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CAS No. : | 98-97-5 | MDL No. : | MFCD00006130 |
Formula : | C5H4N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NIPZZXUFJPQHNH-UHFFFAOYSA-N |
M.W : | 124.10 | Pubchem ID : | 1047 |
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) : | -7.02 cm/s |
Log Po/w (iLOGP) : | 0.28 |
Log Po/w (XLOGP3) : | 0.05 |
Log Po/w (WLOGP) : | 0.17 |
Log Po/w (MLOGP) : | -1.25 |
Log Po/w (SILICOS-IT) : | 0.32 |
Consensus Log Po/w : | -0.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.07 |
Solubility : | 10.6 mg/ml ; 0.0855 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.93 |
Solubility : | 14.7 mg/ml ; 0.118 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 : | 1.45 |
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 |
---|---|---|
99.6% | With sodium hydroxide In water | Step 1: The preparation of piperazine-2-carboxylic acid: Pyrazine-2-carboxylic acid (102.7 g, 0.827 mol) was dissolved in H2O (600 mL), treated with NaOH (66 g, 1.65 mol) and 20percent Pd/C (5.0 g), and hydrogenated for fifteen hours. The reaction was filtered and concentrated. Concentrated HCI was added to the solution and a white precipitate formed. The solid was washed with cold H2O, collected by filtration and dried in vacuo to give 137.2 g (99.6percent) of the desired product as the HCI salt. MS: 131 (M+1 for C5H10N2O2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | for 2 h; Reflux | Pyrazine-2-carboxylic acid (5 g, 40.3 mmol) was dissolved inMeOH (150 ml), and a few drops of H2SO4 were added. The resultingreaction mixture was refluxed for 2 h. Methanol was evaporated and the resulting reaction mixture was extracted withEtOAc, washed with saturated NaHCO3 solution, then with brineand dried over anhydrous Na2SO4. The solvent was removed invacuo to give the methyl pyrazine-2-carboxylate (5.5 g, yield98percent). 1H NMR (CDCl3, 400 MHz) d 9.32 (d, 1H, J = 1.5 Hz), 8.78(d, 1H, J = 2.4 Hz), 8.73 (dd, 1H, J = 2.4, 1.5 Hz), 4.04 (s, 3H). |
94.8% | at 80 - 85℃; for 5 h; | Example 1; Methyl pyrazine-2-carboxylate (Formula 3). 20.0 g (805.8 mmole) of pyrazine-2-carboxylic acid was added to 160 mL of methanol, and 1.0 mL of a concentrated sulfuric acid was gradually dropwise added thereto with stirring. A reaction solution was refluxed at a temperature of 80 to 85°C for 5 hours. The reaction solution was cooled to a temperature of 20 to 22 °C and concentrated to a volume of 25mL. Then, 80 mL of methylenechloride and 40 mL of water were added to the resultant concentrate. The resultant solution was then neutralized by gradual addition of 40 mL of a saturated sodium hydrogen carbonate solution to get a pH of 8.5. An organic layer was separated and a water layer was extracted again with 40 mL of methylenechloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and washed with 20 mL of methylenechloride. A filtrate was concentrated to give 21.1 g of the titled compound as a pale brown solid (yield 94.8percent). Melting point: 60-61 °C |
91% | at 55 - 65℃; for 19 h; Industrial scale | • Charged MeOH (8.8 L) and OT-1 (1758 g) at RT. (0129) • Charged H2S04 (69.5 g) in one portion (21-22 °C exotherm). Heated to (60-65 °C) and stirred at 55-65 °C for 19 hours. (0130) 19 h, 96.0percent OT-2 and 4.0percent OT-1 by HPLC (0131) • Reaction was cooled to 15/30 °C. No precipitate formed. (0132) • NaHC03 (180 g) was charged in lots. The solution bubbled slightly and quickly went from yellow to pink. The mixture was stirred for 5 min at 15/30 °C. (0133) • The mixture was then concentrated to 1.5-2.5 vol at (0134) • Charged NaCl (.700 g) in water (2.5 vol). Upon stirring, solution became clear. (0135) • Stirred for 15 min at 15/30 °C. After stirring, the aqueous layer became slightly cloudy. The solids were filtered off and the layers were separated. (0136) • The aqueous layer was extracted with DCM (3x2 vol.). TLC indicated that extraction was complete after 3rd extraction. (0137) • Organic layers were dried over anhydrous Na2S04 (.4g/g SM) . (0138) • Concentrated to 1.5-2.5 vol under vacuum at (0139) • Charged heptanes (8 vol) over a minimum of 30 min. Pale white slurry. Let stir overnight. • Stirred at -5/- 15 °C for a minimum of 1 hr. Solids were filtered off and rinsed with cold heptanes (0140) • (2x1 vol.) Pulled solids dry on filter for 10 min. Dried in vacuum oven at (0141) Color changed, but no degradation was observed . (0142) Output material: ST-601 (0143) Lot No.: 2463-24- 1 (0144) Appearance: light Brown Solids (0145) Yield: 1721 g (91.0percent) (0146) HPLC purity: 98.9percent (0147) 1 NMR- Conforms to structure |
87% | Stage #1: at -10℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 72 h; Stage #3: With sodium hydrogencarbonate In water |
REFERENCE EXAMPLE 8-42-pyrazinemethanol (Compound CD)Step 1; To methanol (8.0 mL), thionyl chloride (2.08 mL) was added dropwise under a nitrogen atmosphere at -10° C. and the mixture was stirred at the same temperature for 30 minutes. To this, 2-pyrazinecarboxylic acid (1.00 g, 8.06 mmol) was added at the same temperature and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated, a saturated aqueous sodium bicarbonate solution was added to the residue, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol 19/1) to give methyl 2-pyrazinecarboxylate (969 mg, yield: 87percent).1H-NMR (270 MHz, CDCl3, δ); 4.06 (s, 3H), 8.74 (dd, J=1.3, 2.3 Hz, 1H), 8.79 (d, J=1.3 Hz, 1H), 9.34 (d, J=2.3 Hz, 1H). |
72% | for 6 h; Reflux | General procedure: A catalytic amount of concentrated H2SO4 wasadded to a solution of carboxylic acids 16(a–j) (1.0 mmol)in 50 mL of methanol, and the mixture was refluxed for 6 h. It was allowed to cool. The saturated solution ofNaHCO3 was added to the reaction mixture, and it wasextracted with EtOAc (2 X 50 mL). The combined organiclayer was dried Na2SO4 and concentrated to obtain puremethyl esters 17(a–j). |
63.63% | for 5 h; Reflux | [0535] Synthesis of methyl pyrazine-2-carboxylate: [0536] To a stirred solution of pyrazine-2-carboxylic acid (5 g, 40.29 mmol) in MeOH (20 mL) was added concentrated H2S04 (1 mL) drop-wise and stirred under reflux for 5 h. The reaction mixture was cooled to RT; volatiles were evaporated under reduced pressure. The residue was diluted with water and basified to pH~ 8.5 using NaHC03 and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford methyl pyrazine-2- carboxylate (3.5 g, 63.63percent) as an off-white solid. 1H-NMR (DMSO d6, 400 MHz): δ 9.21 (s, 1H), 8.91 (d, 1H), 8.82 (d, 1H), 3.92 (s, 3H); TLC: 50percent EtOAc/Hexane (Rf: 0.4). |
53% | Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 6 h; Stage #2: for 0.5 h; |
To pyrazinecarboxylic acid (5.80 g, 46.5 mmol) in dichloromethane (100 mL) was added oxalyl chloride (5.10 mL, 60.4 mmol) followed by catalytic DMF. The reaction mixture was stirred at 23°C for 6 h. Methanol (30 mL) was then added, and the mixture was stirred for an additional 30 min. The reaction mixture was concentrated in vacuo. The residue was taken up in EtOAc (200 mL), and washed with sat. NaHCO3 (aq) (1X100 mL) and brine (1X100mL). The organic layer was dried (MgSO4), and concentrated in vacuo to provide 3.38 g (53percent) of methyl pyrazine-2-carboxylate which was used without further purification in the next step.1H NMR (400 MHz, CDCl3): d ppm 9.34 (d, 1H), 8.79 (d, 1H), 8.74 (dd, 1H), 4.06 (s, 3H); LCMS (Method A): tR= 0.48 min, m/z 139.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.63% | Stage #1: With sulfuric acid In methanol at 20℃; for 5 h; Reflux Stage #2: With sodium hydrogencarbonate In methanol |
Synthesis of methyl pyrazine-2-carboxylate: To a stirred solution of pyrazine-2-carboxylic acid (5 g, 40.29 mmol) in MeOH (20 mL) was added concentrated H2S04 (1 mL) drop wise and stirred under reflux for 5 h. The reaction mixture was cooled to RT; volatiles were evaporated under reduced pressure. The residue was diluted with water and basified to pH~ 8.5 using NaHC03 and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford methyl pyrazine-2-carboxylate (3.5 g, 63.63percent) as an off- white solid. 1H-NMR (DMSO d6, 400 MHz): δ 9.21 (s, 1H), 8.91 (d, 1H), 8.82 (d, 1H), 3.92 (s, 3H); TLC: 50percent EtOAc/Hexane (Rf: 0.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With potassium carbonate In N,N-dimethyl-formamide for 72 h; | Example 19.1Pyrazine-2-carboxylic acid methyl ester To pyrazine-2-carboxylic acid (15.0 g, 121 mmol) in DMF (150 mL) were added K2CO3 (50 g, 363 mmol) and MeI (9.0 mL, 145 mmol). After stirring for 3 days, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30percent ethyl acetate in hexanes gave the title product (1.28 g, 8percent).1H NMR (300 MHz, CDCl3): δ (ppm) 9.35 (s, 1H), 8.80 (s, 1H), 8.75 (s, 1H), 4.07 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | for 3 h; Reflux | General procedure: Indol-3-acetic acid or 2-pyrazine carboxylic acid (5.5 mmol) were heated under reflux for 3 h in 90 mL ethanol and 15 mL concentrated H2SO4. The solution was neutralized with saturated Na2CO3 solution and filtered. The volume was reduced in vacuum and extracted with four 30 mL aliquots of dichloromethane. The combined fractions were washed with 10 mL of water and dried over anhydrous MgSO4. The dichloromethane was removed using vacuum to yield the ethyl carboxylate derivatives, 8a mp. 1–2 °C(Lit. 1–2 °C, Vlaovic et al., 1990) or 8b mp. 46–47 °C (Lit. 48–49 °C, Yoshino et al., 2006) which crystallized on cooling. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: With 4-methyl-morpholine; N-ethyl-N,N-diisopropylamine; isobutyryl chloride In tetrahydrofuran at 55℃; for 2 h; Inert atmosphere Stage #2: With 10% palladium on activated charcoal; hydrogen In tetrahydrofuran at 68℃; for 2 h; |
(1) Under the protection of nitrogen,Bis(R)-1-amino-3-methylbutylborate decanoate hydrochloride in a molar ratio of 1:2:4.5:7.5,2(S)benzylamino-3-phenylpropionic acid, isobutyl chloride and N-methylmorpholine were added to ether solvent tetrahydrofuran in an amount of 4 L per mol of reactant.Acid catalyzed by N,N-diisopropylethylamine, at a temperature of 55°C,The reaction was carried out in an environment with a pH of 10 for 2 h to produce Compound II;(2) Debenzylation of compound II with Pd/C in a molar ratio of 1:3 in an H2 atmosphere at a reaction temperature of 68°C and a reaction pressure of 6 atm.The reaction time was 2h, to obtain Compound III;(3) Compound III in a molar ratio of 1:5:3.8:3 under the protection of nitrogenPyrazin-2-carboxylic acid, triethylamine and condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride were mixed and the condensation reaction was carried out. The reaction temperature was 38°C.The reaction time was 2.5 h to give compound IV;(4) Compound IV with a mole ratio of 1:7 and an oxidant sodium periodate are added to tetrahydrofuran and mixed for oxidation. The reaction temperature is 68° C., the reaction time is 4 hours, and the compound I is obtained after purification with toluene. Bortezomib. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46 g | Stage #1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In toluene for 0.166667 h; Inert atmosphere Stage #2: With N-ethyl-N,N-diisopropylamine In toluene at 25℃; for 3 h; |
5) Preparation of N- {( 1 R)-3-methyl- 1 -[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6- methano- 1,3 ,2-benzodioxaborol-2-yl jbutyl} -Na-(pyrazin-2-ylcarbonyl)-L-pbenylalaninamide of formula (VII)400 ml toluene and 40.0 g of the compound obtained from example 4 were charged into a reaction flask under nitrogen atmosphere followed by addition of 12.2 g of pyrazine-2- carboxylic acid of formula (VI) and 32.0 g of TBTU. The reaction mixture was stirred for 10 minutes and cooled to 0 ± 5 °C. 64.0 ml N,N’-diisopropyl ethyl amine diluted with 80.0 ml of toluene was added drop wise to the reaction mass and the reaction mass was warmed to 25 °C and stirred for 3 hours.After completion of the reaction, the reaction mass was washed with 2 x 400 ml purified water. The layers were separated and the toluene layer was washed with 400 ml of 1percent phosphoric acid solution, 400 ml of 2percent potassium carbonate solution and fmally with 400 ml of 10percent sodium chloride solution. The toluene layer was dried with sodium sulphate and distilled completely under vacuum at below 37 °C.Yield:46.Og |
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