* 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] Magnetic Resonance in Chemistry, 2009, vol. 47, # 7, p. 617 - 624
2
[ 770-00-3 ]
[ 27825-21-4 ]
[ 23611-75-8 ]
[ 33332-25-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[3] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
[4] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
3
[ 33332-25-1 ]
[ 13924-94-2 ]
Yield
Reaction Conditions
Operation in experiment
39.5%
Stage #1: With sodium azide; triphenylphosphine In dimethyl sulfoxide at 120℃; for 4 h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide at 120℃; for 2 h;
Methyl 5-(chloropyrazine)-2-carboxylate (36 7) (2g, 0.0115mmol) was dissolved in 80mL of 87 DMSO. 88 Sodium azide (3g, 0.0463mmol) and 39 triphenylphosphene (4.6g, 0.1738mmol) were added and the mixture was refluxed at 120°C for 4h. 20mL of 1N 89 HCl was added and the reaction was continued at 120°C for 2h. The mixture was cooled and neutralized by using 90 aqueous NaHCO3 solution and 91 product was extracted in ethyl acetate, dried using Na2SO4. The ethyl acetate fraction was evaporated and washed with n-pentane to get 0.7g (yield 39.5percent) yellow solid of compound 8. 1H NMR (400MHz, DMSO‑d6) δ 8.53 (d, J=1.2Hz, 1H), 7.91 (d, J=1.2Hz, 1H), 7.39 (s, 2H), 3.79 (s, 3H). C6H7N3O2 [M]: 153.14; MS (ESI) m/z: [M-H]+: 152.05.
Reference：
[1] European Journal of Pharmaceutical Sciences, 2018, vol. 124, p. 165 - 181
[2] Tetrahedron Letters, 2013, vol. 54, # 5, p. 414 - 418
[3] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 4, p. 414 - 418
4
[ 33332-25-1 ]
[ 36070-80-1 ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate In tetrahydrofuran; water at 25℃; for 42 h;
Example 29 5- [2 (R)- (3-CHLORO-4-METHANESULFONYL-PHENYL)-3-CYCLOPENTYL-PROPIONYLAMINO]- PYRAZINE-2-CARBOXYLIC acid HYDROXYAMIDE [000197] A solution of methyl 5-chloropyrazine-2-carboxylate (30.00 g, 0.17 mol) in tetrahydrofuran (87 mL) was treated with a solution of potassium carbonate (72.08 g, 0.52 mol) in water (261 mL). The resulting reaction mixture stirred at 25°C for 42 h. The reaction mixture was then acidified to a pH of about 2 with concentrated hydrochloric acid, diluted with a saturated aqueous sodium chloride solution (300 mL), and was continuously extracted with ethyl acetate (4L total) until no product was present in the aqueous layer. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-chloro-pyrazine-2-carboxylic acid (26.54 g, 96percent) as an off-white solid: mp 150-151°C ; EI-HRMS m/e calcd for CSH3CIN202 (M 157.9883, found 157.9877.
92%
Stage #1: With methanol; sodium hydroxide; water In tetrahydrofuran at 0 - 20℃; for 5 h; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water
Dissolve 5-chloro-pyrazine-2-carboxylic acid methyl ester (10.0 g, 57.9 mmol) in THF (65 mL) and MeOH (65 mL). Cool the solution to 0 0C before adding IN NaOH (63.7 mL) with stirring. Warm the mixture to room temperature and stir for 5 h. Concentrate the mixture in vacuo to 1/3 volume. Quench with IN HCl (75 mL) to form a white precipitate. Dilute with CH2Cl2 (200 mL) and filter. Wash the filter cake with water and CH2Cl2. Separate the phases, dry the organic phase over MgSO4, filter, and concentrate. Add the aqueous layer to the concentrated organic residue and concentrate. Purify by silica gel flash column chromatography, eluting with 40percent ethyl acetate/n-hexane, followed by 10percent MeOH, 3percent acetic acid and 87percent EPO <DP n="73"/>CH2Ch- Collect the mixed fractions and concentrate. Take up the resulting solid with CH2CI2 (50 mL) and H2O (50 mL) and stir. Filter the solid and add it to the first filter cake. Add 5.0N NaOH to the filtrate to make the solution basic. Separate the two layers. Discard the organic layer, add 5.0N HCl to the aqueous layer until acidic. Extract with CH2Cl2 (3 x 100 mL). Dry the organic layer over Na2SO4, filter, and concentrate. Add the solid to the pure fractions from the column. Combine the pure filter cakes with the pure fractions from the column, yielding the desired product (8.46 g, 92percent). mass spectrum (exact mass): 157.99.
91%
With hydrogenchloride; potassium carbonate In tetrahydrofuran; water
Preparation of 5-Chloropyrazine-2-carboxylic acid To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 5-chloropyrazine-2-carboxylate (1.0 eq) and tetrahydrofuran (4.92 vols) under a nitrogen atmosphere. The reaction mixture was agitated until all the solid had dissolved, then filtered into a second flask. Water (8.65 vols) was added to the reaction mixture and the mixture agitated for approximately 15 minutes. Potassium carbonate (2.1 eq) was added to the reaction mixture and the mixture agitated for 16 hours at 20-25° C. Then 32percent w/w hydrochloric acid (3.76 eq) was added over 3 hours in small portions, keeping the reaction temperature 20-25° C., to a pH end point of pH2.2. The resultant slurry was heated to approximately 35-40° C. and then distilled under vacuum at this temperature distilling approximately 5.3 vols, to a final volume of approximately 9.3 vols. The mixture was then cooled to 20-25° C. over at least 2 hours, agitated for 10 hours at this temperature and then filtered. The solid was washed with water (2.8 vols), and the wet product produced dried at 35° C. in a vacuum oven. The desired product was obtained as a solid (corrected yield 91percent) 1H NMR δ (400 MHz CDCl3): 7.20 (1H, bs), 8.72 (1H, s), 9.21-9.21 (1H, m); m/z 157 (M-H)+.
91%
Stage #1: With water; potassium carbonate In tetrahydrofuran at 20 - 25℃; for 16.25 h; Inert atmosphere Stage #2: With hydrogenchloride In tetrahydrofuran; water at 20 - 25℃; for 3 h;
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 5-chloropyrazine-2-carboxylate (1.0 eq) and tetrahydrofuran (4.92 vols) under a nitrogen atmosphere. The reaction mixture was agitated until all the solid had dissolved, then filtered into a second flask. Water (8.65 vols) was added to the reaction mixture and the mixture agitated for approximately 15 minutes. Potassium carbonate (2.1 eq) was added to the reaction mixture and the mixture agitated for 16 hours at 20-25° C. Then 32percent w/w hydrochloric acid (3.76 eq) was added over 3 hours in small portions, keeping the reaction temperature 20-25° C., to a pH end point of pH2.2. The resultant slurry was heated to approximately 35-40° C. and then distilled under vacuum at this temperature distilling approximately 5.3 vols, to a final volume of approximately 9.3 vols. The mixture was then cooled to 20-25° C. over at least 2 hours, agitated for 10 hours at this temperature and then filtered. The solid was washed with water (2.8 vols), and the wet product produced dried at 35° C. in a vacuum oven. The desired product was obtained as a solid (corrected yield 91percent) 1H NMR δ (400 MHz CDCl3): 7.20 (1H, bs), 8.72 (1H, s), 9.21-9.21 (1H, m); m/z 157 (M-H)+.
81%
Stage #1: With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water
Example 35-Chloropyrazine-2-carboxylic acidFehler. Es ist nicht moglich, durch die Bearbeitung von Feldfunktionen Objekte zu erstellen. Methyl 5-chloropyrazine-2-carboxylate (CAS [33332-25-1], 1 g, 5.79 mmol) was dissolved in a mixture of THF (50 ml) and water (50 ml). Lithium hydroxide monohydrate (243 mg, 5.79 mmol) was added and the reaction mixture was stirred at RT overnight. The pH was adjusted to 1 with 1M HC1 and the product was extracted with three portions of EtOAc. The combined organic layers were dried over Na2S04 and concentrated under vacuum. The crude material was purified by flash chromatography (Si02, 50 g, 0 to 20percent MeOH in DCM) to yield the title compound as white solid (741 mg, 81percent). MS (ISP): m/z = 159.0 [M+H]+.
68%
With potassium carbonate In tetrahydrofuran; water at 25℃; for 24 h;
A solution ofmethyl 5-chloropyrazine-2-carboxylate (345 mg, 2.0 mmol) inTHF (10 mL) was treated with a solution of potassium carbonate(552 mg, 4.0 mmol) in water (5 mL). The resulting reaction mixturewas stirred at 25 C for 1 day. Extra THF was removed in vacuo. Thereaction mixture was then acidified to a pH of about 2 with concentratedHCl. Compound 10 (216 mg, 68percent) was obtained as abrown solid by filtration. 1H NMR (300 MHz, CDCl3) d: 8.97 (s,1H), 8.19 (s, 1H).
Reference：
[1] Patent: WO2004/52869, 2004, A1, . Location in patent: Page 115 - 116
[2] Patent: WO2006/66173, 2006, A2, . Location in patent: Page/Page column 71-72
[3] Patent: US2010/210621, 2010, A1,
[4] Patent: US2010/210841, 2010, A1, . Location in patent: Page/Page column 18
[5] Organic Process Research and Development, 2017, vol. 21, # 3, p. 346 - 356
[6] Patent: WO2012/168175, 2012, A1, . Location in patent: Page/Page column 42-43
[7] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 789 - 801
[8] Patent: WO2007/7041, 2007, A1, . Location in patent: Page/Page column 143
[9] Patent: US2008/171734, 2008, A1, . Location in patent: Page/Page column 45
[10] Patent: US2008/153800, 2008, A1, . Location in patent: Page/Page column 6
[11] Patent: US2012/15961, 2012, A1, . Location in patent: Page/Page column 49
[12] Patent: WO2006/125958, 2006, A1, . Location in patent: Page/Page column 108
With trimethylaluminum; ammonium chloride In toluene; benzene at 0 - 50℃;
Production Example 195- [2- (4-hydrazinocarbonylmethylphenyl) ethyl] pyrazine-2- carboxamide dihydrochloride step 1[0129] Ammonium chloride (558 mg, 10.4 iranol) was suspended in benzene (5 ml) and 2M-trimethylaluminum toluene solution (5.2 ml, 10.4 mmol) was added dropwise at 0°C. After stirring for 1 hr, a solution of methyl 5-chloropyrazine-2-carboxylate (600 mg, 3.48 mmol) in benzene (5 ml) was added. The reaction mixture was heated to 50°C, and stirred overnight. After cooling, the reaction mixture was poured into water, and neutralized with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:0 -> 98:2) to give 5-chloropyrazine-2-carboxamide (236 mg, yield 43percent) as a white solid.
Reference：
[1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[3] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
[4] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
8
[ 13924-95-3 ]
[ 33332-25-1 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: With trichlorophosphate In chloroform for 2 h; Reflux; Inert atmosphere Stage #2: With sodium hydrogencarbonate In chloroform; water
(62b) Methyl 5-Chloropyrazine-2-carboxylate Methyl 5-hydroxypyrazine-2-carboxylate (673 mg, 4.37 mmol) synthesised in Example (62a) was dissolved in phosphorous oxytrichloride (6.1 mL), and a few drops of N,N-dimethylformamide were added, followed by heating to reflux for 2 hours under nitrogen atmosphere. The reaction solution was poured into ice water, and extraction was carried out three times with chloroform (30 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine (100 mL each), and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure to afford the desired compound (611 mg, yield 81percent) as a gray solid. 1H-NMR (CDCl3, 400 MHz): δ 4.05 (3H, s), 8.71 (1H, d, J=1.6 Hz), 9.10 (1H, d, J=1.2 Hz).
55%
for 1.5 h; Reflux
Preparation 415-Chloro-pyrazine-2-carboxylic acid methyl esterA mixture of 5-hydroxy-pyrazine-2-carboxylic acid methyl ester (Preparation 40, 50 g, 324mmol) and POCI3 (500ml_, 5.36mol) was heated under reflux for 1.5 hours and then poured onto ice. The resulting mixture was extracted with ether (4 χ 500ml_). The organic layers were concentrated in vacuo, and the residue was recrystallised from toluene to give the title compound (30.8g) in a 55percent yield.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2 h;
To a solution of 5-chloropyrazine-2-carboxylic acid (300 mg, 1.89 mmol) in CH2C12 (3.8 mL) was added EDCI (401 mg, 2.09 mmol), DMAP (12.5 mg, 0.102 mmol) and MeOH (0.15 mL, 3.7 mmol) at room temperature. After stirring for 2 h, the reaction was quenched by adding saturated NH4C1 solution. The crude products were extracted with CH2C12 (x3), and the combined organic extracts were washed with brine, dried (MgS04), and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc = 9/1 to 7/1) to afford methyl 5-chloropyrazine-2-carboxylate (213 g, 65percent) as a white solid. NMR (300 MHz, CDCh) δ 9.12 (d, J = 1.8 Hz, 1H), 8.73 (d, J = 1.8 Hz, 1H), 4.07 (s, 3H).
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5344 - 5354
[2] Patent: WO2018/136935, 2018, A1, . Location in patent: Paragraph 00662; 00664; 00761
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5889 - 5908
(5-chloropyrazin-2-yl)methyl methanesulfonate; [00369] To a solution of 5-chloropyrazine-2-carboxylic acid (3.21 g, 20.3 mmol) in diethyl ether (20 mL) and methanol (20.0 mL) was added a 2M solution in diethyl ether of trimethylsilyldiazomethane (20.3 mL, 40.5 mmol). A vigorous bubbling was observed initially, and LCMS after 30 minutes indicated that the reaction was complete.Concentration of the reaction mixture afforded methyl 5-chloropyrazine-2-carboxylate (3.53 g, 20.5 mmol, 101percent yield) as a tan solid. This material was shown to be >95percent pure by NMR analysis and was used in the subsequent step without any purification. lH NMR (400 MHz, CDC13) δ (ppm): 9.09 (s, 1H), 8.70 (s, 1H), 4.04 (s, 3H).[00370] To a 0 °C solution of methyl 5-chloropyrazine-2-carboxylate (3.50 g, 20.3 mmol) in tetrahydrofuran (101 mL) was added a 1M solution in tetrahydrofuran of diisobutylaluminum hydride (42.6 mL, 42.6 mmol). The reaction was stirred at 0 °C for 2 hours, after which it was quenched by the addition of methanol (2 mL). To this mixture was added saturated sodium-potassium tartrate solution, and the resulting reaction mixture was extracted with ethyl acetate (3 x 100 mL), dried (sodium sulfate), filtered and concentrated to brown residue. Purification was achieved by column chromatography on silica gel (Luknova 120 g, 20 mL/min) using 30 to 100percent ethyl acetate in hexanes over 60 minutes to afford (5- chloropyrazin-2-yl)methanol (1.45 g, 10.0 mmol, 50 percent yield) as a tan solid. NMR (400 MHz, CDC13) a (ppm): 8.56 (s, 1H), 8.45 (s, 1H), 4.84 (s, 3H), 2.79 (br. s, 1H).[00371] To a 0 °C solution of (5-chloropyrazin-2-yl)methanol (648 mg, 4.48 mmol) in dichloromethane (12 mL) was added triethylamine (1.87 mL, 13.5 mmol) followed by dropwise addition of methanesulfonyl chloride (0.699 mL, 8.97 mmol). After 20 minutes, analysis by LCMS indicated the complete conversion to the mesylate product. The reaction mixture was concentrated to afford (5-chloropyrazin-2-yl)methyl methanesulfonate (787 mg, 3.53 mmol, 79percent yield) as an oil. The material was used crude in the next step without further purification.
Reference：
[1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 407 - 408
19
[ 13924-96-4 ]
[ 33332-25-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 10, p. 3057 - 3063
20
[ 57005-60-4 ]
[ 33332-25-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 10, p. 3057 - 3063
21
[ 77168-76-4 ]
[ 33332-25-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 10, p. 3057 - 3063
22
[ 34604-60-9 ]
[ 33332-25-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 10, p. 3057 - 3063
23
[ 34604-60-9 ]
[ 33332-25-1 ]
Reference：
[1] Patent: WO2013/14567, 2013, A1,
24
[ 6164-79-0 ]
[ 27825-21-4 ]
[ 33332-25-1 ]
Reference：
[1] Magnetic Resonance in Chemistry, 2009, vol. 47, # 7, p. 617 - 624
25
[ 770-00-3 ]
[ 27825-21-4 ]
[ 23611-75-8 ]
[ 33332-25-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[3] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
[4] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
26
[ 33332-25-1 ]
[ 848952-83-0 ]
Yield
Reaction Conditions
Operation in experiment
50%
With hydrazine In methanol for 48 h; Heating / reflux
Preparation 1; 5-ChloroDvrazine-2-carboxvlic acid hvdrazide; δ-chloropyrazine^-carboxylic acid methyl ester (10.02g, 58.25mmol) and hydrazine monohydrate (12.5ml_, 250mmol) were dissolved in methanol (40OmL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title product, 5.01 g (50percent). 1H NMR(CDCI3, 400MHz) δ: 4.09(d, 2H), 8.52(s, 1 H), 8.66(bs, 1 H), 9.14(s, 1 H). Microanalysis: C5H5CIN4O requires: C 34.80; H 2.92; N 32.47; found C 34.89; H 2.91 , N 32.32. MS APCI+ m/z 173 [MH]+
50%
With hydrazine In methanol for 48 h; Heating / reflux
δ-chloro-pyrazine^-carboxylic acid methyl ester (10.02g, 58.25mmol) and hydrazine monohydrate(12.5mL, 250mmol) were dissolved in methanol (40OmL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title compound, 5.01 g (50percent).1H NMR(CDCI3, 400MHz) δ: 4.09(d, 2H), 8.52(s, 1 H), 8.66(bs, 1 H), 9.14(s, 1 H). Microanalysis:C5H5CIN4O requires: C 34.80; H" 2.92; N 32.47; found C 34.89; H 2.91 , N 32.32. MS APCI+ m/z 173[MH]+
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5344 - 5354
[2] Patent: WO2007/17752, 2007, A1, . Location in patent: Page/Page column 33
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 10, p. 2634 - 2636
[4] Patent: WO2006/100557, 2006, A1, . Location in patent: Page/Page column 24
27
[ 33332-25-1 ]
[ 72788-94-4 ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran at 0℃; for 2 h;
(5-chloropyrazin-2-yl)methyl methanesulfonate; [00369] To a solution of 5-chloropyrazine-2-carboxylic acid (3.21 g, 20.3 mmol) in diethyl ether (20 mL) and methanol (20.0 mL) was added a 2M solution in diethyl ether of trimethylsilyldiazomethane (20.3 mL, 40.5 mmol). A vigorous bubbling was observed initially, and LCMS after 30 minutes indicated that the reaction was complete.Concentration of the reaction mixture afforded methyl 5-chloropyrazine-2-carboxylate (3.53 g, 20.5 mmol, 101percent yield) as a tan solid. This material was shown to be >95percent pure by NMR analysis and was used in the subsequent step without any purification. lH NMR (400 MHz, CDC13) δ (ppm): 9.09 (s, 1H), 8.70 (s, 1H), 4.04 (s, 3H).[00370] To a 0 °C solution of methyl 5-chloropyrazine-2-carboxylate (3.50 g, 20.3 mmol) in tetrahydrofuran (101 mL) was added a 1M solution in tetrahydrofuran of diisobutylaluminum hydride (42.6 mL, 42.6 mmol). The reaction was stirred at 0 °C for 2 hours, after which it was quenched by the addition of methanol (2 mL). To this mixture was added saturated sodium-potassium tartrate solution, and the resulting reaction mixture was extracted with ethyl acetate (3 x 100 mL), dried (sodium sulfate), filtered and concentrated to brown residue. Purification was achieved by column chromatography on silica gel (Luknova 120 g, 20 mL/min) using 30 to 100percent ethyl acetate in hexanes over 60 minutes to afford (5- chloropyrazin-2-yl)methanol (1.45 g, 10.0 mmol, 50 percent yield) as a tan solid. NMR (400 MHz, CDC13) a (ppm): 8.56 (s, 1H), 8.45 (s, 1H), 4.84 (s, 3H), 2.79 (br. s, 1H).[00371] To a 0 °C solution of (5-chloropyrazin-2-yl)methanol (648 mg, 4.48 mmol) in dichloromethane (12 mL) was added triethylamine (1.87 mL, 13.5 mmol) followed by dropwise addition of methanesulfonyl chloride (0.699 mL, 8.97 mmol). After 20 minutes, analysis by LCMS indicated the complete conversion to the mesylate product. The reaction mixture was concentrated to afford (5-chloropyrazin-2-yl)methyl methanesulfonate (787 mg, 3.53 mmol, 79percent yield) as an oil. The material was used crude in the next step without further purification.
29.8%
With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 5 h; Inert atmosphere
To a solution of methyl 5-chloropyrazine-2-carboxylate (8.00 g, 46.40 mmol) in THF (100 mL) was added NaBH4 (3.51 g, 93.00 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0 °C for 5 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate ( 3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep-40 g, 30-40percent EtOAc/n-hexane) to obtain Intermediate 112A (2.00 g, 29.80percent) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ ppm 4.64 (d, J = 5.67 Hz, 2 H), 5.68 (t, J = 5.85 Hz, 1 H), 8.53 (s, 1 H), 8.72 (d, J = 1.13 Hz, 1 H). LCMS (Method-H ): retention time 0.476 min, [M+H] 145.2.
28%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran at -70 - 20℃; Stage #2: With sodium hydroxide In tetrahydrofuran; water at 0℃;
Diisobutylaluminum hydride (4.29 mL, 4.29 mmol) was added dropwise over 5 min to a solution of methyl 5-chloropyrazine-2-carboxylate (185 mg, 1.07 mmol) in tetrahydrofuran (10 mL) at -70 0C under an athmosphere of nitrogen. The reaction mixture was stirred at - 70 0C for 5 min and then allowed to reach ambient temperature and stirred over night. The reaction mixture was cooled on ice and approximately 2 mL of 1 M sodium hydroxide was added dropwise while stirring. The reaction mixuture was diluted with diethyl ether and stirred for 45 min at ambient temperature and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography using a gradient of ethyl acetate in heptane to yield 43 mg (28 percent) of the title product; 1H NMR (400 MHz, DMSO- dβ) δ ppm 8.72 (d, 1 H), 8.52 - 8.55 (m, 1 H), 5.71 (t, 1 H), 4.64 (d, 2 H);
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 23, p. 5674 - 5678
[2] Patent: WO2012/88469, 2012, A1, . Location in patent: Page/Page column 151-152
[3] Patent: WO2018/93569, 2018, A1, . Location in patent: Page/Page column 195; 196
[4] Patent: WO2008/130320, 2008, A2, . Location in patent: Page/Page column 151
[5] Patent: WO2012/81736, 2012, A1, . Location in patent: Page/Page column 44
[6] Organic Process Research and Development, 2017, vol. 21, # 3, p. 346 - 356
With diisobutylaluminium hydride In tetrahydrofuran; toluene at -55℃; for 1 h; Inert atmosphere
Diisobutylaluminium hydride (1.0 M in toluene; 6.4 mL, 6.40 mmol) was added dropwise to a cooled solution of methyl 5-chloropyrazine-2-carboxylate (690 mg, 4.00 mmol) in THF (13.6 mL) at -55 °C. The reaction was stirred under these conditions for 1 hour and then quenched by addition of saturated aqueous NH4C1 (25 mL) and EtOAc (25 mL). An emulsion formed and 2N aqueous HC1 was added to clear the emulsion (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layerwas washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, elution gradient 0 to 50percent EtOAc in heptane. Product fractions were evaporated to dryness to afford 5-chloropyrazine-2-carbaldehyde (385 mg, 68percent) as a beige solid. ‘H NMR (500 MHz, CDC13, 27 °C) 8.75 (1H, d), 8.96 (1H, d), 10.15 (1H, d).
With triethylamine In 1,4-dioxane at 100℃; for 0.5h; Microwave irradiation;
1
To a solution of methyl 5-chloropyrazine-2-carboxylate (250 mg, 1.45 mmol) in 1,4-dioxane was added triethylamine (0.5 mL, 3.62 mmol) and morpholine (0.15 mL, 1.74 mmol). The reaction was heated in a microwave at 100°C for 30 minutes and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL), then the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 x 20 mL) and the organic layers combined. The combined organic layers were dried (MgSCb), filtered and the solvent removed by evaporation to afford methyl 5- morpholinopyrazine-2-carboxylate as an off-white solid. (0485) Yield 305 mg (94%). NMR (400 MHz, CDC13) d 8.81 (d, .1= 1.3 Hz, 1H), 8.13 (d, .1=1.3 Hz, 1H), 3.96 (s, 3H), 3.85-3.81 (m, 4H), 3.75-3.71 (m, 4H).
94%
With triethylamine In 1,4-dioxane at 100℃; for 0.5h; Microwave irradiation;
1
To a solution of methyl 5-chloropyrazine-2-carboxylate (250 mg, 1.45 mmol) in 1,4-dioxane was added triethylamine (0.5 mL, 3.62 mmol) and morpholine (0.15 mL, 1.74 mmol). The reaction was heated in a microwave at 100°C for 30 minutes and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL), then the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 x 20 mL) and the organic layers combined. The combined organic layers were dried (MgSCb), filtered and the solvent removed by evaporation to afford methyl 5- morpholinopyrazine-2-carboxylate as an off-white solid. (0485) Yield 305 mg (94%). NMR (400 MHz, CDC13) d 8.81 (d, .1= 1.3 Hz, 1H), 8.13 (d, .1=1.3 Hz, 1H), 3.96 (s, 3H), 3.85-3.81 (m, 4H), 3.75-3.71 (m, 4H).
89%
With triethylamine In 1,4-dioxane at 45℃; for 16h;
26.a
Example 26 2-Ethyl-2-[5-morpholin-4-yl-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carbonyl]-amino}-butyric acid methyl ester a) 5-Morpholin-4-yl-pyrazine-2-carboxylic acid methyl ester; A mixture of 4.9 g (28 mmol) 5-chloro-pyrazine-2-carboxylic acid methyl ester (commercially available), 3.2 g (37 mmol) morpholine and 7.37 g (73 mmol) NEt3 in 50 mL dioxane was heated to 45° C. for 16 h. Water and NaCl aq. was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with NaCl aq., dried with MgSO4, filtered and evaporated. The residue was recrystallized from ethyl acetate to yield 5.65 g (89%) of the title compound as white solid. m/z (ES+): 224.3 (M+H).
72.2%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
2 Synthesis intermediate MDI-201-1: 5-morpholinepyrazine-2-methyl carboxylate
Dissolve 5-chloro-pyrazine-2-carboxylic acid methyl ester (1.5g, 8.7mmol) in 10ml DMF, add N,N-diisopropylethylamine (3.0ml, 17.4mmol) and morpholine (0.91g , 10.4mmol), stirred overnight at room temperature, under vigorous stirring, water was added, a solid precipitated out, filtered, the filter cake was washed with water, and dried to obtain intermediate MDI-201-1 with a yield of 72.2%
850 mg
With potassium carbonate In dimethyl sulfoxide at 100℃; for 4h;
161.a example 161; step a;
A solution of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and morpholine (756 mg, 8.69 mmol) in DMSO (10 mL) was added K2C03(2.4 g, 17.4 mmol). The mixture washeated to 100 °C for 4 hours and then cooled to r.t. Water (20 mL) was added and the mixture was extracted with EA(20 mLx3).The combined organic phase was washed with water (20 mL) and brine (20 mL).It was then dried over anhydrous Na2SO4 and concentrated to give the desired product as a yellow solid (850 mg) which was used directly next step. ESI-MS m/z:224.1 [M+Hj.
850 mg
With potassium carbonate In dimethyl sulfoxide at 100℃; for 4h;
161.a
A solution of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and morpholine (756 mg, 8.69 mmol) in DMSO (10 mL) was added K2CO3 (2.4 g, 17.4 mmol). The mixture was heated to 100°C for 4 hours and then cooled to r.t. Water (20 mL) was added and the mixture was extracted with EA (20 mLx3).The combined organic phase was washed with water (20 mL) and brine (20 mL). It was then dried over anhydrous Na2SO4 and concentrated to give the desired product as a yellow solid (850 mg) which was used directly next step. ESI-MS m/z: 224.1 [M+H]+.
(62b) Methyl 5-Chloropyrazine-2-carboxylate Methyl 5-hydroxypyrazine-2-carboxylate (673 mg, 4.37 mmol) synthesised in Example (62a) was dissolved in phosphorous oxytrichloride (6.1 mL), and a few drops of N,N-dimethylformamide were added, followed by heating to reflux for 2 hours under nitrogen atmosphere. The reaction solution was poured into ice water, and extraction was carried out three times with chloroform (30 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine (100 mL each), and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure to afford the desired compound (611 mg, yield 81%) as a gray solid. 1H-NMR (CDCl3, 400 MHz): delta 4.05 (3H, s), 8.71 (1H, d, J=1.6 Hz), 9.10 (1H, d, J=1.2 Hz).
55%
With trichlorophosphate; for 1.5h;Reflux;
Preparation 415-Chloro-pyrazine-2-carboxylic acid methyl esterA mixture of <strong>[13924-95-3]5-hydroxy-pyrazine-2-carboxylic acid methyl ester</strong> (Preparation 40, 50 g, 324mmol) and POCI3 (500ml_, 5.36mol) was heated under reflux for 1.5 hours and then poured onto ice. The resulting mixture was extracted with ether (4 chi 500ml_). The organic layers were concentrated in vacuo, and the residue was recrystallised from toluene to give the title compound (30.8g) in a 55% yield.
With N,N-dimethyl-formamide; trichlorophosphate; at 140℃; for 3h;
<strong>[13924-95-3]2-hydroxy-5-carbomethoxy-pyrazine</strong> (15.4 g) was dissolved in phosphorus oxychloride (100 ml) and several drops of dimethylformamide were added, followed by stirring with heating at 140C for 3 hours. After the reaction solution was poured into ice water and extracted with chloroform, the organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried and then concentrated. The resulting crystal was collected by filtration and washed with ether to obtain 2-chloro-5-carbomethoxy-pyrazine (14.0 g).
With potassium carbonate; In tetrahydrofuran; water; at 25℃; for 42h;
Example 29 5- [2 (R)- (3-CHLORO-4-METHANESULFONYL-PHENYL)-3-CYCLOPENTYL-PROPIONYLAMINO]- PYRAZINE-2-CARBOXYLIC acid HYDROXYAMIDE [000197] A solution of methyl 5-chloropyrazine-2-carboxylate (30.00 g, 0.17 mol) in tetrahydrofuran (87 mL) was treated with a solution of potassium carbonate (72.08 g, 0.52 mol) in water (261 mL). The resulting reaction mixture stirred at 25C for 42 h. The reaction mixture was then acidified to a pH of about 2 with concentrated hydrochloric acid, diluted with a saturated aqueous sodium chloride solution (300 mL), and was continuously extracted with ethyl acetate (4L total) until no product was present in the aqueous layer. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-chloro-pyrazine-2-carboxylic acid (26.54 g, 96%) as an off-white solid: mp 150-151C ; EI-HRMS m/e calcd for CSH3CIN202 (M 157.9883, found 157.9877.
92%
Dissolve 5-chloro-pyrazine-2-carboxylic acid methyl ester (10.0 g, 57.9 mmol) in THF (65 mL) and MeOH (65 mL). Cool the solution to 0 0C before adding IN NaOH (63.7 mL) with stirring. Warm the mixture to room temperature and stir for 5 h. Concentrate the mixture in vacuo to 1/3 volume. Quench with IN HCl (75 mL) to form a white precipitate. Dilute with CH2Cl2 (200 mL) and filter. Wash the filter cake with water and CH2Cl2. Separate the phases, dry the organic phase over MgSO4, filter, and concentrate. Add the aqueous layer to the concentrated organic residue and concentrate. Purify by silica gel flash column chromatography, eluting with 40% ethyl acetate/n-hexane, followed by 10% MeOH, 3% acetic acid and 87% EPO <DP n="73"/>CH2Ch- Collect the mixed fractions and concentrate. Take up the resulting solid with CH2CI2 (50 mL) and H2O (50 mL) and stir. Filter the solid and add it to the first filter cake. Add 5.0N NaOH to the filtrate to make the solution basic. Separate the two layers. Discard the organic layer, add 5.0N HCl to the aqueous layer until acidic. Extract with CH2Cl2 (3 x 100 mL). Dry the organic layer over Na2SO4, filter, and concentrate. Add the solid to the pure fractions from the column. Combine the pure filter cakes with the pure fractions from the column, yielding the desired product (8.46 g, 92%). mass spectrum (exact mass): 157.99.
91%
With hydrogenchloride; potassium carbonate; In tetrahydrofuran; water;
Preparation of 5-Chloropyrazine-2-carboxylic acid To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 5-chloropyrazine-2-carboxylate (1.0 eq) and tetrahydrofuran (4.92 vols) under a nitrogen atmosphere. The reaction mixture was agitated until all the solid had dissolved, then filtered into a second flask. Water (8.65 vols) was added to the reaction mixture and the mixture agitated for approximately 15 minutes. Potassium carbonate (2.1 eq) was added to the reaction mixture and the mixture agitated for 16 hours at 20-25 C. Then 32% w/w hydrochloric acid (3.76 eq) was added over 3 hours in small portions, keeping the reaction temperature 20-25 C., to a pH end point of pH2.2. The resultant slurry was heated to approximately 35-40 C. and then distilled under vacuum at this temperature distilling approximately 5.3 vols, to a final volume of approximately 9.3 vols. The mixture was then cooled to 20-25 C. over at least 2 hours, agitated for 10 hours at this temperature and then filtered. The solid was washed with water (2.8 vols), and the wet product produced dried at 35 C. in a vacuum oven. The desired product was obtained as a solid (corrected yield 91%) 1H NMR delta (400 MHz CDCl3): 7.20 (1H, bs), 8.72 (1H, s), 9.21-9.21 (1H, m); m/z 157 (M-H)+.
91%
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 5-chloropyrazine-2-carboxylate (1.0 eq) and tetrahydrofuran (4.92 vols) under a nitrogen atmosphere. The reaction mixture was agitated until all the solid had dissolved, then filtered into a second flask. Water (8.65 vols) was added to the reaction mixture and the mixture agitated for approximately 15 minutes. Potassium carbonate (2.1 eq) was added to the reaction mixture and the mixture agitated for 16 hours at 20-25 C. Then 32% w/w hydrochloric acid (3.76 eq) was added over 3 hours in small portions, keeping the reaction temperature 20-25 C., to a pH end point of pH2.2. The resultant slurry was heated to approximately 35-40 C. and then distilled under vacuum at this temperature distilling approximately 5.3 vols, to a final volume of approximately 9.3 vols. The mixture was then cooled to 20-25 C. over at least 2 hours, agitated for 10 hours at this temperature and then filtered. The solid was washed with water (2.8 vols), and the wet product produced dried at 35 C. in a vacuum oven. The desired product was obtained as a solid (corrected yield 91%) 1H NMR delta (400 MHz CDCl3): 7.20 (1H, bs), 8.72 (1H, s), 9.21-9.21 (1H, m); m/z 157 (M-H)+.
81%
Example 35-Chloropyrazine-2-carboxylic acidFehler. Es ist nicht moglich, durch die Bearbeitung von Feldfunktionen Objekte zu erstellen. Methyl 5-chloropyrazine-2-carboxylate (CAS [33332-25-1], 1 g, 5.79 mmol) was dissolved in a mixture of THF (50 ml) and water (50 ml). Lithium hydroxide monohydrate (243 mg, 5.79 mmol) was added and the reaction mixture was stirred at RT overnight. The pH was adjusted to 1 with 1M HC1 and the product was extracted with three portions of EtOAc. The combined organic layers were dried over Na2S04 and concentrated under vacuum. The crude material was purified by flash chromatography (Si02, 50 g, 0 to 20% MeOH in DCM) to yield the title compound as white solid (741 mg, 81%). MS (ISP): m/z = 159.0 [M+H]+.
68%
With potassium carbonate; In tetrahydrofuran; water; at 25℃; for 24h;
A solution ofmethyl 5-chloropyrazine-2-carboxylate (345 mg, 2.0 mmol) inTHF (10 mL) was treated with a solution of potassium carbonate(552 mg, 4.0 mmol) in water (5 mL). The resulting reaction mixturewas stirred at 25 C for 1 day. Extra THF was removed in vacuo. Thereaction mixture was then acidified to a pH of about 2 with concentratedHCl. Compound 10 (216 mg, 68%) was obtained as abrown solid by filtration. 1H NMR (300 MHz, CDCl3) d: 8.97 (s,1H), 8.19 (s, 1H).
To a solution of methyl-5-chloropyrazine-2-carboxylate (120 mg, 0.70 mmol) in a mixture of acetonitrile (2 mL) and DMF (1 mL) was added lithium chloride (295 mg, 6.95 mmol). The suspension was heated to 160C for 5 mins in a Smith creator microwave after which time the reaction was diluted with water (10 mL). Saturated sodium bicarbonate solution (20 mL) was added and the aqueous layered extracted twice with ethyl acetate (30 mL). The combined organics were discarded and the aqueous layer adjusted to pH 4 with IN hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (20 mL) and the combined organics washed with water (2 x 20 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed to give the title compound as a colourless solid (68 mg). 1H NMR delta (CDCl3): 7.20 (IH, br s), 8.72 (IH, s), 9.21 - 9.21 (IH, m); m/z 157 (M-H)+.
With lithium chloride; In N,N-dimethyl-formamide; acetonitrile; at 160℃; for 0.0833333h;Microwave irradiation;
Intermediate 33: 5-Chloropyrazine-2-carboxylic acid To a solution of methyl-5-chloropyrazine-2-carboxylate (120 mg, 0.70 mmol) in a mixture of acetonitrile (2 mL) and DMF (1 mL) was added lithium chloride (295 mg, 6.95 mmol). The suspension was heated to 160 C. for 5 minutes in a microwave after which time the reaction was diluted with water (10 mL). Saturated sodium bicarbonate solution (20 mL) was added and the aqueous layered extracted with ethyl acetate (2*30 mL). The organic extracts were discarded and the aqueous layer adjusted to pH 4 with 1N hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (20 mL) and the combined organics washed with water (2*20 mL) and brine (10 mL) and dried (MgSO4). The volatiles were removed under reduced pressure to afford the product (68 mg). 1H NMR delta (400 MHZ, CDCl3): 7.20 (1H, br s), 8.72 (1H, s), 9.21-9.21 (1H, m); m/z 157 (M-H)+.
Methyl 5-chloropyrazine-2-carboxylate (CAS no. 33332-25-1)(345.1 g) was dissolved in DMF (1.73 l). Lithium chloride (423.9 g) was added and the mixture heated to 140 C. over one hour. The mixture was evaporated, and the residue dissolved in water (3.4 l) by continued stirring. The solution was acidified by addition of 2N HCl (900 ml) and extracted into ethyl acetate (5×1.73 l). The combined organic extracts were washed with water (2×900 ml), brine (900 ml), dried (MgSO4), and evaporated to give the title compound (298.1 g). 1H NMR 6 (400.132 MHz, DMSO) 8.92 (d, 1H), 9.02 (d, 1H), 13.87 (s, 1H).
Step 1Compound (67) (10 g) was suspended in water (35 ml) and 2 mol/L-aqueous solution of sodium hydroxide (34.8 ml) was added and the mixture was stirred at room temperature for 4.5 hours. 2 mol/L-hydrochloric acid (34.8 ml) was added to neutralize and stirred at room temperature overnight. The precipitated insoluble material was collected by filtration, washed with water and dried under reduced pressure to afford Compound (68) (3.47 g).1H-NMR (DMSO-d6) delta 8.93 (1H, s), 9.03 (1H, s).
To a solution of methyl-5-chloropyrazine-2-carboxylate (120 mg, 0.70 mmol) in a mixture of acetonitrile (2 ml) and DMF (1 ml) was added lithium chloride (295 mg, 6.95 mmol). The suspension was heated to 1600C for 5 mins in a Smith creator microwave after which time the reaction was diluted with water (10 ml). Saturated sodium bicarbonate solution (20 ml) was added and the aqueous layered extracted twice with ethyl acetate (30 ml). The combined organics were discarded and the aqueous layer adjusted to pH 4 with IN hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (20 ml) and the combined organics washed with water (2 x 20 mlL), brine (10 ml) and dried (MgSO4). The volatiles were removed to give the title compound as a colourless solid (68 mg), 1H NMR delta (CDCl3): 7.20 (IH, br s), 8.72 (IH, s), 9.21 - 9.21 (IH, m); m/z 157 (M-H)+.
With caesium carbonate In 1,4-dioxane at 20℃; for 18h;
1
Preparative Example 1. EPO A round bottomed flask was charged with methyl 2-chloropyrazine-5-carboxylate (Lonza, 25.9 g, 145 mmol), 2-S-ethyl piperazine (prepared as per Williams et al J. Med. Chem 1996, 39, 1345, 85% active, 28.0 g, 208 mmol), cesium carbonate (Aldrich, 11O g, 338 mmol) and 1 ,4 dioxane (400 ml). The resulting suspension was stirred at room temperature for 18 hours and then filtered. The solid was washed with ethyl acetate (3X400 ml). The combined organic solutions were concentrated on a rotary evaporator to remove the solvent. The residue was purified by flash chromatography on silica gel using 5% to 10% methanol in dichloromethane as an eluent to provide A3 as a white solid (28.0 g, 77%).
With hydrazine; In methanol; for 48.0h;Heating / reflux;
Preparation 1; 5-ChloroDvrazine-2-carboxvlic acid hvdrazide; delta-chloropyrazine^-carboxylic acid methyl ester (10.02g, 58.25mmol) and hydrazine monohydrate (12.5ml_, 250mmol) were dissolved in methanol (40OmL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title product, 5.01 g (50%). 1H NMR(CDCI3, 400MHz) delta: 4.09(d, 2H), 8.52(s, 1 H), 8.66(bs, 1 H), 9.14(s, 1 H). Microanalysis: C5H5CIN4O requires: C 34.80; H 2.92; N 32.47; found C 34.89; H 2.91 , N 32.32. MS APCI+ m/z 173 [MH]+
50%
With hydrazine; In methanol; for 48.0h;Heating / reflux;
delta-chloro-pyrazine^-carboxylic acid methyl ester (10.02g, 58.25mmol) and hydrazine monohydrate(12.5mL, 250mmol) were dissolved in methanol (40OmL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title compound, 5.01 g (50%).1H NMR(CDCI3, 400MHz) delta: 4.09(d, 2H), 8.52(s, 1 H), 8.66(bs, 1 H), 9.14(s, 1 H). Microanalysis:C5H5CIN4O requires: C 34.80; H" 2.92; N 32.47; found C 34.89; H 2.91 , N 32.32. MS APCI+ m/z 173[MH]+
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
. Methyl 5-chloropyrazine-2-carboxylate (2.0 g, 1 eq., 11.6 mmol) was dissolved in MeOH (15 mL) and the solution was cooled to 0C. Sodium borohydride (1.1 g, 2.5 eq., 29 mmol) was slowly added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a saturated solution of NH4Cl (15 mL) and extracted with DCM (215 mL). The organic extracts were dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 60%) to give the pure title compound as colourless oil (1.59 g, 95%). 1H NMR (400 MHz, DMSO-d6): delta 8.73 (d, J=1.4 Hz, 1H), 8.54 (d, J=1.3 Hz, 1H), 5.68 (t, J=5.8 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H).
50%
(5-chloropyrazin-2-yl)methyl methanesulfonate; [00369] To a solution of 5-chloropyrazine-2-carboxylic acid (3.21 g, 20.3 mmol) in diethyl ether (20 mL) and methanol (20.0 mL) was added a 2M solution in diethyl ether of trimethylsilyldiazomethane (20.3 mL, 40.5 mmol). A vigorous bubbling was observed initially, and LCMS after 30 minutes indicated that the reaction was complete.Concentration of the reaction mixture afforded methyl 5-chloropyrazine-2-carboxylate (3.53 g, 20.5 mmol, 101% yield) as a tan solid. This material was shown to be >95% pure by NMR analysis and was used in the subsequent step without any purification. lH NMR (400 MHz, CDC13) delta (ppm): 9.09 (s, 1H), 8.70 (s, 1H), 4.04 (s, 3H).[00370] To a 0 C solution of methyl 5-chloropyrazine-2-carboxylate (3.50 g, 20.3 mmol) in tetrahydrofuran (101 mL) was added a 1M solution in tetrahydrofuran of diisobutylaluminum hydride (42.6 mL, 42.6 mmol). The reaction was stirred at 0 C for 2 hours, after which it was quenched by the addition of methanol (2 mL). To this mixture was added saturated sodium-potassium tartrate solution, and the resulting reaction mixture was extracted with ethyl acetate (3 x 100 mL), dried (sodium sulfate), filtered and concentrated to brown residue. Purification was achieved by column chromatography on silica gel (Luknova 120 g, 20 mL/min) using 30 to 100% ethyl acetate in hexanes over 60 minutes to afford (5- chloropyrazin-2-yl)methanol (1.45 g, 10.0 mmol, 50 % yield) as a tan solid. NMR (400 MHz, CDC13) a (ppm): 8.56 (s, 1H), 8.45 (s, 1H), 4.84 (s, 3H), 2.79 (br. s, 1H).[00371] To a 0 C solution of (5-chloropyrazin-2-yl)methanol (648 mg, 4.48 mmol) in dichloromethane (12 mL) was added triethylamine (1.87 mL, 13.5 mmol) followed by dropwise addition of methanesulfonyl chloride (0.699 mL, 8.97 mmol). After 20 minutes, analysis by LCMS indicated the complete conversion to the mesylate product. The reaction mixture was concentrated to afford (5-chloropyrazin-2-yl)methyl methanesulfonate (787 mg, 3.53 mmol, 79% yield) as an oil. The material was used crude in the next step without further purification.
29.8%
With sodium tetrahydroborate; In tetrahydrofuran; at 0℃; for 5h;Inert atmosphere;
To a solution of methyl 5-chloropyrazine-2-carboxylate (8.00 g, 46.40 mmol) in THF (100 mL) was added NaBH4 (3.51 g, 93.00 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0 C for 5 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate ( 3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep-40 g, 30-40% EtOAc/n-hexane) to obtain Intermediate 112A (2.00 g, 29.80%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) delta ppm 4.64 (d, J = 5.67 Hz, 2 H), 5.68 (t, J = 5.85 Hz, 1 H), 8.53 (s, 1 H), 8.72 (d, J = 1.13 Hz, 1 H). LCMS (Method-H ): retention time 0.476 min, [M+H] 145.2.
28%
Diisobutylaluminum hydride (4.29 mL, 4.29 mmol) was added dropwise over 5 min to a solution of methyl 5-chloropyrazine-2-carboxylate (185 mg, 1.07 mmol) in tetrahydrofuran (10 mL) at -70 0C under an athmosphere of nitrogen. The reaction mixture was stirred at - 70 0C for 5 min and then allowed to reach ambient temperature and stirred over night. The reaction mixture was cooled on ice and approximately 2 mL of 1 M sodium hydroxide was added dropwise while stirring. The reaction mixuture was diluted with diethyl ether and stirred for 45 min at ambient temperature and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography using a gradient of ethyl acetate in heptane to yield 43 mg (28 %) of the title product; 1H NMR (400 MHz, DMSO- dbeta) delta ppm 8.72 (d, 1 H), 8.52 - 8.55 (m, 1 H), 5.71 (t, 1 H), 4.64 (d, 2 H);
Example 7[0142] [Formula 41] [0143]1) In tetrahydrofuran (75 mL) was dissolved methyl 5-chloropyrazin-2-carboxylate (2.589 g), 1M diisobutyl aluminum hydride-tetrahydrofuran solution (30 mL) was added dropwise to the solution at 0C, and the mixture was stirred at the same temperature for 15 minutes. To the mixture were added water and IN hydrochloric acid, then, a saturated aqueous sodium bicarbonate solution was added to the same to make the pH to 7. The mixture was filtered through Celite, and then, extracted with chloroform 3 times. The organic layer was separated, dried over anhydrous sodium sulfate, and the residue obtained by concentrating the same under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate=90: 10 to 65:35 to 50:50) to obtain (5-chloropyrazin-2-yl)methanol (465 mg). MS (m/z): 147/145 [M+H]+
EXAMPLE 1 5-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid methyl ester To a solution of <strong>[18718-79-1](5-methyl-3-phenyl-isoxazol-4-yl)-methanol</strong> (1.24 g, 6.55 mmol) in THF (12 mL) was added sodium hydride (55% dispersion in mineral oil, 0.31 g, 7.2 mmol) at 0 C. The reaction mixture was stirred for 30 min while it was allowed to warm up to room temperature. Methyl 5-chloropyrazine-2-carboxylate (1.36 g, 7.86 mmol) was added and stirring was continued for 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate. Concentration and purification of the residue by chromatography (SiO2, heptane:ethyl acetate=80:20 to 50:50, 1.00 g, 47%) which was obtained as a light yellow oil. MS: m/e=326.2 [M+H]+.
With trimethylaluminum; ammonium chloride; In toluene; benzene; at 0 - 50℃;
Production Example 195- [2- (4-hydrazinocarbonylmethylphenyl) ethyl] pyrazine-2- carboxamide dihydrochloride step 1[0129] Ammonium chloride (558 mg, 10.4 iranol) was suspended in benzene (5 ml) and 2M-trimethylaluminum toluene solution (5.2 ml, 10.4 mmol) was added dropwise at 0C. After stirring for 1 hr, a solution of methyl 5-chloropyrazine-2-carboxylate (600 mg, 3.48 mmol) in benzene (5 ml) was added. The reaction mixture was heated to 50C, and stirred overnight. After cooling, the reaction mixture was poured into water, and neutralized with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:0 -> 98:2) to give 5-chloropyrazine-2-carboxamide (236 mg, yield 43%) as a white solid.
With ammonia; In methanol; water; at 20℃;
Preparation 10 To a solution of methyl 5-chloropyrazine-2-carboxylate (500 mg) in MeOH (5 mL) was added 28% NH3 aqueous solution (5 mL), and the mixture was stirred at ambient temperature. The precipitated solid was collected by filtration and washed with diisopropyl ether to afford 5-chloropyrazine-2-carboxamide (303 mg) as a solid.
A 5 N sodium hydroxide solution (2 mL) was added to a solution of methyl 5-chloropyrazine-2-carboxylate (150 mg) in ethanol (4 mL), and the mixture was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was made acidic with concentrated hydrochloric acid. Brine and ethyl acetate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated to obtain the title compound (135 mg).1H-NMR (400 MHz, CDCl3) delta (ppm): 1.46 (t, J=7.2 Hz, 3H), 4.51 (q, J=7.2 Hz, 2H), 8.17 (s, 1H), 8.96 (s, 1H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃;
To a solution of <strong>[1196473-37-6]3H-benzo[c][1,2]oxaborole-1,6-diol</strong> (0.37 g, 2.47 mmol) in anhydrous DMF (8 mL) were added Cs2CO3 (2.01 g, 2.71 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (0.468 g, 2.71 mmol) at room temperature. After stirring at 90° C. for 1.5 h, the reaction mixture was cooled to 0° C., diluted with water (10 mL) and acidified to pH 3 using diluted hydrochloric acid. The off-white precipitate was collected, washed with water and dried to give the crude product which was purified by chromatography on silica gel (DCM/MeOH=40:3) to give 0.470 g (66.5percent yield) of product. MS (ESI) m/z=287 [M+H]+.
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1.5h;
To a solution of 20 (0.37 g, 2.47 mmol) in anhydrous DMF (8 mL) were added Cs2CO3 (2.01 g, 2.71 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (0.468 g, 2.71 mmol) at room temperature. After stirring at 90 °C for 1.5 h, the reaction mixture was cooled to 0 °C, diluted with water (10 mL) and acidified to pH 3 using diluted hydrochloric acid. The off-white precipitate was collected, washed with water and dried to give the crude product which was purified by chromatography on silica gel (DCM/MeOH = 40:3) to give 0.47 g (66.5percent) of 21.
With triethylamine In N,N-dimethyl-formamide at 80℃; for 3h;
84.1; 86.1 Step 1: Synthesis of methyl 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrazine- 2-carboxylate
methyl 5-chloropyrazine-2-carboxylate (532 mg, 3.08 mmol) and tert- butyl piperazine-1-carboxylate (631 mg, 3.39 mmol) were dissolved in DMF (4.85 mL). TEA (0.86 mL, 6.17 mmol) was added and the reaction mixture was heated at 80 °C for 3 hours. The reaction mixture was poured into water and filtered. The filtercake was dried under a stream of nitrogen while applying vacuum to yield the title compound (950 mg, 96%).
96%
With triethylamine In N,N-dimethyl-formamide at 80℃; for 3h;
84.1; 86.1 Step 1: Synthesis of methyl 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrazine- 2-carboxylate
methyl 5-chloropyrazine-2-carboxylate (532 mg, 3.08 mmol) and tert- butyl piperazine-1-carboxylate (631 mg, 3.39 mmol) were dissolved in DMF (4.85 mL). TEA (0.86 mL, 6.17 mmol) was added and the reaction mixture was heated at 80 °C for 3 hours. The reaction mixture was poured into water and filtered. The filtercake was dried under a stream of nitrogen while applying vacuum to yield the title compound (950 mg, 96%).
95%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃;
85.1 Step 1:
A mixture of methyl 5-chloropyrazine-2-carboxy- late (1.72 g, 10 mmol), tert-butyl piperazine-1-carboxylate (3.72 g, 20 mmol) and DIPEA (3.87 g, 30 mmol) in 1 ,4-dioxane (20 mE) was stirred at 1000 C. for overnight. The mixture was concentrated to get a residue, which was purified by silica gel to get compound (3.06 g, 95%).
93%
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 12h;
16.1 Step 1: Preparation of Methyl 5-(4-(teft-butoxyearbonyl)piperazin-l-yl)pyrazine-2- carboxylate
To a solution of methyl 5-chloropyrazme-2-carboxylate (2.00 g, 11.59 mmol, 1.00 eq) in dimethyisuifoxide (20 mL) ws added diisopropylethyiam e (3.00 g, 23.18 mmol, 4.04 mL, 2.00 eq), tert-butyl piperazine- 1-carboxy late (2.16 g, 11.59 mmol, 1.00 eq). The mixture was stirred at 100 °C for 12 h. LCMS showed that the reaction ws completed. The mixture was poured into ice water (30 mL) and ethyl acetate (30 mL). The mixture was filtered and the filter cake ws concentrated under reduced pressure to give methyl 5-(4-tert-butoxycarbonylpiperazin-l- yl)pyrazine-2-carboxylate (3.50 g, 10.86 mmol, 93% yield) as a yellow' solid, which was used in next step directly. LCMS: MS (ESI) m/z: 323.8 | 1 · 1 | ’ NMR: (400 MHz, D SO-d-dcV 8.81 (d, J = 1.2 Hz, H). 8.14 (d, J = 1.2 Hz, i l l). 3 96 (s, 3H), 3 80 - 3.68 (m, 4H), 3.63 - 3 51 (m, 4H), 1.49 (s, 9H). Chemical Formula: C35H22N4O4, Molecular Weight: 322.36
With 1-methyl-pyrrolidin-2-one; triethylamine at 60℃; Inert atmosphere;
A 250ml RB flask is charged with R-7 (5.4 g, 28.99 mmol) in 100 mL of NMP. R-8 (5.00 g, 28.99 mmol) is added followed by triethylamine (4.85 ml, 34.79 mmol). The reaction is heated to 60 °C under nitrogen overnight. The reaction is cooled to room temperature, poured into ice water and the precipitated 1-76 (8.60 g) is isolated by filtration; m/z 323.4 [M+H]
With triethylamine In 1-methyl-pyrrolidin-2-one at 60℃; Inert atmosphere;
Synthesis of 2,3<5,6-Tetrahydro-ri,2'1bipyrazinyl-4,5'-dicarboxylic acid 4-tert-butyl ester (Intermediate 1-3.1)Step 1: Synthesis of 2,3,5,6-Tetrahydro-ri,2'lbipyrazinyl-4,5'-dicarboxylic acid 4-tert- butyl ester 5'-methyl ester (R8)A 250ml RB flask is charged with R7 (2.8 g, 16.11 mmol) in 60mL of NMP. R6 (3.0 g, 16.11 mmol) is added followed by triethylamine (2.7 ml, 19.33 mmol). The reaction is warmed to 60 °C under nitrogen and stirred overnight. After 18 h, the reaction is cooled to room temperature, poured into ice water and the resulting solid R8 is isolated by filtration and used without further purification. (5.0 g)
With 2-amino-3,3-dimethylbutane In 1-methyl-pyrrolidin-2-one at 60℃; for 30h;
20.1
Step 1: synthesis of 2,3,5,6-tetrahydro-[l,2']bipyrazinyl-4,5'-dicarboxylic acid -tert- butyl ester 5'-methyl ester (R49).R47 (646 mg, 3.47 mmol) is treated with R48 (598 mg, 3.49 mmol), TEA (580 μ,, 4.16 mmol), and NMP (10.0 mL) and the mixture is heated at 60 °C for 30 minutes. The reaction is cooled to room temperature and poured into ice water and the resulting solid is collected by filtration to afford R49 (1.03 g); m/z 323.1 [M+H].
8.6 g
With triethylamine In 1-methyl-pyrrolidin-2-one at 60℃; Inert atmosphere;
Synthesis of 5'-(3-{1-[4-(2-amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic Acid tert-butyl Ester A 250 ml RB flask is charged with R-7 (5.4 g, 28.99 mmol) in 100 mL of NMP. R-8 (5.00 g, 28.99 mmol) is added followed by triethylamine (4.85 ml, 34.79 mmol). The reaction is heated to 60° C. under nitrogen overnight. The reaction is cooled to room temperature, poured into ice water and the precipitated I-76 (8.60 g) is isolated by filtration; m/z 323.4 [M+H]
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃;
15.1 Step 1
ferf-Butyl piperazine-1 -carboxylate (3.72 g, 20 mmol), methyl 5- chloropyrazine-2-carboxylate (1.72 g, 10 mmol) and DIPEA (2.02 g, 20 mmol) were combined in 1 ,4-dioxane (15 ml_). The mixture was stirred overnight at 100 °C. When the reaction was finished, it was diluted with EA and washed with brine. The crude material was purified by flash column chromatography (EA, 100%). Solid 2 was isolated (6 g, impure).
With Cs2CO3 In N,N-dimethyl-formamide at 100℃; for 4h; Sealed tube;
65 Example 65: N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(piperazin-1-yl)pyrazine-2-carboxamide
Methyl 5-chloropyrazine-2-carboxylate (173 mg, 1 mol), N-Boc piperazine (186 mg, 1 mmol), Cs2CO3 (650 mg, 2 mmol) and DMF (5 mL) were combined in a sealed tube and hot block heated to 100 oC for 4 hours. The reaction mixture was diluted with EtOAc, washed with water (x2), brine and evaporated to dryness to give methyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, which was used crude in next step. MS (ES+) 323 (M+H).
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; Cs2CO3 In 1,2-dimethoxyethane at 60 - 80℃; Inert atmosphere;
Stepl: Synthesis of 1-16.A solution of R14 (2.0 g, 14.3mmol) and thionyl chloride (10.0 mL) with a catalytic amount of DMF is refluxed for 4 hours. The solvent is removed under reduced pressure, MeOH (10.0 mL) and pyridine (1.4 mL, 17.1 mmol) are slowly added and the mixture is stirred overnight at room temperature. The solvent is removed under reduced pressure, the crude is purified via silica gel column chromatography to afford 1-16 (1.12 g); m/z 173 [M+H].
Synthesis of (5-{3-ri-(6-Chloro-pyridin-3-yl)-cvclobutyl1-l,2,4-oxadiazol-5-yl}- pyrazin-2-yl)-(2-methoxy-ethyl)-amine (Intermediate 1-4.12)Step 1: synthesis of 5-chloro-pyrazine-2-carboxylic acid methyl ester (R24)R23 (2.00 g, 14.3 mmol) is treated with R12 (10.0 mL) and to the resulting mixture is added DMF (0.1 mL) dropwise. The reaction mixture is then heated at reflux for 4 hours.The solvent is removed in vacuo and the residue is treated with methanol (10.0 mL) and pyridine (1.39 mL, 17.1 mmol) and the resulting mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by flash chromatography (Si02, 20% ethyl acetate/cyclohexane) to give R24 (1.12 g); m/z 173 [M+H].
With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at -55℃; for 1h;Inert atmosphere;
Diisobutylaluminium hydride (1.0 M in toluene; 6.4 mL, 6.40 mmol) was added dropwise to a cooled solution of methyl 5-chloropyrazine-2-carboxylate (690 mg, 4.00 mmol) in THF (13.6 mL) at -55 C. The reaction was stirred under these conditions for 1 hour and then quenched by addition of saturated aqueous NH4C1 (25 mL) and EtOAc (25 mL). An emulsion formed and 2N aqueous HC1 was added to clear the emulsion (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layerwas washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Product fractions were evaporated to dryness to afford 5-chloropyrazine-2-carbaldehyde (385 mg, 68%) as a beige solid. ?H NMR (500 MHz, CDC13, 27 C) 8.75 (1H, d), 8.96 (1H, d), 10.15 (1H, d).
Example 95 [0308] [Formula 107]CI xj - ~ CI' [0309] 1) In tetrahydrofuran (66 mL) was dissolved methyl 5-chloropyrazine-2-carboxylate (3.3 g), and 1M diisobutylaluminum hydride/hexane solution (38.3 mL) was added dropwise to the solution under nitrogen atmosphere at -70C or lower over 10 minutes, and the resulting mixture was further stirred for 10 minutes. At -60C or lower, 1M diisobutylaluminum hydride/hexane solution (31.3 mL) was added dropwise to the mixture over 20 minutes, and the mixture was further stirred at -70C or lower for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and after stirring at room temperature, filtered with Celite. The filtrate was extracted with ethyl acetate, washed with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=100:0 to 80:20) to obtain 5-chloropyrazine-2-carbaldehyde (970 mg). MS (m/z): 142/144 [M+H]+
Methyl 5-(chloropyrazine)-2-carboxylate (36 7) (2g, 0.0115mmol) was dissolved in 80mL of 87 DMSO. 88 Sodium azide (3g, 0.0463mmol) and 39 triphenylphosphene (4.6g, 0.1738mmol) were added and the mixture was refluxed at 120C for 4h. 20mL of 1N 89 HCl was added and the reaction was continued at 120C for 2h. The mixture was cooled and neutralized by using 90 aqueous NaHCO3 solution and 91 product was extracted in ethyl acetate, dried using Na2SO4. The ethyl acetate fraction was evaporated and washed with n-pentane to get 0.7g (yield 39.5%) yellow solid of compound 8. 1H NMR (400MHz, DMSO-d6) delta 8.53 (d, J=1.2Hz, 1H), 7.91 (d, J=1.2Hz, 1H), 7.39 (s, 2H), 3.79 (s, 3H). C6H7N3O2 [M]: 153.14; MS (ESI) m/z: [M-H]+: 152.05.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
Intermediate 585-(3-Methyl-1 H-1 , -thazol-1 -yl)pyrazine-2-carboxylic acidA mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2CO3 (1 .8 g) and 3- methyl-1 H-1 ,2,4-triazole(1 .2 g) in N,N-dimethylformamide (6 mL) is heated to 100C overnight. Analysis of the crude mixture by LCMS shows saponified product. The product is acidified with 1 N HCI and the precipitate is filtered and washed with water and diethyl ether to afford the title compound. LC (method 20): tR = 1 .21 min; Mass spectrum (APCI): m/z = 206 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
5-(3-Methyl-1H-1,2,4-triazol-1-yl)pyrazine-2-carboxylic acid A mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2CO3 (1.8 g) and <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (1.2 g) in N,N-dimethylformamide (6 mL) is heated to 100 C. overnight. Analysis of the crude mixture by LCMS shows saponified product. The product is acidified with 1N HCl and the precipitate is filtered and washed with water and diethyl ether to afford the title compound. LC (method 20): tR=1.21 min; Mass spectrum (APCI): m/z=206 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
5-(3-Methyl-[1,2,4]triazol-1-yl)-pyrazine-2-carboxylic acid A mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2CO3 (1.8 g) and <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (1.2 g) in N,N-dimethylformamide (6 mL) is heated to 100 C. overnight. Analysis of the crude mixture by LCMS shows saponified product. The product is acidified with 1 N hydrochloric acid and the precipitate is filtered and washed with water and diethyl ether to afford the title compound. LC (method 20): tR=1.21 min; Mass spectrum (APCI): m/z=206 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
Intermediate 1075-(3-Methyl-[i ,2,4ltriazol-i -yl)-ryrazine-2-carboxylic acid: A mixture of methyl 5-chloropyrazine-2-carboxylate (0.75 g), K2003 (1 .8 g) and 3- methyl-i H-i ,2,4-triazole(i .2 g) in N,N-dimethylformamide (6 mL) is heated to 100C overnight. Analysis of the crude mixture by LCMS shows saponified product. The product is acidified with 1 N hydrochloric acid and the precipitate is filtered andwashed with water and diethyl ether to afford the title compound. LC (method 20): tR = 1 .21 mm; Mass spectrum (APCI): m/z = 206 [M+H]
With triethylamine In 1,4-dioxane at 45℃; for 22h;
8.a a) 5-(3,3-Difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid methyl ester
5-Chloro-pyrazine-2-carboxylic acid methyl ester (CAN 33332-25-1; 15 g, 86.92 mmol) was dissolved in dioxane (100 mL). To this solution was added 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7; 13.51 g, 104.31 mmol), and triethyl amine (31.3 mL, 226 mmol). The mixture was stirred 22 hours at 45° C. and afterwards cooled to room temperature. Brine solution (100 mL) was added and the mixture was extracted with ethyl acetate. The organic phases were washed successively with sodium bicarbonate solution (10%, 300 mL) and brine (200 mL); dried with Na2SO4 and filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 200 g, 30% to 50% ethyl acetate in hexane) to give the desired product (15 g, 75.3%) as white solid; LC-MS (UV peak area, ESI) 98.6%, 230.4 (M+H).
75.3%
With triethylamine In 1,4-dioxane at 45℃; for 22h;
8.a a) 5-(3,3-Difluoro-azetidin-l-yl)-pyrazine-2-carboxylic acid methyl ester
a) 5-(3,3-Difluoro-azetidin-l-yl)-pyrazine-2-carboxylic acid methyl ester 5-Chloro-pyrazine-2-carboxylic acid methyl ester (CAN 33332-25-1; 15 g, 86.92 mmol) was dissolved in dioxane (100 mL). To this solution was added 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7; 13.51 g, 104.31 mmol), and triethyl amine (31.3 mL, 226 mmol). The mixture was stirred 22 hours at 45 °C and afterwards cooled to room temperature. Brine solution (100 mL) was added and the mixture was extracted with ethyl acetate. The organic phases were washed successively with sodium bicarbonate solution (10%, 300 mL) and brine (200 mL); dried with Na2S04 and filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 200g, 30% to 50% ethyl acetate in hexane) to give the desired product (15 g, 75.3%) as white solid; LC- MS (UV peak area, ESI) 98.6%, 230.4 (M+H).
75.3%
With triethylamine In 1,4-dioxane at 45℃; for 22h;
2.a a) 5- (3 ,3-Difluoro-azetidin- 1 -yl)-pyrazine-2-carboxylic acid methyl ester
Example 2[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin- 1-yl)-pyrazin-2-yl] -((R)-2-methyl- pyrrolidin- 1-yl)-methanonea) 5- (3 ,3-Difluoro-azetidin- 1 -yl)-pyrazine-2-carboxylic acid methyl ester 5-Chloro-pyrazine-2-carboxylic acid methyl ester (CAN 33332-25-1; 15 g, 86.92 mmol) was dissolved in dioxane (100 mL). To this solution was added 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7; 13.51 g, 104.31 mmol), and triethyl amine (31.3 mL,226 mmol). The mixture was stirred 22 hours at 45°C and afterwards cooled to room temperature. Brine (100 mL) was added and the mixture was extracted with ethyl acetate. The organic phases were washed successively with sodium bicarbonate solution (10%, 300 mL) and brine (200 mL); dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 200g, 30% to 50% ethyl acetatein hexane) to give the desired product (15 g, 75.3%) as white solid; LC-MS (UV peak area, ESI) 98.6%, 230.4 [MH’i.
46%
With triethylamine In 1,4-dioxane at 45℃;
16.a a) Methyl 5 -(3,3 -difluoroazetidin- 1 -yl)pyrazine-2-carboxylate
a) Methyl 5 -(3,3 -difluoroazetidin- 1 -yl)pyrazine-2-carboxylateTo a stirred solution of methyl 5-chloropyrazine-2-carboxylate (2.0 g, CAS 33332-25-1) in dioxane (45 ml) were added 3,3-difluoroazetidine hydrochloride (1.9 g, CAS 288315-03-7) andtriethylamine (4.19 ml). The reaction mixture was stirred at 45 °C overnight. TLC analysis showed the reaction was complete. The reaction mixture was poured into aq. brine and extracted twice with ethyl acetate. The combined organic phases were dried over Na2SO4 and concencentrated in vacuo. The residue was purified by flash column chromatography (silica gel; eluent: 50% ethyl acetate in heptane) to afford methyl 5-(3,3-difluoroazetidin-1-yl)pyrazine-2-carboxylate (1.21 g, 46%) as a white solid. MS (ISP): 230.2 ([M+H]j.
With caesium carbonate; In ethyl acetate; N,N-dimethyl-formamide;
Step 1: Methyl 5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylate To a flask was added methyl 5-chloropyrazine-2-carboxylate (1.5179 g, 8.80 mmol), <strong>[130551-92-7]oxazol-2-ylmethanol</strong> (0.697 ml, 8.80 mmol), and cesium carbonate (0.845 ml, 10.56 mmol) in DMF (25.1 mL) to stir at 40 C. for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine, and dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (100 g), eluting with a gradient of 10-100% EtOAc/hexane, to provide methyl 5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylate (0.547 g, 2.327 mmol, 26.5% yield). MS m/z=236.0 [M+H]+. Calculated for C10H9N3O4: 235.059 1H NMR (400 MHz, DMSO-d6) ppm 3.89 (s, 3H) 5.59 (s, 2H) 7.28 (d, J=0.78 Hz, 1H) 8.18 (d, J=0.78 Hz, 1H) 8.52 (d, J=1.17 Hz, 1H) 8.84 (d, J=1.37 Hz, 1H)
methyl 5-(thiazol-4-ylmethoxy)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42.2%
With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 72h;
A RBF was charged with methyl 5-chloropyrazine-2-carboxylate (1.239 g, 7.18 mmol, Ark Pharm), <strong>[7036-04-6]thiazol-4-ylmethanol</strong> (0.8266 g, 7.18 mmol), cesium carbonate (0.689 ml, 8.61 mmol, Alfa Aesar) and DMF (20.51 ml). The reaction mixture was stirred at 40 C for 3 days. The reaction mixture was allowed to cool to rt and was diluted with water and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgS04, and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and purified by silica gel flah chromatography, eluting with a gradient of 10% to 100% EtOAc in hexane, to provide methyl 5-(thiazol-4-ylmethoxy)pyrazine-2- carboxylate (0.7606 g, 3.03 mmol, 42.2 % yield). MS m/z = 252.1 [M+H]+. Calculated for C10H9N3O3S: 251.036. H NMR (400 MHz, DMSO-cfe) delta ppm 3.89 (s, 2 H) 5.60 (s, 1 H) 7.86 (d, J=1.96 Hz, 1 H) 8.46 (d, J=1.37 Hz, 1 H) 8.86 (d, J=1.37 Hz, 1 H) 9.14 (d, J=1.96 Hz, 1 H)
methyl 5-(cyclopropoxy)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 39h;
Methyl 5-(cyclopropoxy)pyrazine-2-carboxylate Cyclopropanol (542 muL, 8.69 mmol) is added to a suspension of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and potassium carbonate (1.60 g, 11.59 mmol) in dimethylformamide (11.6 mL). The reaction mixture is stirred for 15 hours at room temperature then for 24 hours at 50 C. The reaction is cooled to ambient temperature, diluted with water, and extracted with ethyl acetate (3 times). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The crude product is purified by silica gel flash chromatography, eluting with ethyl acetate/hexane (0:100) to ethyl acetate/hexane (35:65) to give the title compound (610 mg, 54%). ES/MS (m/e): 195.0 (M+1).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;
To a solution of <strong>[36070-80-1]5-chloropyrazine-2-carboxylic acid</strong> (300 mg, 1.89 mmol) in CH2C12 (3.8 mL) was added EDCI (401 mg, 2.09 mmol), DMAP (12.5 mg, 0.102 mmol) and MeOH (0.15 mL, 3.7 mmol) at room temperature. After stirring for 2 h, the reaction was quenched by adding saturated NH4C1 solution. The crude products were extracted with CH2C12 (x3), and the combined organic extracts were washed with brine, dried (MgS04), and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc = 9/1 to 7/1) to afford methyl 5-chloropyrazine-2-carboxylate (213 g, 65%) as a white solid. NMR (300 MHz, CDCh) delta 9.12 (d, J = 1.8 Hz, 1H), 8.73 (d, J = 1.8 Hz, 1H), 4.07 (s, 3H).
methyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With toluene-4-sulfonic acid; In 1,4-dioxane; at 111℃; for 14h;Inert atmosphere;
a. Methyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrazine-2- carboxylate (89). To a 100 mL, one-neck, round-bottomed flask equipped with a magnetic stir bar and charged with 74 (0.8 154 g, 4.01 mmol), methyl 5-chloropyrazine-2-carboxylate (0.6897, 4.04 mmol), andp-TsOH (0.7757 g, 4.08 mmol) was added 1,4-dioxane (15 mL). The flask was fitted with a reflux condenser, evacuated and back-filled with nitrogen, heated to reflux and stirred in an oil bath at 111 C for 14 h. After cooling the reaction to r.t., the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude product that was purified by column chromatography (150 mL Si02, 10% ethyl acetate:hexanes) to give 89 (0.7674 g, 56%) as a white crystalline solid, m.p. 183.2-184.8 C: ?H NMR (400 MHz, CDC13) 8.83 (d, J1.6, 1H), 8.26 (d, J= 1.2, 1H), 7.53 (br s, 1H), 7.33 (d, J 8.4, 1H), 7.32 (d, J 2.4, 1H), 7.21 (dd, J = 8.4, 2.4, 1H), 3.95 (s, 3H), 1.68 (s, 4H), 1.27 (s, 6H), 1.26 (s, 6H); ?3C NMR (100.6 MHz, CDC13) 164.9, 153.8, 146.3, 145.4, 142.1, 134.9, 132.6, 131.6, 127.7, 119.5, 119.2, 52.3, 34.9, 34.8, 34.3, 34.0, 31.7; JR (neat) 3325, 2952, 1713, 1527, 1281 cni?; ES-MS (M+Na)+ calcd for C20H25N3O2Na362.1844, found 362.1846.
Stage #1: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole[1,2-a]pyridine; methyl 5-chloropyrazine-2-carboxylate With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In 1,2-dimethoxyethane; water for 22h; Inert atmosphere; Reflux;
Stage #2: With hydrogenchloride In water
Imidazo [1,2-a] pyridine-6-borate (1.0eq), 5- chloropyrazine-2-carboxylic acid methyl ester (1.0eq), PdCl2 (dppf) 2 (3% mol) and carbonate sodium (2.0 eq) was added to the reaction flask was added a mixed solvent (ethylene glycol dimethyl ether / water = 5/1), nitrogen and heated at reflux for 22 hours.Cooled, filtered, and 2N hydrochloric PH = 7, and extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to dryness to give the crude product, the crude product was purified by silica gel column to give pure product (yield: 59%).
methyl 5-(cyclohex-1-en-1-yl)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In tetrahydrofuran; water; at 40℃; for 15h;Inert atmosphere;
To a solution of methyl 5-chloropyrazine-2-carboxylate (601 mg, 3.48 mmol) in THF (11.6 mL) was added 1-cyclohexene-l-yl-boronic acid (656 mg, 5.21 mmol), K3PO4 (1.47 g, 6.91 mmol), Pd(OAc)2 (39.2 mg, 0.175 mmol), SPhos (144 mg, 0.350 mmol) and H2O (0.13 mL, 7.2 mmol) at room temperature. After stirring for 15 h at 40 °C, the reaction was quenched by adding water. The crude products were extracted with EtOAc (3X), and the combined organic extracts were washed with brine, dried (MgS04), and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc = 9/1 to 4/1) to afford methyl 5-(cyclohex-l-en-l-yl)pyrazine-2-carboxylate (736 mg, 97percent) as a pale yellow solid. NMR (300 MHz, CDCh) delta 9.21 (d, J= 1.2 Hz, 1H), 8.81 (d, J= 1.2 Hz, 1H), 6.98-7.01 (m, 1H), 4.05 (s, 3H), 2.55-2.60 (m, 2H), 2.34-2.38 (m, 2H), 1.81-1.89 (m, 2H), 1.70-1.77 (m, 2H).
Under an argon atmosphere,Methyl 5-chloropyrazine-2-carboxylate (82 mg, 0.47 mmol),4 '- (diphenylamino) biphenylylboronic acid (190 mg, 0.52 mmol) and tetrakis (triphenylphosphine) palladium (27 mg, 0.02 mmol)Was suspended in 1,4-dioxane (5 mL) and 2 M aqueous potassium phosphate solution (0.95 mL, 1.89 mmol) was added. The reaction mixture was stirred at 100 C. for 24 hours. After allowing to cool to room temperature, 1 N hydrochloric acid was added to the reaction mixture to adjust the pH to 1, and the mixture was extracted with chloroform. Sodium sulfate was added to the organic layer, which was separated by filtration, and the solvent was distilled off to obtain a crude product. The crude product was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 100/0 to 95/5) and recrystallization (hexane / dichloromethane)To the target Dye-3 (154 mg, 73%)As a yellow solid.
Under an argon atmosphere, Methyl 5-chloropyrazine-2-carboxylate (35 mg, 0.20 mmol), 4-(dimethylamino) phenylboronic acid pinacol ester (74 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) was suspended in 1,4-dioxane (2.0 mL), and 2 M potassium phosphate aqueous solution (400 muL, 0.80 mmol) was added. The reaction mixture was stirred at 100 C. for 24 hours. After allowing to cool to room temperature, ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture, and the aqueous layer was separated.The aqueous layer was adjusted to pH = 1 by adding 1N hydrochloric acid, and then extracted with ethyl acetate.Sodium sulfate was added to the ethyl acetate layer, which was separated by filtration, and the solvent was distilled off to obtain a crude product. This was purified by ODS column chromatography (developing solvent: DMF / water = 100/0 to 50/50) Dye-1 for the purpose as described above was obtained as a yellow solid (27 mg, 53%).
methyl 5-[2-(trifluoromethyl)benzamido]pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 6h;Inert atmosphere;
Methyl S-chloropyrazine-2-carboxylate (879 mg), <strong>[360-64-5]2-<strong>[360-64-5]trifluoromethylbenzamide</strong></strong> (1.OS g), Cs2CO3 (2.31 g), xantphos (0.268 g), and Pd2(dba)3 (0.141 g) were stirred in dioxane (25.5 mL) under argon atmosphere at 80C for 6 hours. The mixture was cooled, and then AcOEt and water were added thereto and the mixture was stirred. Then, insoluble substances were filtered through Celite. The filtrate was separated, and the organic layer was washed with water and saturated brine, dried over anhydrous Na2 SO4, and filtered. The solvent was removed, and then the resulted residue was purified by column chromatography (Hexane/AcOEt). The resultant was confirmed as methyl S-[(2-(trifluoromethyl)benzamidojpyrazine-2-carboxylate (1.69 g) by 1H-NMR (CDC13MeOH (16.5 mL) was added thereto, and then thereto was added SN aqueous NaOH solution (4.1 mL) under ice cooling. The mixture was stirred at room temperature for 4 hours. The mixture was adjusted to pH=4 by addition of 5N HC1 (4.1 mL) and the resulted precipitate was filtered and dried at 60C to give5- [2-(trifluoromethyl)benzamidojpyrazine-2-carboxylic acid (1.56 g).
methyl 5-[2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In butan-1-ol; for 16h;Reflux;
To solution of methyl 5-chloropyrazine-2-carboxylate (5 g, 29.1 mmol) in n-Butanol (50 mL) was added <strong>[298690-72-9]2-(3-fluorophenyl)pyrrolidine</strong> (4.70 g, 29.1 mmol) at room temperature. Resulting reaction mixture was stirred at reflux for 16 h. On completion, n-Butanol was concentrated under reduced pressure, diluted with water (150 mL) and extracted with ethyl acetate (2 x 150 mL). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (11 g, crude) as a brown solid. JH NMR(CDCL3, 400 MHz): d (ppm) 8.79 (s, 1H) 7.76 (s, 1H) 7.26 - 7.30 (m, 1H) 6.99 - 6.95 (m, 2H) 6.89 - 6.95 (m, 1H) 5.15 (m, 1H) 3.94 - 3.96 (m, 1H) 3.97 (s, 3H) 3.66 - 3.79 (m, 1H) 2.5 (m, 1H) 2.03 - 2.09 (m, 3 H); LCMS (ESI): m/z 302 [M + H+].
methyl (S)-5-([1,3’-bipyrrolidin]-1‘-yl)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With Cs2CO3 In N,N-dimethyl-formamide at 100℃; for 16h; Sealed tube;
92 Example 92: (S)-5-([1,3'-Bipyrrolidin]-1'-yl)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2- carboxamide
Methyl 5-chloropyrazine-2-carboxylate (473 mg, 2.74 mmol), (S)-1,3'-bipyrrolidine (384 mg, 2.74 mmol), cesium carbonate (1.14 g, 3.5 mmol) and DMF (10 mL) were combined in a sealed tube and heated to 100 oC for 16 hours. The reaction mixture was filtered to remove the cesium salts, rinsing with EtOAc. The combined organic filtrate was evaporated to dryness to give methyl (S)-5-([1,3'- bipyrrolidin]-1'-yl)pyrazine-2-carboxylate, which was used crude without further purification.
With Cs2CO3 In N,N-dimethyl-formamide at 100℃; for 16h; Sealed tube;
92 Example 92: (S)-5-([1,3'-Bipyrrolidin]-1'-yl)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2- carboxamide
Methyl 5-chloropyrazine-2-carboxylate (473 mg, 2.74 mmol), (S)-1,3'-bipyrrolidine (384 mg, 2.74 mmol), cesium carbonate (1.14 g, 3.5 mmol) and DMF (10 mL) were combined in a sealed tube and heated to 100 oC for 16 hours. The reaction mixture was filtered to remove the cesium salts, rinsing with EtOAc. The combined organic filtrate was evaporated to dryness to give methyl (S)-5-([1,3'- bipyrrolidin]-1'-yl)pyrazine-2-carboxylate, which was used crude without further purification.
methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With Cs2CO3 In N,N-dimethyl-formamide at 100℃; for 23h; Sealed tube;
106; 107 Example 106: (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(1- (methylamino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxamide and Example 107: (R)-5-(3-(1-aminocyclopropyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)pyrazine-2-carboxamide
Methyl 5-chloropyrazine-2-carboxylate (191 mg, 1.1 mmol), tert-butyl (R)-(1-(pyrrolidin-3- yl)cyclopropyl)carbamate (250 mg, 1.1 mmol), cesium carbonate (487 mg, 1.5 mmol) and DMF (4 mL) were combined in a sealed tube and hot block heated to 100 oC for 23 hours. The reaction mixture was then diluted with EtOAc, washed with water (3x), brine (1x) and evaporated to dryness to give methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate, which was used crude without further purification.
methyl (S)-5-(7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]heptan-5-yl)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 16h;
371; 372 Example 371: (S)-5-(7-amino-5-azaspiro[2.4]heptan-5-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)pyrazine-2-carboxamide and Example 372: (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5- (7-(methylamino)-5-azaspiro[2.4]heptan-5-yl)pyrazine-2-carboxamide
A suspension of tert-butyl (S)-(5-azaspiro[2.4]heptan-7-yl)carbamate (497 mg, 2.34 mmol), methyl 5-chloropyrazine-2-carboxylate (406 mg, 2.35 mmol), and cesium carbonate (849 mg, 2.61 mmol) in DMF (10 mL) was stirred at 100 oC for 16 h. After cooling to r.t., the solids were removed by filtration, washing with EtOAc (10 mL). The filtrate was concentrated to give crude methyl (S)-5-(7- ((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]heptan-5-yl)pyrazine-2-carboxylate, which was used without further purification.
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