.41-4.58 (1H, brs), 4.16-4.22 (1H, m), 3.61-3.75 (1H, brs), 3.12-3.40 (2H, m, partially masked by solvent), 2.45 (3H, s), 1.96-2.16 (2H, m), 1.56-1.72 (2H, m) ppm. LRMS (electrospray): m/z [M-H]+ 466. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 14h;Inert atmosphere; | Step A: Preparation of N-methoxy-N-methylpyrirnidine-5-carboxamide. [00245] To a stirred mixture of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (2.5 g, 20.15 mmol), and N,0- dimethyl hydroxylamine hydrochloride (2.49 g, 25.5 mmol) in DCM (50 mL), EDC HC1 (4.63 g, 24.17 mmol) and DMAP (3.69 g, 30.2 mmol) were added under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure; the obtained crude material was purified by flash column chromatography (100-200, Si02, 50-70 percent EA/Hexanes) to get N-methoxy-N-methylpyrimidine-5- carboxamide as a pale brown liquid. The product was confirmed by 1H NMR and LCMS. (2.8 g, 83percent). 1H NMR (400MHz, CDC13) delta 9.28 (s, 1H), 9.10 (s, 2H), 3.59 (s, 3H), 3.41 (s, 3H); ESIMS m/z 167.97 [M+H]+. |
21% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h; | Combine EDCI (0.99 g, 5.18 mmol) with a solution OF O, N- dimethylhydroxylamine hydrochloride (0.51 g, 5.23 MMOL), PYRIMIDINE-5-CARBOXYLIC (540 mg, 4.35 MMOL), triethylamine (1.5 mL, 10.4 mmol), and DMAP (0.64 g, 5.24 mmol) in DMF (10 mL) and stir at RT. After 24 h, treat the reaction mixture with saturated NAHC03 and extract with CH2CI2. Wash the organic layer with water, dry over sodium sulfate, filter, and concentrate under reduced pressure. Purification by flash chromatography eluting with a linear gradient of 15percent to 30percent EtOAc in hexanes gives the title compound (0.15 g, 21percent). MS (ES) 168.2 (M+1) + ;'H NMR (400 MHz, CHCI3) 8 9.21 (s, 1H), 9.02 (s, 2H), 3.53 (s, 3H), 3.34 (s, 3H). |
1,1?-carbonyldiimidazole (1.23 g, 7.57 mmol) was added to a suspension of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (783 mg, 6.31 mmol) in DCM (20 mL) and the mixture was stirred at room temperature for 15 min before addition of N,O-dimethylhydroxylamine hydrochloride (739 mg, 7.57 mmol). The mixture was stirred at room temperature for 5 d, then was diluted with saturated aqueous NH4Cl and water and extracted with DCM. The organic phase was washed with water, and the aqueous phases were back-extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as a light yellow oil which was used without further purification in the next reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; diisopropyl-carbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h; | Pyrimidine-5-carboxylic acid (113 mg, 0.91 mMol), (5R)-3- (3-fluoro-4- {6- [ (5S)-5- (HYDROXYMETHYL) -4, 5-DIHYDROISOXAZOL-3-YL] PYRIDIN-3-YL LPHENYL)-5-(LH-1, 2, 3-TRIAZOL-1- YLMETHYL)-1, 3-oxazolidin-2-one (Example 1: 200mg, 0.46 MMOL), 4- (dimethylamino) pyridine (5 mg, 0.041 mmol) and DMF (2 ml) were combined and warmed to give a clear solution. The solution was allowed to cool to room temperature, and then diisopropylcarbodiimide (0.15 ml, 0.96 mmol) was added. The mixture was stirred for 18 hours to give a suspension, which was diluted with ether (50 ml) and hexane (25 ml). The solids were collected, rinsed with ether, dissolved in 1: 1 acetonitrile : methanol, adsorbed on silica gel and purified by chromatography (silica gel; elution with 1 to 10percent methanol in dichloromethane). The product containing fractions were pooled and evaporated to give the title compound as a white solid, 160 mg. Mp 253-264 oC. MS (electrospray) : 545 (M+1) for C26H21FN805 1H-NMR (400 MHZ, DMSO-D6) # : 3.52 (dd, 1H); 3.68 (dd, 1H); 3.96 (dd, 1H); 4.30 (t, 1H); 4.47 (dd, 1H); 4.58 (dd, 1H); 4. 86 (d, 2H); 5. 18 (m, 2H); 7.42 (dd, 1H); 7.59 (dd, 1H); 7.70 (t, 1H) ; 7.77 (s, 1H) ; 8.01 (d, 1H); 8.08 (dm, 1H) ; 8.18 (s, 1H); 8.83 (s, 1H) ; 9.17 (s, 2H); 9.39 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); for 18h; | To a solution of the above compound (123 mg, 0.371 mmol) in DMF (2 ML) was added 5-PYRIMIDINECARBOXYLIC acid (46 mg, 0.371 mmol), HOAT (51MG, 0. 371MMOL), triethylamine (38 mg, 0. 371MMOL) and EDC (71 mg, 0.371 mmol) and the mixture stirred for 18 h. This mixture was purified directly on Gilson LC using Waters PrepPak and eluting with an 5-95% aq ACN gradient over 20MIN. The desired fractions were lyophilized and the resulting amorphous solid was dissolved in CH2C12, washed with aq. Na2CO3, dried over MGS04, filtered and the solvent removed in vacuo to give N- [1- ( { [(LR)-L-(2 -AMINO-3, 3 -DIFLUORO-1, 1 -BIPHENYL-4-YL) ethyl] amino} carbonyl) cyclopropyl] pyrimidine-5- carboxamide the title compound. Low resolution mass spectrometry: (M+H+) = 438.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 6. PREPARATION OF {(1S,4S)-5-[(S)-1-(2-CHLORO-4-METHOXY-3-METHYL-PHENYL)- ETHYL]-2,5-DIAZA-BICYCLO[2.2.1]HEPT-2-YL(at)-(1-OXY-PYRIDIN-4-YL)-METHANONE [0161] Isonicotinic acid N-oxide (8.3 mg, 0.06 mmol), BOP (33.2 mg, 0.075 mmol), and Et3N (17.4 pL, 0.125 mmol) are added to a solution of (lS,4S)-2-[(S)-1-(2-chloro-4-methoxy-3- methylphenyl)-ethyl]-2,5-diazabicyclo [2.2.1]heptane (14 mg, 0.05 mmol) in anhydrous DMA (1 mL). The reaction mixture is stirred at room temperature for 16 h, diluted with EtOAc, washed with aqueous NaOH IN (2 x 8 mL) and brine, dried with NazS04, filtered and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography eluting with CH2C12- MeOH-NH40H (90-9-1) to afford the title compound as a yellow oil. LC/MS: 402 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; | Into a solution of the above amine (0.050 g, 0.13 mmol), <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (0.017 g, 0.14 mmol) and 1-hydroxybenzotriazole hydrate (0.008 g, 0.05 mmol) in THF (1.3 mL) was added triethylamine (0.019 g, 0.19 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.034 g, 0.018 mmol). After stirring overnight, the reaction mixture was diluted with ethyl acetate and washed with 5percent sodium bicarbonate, and then with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel chromatography eluted with 1-9percent methanol in methylene chloride to provide the title compound. LRMS (ES, M+H+): 503 1H NMR (CD3OD): delta 9.32 (s, 1H), 9.29 (s, 2H), 8.22 (bs, 1H), 7.91 (bd, J=8 Hz, 1H), 7.67 (bd, J=8 Hz, 1H), 7.55 (dt, J=8 and 5.6 Hz, 1H), 7.49 (m, 2H), 7.24 (m, 2H), 7.15 (m, 2H), 4.69 (s, 2H), 3.69 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 45 N-(4-Ethoxy-2-nitrophenyl)-5-pyrimidinecarboxamide The title compound was prepared from <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.16 (s, 1H), 9.43 (s, 1H), 9.32 (s, 2H), 8.81 (d, J=9.3, 1H), 7.76 (d, J=3.0, 1H), 7.34-7.27 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; acetic acid; In tetrahydrofuran; ethanol; water; | 1) Crude <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (1.24 g, 10 mmol) was dissolved in 100 ml THF (dry), 3 ml water, and cooled to 0° C. in the reaction vessel of a Mini-Diazald.(R). apparatus (Aldrich Chemical). Diazald.(R). (3 g, 14 mmol) dissolved in ether (27.5 ml) was added dropwise over 15 minutes to KOH (3 g) in ethanol/water (11 ml) at 65° C. to generate diazomethane. Ether (20 ml) was added dropwise, after the Diazald.(R). solution, to co-distill the remaining diazomethane into the reaction flask. The reaction was allowed to stir 3 hours until nitrogen evolution had stopped, and excess diazomethane was then destroyed by adding acetic acid. The solvents were evaporated in vacuo,. the residue taken up in 50 ml water, basified to pH 9 (NaCO3), and extracted with chloroform (3*100 ml). After drying (MgSO4), filtering, and evaporating the solvent in vacuo, 1.26 g (91percent) crude crystals were obtained. Recrystallization from chloroform/hexane gave 606 mg (44percent) light yellow crystals mp 81.6°-86.6° C. Microanalysis calc.: C 52.17, H 4.38, N 20.29; found: C 51.95, H 4.31, N 19.96. 400 MHz nmr indicated product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.11 g yellow oil (92%) | With hydrogenchloride;Pd-on-carbon; In water; | Example 2 1,4,5,6-Tetrahydropyrimidine-5-carboxylic Acid Hydrochloride Pyrimidine-5-carboxylic acid (5.0 g, 40 mmol) was suspended in a mixture of 150 ml water and concentrated hydrochloric acid (4.0 g, 40.5 mmol). The mixture was hydrogenated at 26 psig over 1.0 g Pd-on-carbon 10percent in a Parr hydrogenator for 3 h. The suspension was filtered and the filter rinsed twice with hot water (20 ml). The filtrate was evaporated in vacuo to give 6.11 g yellow oil (92percent). The oil was crystallized from anhydrous methanol/tetrahydrofuran (THF) to give 5.77 g (87percent) white crystals in two crops. 300 MHz nmr indicated product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 20h; | EXAMPLE 15:; Pvrimidine-5-carboxylic acid (4-f4-(2-terf-butvl-6-cyclobutvl-pvrimidin-4-vl)-piperazin-1 -vll-butyD-amide; 0.1 g of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (0.805 mmol) and 0.28 g of 4-[4-(2-te/Y-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (0.805 mmol) were dissolved in 10 ml of dichloromethane. 0.46 g of diisopropylethylamine (3.17 mmol), 0.054 g of hydroxybenzotriazole (HOBt, 0.4 mmol), and 0.17 g of N-ethyl-N'-(3-dimethylamino-propyl)-carbodiimid hydrochloride (EDCI, 0.88 mmol) were added at 0°C. The reactionmixture was stirred for 16 h at room temperature. Then, 0.085 g of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimid hydrochloride were added and the reaction mixture was stirred for 4 h. The solvent was evaporated and the residue partitioned between and ethyl acetate and saturated aqueous sodium chloride. 4 ml of acetone were added to improve phase separation. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5-10percent). Evaporation of the solvent yielded 0.16 g of the title compound as a white solid.MS (ESI) m/z: 452.2 [M+H]+1H-NMR (DMSO): 5 [ppm] 9.3 (s, 1H), 9.2 (s, 2H), 8.7 (t, 1H), 6.4 (s, 1H), 3.5-3.65 (m, br, 4H), 3.25-3.45 (m, 4H), 2.4 (m, 3H), 2.35 (m, 2H), 2.1-2.3 (m, 3H), 1.95 (m, 1H), 1.85 (m, 1H), 1.5-1.65 (m, 4H), 1.3 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In dichloromethane; | (a) 5-pyrimidyl carboxylic acid, 1.9 gm, was added to 30 ml of methylene chloride. 2.4 gm of carbonyldiimidazole was added to the system. The system was stirred at room temperature for 3 hours to form the 5-pyrimidyl carboxylic acid imidazolide. | |
In dichloromethane; | (a) 5-pyrimidyl carboxylic acid, 1.9 gm, was added to 30 ml of methylene chloride. 2.4 gm of carbonyldimidazole was added to the system. The system was stirred at room temperature for 3 hours to form the 5-pyrimidyl carboxylic acid imidazolide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 17h; | Example 6; Pyrimidine-5-carboxylic acid {2-[l-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4- ylamino]-benzooxazol-7-yl}- amide; 0.40 g (0.94 mMol) of N2-[ l-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]- benzooxazole-2,7-diamine (example 3]) was suspended in 10 mL Of MeCl2 at RT under Ar; then, 0.116 g ( 1.0 eq.) of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong>, 0.219 g ( 1.20 eq.) of N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride and 0.151 g ( 1.30 eq.) of Lambdaf,iV-dimethyl-4-aminopyridine were added. The reaction mixture became a clear solution after stirring for 1 h at RT. After 16 h, the solution was evaporated i.v. and the residue was purified by chromatography (silicagel, eluent: gradient of MeCl2 / MeOH) to yield 0.115 g of the title compound as colorless foam.MS: 535.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; trifluoroacetic acid; In diethyl ether; dichloromethane; water; acetonitrile; | EXAMPLE 166 5-[(2-methyl-1-pyrrolidinyl)carbonyl]pyrimidine The desired product can be prepared by substituting <strong>[4595-61-3]5-pyrimidinecarboxylic acid</strong> for 6-methylnicotinic acid in Example 1. After workup the crude compound is purified by HPLC on a C-18 column with a solvent system increasing in gradient over 50 minutes from 5percent to 100percent acetonitrile/water containing 0.01percent TFA to provide the product as the trifluoroacetate salt. This dissolved in dichloromethane and shaken with basic resin MP carbonate for four hours. The resin is removed by filtration and the filtrate is concentrated in vacuo. The free base is dissolved in diethyl ether and treated dropwise with 1.0 M HCl in diethyl ether. The precipitate isolated by filtration to provide the desired product as the hydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Step 10: Preparation of N-r7-methoxy-8-(3-morpholin-4-ylpropoxy)-2.3- dihvdroimidazopi ^-ciquinazolin-S-vnpyrimidine-delta-carboxamide .; <n="71"/>7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-amine (100 mg, 0.22 mol) was dissolved in DMF (5 ml_), and <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (41 mg, 0.33 mmol) was added. PYBOP (173 mg, 0.33 mmol) and diisopropylethylamine (0.16 ml_, 0.89 mmol) were subsequently added, and the mixture was stirred at rt overnight. EtOAc was added, and the precipitate was isolated by vacuum filtration to give the title compound (12 mg, 11percent): HPLC MS RT = 1.07 min, MH+= 466.2; 1H NMR (DMSO-cfe + 2 drops TFA-cQ delta: 9.48 (2H, s), 9.39 (1 H, s), 8.05 (1 H, d), 7.47 (1 H, d), 4.59 (2H, m), 4.35 (2H, br t), 4.26 (2H, m), 4.02 (3H, s), 4.00 (2H, m), 3.67 (2H, br t), 3.52 (2H, m), 3.33 (2H1 m), 3.16 (2H, m), 2.27 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 96h; | Example 159(3S,4S)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-1-(pyrimidin-5-ylcarbonyl)piperidine-4-carboxamideTo a solution of (3S,4S)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methylpiperidine-4-carboxamide monohydrochloride (150 mg) synthesized by a known method (WO2006/004195), <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (47.1 mg) and Et3N (119 muL) in THF (5 mL) were added WSC.HCl (83.5 mg) and HOBt.H2O (66.7 mg), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 50?100% ethyl acetate/hexane) to give the title compound (135 mg, 80%) as a white amorphous solid.MS (ESI+):597 (M+H)[alpha]D25+80.1 (c 0.95, MeOH)elemental analysis value: C29H27N4O2F7.0.3H2OFound C, 57.82; H, 4.65; N, 9.16Calculated C, 57.87; H, 4.62; N, 9.311H-NMR (300 MHz, CDCl3):delta 1.46 (3H, d, J=7.0 Hz), 1.81-2.15 (2H, m), 2.27-2.53 (3H, m), 2.59 (3H, s), 2.73-3.02 (1H, m), 3.13-3.41 (1H, m), 3.20 (1H, dt, J=10.8, 4.1 Hz), 3.45-4.04 (2H, m), 4.72-5.09 (1H, m), 5.91 (1H, q, J=6.9 Hz), 6.78-6.89 (2H, m), 7.02-7.19 (1H, m), 7.58 (2H, s), 7.77 (1H, s), 8.86 (2H, s), 9.29 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 96h; | Example 158(3S,4S)-N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methyl-1-(pyrimidin-5-ylcarbonyl)piperidine-4-carboxamideTo a solution of (3S,4S)-N-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-3-(4-fluoro-2-methylphenyl)-N-methylpiperidine-4-carboxamide monohydrochloride (150 mg) synthesized by a known method (WO2006/004195), <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (47.1 mg) and Et3N (119 muL) in THF (5 mL) were added WSC.HCl (83.5 mg) and HOBt.H2O (66.7 mg), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 50?100% ethyl acetate/hexane) to give the title compound (137 mg, 81%) as a white crystal powder.MS (ESI+):597 (M+H)[alpha]D25-73.7 (c 0.90, MeOH)elemental analysis value: C29H27N4O2F7.0.2H2OFound C, 58.08; H, 4.48; N, 9.20Calculated C, 58.04; H, 4.60; N, 9.34Melting point: 185-188 C.1H-NMR (300 MHz, CDCl3):delta 1.47 (3H, d, J=6.4 Hz), 1.81-2.15 (2H, m), 2.39-2.56 (3H, m), 2.68 (3H, s), 2.85-3.02 (1H, m), 3.05-3.37 (2H, m), 3.46-4.01 (2H, m), 4.68-5.04 (1H, m), 5.91 (1H, q, J=6.6 Hz), 6.70-6.88 (2H, m), 6.94-7.09 (1H, m), 7.26 (2H, s), 7.73 (1H, s), 8.86 (2H, s), 9.28 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; | (R)-4-{l-[(l-Amino-cyclopropanecarbonyl)-amino]-ethyl}-benzoic acid methyl ester (74.5 mg, 0.284 mmol) was added to a stirred solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (42.3 mg, 0.341 mmol), HATU (129.6 mg, 0.341 mmol) and DIPEA (247.3 muL, 1.420 mmol) in DMF (2 mL). After stirring overnight the reaction mixture was concentrated in vacuo and the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (50 mL). After extraction of the aqueous layer with EA (2 x 30 mL) the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound which was used for the next reaction without further purification. MS (m/z): 368.9 [M+H*] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PS-carbodiimide; triethylamine; In dichloromethane; at 120℃; for 1h;Microwave irradiation; | Example 1.32: Preparation of (tf)-(5-(4-(2-(2-Methylpyrrolidin-l- yl)ethyl)phenyl)isoindolin-2-yl)(pyrimidin-5-yl)methanone (Compound 29).In a 10 mL microwave vial were placed (R)-5-(4-(2-(2-methylpyrrolidin-l- yl)ethyl)phenyl)isoindoline (0.100 g, 0.326 mmol), <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (0.0607 g, 0.489 mmol), triethylamine (0.0910 mL, 0.653 mmol), PS-carbodiimide (1.02 g, 1.63 mmol), and CH2Cl2 (3 mL). The reaction was heated under microwave irradiation at 1200C for 1 h. The <n="78"/>mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by HPLC to give the TFA salt of the title compound as a white solid (0.060 mg). LCMS m/z = 413.2 [M+H]+; 1H NMR (400 MHz, Methanol-*/,) delta ppm 1.26-1.31 (m, 3H), 1.48 (dd, J = 6.44, 3.66 Hz, 4H), 2.10 (s, 2H), 3.03-3.18 (m, 2H), 3.44-3.58 (m, IH), 3.69-3.80 (fn, IH), 4.91-4.96 (m, IH), 4.96-5.00 (m, IH), 5.01-5.08 (m, 2H), 7.34-7.50 (m, 4H), 7.54-7.67 (m, 4H), 9.10 (s, 2H), 9.30 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium-on-charcoal; In water; | 3-Bromopyrimidine (compound 21) may be carboxylated by treatment with n-butyl lithium and carbon dioxide in tetrahydrofuran to give the acid 22. The latter compound may be hydrogenated using any suitable catalyst such as Pd/C in a solvent such as water to provide tetrahydropyrimidine 23. Formation of the methyl ester from 23, may be carried out using standard conditions such as HCl in methanol to give compound 24. Alternatively, ethanol in HCl could be used to generate the ethyl ester. Any suitable N-protecting group may be installed to give intermediate 19. Exemplary N-protecting groups include trityl, Mmt, 4,4'- dimethoxytrityl, and 4,4',4"-trimethoxytrityl (suitable protecting conditions include the use of the corresponding chloride, and a base such as DBU in a solvent such as dichloromethane, at ambient temperature for 2-24 hours). [0077] Where a thiadiazole is desired, the oxygen in the above syntheses may be replaced with a sulfur. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | 5.115 PYRIMIDINE-5-CARBOXYLIC ACID [2-(2,6-DIOXOPIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLMETHYL]AMIDE A mixture of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (0.25 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 2 hours. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The solvent was evaporated under vacuum, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting with 95:5 methylene chloride-methanol, providing 0.39 g of the product in 50percent yield: mp >260° C.; 1H NMR (DMSO-d6) delta 2.05-2.10 (m, 1H), 2.53-2.65 (m, 2H), 2.83-2.91 (m, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.18 (dd, J=12.4 Hz, d=5.4 Hz, 1H), 7.84 (s, 3H), 9.24 (s, 2H), 9.35 (s, 1H), 9.52 (t, J=5.7 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) delta 22.0, 30.9, 38.3, 48.9, 122.1, 127.3, 127.5, 131.6, 133.4, 134.9, 138.4, 156.0, 160.1, 163.5, 167.0, 167.5, 169.8, 172.8; Anal. calcd for C19H15N5O5.0.3H2O: C, 57.23; H, 3.94; N, 17.56. Found: C, 57.27; H, 3.71; N, 17.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (0.088 g, 0.709 mmol), lambda/-[3-(dimethylamino)propyl]-lambda/'-ethylcarbodiimide hydrochloride (0.136 g, 0.709 mmol) and 1H- 1,2,3-benzotriazol-1-ol (0.072 g, 0.534 mmol) in DMF (4 mL) was heated at 4O0C for 15 minutes. Finally, 3"-fluoro-3,2':3',4"-terpyridine-5',61-diamine (Intermediate 1, 0.15 g,0.534 mmol) in DMF (4 mL) was added and the mixture was stirred at room temperature overnight. The crude mixture was extracted between ethyl acetate and water. The organic layer was washed with 4percent sodium bicarbonate aqueous solution and water, dried (MgSO4) and evaporated. The residue (0.2 g) was used in the next step without further purification.ESI/MS m/e: 388 ([M+H]+, C20H14FN7O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (200 mg, 0.70 mmol) in pyridine (1.0 mL) is added thionyl chloride (61 mu, 0.84 mmol). The mixture is stirred at room temperature for 15 minutes before 1-14 (91 mg, 0.74 mmol) is added. The resulting mixture is heated at 110 °C for 18 h then concentrated in vacuo. The residue is partitioned between EtOAc and saturated aqueous NaHC03, washed with brine, dried with Na2S04, filtered, and concentrated in vacuo to give the title compound (236 mg); m/z 373.0, 375.0 [M, M+2H] | ||
236 mg | Synthesis of 5-{3-[2-(4-bromophenyl)-3-methylbutan-2-yl]-1,2,4-oxadiazol-5-yl}pyrimidine To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (200 mg, 0.70 mmol) in pyridine (1.0 mL) is added thionyl chloride (61 muL, 0.84 mmol). The mixture is stirred at room temperature for 15 minutes before I-14 (91 mg, 0.74 mmol) is added. The resulting mixture is heated at 110° C. for 18 h then concentrated in vacuo. The residue is partitioned between EtOAc and saturated aqueous NaHCO3, washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give the title compound (236 mg); m/z 373.0, 375.0 [M, M+2H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | To a mixture of l-(7H-pynOlo[2,3-JJpyrimidin-4-y^ D2 (65.2 mg), 5- pyrimidinecarboxylic acid (37.2 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0.180 mmol) in DMF (1.5 mL) was added DIPEA (252 mu,, 1.440 mmol). The reaction mixture was stirred at room temperature until reaction was complete then solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E14 (21 mg), NMR ( 6-DMSO) delta 11.70 (1H, brs), 9.30 (1H, s), 9.15 (2H, s), 8.65 (1H, d), 8.17 (1H, s), 7.17 (1H, d), 6.60 (1H, d), 4.65 (2H, dt), 4.15 (1H, m), 3.25 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 324 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; | 117. f-)-2-f(3.,4-trans)-4-methyl-l-fpyrimi(iine-5-carbonyl)pyrroli(iin-3-yl)- 7-ftetrahvdro-2H-pyran-4-yl)imidazo[5,l- 1 [l,2,41triazin-4f3H -one [1076] To a stirred solution of (-)-2-((3,4-trans)-4-methylpyrrolidin-3-yl)-7- (tetrahydro-2H-pyran-4-yl)imidazo[5,l- J[l,2,4]triazin-4(3H)-one (100 mg, 0.33 mmol) in DMF (10 mL) were added EDCI (95 mg, 0.49 mmol), HOBt (67 mg, 0.49 mmol), DIPEA (0.2 mL, 0.99 mmol) and <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (53 mg, 0.42 mmol) at 0 °C under argon atmosphere. The resulting reaction mixture was allowed to warm to room temperature and stirred for 8 h. The reaction mass was diluted with water (100 mL) and extracted with DCM (3 x 50 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford (-)-2-((3,4-trans)-4-methyl-l-(pyrimidine-5-carbonyl)pyrrolidin-3-yl)-7- (tetrahydro-2H-pyran-4-yl)imidazo[5,l: ][l,2,4]triazin-4(3H)-one (50 mg, 37percent) as an off-white solid. 1H-NMR (DMSO d6, 400 MHz): delta 9.28 (s, 1H), 9.02 (d, 2H), 7.62- 7.60 (m, 1H), 4.01-3.96 (m, 4H), 3.81-3.74 (m, 2H), 3.50-3.47 (m, 2H), 3.24-3.21 (m, 1H), 3.01-2.96 (m, 1H), 2.71-2.64 (m, 1H), 1.87-1.81 (m, 4H), 1.08 (d, 3H); Mass (ESI): 410.4 [M++l]; LC-MS: 93.25percent; 410.3 (M++l); (column; X-bridge C-18, (50x3.0 mm, 3.5mu); RT 1.76 min. 0.05percent TFA in water: ACN; 0.8 ml/min); UPLC (purity): 98.82percent; (column; Acquity BEH C-18, (50x2.1 mm, 1.7mu); RT 1.26 min. 0.025percent TFA (Aq): ACN; 0.50 ml/min; Chiral HPLC: 100percent, R, = 13.15 min (Chiralpak IA, 250 x 4.6mm, 5mu; mobile phase (A) 0.1percent DEA in n-Hexane (B) DCM:MeOH (70:30) (A: B : 70:30); flow Rate: 1.00 mL/min); Optical rotation [a]D20: -27.21° (c = 0.25, DCM). TLC: 10percent MeOH/DCM (Rf: 0.7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h; | To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (250 mg,2.00 mmol, 1.1 equiv; [CAS RN 4595-61-3]) in anhydrous DCM (8 mL) was added 3-(4-chloro-phenyl)-prop-2-yn-1-ol(310 mg, 1.83 mmol, 1.0 equiv; [CAS RN 37614-57-6]), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) hydrochloride (420 mg,2.20 mmol, 1.2 equiv; [CAS RN 25952-53-8]) and4-dimethylaminopyridine (54 mg, 0.44 mmol, 0.2 equiv). The reaction mixturewas stirred at rt for 2 h and then quenched by addition of a sat. solution ofNaHCO3 (20 mL). The crude product was extracted with DCM (3 x 50 mL). Thecombined organic layers were dried over MgSO4, concentrated underreduced pressure and the product purified by MPLC eluting with a gradient ofDCM / methanol. The title compound was isolated as white solid (366 mg, 74percent).1H NMR (600 MHz, CDCl3): d = 5.21 (s, 2H), 7.31 (dt, J = 3.1, 5.5 Hz, 2H), 7.40 (dt, J = 3.1, 5.5 Hz, 2H), 9.34 (s, 2H), 9.40(s, 1H). 13C NMR (150 MHz, CDCl3): d = 54.1, 83.0, 86.5, 120.4, 123.9,128.9, 133.3, 135.4, 158.3, 161.9, 163.2. MS (EI+): m/z[M]+ 272.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (1.38 g, 11.13 mmol, 1.1equiv; [CAS RN 4595-61-3]) in DMF (44 mL) was added 3-(4-trifluoromethyl-phenyl)-prop-2-yn-1-ol(2.02 g, 10.1 mmol, 1.0 equiv; [CAS RN 173546-21-9]), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) hydrochloride (2.33 g, 12.1 mmol, 1.2 equiv; [CASRN 25952-53-8]) and 4-dimethylaminopyridine (0.25 g, 2.0 mmol, 0.2 equiv). The reaction mixturewas stirred at rt for 2 h and then concentrated by evaporation under reducedpressure. A sat. solution of NaHCO3 (50 mL) was added and the crude productextracted with DCM (3 x 100 mL). The combined organic layers were dried over MgSO4,concentrated under reduced pressure and the product purified by MPLC elutingwith a gradient of DCM / methanol. The title compound was isolated as whitesolid (2.36 g, 76percent). 1H NMR (600 MHz, CDCl3): d = 5.23 (s, 2H), 7.57 ? 7.60 (m, 4H), 9.35 (s, 2H), 9.41 (s, 1H). 13CNMR (150 MHz, CDCl3): d = 54.0, 84.5, 86.1, 123.9 (q, JCF= 270.6 Hz), 123.9 (br s), 125.5 (q, JCF= 3.7 Hz), 125.7 (d, JCF =1.4 Hz), 131.0 (q, JCF =32.6 Hz), 132.3, 158.3, 161.9, 163.1. 19F NMR (280MHz, CDCl3): d = -63.0. HRMS (ESI+): m/z [M]+ calcd for C15H9F3N2O2:306.0616, found: 306.0610. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (1.41 g, 11.37 mmol, 1.1equiv; [CAS RN 4595-61-3]) in DMF (44 mL) was added 3-(3-trifluoromethyl-phenyl)-prop-2-yn-1-ol(2.07 g, 10.3 mmol, 1.0 equiv; [CAS RN 65126-85-4]), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) hydrochloride (2.38 g, 12.4 mmol, 1.2 equiv; [CASRN 25952-53-8]) and 4-dimethylaminopyridine (0.25 g, 2.1 mmol, 0.2 equiv). The reaction mixturewas stirred at rt for 18 h and then concentrated by evaporation under reducedpressure. A sat. solution of NaHCO3 (50 mL) was added and the crude productextracted with DCM (3 x 100 mL). The combined organic layers were dried over MgSO4,concentrated under reduced pressure and the product purified by MPLC elutingwith a gradient of DCM / methanol. The title compound was isolated as light yellowoil (2.24 g, 72percent). 1H NMR (600 MHz, CDCl3): d = 5.23 (s, 2H), 7.47 (dd, J = 7.9, 7.9 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.74 (s, 1H), 9.36 (s,2H), 9.41 (s, 1H). 13C NMR (150 MHz, CDCl3): d = 54.0, 83.7, 86.0, 122.9, 123.7 (q, JCF = 270.6 Hz), 123.9, 125.8(q, JCF = 3.6 Hz), 128.9(q, JCF = 3.9 Hz), 129.1,131.2 (d, JCF = 32.5 Hz),135.2 (q, JCF = 1.1 Hz),158.3, 161.9, 163.1. 19F NMR (375MHz, CDCl3): d = -63.0. HRMS (ESI+): m/z [M]+ calcd for C15H9F3N2O2:306.0616, found: 306.0615. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h; | To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (150mg, 1.21 mmol, 1.0 equiv; [CAS RN 4595-61-3]) in DMF (5 mL) at0°C was added 3-(4-chloro-phenyl)-prop-2-ynylamine (200 mg, 1.21 mmol,1.0 equiv; [CAS RN 944818-98-8]) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) hydrochloride (284 mg, 1.45 mmol, 1.2 equiv; [CASRN 25952-53-8]). Thecooling bath was removed and the reaction stirred at rt for 18 h. A sat.solution of NaHCO3 (50 mL) was added and the crude productextracted with diethyl ether (3 x 50 mL). The combined organic layers were driedover MgSO4, concentrated under reduced pressure and the productpurified by MPLC eluting with a gradient of DCM / methanol. The title compoundwas isolated as white solid (276 mg, 84percent). 1H NMR (600 MHz, [D6]DMSO): d = 4.38 (d, J = 5.4 Hz,2H), 7.44 ? 7.47 (m, 4H), 9.19 (s, 2H), 9.33 (s,1H), 9.42 (br t, J = 5.4Hz, 1H). 13C NMR (150 MHz, [D6]DMSO): d = 29.3, 80.9, 87.6, 121.0, 127.3, 128.9, 133.2, 133.4, 156.0, 160.2, 162.9. HRMS (ESI+): m/z [M]+ calcd for C14H10ClN3O:271.0512, found: 271.0510. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h; | To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (2.12 g, 17.08 mmol, 1.0equiv; [CAS RN 4595-61-3]) in DMF (75 mL) at 0°C was added 3-(4-trifluoromethyl-phenyl)-prop-2-ynylamine (3.41 g, 17.1 mmol, 1.0 equiv; [CASRN 486437-19-8]) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide)hydrochloride (4.01 g, 20.5 mmol, 1.2 equiv; [CAS RN 25952-53-8]). The cooling bath wasremoved and the reaction stirred at rt for 18 h. A sat. solution of NaHCO3(200 mL) was added and the crude product extracted with diethyl ether (3 x 150 mL). Thecombined organic layers were dried over MgSO4, concentrated underreduced pressure and the product purified by MPLC eluting with a gradient ofDCM / methanol. The title compound was isolated as white solid (4.33 g, 83percent). 1H NMR (600 MHz, [D6]DMSO): d = 4.43(d, J = 5.3 Hz, 2H), 7.65 ? 7.68 (m, 2H), 7.73 ? 7.77(m, 2H), 9.20 (s, 2H), 9.34 (s, 1H), 9.46 (br t, J = 5.3 Hz, 1H). 13C NMR (150 MHz, [D6]DMSO): d = 29.3,80.7, 89.4, 124.0 (q, JCF = 269.3 Hz), 125.6 (q, JCF= 3.8 Hz), 126.4 (q, JCF = 1.5 Hz), 127.2, 128.6 (q, JCF= 32.1 Hz), 132.2, 156.0, 160.2, 162.9. 19F NMR (375 MHz, [D6]DMSO): d = -61.3. HRMS (ESI+): m/z [M]+calcd for C15H10F3N3O: 305.0776,found: 305.0781. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h; | To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (773 mg, 6.04 mmol, 1.0equiv; [CAS RN 4595-61-3]) in DMF (25 mL) at 0°C was added 3-(3-trifluoromethyl-phenyl)-prop-2-ynylamine (1.20 g, 6.04 mmol, 1.0 equiv; [CAS RN 929974-93-6]) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) hydrochloride (1.39 g, 7.25 mmol, 1.2 equiv; [CASRN 25952-53-8]). Thecooling bath was removed and the reaction stirred at rt for 18 h. A sat.solution of NaHCO3 (100 mL) was added and the crude productextracted with diethyl ether (3 x 80 mL). The combined organic layers were driedover MgSO4, concentrated under reduced pressure and the productpurified by MPLC eluting with a gradient of DCM / methanol. The title compoundwas isolated as white solid (1.66 g, 90percent). 1H NMR (600 MHz, [D6]DMSO): d = 4.41(d, J = 5.3 Hz, 2H), 7.62 ? 7.65 (m, 1H), 7.75 ? 7.77(m, 3H), 9.20 (s, 2H), 9.34 (s, 1H), 9.44 (br t, J = 5.3 Hz, 1H). 13C NMR (150 MHz, [D6]DMSO): d = 29.3,80.5, 88.4, 123.2, 123.7 (q, JCF = 270.9 Hz), 125.3, 127.3, 127.8 (q, JCF= 3.8 Hz), 129.6 (q, JCF = 31.9 Hz), 130.0, 135.3, 156.0, 160.2, 162.9. 19F NMR (375 MHz, [D6]DMSO): d = -61.5. HRMS (ESI+): m/z [M]+calcd for C15H10F3N3O: 305.0776,found: 305.0770. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.5% | To a solution of <strong>[4595-61-3]pyrimidine-5-carboxylic acid</strong> (41mg, 0.33 mmol) in DCM (10 mL) was added HATU (120.54 mg, 0.33 mmol) and (Et)3N (64.9 mg, 0.642 mmol). After stirred at room temperature for 30 min, l-(3-aminophenoxy)-3-(3,4-dihydroisoquinolin- 2(lH)-yl)propan-2-ol (lOOmg 0.32mmol) was added and the combined reaction mixture was stirred for lh. The residue was diluted with DCM (100 mL) and washed by water (30 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated to obtain the crude product which was purified by preparative HPLC separation to give the desired product as the formate salt (37.5 mg, 38.5percent). 1H NMR (400 MHz, CDC13): delta 10.70 (s, 1H), 9.30 (d, J=L6 Hz, 1H), 8.95 (d, J = 2.8 Hz, 1H), 8.82 (dd, J = 1.6, 2.4 Hz, 1H), 8.17 (s, 1H), 7.63- 7.62 (m, 1H), 7.50 (d, J = 8 Hz, 1H), 7.29-7.25 (m, 1H), 7.11- 7.05 (m, 4H), 6.76-6.74 (m, 1H),4.12-4.10 (m, 1H), 4.06-4.02 (m, 1H), 3.94-3.89 (m, 1H), 3.68 (s, 1H), 2.82-2.65 (m, 4H) ,2.61-2.56 (m, 2H) ppm. LCMS (m/z): 305.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.564 g | With hydrogenchloride; In water; | A solution of 5-bromopyrimidine (1.00g, 6.29mmol) in dry Et2O and dry THF (1:1, 60mL) was cooled to between?105°C and?110°C on an EtOH/liquid N2 bath and stirred for 15min. nBuLi (4.10mL, 2.3M, 9.44mmol), cooled to?78°C, was added dropwise under stirring at the same temperature, and the mixture was stirred for additional 10min. Pellets of dry ice was covered with precooled dry Et2O (50mL). The reaction mixture was poured into this mixture and allowed to heat to room temperature. The ether was extracted with water (3×50mL) and 1N NaOH (50mL), and the combined water phases were acidified with 1N HCl. The water was reduced to a quarter volume by freezedrying resulting in precipitation of a white solid. The solid was separated by filtration to give 0.564g (56percent) of product as a white solid. mp. (decomp.) >256°C. 1H NMR (DMSO-d6) delta 9.39 (s, 1H), 9.21 (s, 2H) 3.34 (br s., 1H). 13C NMR (DMSO-d6) delta 164.8, 161.1, 157.7, 124.9. Anal. (C5H4N2O20.2HCl) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Compound 25 BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Pyrimidine-5-carboxylic acid (3.5 eq, 0.305 mmol, 67 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 percent, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 percent MeOH) yielded the product as an yellow solid (55 mg, 65 percent). The solid (1 eq, 0.058 mmol, 53 mg) and phenylsilane (8 eq, 0.467 mmol, 0.057 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (9 mg, 20 percent). H-NMR (DMSO-ds, 400 MHz): delta [ppm] 3.08 (m, 1 H), 3.17 (dd, Ji = 17.1 Hz, J2 = 5.2 Hz, 1 H), 3.77 (s, 3H), 3.92 (s, 3H), 4.99 (m, 1 H), 7.56 (d, J = 8.9 Hz, 1 H), 7.81 (m, 3H), 7.91 (d, J = 8.9 Hz, 2H), 7.99 (d, J= 8.4 Hz, 5H) 8.32 (d, J = 9.4 Hz, 1 H), 9.1 1 (d, J = 7.5 Hz, 1 H), 9.32 (s, 2H), 9.39 (s, 1 H), 9.70 (s, 1 H), 10.61 (s, 1 H), 10.87 (s, 1 H), 1 1 .15 (s, 1 H), 1 1 .57 (s, 1 H). HR-MS: [M-H]- calculated: 787.21068 [M-H]- found: 787.21283 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h; | General procedure: Compound 6 was dissolved in 10 mL of dimethyl formamide and treated with EDC*HCl (1.2 equiv.), NHS (1.2 equiv.) and substitutional carboxylic acid (1.2 equiv.). The reaction mixture was stirred overnight at room temperature. TLC was used to monitor the progress of the reaction. After the reaction complete, the mixture was poured into 40 mL of water and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed by brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, ethyl acetate/petroleum ether 1:1) to afford 7a as a purple solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | General procedure: General CoulinQ Procedure I Methanesulfonyl chloride (1 .5 eq.) was added to a stirred solution of N-methylimidazole (1 .0 eq.) in dichloromethane (25 mL), cooled to 0 °C and the reaction mixture was stirred for 10 to 15 mi Carboxylic acid A (1 .0 eq.) was added at 0 °C and again the reaction mixture was stirred for 20 mm at 10 °C to 15 °C. Amine B (1 .2 eq.) was added to the reaction mixture, whichwas subsequently heated in a sealed glass tube at 55 °C to 60 °C for 16 h. After completion of the reaction, volatiles were removed under reduced pressure. The residual material was triturated with dichloromethane (50 mL), filtered and the wet cake was washed with dichloromethane (100 mL)then dried under reduced pressure to obtain pure product. Additional purificationby flash chromatography over silica was performed when necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.9% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | General procedure: General CoulinQ Procedure 3 1-Propanephosphonic acid cyclic anhydride (1.5 eq.) and DIPEA (4eq.) were added to a stirred solution of Carboxylic acid A (1 .0 eq.) and Amine B (1 .2 eq.) in DMF (25 mL) at RT. The reaction mixture was stirred for 16 h at RT. The reaction mixture was then poured into ice water, stirred for 5 mm. and the resulting precipitate was filtered and washed with water. The wet cake was dried under reduced pressure and washed with diethyl etherand n-pentane to obtain a crude product. Additional purification by flash chromatography over silica was performed when necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.2% | With 1-[(1-(cyano-?2-?ethoxy-?2-?oxoethylidenaminooxy)?dimethylamino-?morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h; | General procedure: General CouIinQ Procedure 4 COMU (1 .5 eq.) and DIPEA (4 eq.) were added to a stirred solutionCarboxylic acid A (1.0 eq.) and Amine B (1.2 eq.) in THF (2 mL) at RT. Thereaction mixture was stirred for 16 h at RT. The reaction mixture was then poured in ice water, stirred for 5 mm. and the resulting precipitate was filtered and washed with water. The cake was dried under reduced pressure and washed with diethyl ether and n-pentane to obtain a crude product. Additional purification by flash chromatography over silica was performedwhen necessary. |
Tags: 4595-61-3 synthesis path| 4595-61-3 SDS| 4595-61-3 COA| 4595-61-3 purity| 4595-61-3 application| 4595-61-3 NMR| 4595-61-3 COA| 4595-61-3 structure
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