* 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.
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. <B> 20, # 9, p. 793 - 795
2
[ 19847-12-2 ]
[ 64-17-5 ]
[ 98-96-4 ]
[ 1339045-85-0 ]
[ 6924-68-1 ]
Yield
Reaction Conditions
Operation in experiment
65%
Cooling with ice
To a solution of pyrazinecarbonitrile (1.00 g, 9.5 mmol) in dry ethanol (30 ml) was introduced a stream of dry HCl gas bubbled through the solution with stirring. Shortly after the HCl was introduced the temperature quickly rose requiring cooling with an ice/water bath. At this time a heavy white precipitate had fonned and after 2 h the gas inlet was replaced with a calcium' chloride drying tube and the reaction mixture stirred overnight. The HC1 gas stream was re-introduced into the reaction mixture for 2 h before again replacing the gas inlet with a drying tube and stirring for 1 h. Dry diethyl ether (45 ml) was then added to the mixture and stirring continued for 10 min before the solid was filtered under nitrogen using a Schlenk apparatus. The collected material was washed with dry diethyl ether (3 x 20 ml) and dried under vacuum to give 1.59 g of a highly moisture- sensitive white powder. nmr revealed the solid to be a mixture of the desired ethyl pyrazine-2-carbimidate hydrochloride (65percent) and the two hydrolysis products pyrazine-2- carboxamide (30percent) and ethyl pyrazine-2-carboxylate (5percent).*H nmr (400 MHz, de-dmso) δ 1.49, t (J = 7.0 Hz), 3H, OEt; 4.73, q (J = 6.9 Hz), 2H, OEt; 7.85, br, lH, C=NH2+; 8.24, br, 1H, C=NH2+; 8.93, dd (J = 1.6, 2.4 Hz), 1H, H6; 9.06, d (J = 2.4 Hz), 1H, H5; 9.33, d (J = 1.2 Hz), 1H, H3.
General procedure: A mixture of the ester derivative 8a or 8b (5.5 mmol) and hydrazine hydrate (11 mmol) in 50 mL of ethanol was heated under reflux for 6 h. The reaction mixture was left overnight at room temperature, and the solid which separated was collected by filtration. The solid was then washed with ethanol, dried, and recrystallized from ethanol (Yoshino et al., 2006; Vlaovic et al., 1990).
Reference：
[1] Medicinal Chemistry Research, 2015, vol. 24, # 6, p. 2529 - 2550
[2] European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 452 - 461
[3] Journal of the Chemical Society, Dalton Transactions, 2002, # 21, p. 4048 - 4054
[4] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
4
[ 98-97-5 ]
[ 64-17-5 ]
[ 6924-68-1 ]
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.
Reference：
[1] Medicinal Chemistry Research, 2015, vol. 24, # 6, p. 2529 - 2550
[2] Journal of Organic Chemistry, 1994, vol. 59, # 24, p. 7284 - 7291
[3] Journal of the Chemical Society, Dalton Transactions, 2002, # 21, p. 4048 - 4054
[4] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
To a solution of pyrazinecarbonitrile (1.00 g, 9.5 mmol) in dry ethanol (30 ml) was introduced a stream of dry HCl gas bubbled through the solution with stirring. Shortly after the HCl was introduced the temperature quickly rose requiring cooling with an ice/water bath. At this time a heavy white precipitate had fonned and after 2 h the gas inlet was replaced with a calcium' chloride drying tube and the reaction mixture stirred overnight. The HC1 gas stream was re-introduced into the reaction mixture for 2 h before again replacing the gas inlet with a drying tube and stirring for 1 h. Dry diethyl ether (45 ml) was then added to the mixture and stirring continued for 10 min before the solid was filtered under nitrogen using a Schlenk apparatus. The collected material was washed with dry diethyl ether (3 x 20 ml) and dried under vacuum to give 1.59 g of a highly moisture- sensitive white powder. nmr revealed the solid to be a mixture of the desired ethyl pyrazine-2-carbimidate hydrochloride (65percent) and the two hydrolysis products pyrazine-2- carboxamide (30percent) and ethyl pyrazine-2-carboxylate (5percent).*H nmr (400 MHz, de-dmso) δ 1.49, t (J = 7.0 Hz), 3H, OEt; 4.73, q (J = 6.9 Hz), 2H, OEt; 7.85, br, lH, C=NH2+; 8.24, br, 1H, C=NH2+; 8.93, dd (J = 1.6, 2.4 Hz), 1H, H6; 9.06, d (J = 2.4 Hz), 1H, H5; 9.33, d (J = 1.2 Hz), 1H, H3.
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.
496 mg
With sulfuric acid; In ethanol; at 100℃; for 48.0h;
To a stirred solution of Pyrazine-2-carboxylic acid (500 mg) in Ethanol (30 ml) was added Cone H2S04 (lml) drop wise and refluxed for 2 days at 100 degree Celsius. Reaction was monitored by NMR. The reaction mixture was concentrated under reduced pressure to obtain crude which was treated with Saturated Sodium Bicarbonate Solution, Extratced with DCM (3 X 150 ml), Organic Layer dried over anhydrous sodium sulphate and Concentrated under vacuum to obtain Product ethyl pyrazine-2-carboxylate (496 mg, Brown Solid). XH NMR (400 MHz, DMSO- di) d 9.16 - 9.26 (m, 1H), 8.90 (d, J = 2.19 Hz, 1H), 8.82 (s, 1H), 4.39 (q, J= 7.16 Hz, 2H), 1.35 (t,.7= 7.24 Hz, 3H).
With hydrazine hydrate; In ethanol; for 6.0h;Reflux;
General procedure: A mixture of the ester derivative 8a or 8b (5.5 mmol) and hydrazine hydrate (11 mmol) in 50 mL of ethanol was heated under reflux for 6 h. The reaction mixture was left overnight at room temperature, and the solid which separated was collected by filtration. The solid was then washed with ethanol, dried, and recrystallized from ethanol (Yoshino et al., 2006; Vlaovic et al., 1990).
340 mg
With hydrazine hydrate; In ethanol; for 3.0h;Reflux;
To as stirred solution of Ethyl pyrazine-2-carboxylate (450 mg, leq, 0.986 mmoles) in ethanol (20 ml) was added hydrazine Hydrate (65.13 mg, l.2eq, and 1.184 m moles). Reaction mixture was refluxed for 3 hour. Reaction was monitored by NMR. Reaction Mixture was concentrated under reduced pressure to obtained ppt. was triturated with hexane to obtained pyrazine-2-carbohydrazide (340 mg, Brown Solid). XH NMR (400 MHz, DMSO-ri6) d 10.13 (br. s., 1H), 9.13 (d, J = 1.32 Hz, 1H), 8.83 (d, J= 2.19 Hz, 1H), 8.59 - 8.78 (m, 1H), 4.65 (br. s., 2H).
With sodium methylate; In toluene; at 90℃; for 40.0h;Heating / reflux;
Dissolve NaOMe (1.5 eq) in toluene and heat 90C. Add a solution of 2-pyrazine methylester (1.0 eq) and methyl acetate (2.0 eq) in toluene dropwise and heat at 90C. After 20 hours, cone. in vacuo at RT. Slurry in excess methyl acetate and reflux 20 hours. Cool to RT. Add water. Extract with EtOAc, dry (Na2SO4), filter and cone. in vacuo to give the title compound: TLC Rf= 0.58 (1: 1 EtOAc/hexanes)
Ethyl pyrazine carboxylate (4.0 g, 13.14 mmol) in 200 mL of DCM was treated at O0C with meta-chloroperbenzoic acid (57- 80%, 5.67 g). The mixture was allowed to warm to ambient temperature and stirred for 72 h, when an additional 4.28 g of meta-chloroperbenzoic acid was added. After an additional 4 d, 6 mL of acetone was added and stored for 2.5 d. Then 2.2 g of sodium metabisulfite in 5 mL of water was added and stirred for 2 h. Ethyl acetate was added and the mixture was washed with brine, dried over sodium sulfate, filtered and concentrated to leave a solid which was purified by chromatography (silica gel, elution with ethyl acetate/pentane), affording 3.35 g of the N-oxide. The N-oxide thus prepared (2.0 g, 11.89 mmol) in 10.53 mL of phosphorous oxychloride and 18 mL of toluene was heated at 100C for 1.5 h. The mixture was carefully treated with ice and then with saturated aqueous sodium carbonate solution. The product was extracted into ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (elution with ethyl acetate/pentane) to give 1.27 g of 6-chloro-pyrazine-2- carboxylic acid ethyl ester. .
With thionyl chloride; dihydrogen peroxide; In ethanol; acetic acid; toluene;
Compound 25--Ethyl pyrazine carboxylate To 20 g of pyrazine carboxylic acid were added 25 ml of SOCl2 and the mixture was refluxed for 30 minutes, evaporated, the residue was dissolved in 30 m. of toluene and evaporated again. The residue was dissolved in 50 ml toluene and dropped into 150 ml ethanol over a period of 30 minutes and the resulting mixture was stirred overnight at room temperature. Evaporation and filtration on silica gel with ethyl acetate yielded 23.3 g (93.9%) of an orange oil which solidified overnight to crystals of m.p. 45 C. Compound 26--Ethyl pyrazine carboxylate-4-oxide 3.4 g hydrogen peroxide (30%) was added in three portions over a period of 1 hour to a solution of 3.06 g of ethyl pyrazine carboxylate (prepared as above) in 15 ml of glacial acetic acid at 65 C. After stirring for 16 hours another 3.4 g hydrogen peroxide were added and the solution was stirred for 48 additional hours. The volume of the mixture was reduced, 30 ml of ethanol were added and the solution was filtered. The liquid was evaporated and the residue purified on silica gel with toluene/ethyl acetate to give 0.5 g (14.80) of white ethyl pyrazinecarboxylate-4-oxide; m.pt. 128 C.
ethyl 3-ethoxycarbonyl-4-(pyrazin-2-yl)-4-oxobutyrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; toluene;
Ethyl 3-ethoxycarbonyl-4-(pyrazin-2-yl)-4-oxobutyrate can be prepared by adding, over a period of 5 minutes at a temperature of about 35 C, a solution of 2-ethoxycarbonylpyrazine (228 g) and ethyl succinate (261 g) in anhydrous toluene (700 cc) to a suspension of sodium tert.-butoxide (144 g) in anhydrous toluene (300 cc). Thereafter the reaction mixture is stirred for 12 hours at a temperature of about 20 C, and then 12N hydrochloric acid (130 cc) and distilled water (1300 cc) are added. The organic phase is decanted, washed with distilled water (500 cc) and then dried over magnesium sulphate. After filtration and concentration to dryness under reduced pressure, ethyl 3-ethoxycarbonyl-4-(pyrazin-2-yl)-4-oxobutyrate (364 g) is obtained in the form of a red oil.
To a solution of pyrazinecarbonitrile (1.00 g, 9.5 mmol) in dry ethanol (30 ml) was introduced a stream of dry HCl gas bubbled through the solution with stirring. Shortly after the HCl was introduced the temperature quickly rose requiring cooling with an ice/water bath. At this time a heavy white precipitate had fonned and after 2 h the gas inlet was replaced with a calcium' chloride drying tube and the reaction mixture stirred overnight. The HC1 gas stream was re-introduced into the reaction mixture for 2 h before again replacing the gas inlet with a drying tube and stirring for 1 h. Dry diethyl ether (45 ml) was then added to the mixture and stirring continued for 10 min before the solid was filtered under nitrogen using a Schlenk apparatus. The collected material was washed with dry diethyl ether (3 x 20 ml) and dried under vacuum to give 1.59 g of a highly moisture- sensitive white powder. nmr revealed the solid to be a mixture of the desired ethyl pyrazine-2-carbimidate hydrochloride (65%) and the two hydrolysis products pyrazine-2- carboxamide (30%) and ethyl pyrazine-2-carboxylate (5%).*H nmr (400 MHz, de-dmso) delta 1.49, t (J = 7.0 Hz), 3H, OEt; 4.73, q (J = 6.9 Hz), 2H, OEt; 7.85, br, lH, C=NH2+; 8.24, br, 1H, C=NH2+; 8.93, dd (J = 1.6, 2.4 Hz), 1H, H6; 9.06, d (J = 2.4 Hz), 1H, H5; 9.33, d (J = 1.2 Hz), 1H, H3.
ethyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate[ No CAS ]
[ 141-97-9 ]
Yield
Reaction Conditions
Operation in experiment
84%
With lithium hexamethyldisilazane; In tetrahydrofuran; at -40℃; for 0.333333h;Inert atmosphere;
General procedure: To the solution of ester (10 mmol) in THF (20 mL) and ethyl acetate (70 mmol), LiHMDS (30 mmol) was added very quickly at -40 C, and stirred at this temperature for 20 min. After completion of the reaction, reaction mixture was quenched with acetic acid (50 mmol) and then basified using 10% NaHCO3 solution, extracted with ethyl acetate (2×100 mL), the combined organic layer was washed with water and brine solution and dried over Na2SO4. The specific purification procedure for each compound has been included along with their characterization data.
With lithium hexamethyldisilazane; In tetrahydrofuran; at -40℃; for 0.333333h;Inert atmosphere;
General procedure: To the solution of ester (10 mmol) in THF (20 mL) and ethyl acetate (70 mmol), LiHMDS (30 mmol) was added very quickly at -40 C, and stirred at this temperature for 20 min. After completion of the reaction, reaction mixture was quenched with acetic acid (50 mmol) and then basified using 10% NaHCO3 solution, extracted with ethyl acetate (2×100 mL), the combined organic layer was washed with water and brine solution and dried over Na2SO4. The specific purification procedure for each compound has been included along with their characterization data.
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