Abstract: Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.
Abstract: Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the CoA biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative mols. were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic anal. of these analogs may lead to a next generation POA analog for treating TB.
* 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.
A 500ml three-neck flask, was added at a concentration of 20percent sodium hydroxide (30g) solution, and sodium hypochlorite solution (100ml), was added 2-cyano-pyrazine (21g, 0.2mol) at room temperature, the reaction was stirred for 1h. Then for 4h at 50 ~ 60 , with dichloromethane (4 × 200ml) was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid 15.7g, yield 82.6percent.
Reference：
[1] Patent: CN105622526, 2016, A, . Location in patent: Paragraph 0020; 0021; 0022
[2] Patent: CN108570011, 2018, A, . Location in patent: Paragraph 0012; 0013; 0014
2
[ 19847-12-2 ]
[ 22047-25-2 ]
Reference：
[1] Journal of the American Chemical Society, 1992, vol. 114, # 5, p. 1838 - 1843
3
[ 19847-12-2 ]
[ 917-64-6 ]
[ 22047-25-2 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1999, vol. 64, # 7, p. 1159 - 1179
[2] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 7, p. 1093 - 1101
[3] Molecules, 2009, vol. 14, # 10, p. 4197 - 4212
4
[ 19847-12-2 ]
[ 75-16-1 ]
[ 22047-25-2 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 3617,3618,3620
[2] Patent: US2677686, 1952, ,
5
[ 98-96-4 ]
[ 19847-12-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 325℃; for 1 h;
General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99percent).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
34%
With trichlorophosphate In acetonitrile for 6 h; Inert atmosphere; Reflux
In a dried 500 ml, three necked, jacketed flask fitted with a mechanical stirrer, temperature probe, a reflux condenser, a circulation bath, and a positive nitrogen atmosphere set-up was charged with 2-pyrazinecarboxamide 20.0 gm (0.162 mol), acetonitrile 240 ml, and POCl3 59.6 gm (0.389 mol). The white slurry was agitated and heated to reflux. The reaction mixture was maintained at reflux for at least 6 hours. Then the excess POCl3 was distilled off under reduced pressure. After aqueous work up, the reaction mixture was extracted with 4.x.70 ml ethyl acetate. The combine ethyl acetate extracts were washed with 3.x.70 ml water, distilled under reduced pressure to remove ethyl acetate and to afford cyanopyrazine as a brown oil: 5.76 gm (34percent yield); HPLC purity, >98 area percent; 1H NMR (300 MHz, CDCl3) δ 8.67 (pair d, J=1.7 and 2.5 1H), 8.75 (d, J=2.5, 1H), 8.87 (d, J=1.3 1H); 13C NMR (300 MHz, CDCl3) δ 115.1, 130.7, 145.3, 147.3, 148.1.
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 7, p. 1093 - 1101
[2] Patent: CN104557357, 2018, B, . Location in patent: Paragraph 0150; 0151; 0152; 0160
[3] Chemical Communications, 2007, # 3, p. 301 - 303
[4] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 10, p. 731 - 742
[5] Patent: US2009/292122, 2009, A1, . Location in patent: Page/Page column 12-13
[6] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1958, vol. 247, p. 822
[7] Patent: US4442095, 1984, A,
[8] Patent: US4442097, 1984, A,
[9] Patent: US4442096, 1984, A,
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 11, p. 2877 - 2882
12
[ 768-36-5 ]
[ 19847-12-2 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
13
[ 98-97-5 ]
[ 19847-12-2 ]
Reference：
[1] Patent: CN104557357, 2018, B,
14
[ 32046-03-0 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
15
[ 109-08-0 ]
[ 290-37-9 ]
[ 19847-12-2 ]
[ 98-96-4 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 29, p. 8394 - 8396
16
[ 768-36-5 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
[ 36070-75-4 ]
[ 55557-52-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
17
[ 25594-31-4 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
[ 36070-75-4 ]
[ 55557-52-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
18
[ 19847-12-2 ]
[ 98-96-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 100℃; for 0.333333 h;
A solution of nitrile 3 in ethanol/H2O (0.6 M, 8:1 v/v) was passed through the column reactor R2 (100 mm × 10 mm, 5 g hydrous zirconia) heated at 100 °C, with a residence time of 20 minutes, to obtain a quantitative recovery of the primary amide 2 after concentration of the reactor output (>98percent yield). White solid; m.p. 191–194 °C; δ H (400 MHz, d6-DMSO, 25 °C) 7.84 (1H, br. s), 8.24 (1H, br. s), 8.70 (1H, dd, J = 2.5 Hz, J 1.5 Hz), 8.85 (1H, d, J = 2.5 Hz), 9.17 (1H, d, J = 1.5 Hz); δ C (100 MHz, CDCl3, 25 °C) 143.46 (CH), 143.69 (CH), 145.18 (C), 147.46 (CH), 165.13 (C); FTIR (neat, ν): 3422, 3132, 1669, 1583, 1525, 1481, 1432, 1373, 1171, 1089, 1046, 1021, 870, 791 cm−1; LC-MS: retention time 0.28 min, m/z [M + H]+ = 124.19; HRMS (ESI): m/z calcd for C5H6ON3+: 124.0505; found 124.0504. Elemental analysis: calcd C = 48.78percent, H = 4.09percent, N = 34.13percent; found C = 48.60percent, H = 4.19percent, N = 33.70percent.
96%
at 110℃; for 6 h;
General procedure: Two milli liter water at room temperature was added to astirred mixture of nitrile (1mmol) and catalyst (40mg) thenheated with an oil bath maintained at 110°C, and stirred. After completion of the reaction (monitored by TLC), thecatalyst was removed from the reaction mixture by externalmagnet. Then the mixture was extracted with ethyl acetate,subsequently purified by column chromatography on silicagel to provide the corresponding amide products.
65%
With copper(l) iodide; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene In nitromethane; water at 20 - 80℃; for 0.25 h;
To a nitromethane (0.10 mL) solution of pyrazine-2-carbonitrile (4e) (30 mg, 0.285 mmol) were addedH2O (1.0 mL), DBU (87 mg, 0.571 mmol), copper (I) iodide (11 mg, 0.0571 mmol), cesium (I)carbonate (47 mg, 0.143 mmol), 4-dimethylaminopyridine (35 mg, 0.285 mmmol) at roomtemperature. The reaction mixture was heated at 80 °C for 15 min and then poured into water (50mL). The organic layer was separated and the aqueous layer was extracted with AcOEt. Thecombined organic layer was dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (2:1) to givepyrazine-2-carboxamide (5e) S11 (23 mg, 65percent) as pale yellow powders.5e: mp 187-188 °C,
92 %Chromat.
Stage #1: With dimethyl sulfoxide; sodium hydroxide In ethanol; water at 25℃; for 0.0416667 h; Flow reactor Stage #2: With dihydrogen peroxide In ethanol; water at 25℃; for 0.0694444 h; Flow reactor
General procedure: 0.6 mmol benzonitrile and 0.6 mmol DMSO were solved in 3 mL EtOH and pumped into inlet A, 50 μL 1 M NaOH (aq) solved in 1 mL EtOH and pumped into inlet B, 30percent H2O2 (aq) was solved in 7 mL ethanol and pumped into inlet C (flow rate A: B: C = 1.54 μl/min:0.46 μl/min:0.3 μl/min for a 400s residence time). The whole system was maintained on 25 °C. The flow system was equilibrated for 30 min, then the product stream was quenched and collected in a glass vessel with saturated aqueous NaHSO3 in it for 2 h. After being filtered, 5.0 ml of this solution was injected to the HPLC instrument for analysis. The conversion of the reaction was determined by relative area percentage of nitriles and corresponding amides. Conversion = Area (benzamide)/[Area (benzamide) + Area (benzonitrile)].
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2003, vol. 42, # 11, p. 2814 - 2819
[2] Organic Letters, 2014, vol. 16, # 4, p. 1060 - 1063
[3] Chemistry - A European Journal, 2017, vol. 23, # 32, p. 7761 - 7771
[4] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 641 - 652
[5] ACS Catalysis, 2015, vol. 5, # 1, p. 20 - 26
[6] Chemical Communications, 2009, # 22, p. 3258 - 3260
[7] Organic Syntheses, 2017, vol. 94, p. 34 - 45
[8] New Journal of Chemistry, 2018, vol. 42, # 18, p. 15221 - 15230
[9] Catalysis Letters, 2018, vol. 148, # 11, p. 3378 - 3388
[10] Journal of Organic Chemistry, 2015, vol. 80, # 8, p. 4148 - 4151
[11] ChemSusChem, 2012, vol. 5, # 8, p. 1392 - 1396
[12] Applied Catalysis A: General, 2012, vol. 421-422, p. 114 - 120
[13] ChemSusChem, 2013, vol. 6, # 8, p. 1341 - 1344
[14] New Journal of Chemistry, 2016, vol. 40, # 1, p. 358 - 364
[15] Synthetic Communications, 2002, vol. 32, # 11, p. 1731 - 1734
[16] ACS Catalysis, 2014, vol. 4, # 6, p. 1901 - 1910
[17] Green Chemistry, 2014, vol. 16, # 4, p. 2136 - 2141
[18] Dalton Transactions, 2016, vol. 45, # 34, p. 13590 - 13603
[19] Green Chemistry, 2016, vol. 18, # 18, p. 4865 - 4870
[20] Synlett, 2018, vol. 29, # 15, p. 2061 - 2065
[21] Synthetic Communications, 2000, vol. 30, # 10, p. 1713 - 1718
[22] Chemistry - A European Journal, 2011, vol. 17, # 41, p. 11428 - 11431
[23] Inorganica Chimica Acta, 2016, vol. 442, p. 134 - 144
[24] Tetrahedron, 2018, vol. 74, # 13, p. 1527 - 1532
19
[ 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.
Reference：
[1] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 169 - 171
21
[ 109-08-0 ]
[ 290-37-9 ]
[ 19847-12-2 ]
[ 98-96-4 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 29, p. 8394 - 8396
22
[ 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.
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
24
[ 768-36-5 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
[ 36070-75-4 ]
[ 55557-52-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
25
[ 25594-31-4 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
[ 36070-75-4 ]
[ 55557-52-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
26
[ 768-36-5 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
[ 36070-75-4 ]
[ 55557-52-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
27
[ 25594-31-4 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
[ 36070-75-4 ]
[ 55557-52-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
28
[ 19847-12-2 ]
[ 55557-52-3 ]
Yield
Reaction Conditions
Operation in experiment
51%
With sulfuryl dichloride In N,N-dimethyl-formamide; toluene at 20℃; for 5.6 h; Cooling with ice
To a solution of pyrazine-2-carbonitrile 13 (6.90 g, 65.65 mmol) in toluene (48 mL) and DMF (5 mL) was added sulfuryl chloride (21.2 mL, 260.8 mmol) over 10 min. The reaction mixture was stirred for 30 min in an ice bath, then allowed to warm up to room temperature gradually, after which it was stirred for 5 h. The toluene layer was decanted, and the reddish oil residue was extracted three times with diethyl ether. The combined toluene and ether layers were quenched with ice water and cooled in an ice bath. The combined layers were then neutralized with solid NaHCO3, then separated, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to afford the title compound. The crude product was purified by silica gel chromatography (eluent: 100percent dichloromethane) to give 3-chloropyrazine-2-carbonitrile 14 as a white powder (4.7 g, 51percent). Rf = 0.76 (dichloromethane); mp 44-46 °C (lit. [14] : 47-48 °C); IR (KBr) νmax (cm-1): 3088 (νCHar), 2242 (νCN), 1377 (νC=C), 1087 (νC-N); 1H NMR (400 MHz, DMSO-d6): δ 8.91 (d, 1H, J = 2.4 Hz, H-6), 8.88 (d, 1H, J = 2.4 Hz, H-5); 13C NMR (100 MHz, DMSO-d6): δ 150.67 (C-3), 147.97 (C-5), 144.26 (C-6), 129.87 (C-2), 114.66 (CN); MS (ESI) m/z (percent): 140.3 (100) [M + H]+, 142.3 (40) [M + H + 2]+. Anal. calcd for C5H2ClN3: C, 43.04; H, 1.44; N, 30.11. Found: C, 43.18; H, 1.45; N, 30.16.
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 171 - 183
[2] Patent: EP1582521, 2005, A1, . Location in patent: Page/Page column 133-134
[3] Magnetic Resonance in Chemistry, 2009, vol. 47, # 7, p. 617 - 624
29
[ 768-36-5 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
[ 36070-75-4 ]
[ 55557-52-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
30
[ 25594-31-4 ]
[ 19847-12-2 ]
[ 6863-74-7 ]
[ 36070-75-4 ]
[ 55557-52-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
31
[ 19847-12-2 ]
[ 20010-99-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With Ni-doped silica; hydrogen In toluene at 140℃; for 4 h; Autoclave; Inert atmosphere
The synthesis of 2-aminomethyl pyradine(2-AMPZ) was carried out by a method shown below, byreference to the method described in literature (JP A 2001-894594). 2-cyanopyradine used was from Sigma-Aldrich Co.LLC.1.05 g of 2-cyanopyradine (10 mmol) and 100mg of60 wt percent-Ni/5i02 were placed in an autoclave (5U53 16) with20 mL of toluene and replaced with argon gas. This waspressurized with hydrogen gas to 50 atm, stirred at 140°C. for4 hours. The reaction solution was filtered and concentratedto give 2-aminomethyl pyradine (2-AMPZ) quantitatively.10152] ‘H-NMR spectrum (399.78 MHz, CDC13):ö8.60-8.45 (m, 3H), 4.07 (s, 2H), 1.79 (br, 2H)
98%
With hydrogen In 1,4-dioxane at 60℃; for 8 h; Autoclave
Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane under stirring, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was hydrogenated for 8 hours under 40 atmosphere at 60 °C, filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methylamine 1h (10.7 g, yield 98percent) as a brown oil. MS m/z (ESI): 110 [M+1]
98%
With hydrogen In 1,4-dioxane at 60℃; for 8 h; Autoclave
Step 6 C-Pyrazin-2-yl-methylamine Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was reacted in hydrogen atmosphere for 8 hours under 40 atmosphere at 60 °C and filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methyl amine 1h (10.7 g, yield 98percent) as a brown oil. MS m/z (ESI): 110 [M+1].
98%
With hydrogen In 1,4-dioxane at 60℃; for 8 h;
Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was reacted in hydrogen atmosphere for 8 hours under 40 atmosphere at 60° C. and filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methyl amine 1h (10.7 g, yield 98percent) as a brown oil. MS m/z (ESI): 110 [M+1].
98%
With pyridine; hydrogen In 1,4-dioxane at 60℃; for 8 h; Autoclave
2-cyano-pyrazol 1g (10.5 g, 100 mmol) was dissolved in 150 mL 1,4- dioxane was added 1.0 g Raney nickel in 250 mL autoclave at 60 , 40 atm of hydrogen the reaction was stirred for 8 hours. Filtered, and the filtrate was concentrated under reduced pressure, to give C- pyridin-2-yl - methylamine 1h (10.7 g, brown oil). Yield: 98percent.
98.9%
With hydrogen In 1,4-dioxane at 60℃; for 48 h;
Pyrazine-2-carbonitrile (19 g, 180 mmol) was dissolved in 1,4-dioxane (280 mL), and then Raney nickel (1.9 g) was added. The reaction mixture was reacted in hydrogen atmosphere at 60°C for 48 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (1) (19 g, 98.9percent) as a brown oil. 1H MR (400 MHz, DMSO-d6): δ 871 (s, 1H), 8.54-8.53 (m, 2H), 8.48 (d, J = 2.4Hz, 1H), 3.86 (s, 2H), 1.97 (br, 2H).
Stage #1: With sodium methylate In methanol at 20 - 30℃; for 6 h; Stage #2: at 25℃; for 22 h;
To a solution of sodium methoxide (NaOCH3) (51.4 g, 0.952 mol) in methanol (3800 ml) there is added cyanopyrazine (1.00 KG, 9.53 mol) slowly at room temperature. The mixture is heated to 30° C. and stirred for 6 h. The mixture is cooled to 25° C. followed by the addition of ammonium chloride (NH4Cl) (572 g, 10.5 mol). The reaction mixture is stirred for 22 h and methyl t-butyl ether (4000 mL) is added and the mixture is stirred for 15 min forming a solid. The solid is filtered and washed with methyl t-butyl ether (2.x.1000 mL) then dried at 40° C./0-10 mmHg for 17 h to give white solid product (1435 g) in 95percent yield with 95percent HPLC purity. 1H NMR (DMSO-D6): δ 9.7 (bs, 3H), 9.49 (d, 1H, J=1.5 Hz), 9.04 (m, 1H), 8.93 (t, 1H, J=1.5 Hz)
1.2 g
Stage #1: With sodium methylate In methanol at 20℃; for 12 h; Stage #2: With ammonium chloride In methanol for 3 h; Reflux
To a solution of pyrazine-2-carbonitrile (1.0 g, 9.52 mmol) in methanol (20 mL) was addedNaOCH3 (0.10 g, 1.90 mmol). The resulting mixture was heated with stirring at rt for 12 hrs. Tothe reaction mixture was added NH4C1 (0.51 g, 9.52 mmol). After being heated under reflux for 3 hrs, the resulting reaction mixture was concentrated in vacuo. The residue was suspended in ethanol (30 mL). The suspension was heated under reflux for 1 hr, then cooled to rt and filtered. The filtrate was concentrated in vacuo to give pyrazine-2-carboxamidine hydrochloride (1.2 g),which was used in the next step without further purification.
Reference：
[1] Patent: US2006/281760, 2006, A1, . Location in patent: Page/Page column 5; 8
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 1, p. 111 - 118
[3] Patent: US2005/75357, 2005, A1, . Location in patent: Page/Page column 35
[4] Patent: WO2005/79798, 2005, A1, . Location in patent: Page/Page column 150
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 299 - 301
[6] Synthesis, 2010, # 7, p. 1091 - 1096
[7] Patent: WO2016/107832, 2016, A1, . Location in patent: Page/Page column 67
Stage #1: With sodium methylate In methanol at 10 - 35℃; for 0.416667 h; Stage #2: With acetic acid In methanol at 50℃; for 1 h; Stage #3: With hydrogenchloride In methanolReflux
Step 1: 2-(1H-Imidazol-2-yl)pyrazine 2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL). To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25percent solution in methanol). After stirring for 25 minutes at room temperature, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50° C. for 1 hour. MeOH (40 mL) and 6N HCl (12 mL) were added and the reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between 1:1 Et2O and water (60 mL) and the layers were separated. The aqueous layer was basified to pH 9/10 and extracted with 10percent MeOH in DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the desired compound (1.49 g yellow solid). 1H NMR (400 MHz, MeOH-d4) δ ppm: 7.67 (s, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 5.72 (s, 2H)
With sodium azide In N,N-dimethyl-formamide at 120℃; for 1h;
Typical procedure for the preparation of 5-substituted 1H-tetrazoles
General procedure: Cu(II)-NaY (0.1 g) was added to a mixture of benzonitrile (0.206 g, 2.0 mmol) and sodium azide (0.169 g, 2.6 mmol) in DMF (5 mL) and mixture was stirred at 120 °C for 3 h. After completion of reaction (as monitored by TLC), the catalyst was centrifuged, washed with ethyl acetate and the centrifugate was treated with ethyl acetate (30 mL) and 5 N HCl (20 mL) and stirred vigorously. The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (20 mL). The combined organic layers were washed with water and concentrated to give the crude solid crystalline 5-phenyltetrazole. The product was characterizedby 1H NMR , 13C NMR and mass spectroscopic analysis.
98%
With sodium azide; water; zinc(II) chloride at 25℃; for 24h; Micellar solution;
98%
With sodium azide; zinc(II) chloride In water at 25℃; for 24h;
98%
With sodium azide; scandium tris(trifluoromethanesulfonate) In water; isopropyl alcohol at 160℃; for 1h; Microwave irradiation; Sealed tube;
EXPERIMENTAL
General procedure: Synthesis of 5-(4-chlorophenyl)-1H-tetrazole (2c) was achieved as follows: 4-chlorobenzonitrile 1c (274 mg, 2 mmol), NaN3 (260 mg, 4 mmol), Sc(OTf)3(197 mg, 0.4 mmol), and 8mL of a 3:1 isopropanol=water mixture were added to a30-mL Pyrex microwave vessel and capped. The microwave vessel was then placedin a Milestone Start Synth microwave reactor. The reaction was magnetically stirredand heated for 1 h at 160 C. The reaction was monitored by thin-layer chromatography(TLC) using an ether=hexane mixture (typically 50=50) for development.The reaction mixture was then diluted with saturated aqueous sodium bicarbonate(20 mL) and washed with ethyl acetate (215mL). The aqueous sodium bicarbonatelayer was cooled with ice and acidified to a pH of 2 or less with concentratedhydrochloric acid, which was added dropwise. The precipitate formed was extractedwith ethyl acetate (315 mL). The combined organic layers were dried with anhydroussodium sulfate and decanted into a tared round-bottom flask. The organiclayer was concentrated under reduced pressure by rotary evaporation at 40 C andthen under high vacuum. The tetrazole product was recrystallized from ethyl acetateand hexane. All reagents mentioned were not unpurified.
91%
With sodium azide; acetic acid; 1-methyl-3-octylimidazol-3-ium chloride at 130℃; for 48h;
91%
With sodium azide; tetrabutylammomium bromide at 105℃; for 8h; Sealed tube; Green chemistry;
2-(1H-Tetrazol-5-yl)pyrazine14 (2o) Table 2, entry 14
General procedure: A screw capped vial was charged with nitrile (2 mmol), NaN3(2.4 mmol, 1.2 equiv.) and tetrabutylammonium bromide (2.4 mmol,1.2 equiv.). The resulting mixture was stirred at 105 °C and monitoredby TLC. After completion of the reaction, the reaction mixture wascooled to room temperature and dissolved with water (5 mL). Then, theaqueous solution was acidified with 1M HCl to pH = 3. If a precipitatewas formed, the suspension was filtered and the filter cake was washedwith water to afford the pure product. Otherwise, the aqueous solutionwas extracted with EtOAc (3 × 4 mL). The organic phase was washedwith 1M HCl (3 × 4 mL), dried with anhydrous Na2SO4, filtered andevaporated under vacuum to afford the pure product.
90%
With sodium azide; acetic acid; urea In water; N,N-dimethyl-formamide at 60 - 110℃; for 9h;
Typical procedure for preparation
General procedure: The procedure for the synthesis of the tetrazole 2a is representative. A mixture of sodium azide (0.39 g 0.0060 mol), urea (0.36 g, 0.0060 mol) and water (2.5 mL) was taken in a round-bottom flask and stirred at 60 °C for 1 h. Charged benzonitrile 1a (0.5 g 0.0048 mol), acetic acid(0.5 mL) and DMF (2.5mL) at 60 °C and heat to 110°C stirred for 8 h. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to room temperature and diluted the reaction mass with water (2.5 mL)and ethyl acetate (5.0 mL) at 25-35 °C. Add 5N aqueous hydrochloric acid (2.5 mL) at 25-35 °C. Stirred for 20- 30 min, the resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (2.5 mL). The combined organic layer was washed with 40 % aq.NaCl solution (2.5 mL) and dried over anhydrous Na2SO4 and concentrated to give a crude product, which was isolated using chilled water after 3-4 h maintenance, and eventually filtered off to give 0.67 g (95%) of an off-white solid.
88%
Stage #1: 2-pyrazine carbonitrile With sodium azide In water at 100℃; for 0.75h; Green chemistry;
Stage #2: With hydrogenchloride In water at 20℃; for 0.00833333h; Green chemistry; chemoselective reaction;
82%
With sodium azide In N,N-dimethyl-formamide at 120℃; for 5h;
82%
With antimony(III) trioxide; sodium azide In N,N-dimethyl-formamide at 120℃; for 4h;
78%
With bismuth(III) chloride; sodium azide In water; isopropyl alcohol at 160℃; for 1h; Microwave irradiation;
Typical ExperimentalMethodology: Synthesisof5-(Furan-2-yl)-1Htetrazole (2m)
General procedure: 2-Furonitrile 1m (186 mg, 2 mmol), NaN3 (260 mg, 4 mmol), BiCl3 (126 mg, 0.4 mmol), and 8 mL of a 3:1 isopropanol/water mixture were added to a 30-mL Pyrex microwave vessel, which was then capped. The microwave vessel was then placed in a Milestone Start Synth microwave reactor. The reaction was magnetically stirred and heated for 1 h at 150°C. The reaction was monitored by thin-layer chromatography (TLC) using an ether/hexane mixture (typically 50/50) for development. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate (20 mL) and was hed with ethyl acetate (2×15 mL). The aqueous sodium bicarbonate layer was cooled with ice and acidified to a pH of 2 or less with concentrated hydrochloric acid, which was added dropwise. The precipitate formed was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried with anhydrous sodium sulfate and decanted into a tared round-bottom flask. The organic layer was concentrated under reduced pressure by rotary evaporation at 40°C and then under high vacuum. The tetrazole product was recrystallized from ethyl acetate and hexane.
78%
With sodium azide In N,N-dimethyl-formamide at 140℃; for 2.5h;
76%
With sodium azide; zinc hydroxyapatite In N,N-dimethyl-formamide at 120℃; for 5h;
72%
Stage #1: 2-pyrazine carbonitrile With sodium azide; cadmium(II) chloride In N,N-dimethyl-formamide at 80℃; for 4h;
Stage #2: With hydrogenchloride; water In ethyl acetate
69%
With sodium azide; acetic acid In 1-methyl-pyrrolidin-2-one; water at 220℃; for 0.0833333h; Microwave irradiation;
65%
With sodium azide; cerium(III) chloride heptahydrate In water; isopropyl alcohol at 160℃; for 1h; Microwave irradiation;
General Methodology for the Synthesis of 5-Substituted 1H-Tetrazoles
General procedure: Synthesis of 5-(thiophen-3-yl)-1H-tetrazole (2a). 3-Thiophenecarbonitrile 1a (218 mg, 2 mmol), NaN3 (260 mg,4 mmol), CeCl3·7H2O (75 mg, 0.2 mmol), and 8 mL of a 3:1isopropanol/water mixture were added to a 30-mL Pyrexmicrowave vessel and capped. The microwave vessel wasthen placed in a multi-mode microwave reactor. The reactionwas magnetically stirred and heated for 1 hour at 160 °C.The pressure in the vessel was not determined. The reactionwas monitored by TLC using an ether/hexane mixture (typically50/50) for development. After cooling, the reactionmixture was diluted with saturated aqueous sodium bicarbonate(20 mL) and washed with ethyl acetate (2 x 15 mL).The aqueous sodium bicarbonate layer was cooled with iceand acidified to a pH of 2 or less with concentrated hydrochloricacid, which was added drop-wise. The precipitateformed was extracted with ethyl acetate (3 x 15 mL). Thecombined organic layers were dried over anhydrous sodiumsulfate and decanted into a tared round bottom flask. Theorganic layer was concentrated under reduced pressure. Thetetrazole product was recrystallized from ethyl acetate andhexane. All reagents mentioned above were used unpurified.
64%
With diisobutylaluminum azide In toluene at -40 - 0℃; for 3h;
With sodium azide; acetic acid; isopropyl alcohol at 150℃;
97 %Chromat.
With sodium azide; zinc dibromide In 1-methyl-pyrrolidin-2-one; water at 190℃; for 0.333333h;
97 %Chromat.
Stage #1: 2-pyrazine carbonitrile With sodium azide; zinc dibromide In 1-methyl-pyrrolidin-2-one; water at 190℃; for 0.333333h; Stainless steel syringe;
Stage #2: With hydrogenchloride In 1-methyl-pyrrolidin-2-one; water
1; 2.A
In order to expand the scope of this flow method, a variety of nitriles were subjected to the optimized conditions in the entry 6 (Table 1), and the results are summarized in Tables 3 and 4 {Method A). For substrates 2 and 3, where no electron- donating or electron- withdrawing group was present on the aromatic ring, or substrate 4 where the nitrile was rendered electron poor by the presence of electron- withdrawing group at the para position, the reactions proceeded to 100% conversions without the formation of any side product. Similarly, meta tolunitrile (5) and the hetero aromatic substrates (6-8) also showed excellent conversions. Electron rich nitriles 10 and 10 reacted to give moderate but clean conversions to the corresponding tetrazoles. The biphenyl nitriles 9, 13 and 14 also proved to be good substrates for this reaction regardless of position of the phenolic hydroxy group on the second aromatic ring.Notably, chiral nitrile 15 provided 15a, a derivative of which (no CBZ group) has found utility as an organocatalyst, in > 99% ee and 92% yield based on conversion. To test if an increase in the ¾ can drive the reaction of moderately yielding substrates to completion, the model substrate 1 was reacted at a ¾ of 30 min (Table 4). There was no significant change in the conversion observed; instead a small amount of hydrolysis product la was formed. However, significant improvement in the reaction rate was observed by doubling the concentration of the reaction (0.4 M). For nitrile 1, the conversion increased from 65% to 81% (¾ = 30 min), while similar improvement in conversions were observed for substrates 11 and 13-15 when the reaction concentration was doubled.As this continuous flow method has the advantage of using high temperatures in a safe manner, it was determined that the presence of a catalyst (e.g., ZnBr2) was not essential for all reactions carried out at these temperatures. To test this, the flow process was repeated with selected substrates without the use of ZnBr2 (Tables 3 and 4, Method B). The non- substituted benzo- and napthonitrile substrates (2 and 3), electron poor nitrile (4), and the heterocyclic substrates (6, 7 and 8), all showed excellent conversions to corresponding tetrazoles in the absence of ZnBr2. The conversions were found to decrease moderately in case of biphenyl substrates 9, 13 and 14 indicating decrease in the reaction rate of these substrates in the absence of ZnBr2. Similar decrease in conversion was observed for the electron rich substrates (1 and 12), but it was noted that there was no side product observed in the absence of ZnBr2 even at 30 min of residence time. This shows that ZnBr2 may be promoting the competing side reaction. Thus, the use of ZnBr2 may be useful for enhancing the conversion of the electron-rich nitriles, but can also lead to formation of side product. In many, if not all instances, reactions without ZnBr2 can give clean conversions. To demonstrate the scale-up capabilities of this, the synthesis of 3a was carried out using aUniqsis FlowSyn continuous flow reactor. FlowSyn is an integrated continuous flow reactor system that uses a pair of high pressure pumps to deliver reagent solutions through a 'T'-mixer into the electrically heated flow coil or column reactors. The homogenous solution of reagents ([3] = 1M; [NaN3] = 1.05 M) in NMP:H20 (7:3) was pumped using a single pump through a coiled PFA tubing reactor (volume of heated zone ~ 6.9 mL) with a flow rate of 0.35 mL/min (tr = 20 min) at 190 °C (see Example 2). The flow process was run continuously for 2.5 h to obtain 9.7 g of 3a in 96 % yield. This corresponds to a product output of 4.85 g/h or 116 g/day for the tetrazole 3a.Overall, the method performed is a safer alternative for currently used methods to synthesize 5-substituted tetrazoles as the hazards due to accumulation and condensation of HN3 are greatly minimized. Only uses a slight excess of NaN3 (1.05 equiv) was used, and hence the production of azide waste is minimal. The method is highly efficient and clean, and works for a wide range of substrates. In case of substrates where the reaction does not go to completion, the remaining NaN3 in the reaction can be quenched by introducing streams of sodium nitrite and sulfuric acid after the reaction is complete. The incorporation of this quenching procedure increases the overall safety of the process. Therefore, given the widespread applications of tetrazoles in chemical andpharmaceutical industry, this method can serve as a safe and highly efficient alternative for synthesis of tetrazoles.EXAMPLE 2This example provides additional experimental details and data in connection with Example 1.General protocol for continuous flow synthesis of tetrazoles (Method A):Sodium azide (68 mg, 1.05 mmol) was added to a solution of zinc bromide (111 mg, 0.5 mmol) in 0.5 mL water. To this solution was added the nitrile substrate (1 mmol) dissolved in 4.5 mL of N-methylpyrrolidone (NMP) and the resulting clear solution was filled in a 10 mL stainless steel syringe (Harvard Apparatus, High Pressure stainless steel syringe with 1/16 inch SWAGELOK), which was then charged to a syringe pump (Harvard PHD 2000) (see FIG. 3A and 3B). The syringe was connected to a 41 cm tubular coiled reactor (Upchurch Scientific PFA tubing; 1/16 x 0.03 in.) with the help of SWAGELOK fittings (stainless steel front ferrule, stainless steel back ferrule and 316 stainless steel nut for 1/16 in.). The tubular reactor was coiled in such a way that 26.4 cm (constituting an internal volume of 120 L) of the middle portion of the tubing was dipped in the oil bath (heating source). A 250 psi back pressure regulator (Upchurch Scientific) was installed at the distal end of this tubing followed by short outlet tubing. The reaction mixture was pumped through the tubular reactor at a rate of 6 μ/ιηη, and the temperature of the oil bath was set to 190 °C. This resulted in a 20 min residence time for reaction mixture in the part of tubing immersed in the oil bath. After the reactor reached equilibrium (flowing approximately 3 full-reactor volumes), 1 mL of output was collected and diluted with 10 mL of water. The solution was acidified to pH 1 using 3 N HC1 and stirred vigorously. Note: for the heterocyclic substrates 10, 11 and 12, the reaction was basified and stirred vigorously until a white precipitate (zinc hydroxide) was observed. The precipitate was filtered and the pH of the filtrate was adjusted to 6.5. The resulting precipitate was extracted with ethyl acetate, and the organic layer concentrated to yield the product. A white precipitate appeared which was extracted into non-aqueous layer using 10 mL of ethyl acetate. The organic layer was separated and concentrated to yield a crude product. This crude product was taken in 20 mL of 0.25 N sodium hydroxide solution and stirred vigorously until a white precipitate of zinc hydroxide was observed. The resulting precipitate was filtered and the filtrate was acidified to pH 1 using 3 N HC1. The tetrazole product precipitated upon stirring, which was then filtered, washed with 10 mL of 3 N HC1, and dried to obtain a pure product.The parts used to assemble the apparatus shown in FIG. 3B include at least the following: PHD 22/2000 Remote Syringe Pump from Harvard Apparatus (syringe rack high pressure); PFA tubing (1/16 x 0.03 inch) from Upchurch Scientific;SWAGELOK fitting from Upchurch Scientific (Stainless Steel Nut for 1/16 inch; Stainless Steel Front Ferrule; Stainless Steel Back Ferrule); 250 psi Back Pressure Regulator from Upchurch Scientific (or alternatively, a 100 psi PEEK back pressure regulator); Flat Bottom Fitting from Upchurch Scientific; Nut (PEEK); Flangeless Ferrule (TEFZEL); High Pressure 8 mL Stainless Steel Syringe with 1/16 inchSWAGELOK ; 5/16 Wrenches (2); Aluminium or any other flexible wire; Glass Vials; Oil Bath with High Temperature Oil and a Magnetic Stirrer -1
With sodium azide; ammonium chloride In N,N-dimethyl-formamide
With sodium azide; acetic acid In butan-1-ol at 135℃; for 96h;
General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99%).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
34%
With trichlorophosphate; In acetonitrile; for 6h;Inert atmosphere; Reflux;
In a dried 500 ml, three necked, jacketed flask fitted with a mechanical stirrer, temperature probe, a reflux condenser, a circulation bath, and a positive nitrogen atmosphere set-up was charged with 2-pyrazinecarboxamide 20.0 gm (0.162 mol), acetonitrile 240 ml, and POCl3 59.6 gm (0.389 mol). The white slurry was agitated and heated to reflux. The reaction mixture was maintained at reflux for at least 6 hours. Then the excess POCl3 was distilled off under reduced pressure. After aqueous work up, the reaction mixture was extracted with 4×70 ml ethyl acetate. The combine ethyl acetate extracts were washed with 3×70 ml water, distilled under reduced pressure to remove ethyl acetate and to afford cyanopyrazine as a brown oil: 5.76 gm (34% yield); HPLC purity, >98 area %; 1H NMR (300 MHz, CDCl3) delta 8.67 (pair d, J=1.7 and 2.5 1H), 8.75 (d, J=2.5, 1H), 8.87 (d, J=1.3 1H); 13C NMR (300 MHz, CDCl3) delta 115.1, 130.7, 145.3, 147.3, 148.1.
With sodium carbonate; In trichlorophosphate;
A. Cyanopyrazine In 10 ml of phosphoryl chloride at reflux temperature there was stirred pyrazineamide (20 g; 0.162 M) for 1 hour. Excess phosphoryl chloride was then removed and water aspirated. Ice was added to the residue, followed by sodium carbonate until basic, then extraction with 150 ml of ether five times. The combined extracts were dried over sodium sulfate, and the solvent then removed in vacuo to give the title compound (12.9 g).
With sodium carbonate; In trichlorophosphate;
A. Cyanopyrazine In 100 ml of phosphoryl chloride at reflux temperature there was stirred pyrazineamide (20 g; 0.162 M) for 1 hour. Excess phosphoryl chloride was then removed and water aspirated. Ice was added to the residue, followed by sodium carbonate until basic, the extraction with 150 ml of ether five times. The combined extracts were dried over sodium sulfate, and the solvent then removed in vacuo to give title compound (12.9 g).
With hydrazine hydrate monohydrate In ethanol for 24h;
2.4. General procedure for synthesis of ligands (L1 and L2)
The ligands were synthesized following the reported procedure[37]. Reaction of pyrazine 2-carbonitrile (2 mmol) and hydrazine hydrate (3.5 mmol) under stirring for 24 h resulted to the formation of yellow crystalline solid of pyrazine 2-carbohydrazonamide, thecompound was washed with diethyl ether and dried. Pyrazine 2-carbohydrazonamide was further reacted in 1:1M ratio with thedesired pyridine in ethanol and the mixture was reflux at 60 C forabout 4 h. The yellow solid, which formed,waswashed with diethylether and dried at room temperature (Scheme 1).
Multi-step reaction with 2 steps
1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1 h / Reflux
2: hydrazine hydrazine hydrate / 0.25 h / Reflux
Multi-step reaction with 2 steps
1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1 h / Reflux
2: hydrazine hydrazine hydrate / ethanol / 0.25 h / Reflux
With Ni-doped silica; hydrogen; In toluene; at 140℃; under 38002.6 Torr; for 4h;Autoclave; Inert atmosphere;
The synthesis of 2-aminomethyl pyradine(2-AMPZ) was carried out by a method shown below, byreference to the method described in literature (JP A 2001-894594). 2-cyanopyradine used was from Sigma-Aldrich Co.LLC.1.05 g of 2-cyanopyradine (10 mmol) and 100mg of60 wt %-Ni/5i02 were placed in an autoclave (5U53 16) with20 mL of toluene and replaced with argon gas. This waspressurized with hydrogen gas to 50 atm, stirred at 140C. for4 hours. The reaction solution was filtered and concentratedto give 2-aminomethyl pyradine (2-AMPZ) quantitatively.10152] ?H-NMR spectrum (399.78 MHz, CDC13):oe8.60-8.45 (m, 3H), 4.07 (s, 2H), 1.79 (br, 2H)
98%
With hydrogen;Raney nickel; In 1,4-dioxane; at 60℃; under 30402.0 Torr; for 8h;Autoclave;
Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane under stirring, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was hydrogenated for 8 hours under 40 atmosphere at 60 C, filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methylamine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1]
98%
With hydrogen;Raney Nickel; In 1,4-dioxane; at 60℃; under 30402.0 Torr; for 8h;Autoclave;
Step 6 C-Pyrazin-2-yl-methylamine Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was reacted in hydrogen atmosphere for 8 hours under 40 atmosphere at 60 C and filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methyl amine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1].
98%
With hydrogen;Raney nickel; In 1,4-dioxane; at 60℃; under 30402.0 Torr; for 8h;
Pyrazine-2-carbonitrile 1g (10.5 g, 100 mmol) was dissolved in 150 mL of 1,4-dioxane, then Raney nickel (1.0 g) was added into a 250 mL autoclave. The reaction mixture was reacted in hydrogen atmosphere for 8 hours under 40 atmosphere at 60 C. and filtered and concentrated under reduced pressure to obtain the title compound C-pyrazin-2-yl-methyl amine 1h (10.7 g, yield 98%) as a brown oil. MS m/z (ESI): 110 [M+1].
98%
With pyridine; hydrogen; In 1,4-dioxane; at 60℃; under 30402.0 Torr; for 8h;Autoclave;
2-cyano-pyrazol 1g (10.5 g, 100 mmol) was dissolved in 150 mL 1,4- dioxane was added 1.0 g Raney nickel in 250 mL autoclave at 60 , 40 atm of hydrogen the reaction was stirred for 8 hours. Filtered, and the filtrate was concentrated under reduced pressure, to give C- pyridin-2-yl - methylamine 1h (10.7 g, brown oil). Yield: 98%.
98.9%
With hydrogen; In 1,4-dioxane; at 60℃; for 48h;
Pyrazine-2-carbonitrile (19 g, 180 mmol) was dissolved in 1,4-dioxane (280 mL), and then Raney nickel (1.9 g) was added. The reaction mixture was reacted in hydrogen atmosphere at 60C for 48 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (1) (19 g, 98.9%) as a brown oil. 1H MR (400 MHz, DMSO-d6): delta 871 (s, 1H), 8.54-8.53 (m, 2H), 8.48 (d, J = 2.4Hz, 1H), 3.86 (s, 2H), 1.97 (br, 2H).
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 3345.86 Torr; for 16h;
Preparation 53; C-Pyrazin-2-yl-methylamine; In a Parr bottle, charge pyrazine-2-carbonitrile (1 g) in absolute ethanol (10mol). Add 10% Pd-C (w/w, 0.4g) and place on a Parr Hydrogenation Apparatus under 50 psig hydrogen at ambient temperature for sixteen hours. Filter the mixture through a pad of Celite. Purify material on SCX column. Use crude basic material in next step without further purification.
With ammonia; hydrogen;Raney nickel; In methanol; under 2585.81 Torr; for 1.5h;
Example 8. Synthesis of the primary amine, pyrazin-2-ylmethanaminechromatography 17 3. TFA / CH2CI2 18[0096] Raney nickel catalyst was carefully washed with THF and methanol making sure that the catalyst remained moist. The weight of the moist catalyst was 2.5 g after washing. This material was added to a solution of pyrazinecarbonitrile (17) (3.0 g) in 7N methanolic ammonia (120 mL). The mixture was shaken under a 50 p.s.i. atmosphere of hydrogen for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to provide the crude title compound. Purification was accomplished by conversion of the crude amine to the tert-butyl carbamate with excess di-fert-butyl dicarbonate in methylene chloride. Column chromatography (70:27:3 hexanes:ethyl acetate:methanol) provided 0.5O g of pure tert-butyl pyrazin-2-ylmethylcarbamate. Pure pyrazin-2- ylmethanamine (18) was obtained as the TFA salt from deprotection of the carbamate with 1:1 TFA / CH2Cl2. EPO <DP n="33"/>[0097]
With ammonia; hydrogen;nickel; In methanol; under 2585.81 Torr; for 1.5h;
Example 8 Synthesis of the primary amine, pyrazin-2-ylmethanamine Raney nickel catalyst was carefully washed with THF and methanol making sure that the catalyst remained moist. The weight of the moist catalyst was 2.5 g after washing. This material was added to a solution of pyrazinecarbonitrile (17) (3.0 g) in 7N methanolic ammonia (120 mL). The mixture was shaken under a 50 p.s.i. atmosphere of hydrogen for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to provide the crude title compound. Purification was accomplished by conversion of the crude amine to the tert-butyl carbamate with excess di-tert-butyl dicarbonate in methylene chloride. Column chromatography (70:27:3 hexanes:ethyl acetate:methanol) provided 0.50 g of pure tert-butyl pyrazin-2-ylmethylcarbamate.
With ammonia; hydrogen;nickel; In methanol; under 2585.81 Torr; for 1.5h;
Raney nickel catalyst was carefully washed with THF and methanol making sure that the catalyst remained moist. The weight of the moist catalyst was 2.5 g after washing. This material was added to a solution of pyrazinecarbonitrile (17) (3.0 g) in 7N methanolic ammonia (120 mL). The mixture was shaken under a 50 p.s.i. atmosphere of hydrogen for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to provide the crude title compound. Purification was accomplished by conversion of the crude amine to the tert-butyl carbamate with excess di-terf-butyl dicarbonate in methylene chloride. Column chromatography (70:27:3 hexanes:ethyl acetate methanol) provided 0.50 g of pure tert-butyl pyrazin-2-ylmethylcarbamate. Pure pyrazin-2-yhnethanamine (18) was obtained as the TFA salt from deprotection of the carbamate with 1:1 TFA / CH2Cl2.
With 60% Ni/SiO2; hydrogen; In toluene; at 140℃; under 38002.6 Torr; for 4h;Autoclave; Inert atmosphere;
The synthesis of 2-aminomethylpyrazine (2-AMPZ) was synthesized according to the method described below with reference to the method described in the literature (Japanese Patent Laid-Open No. 2001-894594). 2-cyanopyrazine is 1.05 g (10 mmol) of 2-cyanopyrazine using Aldrich reagent and 100 mg of 60 wt% Ni / SiO2 was charged into a SUS316 autoclave together with 20 mL of toluene and purged with argon gas.This was pressurized to 50 atm with hydrogen gas and stirred at 140 C. for 4 hours.The reaction solution was filtered and concentrated to quantitatively obtain 2-aminomethylpyrazine (2-AMPZ).
A solution of nitrile 3 in ethanol/H2O (0.6 M, 8:1 v/v) was passed through the column reactor R2 (100 mm × 10 mm, 5 g hydrous zirconia) heated at 100 C, with a residence time of 20 minutes, to obtain a quantitative recovery of the primary amide 2 after concentration of the reactor output (>98% yield). White solid; m.p. 191-194 C; delta H (400 MHz, d6-DMSO, 25 C) 7.84 (1H, br. s), 8.24 (1H, br. s), 8.70 (1H, dd, J = 2.5 Hz, J 1.5 Hz), 8.85 (1H, d, J = 2.5 Hz), 9.17 (1H, d, J = 1.5 Hz); delta C (100 MHz, CDCl3, 25 C) 143.46 (CH), 143.69 (CH), 145.18 (C), 147.46 (CH), 165.13 (C); FTIR (neat, nu): 3422, 3132, 1669, 1583, 1525, 1481, 1432, 1373, 1171, 1089, 1046, 1021, 870, 791 cm-1; LC-MS: retention time 0.28 min, m/z [M + H]+ = 124.19; HRMS (ESI): m/z calcd for C5H6ON3+: 124.0505; found 124.0504. Elemental analysis: calcd C = 48.78%, H = 4.09%, N = 34.13%; found C = 48.60%, H = 4.19%, N = 33.70%.
96%
With water; at 110℃; for 6h;
General procedure: Two milli liter water at room temperature was added to astirred mixture of nitrile (1mmol) and catalyst (40mg) thenheated with an oil bath maintained at 110C, and stirred. After completion of the reaction (monitored by TLC), thecatalyst was removed from the reaction mixture by externalmagnet. Then the mixture was extracted with ethyl acetate,subsequently purified by column chromatography on silicagel to provide the corresponding amide products.
65%
With copper(l) iodide; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In nitromethane; water; at 20 - 80℃; for 0.25h;
To a nitromethane (0.10 mL) solution of pyrazine-2-carbonitrile (4e) (30 mg, 0.285 mmol) were addedH2O (1.0 mL), DBU (87 mg, 0.571 mmol), copper (I) iodide (11 mg, 0.0571 mmol), cesium (I)carbonate (47 mg, 0.143 mmol), 4-dimethylaminopyridine (35 mg, 0.285 mmmol) at roomtemperature. The reaction mixture was heated at 80 C for 15 min and then poured into water (50mL). The organic layer was separated and the aqueous layer was extracted with AcOEt. Thecombined organic layer was dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (2:1) to givepyrazine-2-carboxamide (5e) S11 (23 mg, 65%) as pale yellow powders.5e: mp 187-188 C,
With C40H45ClN3O2PRu; In methanol; water; at 20℃; for 4h;Inert atmosphere; Schlenk technique; Green chemistry;Catalytic behavior;
General procedure: Organic nitrile (1 mmol) and distilled water (1 mL) were sequentially added to 3 mL methanol solution of the [Ru-NHC] catalyst (0.5 mol%) and the reaction mixture was stirred at room temperature. The progress of the reaction in each case was monitored by TLC analysis. After completion of reaction the catalyst was extracted from the reaction mixture by the addition of CH2Cl2/petroleum ether followed by filtration. The filtrate was subjected to GC analysis and the product was identified with authentic samples.
92%Chromat.
General procedure: 0.6 mmol benzonitrile and 0.6 mmol DMSO were solved in 3 mL EtOH and pumped into inlet A, 50 muL 1 M NaOH (aq) solved in 1 mL EtOH and pumped into inlet B, 30% H2O2 (aq) was solved in 7 mL ethanol and pumped into inlet C (flow rate A: B: C = 1.54 mul/min:0.46 mul/min:0.3 mul/min for a 400s residence time). The whole system was maintained on 25 C. The flow system was equilibrated for 30 min, then the product stream was quenched and collected in a glass vessel with saturated aqueous NaHSO3 in it for 2 h. After being filtered, 5.0 ml of this solution was injected to the HPLC instrument for analysis. The conversion of the reaction was determined by relative area percentage of nitriles and corresponding amides. Conversion = Area (benzamide)/[Area (benzamide) + Area (benzonitrile)].
To a solution of sodium methoxide (NaOCH3) (51.4 g, 0.952 mol) in methanol (3800 ml) there is added cyanopyrazine (1.00 KG, 9.53 mol) slowly at room temperature. The mixture is heated to 30 C. and stirred for 6 h. The mixture is cooled to 25 C. followed by the addition of ammonium chloride (NH4Cl) (572 g, 10.5 mol). The reaction mixture is stirred for 22 h and methyl t-butyl ether (4000 mL) is added and the mixture is stirred for 15 min forming a solid. The solid is filtered and washed with methyl t-butyl ether (2×1000 mL) then dried at 40 C./0-10 mmHg for 17 h to give white solid product (1435 g) in 95% yield with 95% HPLC purity. 1H NMR (DMSO-D6): delta 9.7 (bs, 3H), 9.49 (d, 1H, J=1.5 Hz), 9.04 (m, 1H), 8.93 (t, 1H, J=1.5 Hz)
To 20 mL of methyl alcohol is added sodium (109 mg, 4.74 mmol) with stirring. After disappearance of the solid, 2-pyrazinecarbonitrile (5.0 g, 47.6 mmol) is added. The mixture is stirred at room temperature for 6 h, and ammonium chloride (2.8 g, 52.3 mmol) is added. The mixture is then stirred at room temperature for 18 h. Diethyl ether (50 mL) is added to the reaction mixture, and the precipitates are collected by filtration. The solid was washed with diethyl ether (×2) and dried in vacuum oven to give 2-pyrazinecarboxamidine hydrochloride as a white solid (6.5 g). MS: m/z 123.1 (M+H).
To pyrazinecarbonitrile (11.7g, O. llmol), 28% methanol solution of sodium methoxide (2. 0g, lOmmol) was added and the mixture was refluxed for 4 hours and, after adding ammonium chloride (6.4g, 0. 12mol), for further 6 hours. After finishing the. reaction, the precipitation, formed by adding diethyl ether (50ml) to the mixture, was filtered, washed with diethyl ether and then with acetone, and dried in a desiccator to obtain amidinopyrazine hydrochloride (17.2g), which was used in further reaction without purification.
1.2 g
To a solution of pyrazine-2-carbonitrile (1.0 g, 9.52 mmol) in methanol (20 mL) was addedNaOCH3 (0.10 g, 1.90 mmol). The resulting mixture was heated with stirring at rt for 12 hrs. Tothe reaction mixture was added NH4C1 (0.51 g, 9.52 mmol). After being heated under reflux for 3 hrs, the resulting reaction mixture was concentrated in vacuo. The residue was suspended in ethanol (30 mL). The suspension was heated under reflux for 1 hr, then cooled to rt and filtered. The filtrate was concentrated in vacuo to give pyrazine-2-carboxamidine hydrochloride (1.2 g),which was used in the next step without further purification.
Alternatively, 2-pyrazinecarboxamidine hydrochloride can be prepared as follows: A solution of 2-pyrazinecarbonitrile (21 g, 200 mmol) in a mixture of 10 mL of methyl alcohol and 120 mL of diethyl ether is treated with hydrogen chloride gas at 0 C. The mixture is then stored at 5 C. for 3 days. The precipitates are collected by filtration and and dried. This solid is then suspended in 100 mL of ethyl alcohol and the mixture is treated with ammonium gas at 0 C. The mixture is then stored at 5 C. for 4 days, and filtered. Concentration of the filtrate gives 2-pyrazinecarboxamidine hydrochloride as a tan solid (2.8 g).
With sulfuryl dichloride; In N,N-dimethyl-formamide; toluene; at 20℃; for 5.6h;Cooling with ice;
To a solution of pyrazine-2-carbonitrile 13 (6.90 g, 65.65 mmol) in toluene (48 mL) and DMF (5 mL) was added sulfuryl chloride (21.2 mL, 260.8 mmol) over 10 min. The reaction mixture was stirred for 30 min in an ice bath, then allowed to warm up to room temperature gradually, after which it was stirred for 5 h. The toluene layer was decanted, and the reddish oil residue was extracted three times with diethyl ether. The combined toluene and ether layers were quenched with ice water and cooled in an ice bath. The combined layers were then neutralized with solid NaHCO3, then separated, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to afford the title compound. The crude product was purified by silica gel chromatography (eluent: 100% dichloromethane) to give 3-chloropyrazine-2-carbonitrile 14 as a white powder (4.7 g, 51%). Rf = 0.76 (dichloromethane); mp 44-46 C (lit. [14] : 47-48 C); IR (KBr) numax (cm-1): 3088 (nuCHar), 2242 (nuCN), 1377 (nuC=C), 1087 (nuC-N); 1H NMR (400 MHz, DMSO-d6): delta 8.91 (d, 1H, J = 2.4 Hz, H-6), 8.88 (d, 1H, J = 2.4 Hz, H-5); 13C NMR (100 MHz, DMSO-d6): delta 150.67 (C-3), 147.97 (C-5), 144.26 (C-6), 129.87 (C-2), 114.66 (CN); MS (ESI) m/z (%): 140.3 (100) [M + H]+, 142.3 (40) [M + H + 2]+. Anal. calcd for C5H2ClN3: C, 43.04; H, 1.44; N, 30.11. Found: C, 43.18; H, 1.45; N, 30.16.
With sulfuryl dichloride; In N,N-dimethyl-formamide; toluene; at 0 - 20℃;
Reference Example 32: 3-Chloropyrazine-2-carbonitrile Pyrazine-2-carbonitrile (26.36 g) is dissolved in toluene (187 ml)/N,N-dimethylformamide (19 ml), and thereto is added dropwise sulfuryl chloride (135 g) under ice-cooling. After completion of addition, the reaction solution is warmed to room temperature gradually and stirred overnight. The toluene layer is separated and the residual red oil is extracted with diethyl ether. The organic layers are combined, cooled with ice, and after pouring thereto ice-water, neutralized by adding saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, and aqueous layer is extracted with diethyl ether. The organic layers are combined, washed with water, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 4/1) to give the title compound (16.58 g). 1H-NMR(CDCl3, 300MHz) delta:8.66(1H,d,J=2.4Hz), 8.61(1H,d,J=2.4Hz).
A solution of pyrazinecarbonitrile (2.0 g, 19 mmol) in methanol (20 mL) was treated with sodium methoxide in methanol (25wt%, 1.3 mL, 5.7 mmol) at room temperature. After 30 minutes, a solution of tert-butyl 4-(hydrazinocarbonyl)piperidme-1-carboxylate (4.6 g, 19 mmol) in methanol (20 mL) was added and the reaction was heated to reflux for 19 hours. The reaction mixture was concentrated, dissolved in ethoxyethanol (50 mL) and heated to reflux for 22 hours. The reaction was cooled to room temperature, quenched with acetic acid (0.38 mL, 6.6 mmol) and concentrated. The residue was suspended in ether and filtered to give tert-butyl 4-(5-pyrazin-2-yl-1H-1,2,4-triazol-3- yl)piperidine-1-carboxylate as a solid. EtaRMS (MH-H+): observed = 331.1876, calculated = 331.1877; 1H NMR (400 MHz, CD3OD): delta 9.29 (d, J = 1.6 Hz, IH), 8.70 (dd, J = 2.4, 1.6 Hz, IH), 8.64 (d, J = 2.4 Hz, 2H), 4.19-4.15 (m, 2H), 3.15-3.09 (m, IH), 2.97 (m, 2H), 2.07-2.03 (m, 2H), 1.84-1.75 (m, 2H), 1.48 (s, 9H).
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.
Example 3 :f4aS RJaS)-7a-f2-fluoro-5-f2-fpyrazin-2-yl)-lH-imidazol-5-vDphenvn-5-methYl- 4a. .7.7a -t etrah ydro-4 H - f tiro Gamma3 ,4-d] f 1.3]thiazin-2-amineStep 1 : 2-(lH midazol-2-yl)py 2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL). To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25% solution in methanol). After stirring for 25 minutes at room temperature,, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50C for 1 hour. MeOH (40 mL) and 6N HC1 (12 mL) were added and the reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between 1 : 1 Et20 and water (60 mL) and the layers were separated. The aqueous layer was basified to pH 9/10 and extracted with 10% MeOH in DCM. The combined organic extracts were dried (MgSOa), filtered and concentrated to give the desired compound ( 1.49 g yellow solid). 1 H NMR (400 MHz, eOH-d,) delta ppm: 7.67 (s, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.99 (d, J=2.5 Hz, 1 H), 5.72 (s, 2 H)
1.49 g
Step 1: 2-(1H-Imidazol-2-yl)pyrazine 2,2-Diethoxyethanamine (3 g, 2.25 mmol) was dissolved in dry methanol (20 mL). To this was added sodium methoxide (1.22 g, 22.5 mmol, as a 25% solution in methanol). After stirring for 25 minutes at room temperature, pyrazine-2-carbonitrile (2.37 g, 22.5 mmol) and acetic acid (1.35 g, 22.5 mmol) were added and the subsequent solution was stirred at 50 C. for 1 hour. MeOH (40 mL) and 6N HCl (12 mL) were added and the reaction was stirred at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between 1:1 Et2O and water (60 mL) and the layers were separated. The aqueous layer was basified to pH 9/10 and extracted with 10% MeOH in DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated to give the desired compound (1.49 g yellow solid). 1H NMR (400 MHz, MeOH-d4) delta ppm: 7.67 (s, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 5.72 (s, 2H)
Multi-step reaction with 3 steps
1: hydroxylamine hydrochloride; sodium carbonate / water / 14 h / 70 °C
2: acetone / 0.5 h / 20 °C
3: toluene / 2 h / Reflux; Molecular sieve
General procedure: The respective heteroarylcarbonitrile (5 mmol) wasrefluxed with 0.6 cm3 DBU (4 mmol) in 10 cm3 of methanolfor 0.5 h. Then 0.77 g <strong>[33263-43-3]4-chloropyridine-3-sulfonamide</strong>(4 mmol) were added and the mixture was refluxed foranother 3 h. Methanol was removed under vacuum and30 cm3 of water were added to the residue. The clearsolution was acidified with glacial acetic acid. The precipitatewas filtered off and recrystallized from a suitablesolvent.
Stage #1: 2-pyrazine carbonitrile; phenylboronic acid With Selectfluor; trifluoroacetic acid In dichloromethane; water at 20℃; for 0.0166667h;
Stage #2: With silver nitrate In dichloromethane; water at 50℃;
Stage #1: 2-pyrazine carbonitrile With trifluoroacetic acid In dichloromethane; water for 0.25h;
Stage #2: phenylboronic acid With ferrous(II) sulfate heptahydrate; dipotassium peroxodisulfate In dichloromethane; water at 20℃; for 5h;
Stage #3: With sodium hydroxide In dichloromethane; water at 20℃; Overall yield = 84 %;
Representative Procedure for the FeSO4-Mediated Direct Arylation of 4-Cyanopyridine (1a) with PhB(OH)2 (2a
General procedure: TFA (0.75mmol) was added to a DCM/distilled H2O solution(2.5 mL, v/v = 1:1) of 1a (0.5mmol), and then stirred for 15 min. 2a (0.75mmol), K2S2O8 (1.5mmol) were added under air, sequentially an aqueous solution of FeSO4*7H2O in distilled H2O (1.25 mL) was slowly added by syringe pump(10 μL min-1). After complete addition, the reaction mixture was stirred for 5 h at ambient temperature. The mixture was neutralized by NaOH solution (1.0 M), the obtained aqueous phase was extracted with ether. The combined ethereal solution was dried over Na2SO4 and filtered. After evaporating the solvent, the arylated products 2-3aa and 3-3aa were isolated by flash chromatography (hexane:EtOAc = 5:1) in 67% and 27%yields, respectively.
In neat (no solvent) at 150℃; for 1h; Microwave irradiation;
4.2. General procedure for the synthesis of the 4-substitutedoxazolines 2a-o
General procedure: The synthesis of (S)-4-phenyl-2-(pyrazin-2-yl)-4,5-dihydrooxazole2b is representative. Pyrazin-2-carbonitrile (15.3 mg, 0.145 mmol, 1 equiv) was mixed with L-(+)-(a)-phenylglycinol (22 mg, 0.160 mmol, 1.1 equiv) in the G4 vial in a Monowave 300 vessel. The resulting mixture was irradiated using the closed vessel mode at 150 °C for 60 min. The reaction mixture was quenched with ethyl acetate and filtered by silica. The filtrate was dried over magnesium sulfate ,and concentrated by evaporation under vacuum to give the corresponding (S)-4-phenyl-2-(pyrazin-2-yl)-2-oxazoline 2b (32.2 mg, 0.143 mmol, 98% yield, entry 2b).
In neat (no solvent) at 150℃; for 1h; Microwave irradiation;
4.2. General procedure for the synthesis of the 4-substitutedoxazolines 2a-o
General procedure: The synthesis of (S)-4-phenyl-2-(pyrazin-2-yl)-4,5-dihydrooxazole2b is representative. Pyrazin-2-carbonitrile (15.3 mg, 0.145 mmol, 1 equiv) was mixed with L-(+)-(a)-phenylglycinol (22 mg, 0.160 mmol, 1.1 equiv) in the G4 vial in a Monowave 300 vessel. The resulting mixture was irradiated using the closed vessel mode at 150 °C for 60 min. The reaction mixture was quenched with ethyl acetate and filtered by silica. The filtrate was dried over magnesium sulfate ,and concentrated by evaporation under vacuum to give the corresponding (S)-4-phenyl-2-(pyrazin-2-yl)-2-oxazoline 2b (32.2 mg, 0.143 mmol, 98% yield, entry 2b).
In neat (no solvent) at 150℃; for 1h; Microwave irradiation;
4.2. General procedure for the synthesis of the 4-substitutedoxazolines 2a-o
General procedure: The synthesis of (S)-4-phenyl-2-(pyrazin-2-yl)-4,5-dihydrooxazole2b is representative. Pyrazin-2-carbonitrile (15.3 mg, 0.145 mmol, 1 equiv) was mixed with L-(+)-(a)-phenylglycinol (22 mg, 0.160 mmol, 1.1 equiv) in the G4 vial in a Monowave 300 vessel. The resulting mixture was irradiated using the closed vessel mode at 150 °C for 60 min. The reaction mixture was quenched with ethyl acetate and filtered by silica. The filtrate was dried over magnesium sulfate ,and concentrated by evaporation under vacuum to give the corresponding (S)-4-phenyl-2-(pyrazin-2-yl)-2-oxazoline 2b (32.2 mg, 0.143 mmol, 98% yield, entry 2b).
With ammonium hydroxide; In N,N-dimethyl-formamide; at 20℃;Darkness;
The synthesis of 5 was similar to that of 4, but with pzn(21.0 mg, 0.2 mmol) in place of pza. The resultant solution wasallowed to evaporate slowly in darkness at room temperature forseveral days to afford the product as block-shaped clear lightbrown crystals of 5. (Yield: 68%, based on silver). Anal. Calc. (found)for AgC11H8N3O3: C, 39.08 (38.97); H, 2.38 (2.42); N, 12.43(12.52)%. IR (KBr): m (cm1) = 3421 (s), 3294 (s), 3071 (s), 1657(s), 1549 (s), 1453 (m), 1403 (s), 1358 (s), 1256 (s), 1173 (m),1059 (m), 1021 (m), 804 (s), 740 (m), 671 (m), 625 (w), 562 (m),454 (m).
With ammonium hydroxide; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
The synthesis of 6 was similar to that of 5, but with H2pma (50.8 mg, 0.2 mmol) in place of H2pna. The resultant solution was allowed to evaporate slowly in darkness at room temperature for several days to afford the product as plate-shaped clear yellow crystals of 6. (Yield: 75%, based on silver). Anal. Calc. (found) for AgC10H10N3O7: C, 30.64 (30.75); H, 2.57 (2.62); N, 10.72 (10.95)%. IR (KBr): ν (cm-1) = 3275 (s), 3020 (s), 1650 (s), 1568 (s), 1479 (s), 1415 (s), 1371 (s), 1313 (s), 1180 (m), 1135 (m), 1053 (m), 1015 (m), 918 (w), 780 (w), 855 (m), 804 (m), 759 (m), 689 (w), 625 (w), 568 (w), 530 (m), 434 (w).
With tert.-butylhydroperoxide; iodine; zinc(II) iodide; In water; N,N-dimethyl-formamide; at 20℃; for 8.0h;
General procedure: To an oven dried rb flask with a magnetic stir bar were added 2-amiobenzyl alcohol 1 (123.0 mg, 1.0 mmol), nitrile derivative (108.0 mg, 1.0 mmol) 2, anhydrous zinc iodide (0.3 equiv, 96 mg) and the mixture was stirred in 5 mL DMF at room temperature for 1h. Then iodine (127 mg, 0.5 mmol) and aq. TBHP (70% solution in water, 0.66 mL, 5.0 mmol) were added successively and stirring continued for another 7h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by aq. Na2S2O3 solution (10%, 20 ml), extracted with EtOAc (10 mL × 3), and the combined organic part was dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a crude mass which was purified by column chromatography using silica gel (60-120 mesh size) (25% EtOAc/hexane) to afford pure 3a (140 mg; 72% yield).
With tert.-butylhydroperoxide; iodine; zinc(II) iodide; In water; acetonitrile; at 20℃; for 3.0h;
General procedure: To an oven dried rb flask with a magnetic stir bar were added 2-amiobenzamide 1a (136.0 mg, 1.0 mmol), nitrile derivative 2 (108.0 mg, 1.0 mmol), anhydrous zinc iodide (0.3 equiv, 96 mg) and the mixture were stirred in 5 mL acetonitrile for 1h at room temperature. Then iodine (51 mg, 0.2 mmol) and aq. TBHP (70% solution in water, 0.26 mL, 2.0 mmol) were added successively and the mixture stirred at rt for another 2 h. After completion of the reaction (TLC monitoring), the reaction mixture was quenched by aq. Na2S2O3 solution (5%, 20 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic part was dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure left a crude mass which was purified by column chromatography using silica gel (25% EtOAc/hexane) to afford 3a (155 mg; 80% yield).
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