* 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.
Stage #1: With sodium tetrahydroborate In water for 0.5 h; Stage #2: With water; potassium carbonate In ethanol for 0.5 h;
The 4- (3-CHLORO-4- (2-PYAZINYLMETHOXY) anilino) -5-fluoroquinazoline used as starting material was obtained as follows: Methylpyrazine carboxylate (8.5g) was stirred in water (200 ml) and sodium borohydride (11.65 g) was added in one portion, resulting in a vigorous exotherm. The reaction mixture was stirred vigorously for 30 minutes, and then ethanol (80 ML) and saturated potassium carbonate (150 ml) were added. The mixture was stirred for 30 minutes and then extracted with ethyl acetate (5 x 150 ml) and DCM (5 x 150 ml). The combined extracts were dried and concentrated to give pyrazin-2-ylmethanol as a yellow oil (5.43 g, 80percent), which was used without purification; NMR spectrum (DMSO-D6) 4.65 (s, 2H), 5.57 (br s, 1H), 8.54 (d, 2H), 8.71 (s, 1H).
75%
With sodium tetrahydroborate; calcium chloride In ethanol at 25℃; for 5 h;
To methyl pyrazine-2-carboxylate (3.35 g, 24.3 mmol) in EtOH (60 mL) was added calcium chloride (4.03 g, 36.4 mmol) followed by sodium borohydride (1.38 g, 36.4 mmol). The reaction mixture was stirred at 23°C for 5 h. The mixture was quenched with a mixture of acetic acid (4.20 mL, 72.8 mmol) and water (1.31 mL, 72.8 mmol), and stirred for 30 min. The mixture was filtered through a pad a silica gel, and the pad was washed with 5-10percent MeOH/DCM containing 0.3percent conc. NH3 (aq). The combined filtrates were concentrated in vacuo, and the crude residue was purified by FCC (SiO2, elution with 0-10percent MeOH/DCM)to provide 2.01 g (75percent) of pyrazin-2-ylmethanol. 1H NMR (400 MHz, d6-DMSO): d ppm 8.71 (m, 1H), 8.56 (dd, 1H), 8.54 (d, 1H), 5.61 (t, 1H), 4.63 (d, 2H); LCMS (Method E): tR= 0.56 min, m/z 111.3 (M+H)+. Step 3: 2-(Chloromethyl)pyrazine
36%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.25 h; Inert atmosphere Stage #2: With sodium hydroxide In tetrahydrofuran; water at 20℃; for 1 h;
Step 2; Lithium aluminum hydride (40.0 mg, 1.06 mmol) was suspended in tetrahydrofuran (1.0 mL). To this, a solution of methyl 2-pyrazinecarboxylate (66.0 mg, 0.478 mmol) in tetrahydrofuran (0.5 mL) was added dropwise under a nitrogen atmosphere at 0° C. and the mixture was stirred at the same temperature for 15 minutes. Then, water (40 μL), a 15percent aqueous sodium hydroxide solution (40 μL) and water (120 μL) were successively added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through Celite and the mother liquid was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give 2-pyrazinemethanol (Compound CD) (19.0 yield: 36percent).1H-NMR (270 MHz, CDCl3, δ): 3.11 (brd, J=5.6 Hz, 1H), 4.85 (d, J=5.6 Hz, 1H), 8.52-8.55 (m, 2H), 8.64 (s, 1H).
0.3 g
Stage #1: at 0 - 20℃; Inert atmosphere Stage #2: at 20℃; for 1 h; Inert atmosphere
[0537] Synthesis of pyrazin-2-ylmethanol: [0538] To a stirred solution of methyl pyrazine-2-carboxylate (0.5 g, 3.62 mmol) in H20 (10 mL) was added NaBH4 (685 g, 18.02 mmol) portion wise at 0 °C, and the reaction mixture was allowed to warm to RT and stirred for 30 min under inert atmosphere. To this saturated K2C03 (10 mL) and EtOH (5 mL) was added and stirring was continued for another 1 h at RT. The progress of the reaction was monitored by TLC; the reaction mixture was extracted with EtOAc. The combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford crude pyrazin-2-ylmethanol (0.3 g). LC-MS: 99.91percent; 111.9 (M++l) (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 0.72 min. 0.1percent TFA in water: ACN; 0.8 ml/min); TLC: 100percent EtOAc (Rf: 0.2).
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 3, p. 1431 - 1440
[2] Patent: WO2004/93880, 2004, A1, . Location in patent: Page/Page column 86
[3] Patent: WO2017/214359, 2017, A1, . Location in patent: Page/Page column 73
[4] Synthetic Communications, 2005, vol. 35, # 24, p. 3187 - 3190
[5] Patent: US2011/237584, 2011, A1, . Location in patent: Page/Page column 132
[6] Bulletin des Societes Chimiques Belges, 1982, vol. 91, # 2, p. 153 - 162
[7] Molecules, 2009, vol. 14, # 10, p. 4197 - 4212
[8] Patent: WO2012/40230, 2012, A1, . Location in patent: Page/Page column 90
[9] Patent: WO2013/142269, 2013, A1, . Location in patent: Paragraph 0537; 0538
[10] Journal of the American Chemical Society, 2014, vol. 136, # 23, p. 8350 - 8360
[11] Patent: WO2017/156181, 2017, A1, . Location in patent: Paragraph 00340
[12] Supramolecular Chemistry, 2018, vol. 30, # 4, p. 296 - 304
2
[ 6164-79-0 ]
[ 144-55-8 ]
[ 87-69-4 ]
[ 6705-33-5 ]
Reference：
[1] Patent: US6255305, 2001, B1,
3
[ 6164-79-0 ]
[ 98-96-4 ]
Reference：
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 664
[2] Yakugaku Zasshi, 1956, vol. 76, p. 470[3] Chem.Abstr., 1956, p. 14777
[4] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 22, p. 622
[5] Journal of Chemical Thermodynamics, 2005, vol. 37, # 1, p. 49 - 53
4
[ 67-56-1 ]
[ 98-97-5 ]
[ 6164-79-0 ]
Yield
Reaction Conditions
Operation in experiment
98%
for 2 h; Reflux
Pyrazine-2-carboxylic acid (5 g, 40.3 mmol) was dissolved inMeOH (150 ml), and a few drops of H2SO4 were added. The resultingreaction mixture was refluxed for 2 h. Methanol was evaporated and the resulting reaction mixture was extracted withEtOAc, washed with saturated NaHCO3 solution, then with brineand dried over anhydrous Na2SO4. The solvent was removed invacuo to give the methyl pyrazine-2-carboxylate (5.5 g, yield98percent). 1H NMR (CDCl3, 400 MHz) d 9.32 (d, 1H, J = 1.5 Hz), 8.78(d, 1H, J = 2.4 Hz), 8.73 (dd, 1H, J = 2.4, 1.5 Hz), 4.04 (s, 3H).
94.8%
at 80 - 85℃; for 5 h;
Example 1; Methyl pyrazine-2-carboxylate (Formula 3). 20.0 g (805.8 mmole) of pyrazine-2-carboxylic acid was added to 160 mL of methanol, and 1.0 mL of a concentrated sulfuric acid was gradually dropwise added thereto with stirring. A reaction solution was refluxed at a temperature of 80 to 85°C for 5 hours. The reaction solution was cooled to a temperature of 20 to 22 °C and concentrated to a volume of 25mL. Then, 80 mL of methylenechloride and 40 mL of water were added to the resultant concentrate. The resultant solution was then neutralized by gradual addition of 40 mL of a saturated sodium hydrogen carbonate solution to get a pH of 8.5. An organic layer was separated and a water layer was extracted again with 40 mL of methylenechloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and washed with 20 mL of methylenechloride. A filtrate was concentrated to give 21.1 g of the titled compound as a pale brown solid (yield 94.8percent). Melting point: 60-61 °C
91%
at 55 - 65℃; for 19 h; Industrial scale
• Charged MeOH (8.8 L) and OT-1 (1758 g) at RT. (0129) • Charged H2S04 (69.5 g) in one portion (21-22 °C exotherm). Heated to (60-65 °C) and stirred at 55-65 °C for 19 hours. (0130) 19 h, 96.0percent OT-2 and 4.0percent OT-1 by HPLC (0131) • Reaction was cooled to 15/30 °C. No precipitate formed. (0132) • NaHC03 (180 g) was charged in lots. The solution bubbled slightly and quickly went from yellow to pink. The mixture was stirred for 5 min at 15/30 °C. (0133) • The mixture was then concentrated to 1.5-2.5 vol at (0134) • Charged NaCl (.700 g) in water (2.5 vol). Upon stirring, solution became clear. (0135) • Stirred for 15 min at 15/30 °C. After stirring, the aqueous layer became slightly cloudy. The solids were filtered off and the layers were separated. (0136) • The aqueous layer was extracted with DCM (3x2 vol.). TLC indicated that extraction was complete after 3rd extraction. (0137) • Organic layers were dried over anhydrous Na2S04 (.4g/g SM) . (0138) • Concentrated to 1.5-2.5 vol under vacuum at (0139) • Charged heptanes (8 vol) over a minimum of 30 min. Pale white slurry. Let stir overnight. • Stirred at -5/- 15 °C for a minimum of 1 hr. Solids were filtered off and rinsed with cold heptanes (0140) • (2x1 vol.) Pulled solids dry on filter for 10 min. Dried in vacuum oven at (0141) Color changed, but no degradation was observed . (0142) Output material: ST-601 (0143) Lot No.: 2463-24- 1 (0144) Appearance: light Brown Solids (0145) Yield: 1721 g (91.0percent) (0146) HPLC purity: 98.9percent (0147) 1 NMR- Conforms to structure
87%
Stage #1: at -10℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 72 h; Stage #3: With sodium hydrogencarbonate In water
REFERENCE EXAMPLE 8-42-pyrazinemethanol (Compound CD)Step 1; To methanol (8.0 mL), thionyl chloride (2.08 mL) was added dropwise under a nitrogen atmosphere at -10° C. and the mixture was stirred at the same temperature for 30 minutes. To this, 2-pyrazinecarboxylic acid (1.00 g, 8.06 mmol) was added at the same temperature and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated, a saturated aqueous sodium bicarbonate solution was added to the residue, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol 19/1) to give methyl 2-pyrazinecarboxylate (969 mg, yield: 87percent).1H-NMR (270 MHz, CDCl3, δ); 4.06 (s, 3H), 8.74 (dd, J=1.3, 2.3 Hz, 1H), 8.79 (d, J=1.3 Hz, 1H), 9.34 (d, J=2.3 Hz, 1H).
72%
for 6 h; Reflux
General procedure: A catalytic amount of concentrated H2SO4 wasadded to a solution of carboxylic acids 16(a–j) (1.0 mmol)in 50 mL of methanol, and the mixture was refluxed for 6 h. It was allowed to cool. The saturated solution ofNaHCO3 was added to the reaction mixture, and it wasextracted with EtOAc (2 X 50 mL). The combined organiclayer was dried Na2SO4 and concentrated to obtain puremethyl esters 17(a–j).
63.63%
for 5 h; Reflux
[0535] Synthesis of methyl pyrazine-2-carboxylate: [0536] To a stirred solution of pyrazine-2-carboxylic acid (5 g, 40.29 mmol) in MeOH (20 mL) was added concentrated H2S04 (1 mL) drop-wise and stirred under reflux for 5 h. The reaction mixture was cooled to RT; volatiles were evaporated under reduced pressure. The residue was diluted with water and basified to pH~ 8.5 using NaHC03 and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford methyl pyrazine-2- carboxylate (3.5 g, 63.63percent) as an off-white solid. 1H-NMR (DMSO d6, 400 MHz): δ 9.21 (s, 1H), 8.91 (d, 1H), 8.82 (d, 1H), 3.92 (s, 3H); TLC: 50percent EtOAc/Hexane (Rf: 0.4).
53%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 6 h; Stage #2: for 0.5 h;
To pyrazinecarboxylic acid (5.80 g, 46.5 mmol) in dichloromethane (100 mL) was added oxalyl chloride (5.10 mL, 60.4 mmol) followed by catalytic DMF. The reaction mixture was stirred at 23°C for 6 h. Methanol (30 mL) was then added, and the mixture was stirred for an additional 30 min. The reaction mixture was concentrated in vacuo. The residue was taken up in EtOAc (200 mL), and washed with sat. NaHCO3 (aq) (1X100 mL) and brine (1X100mL). The organic layer was dried (MgSO4), and concentrated in vacuo to provide 3.38 g (53percent) of methyl pyrazine-2-carboxylate which was used without further purification in the next step.1H NMR (400 MHz, CDCl3): d ppm 9.34 (d, 1H), 8.79 (d, 1H), 8.74 (dd, 1H), 4.06 (s, 3H); LCMS (Method A): tR= 0.48 min, m/z 139.3 (M+H)+.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 12, p. 2843 - 2851
[2] Journal of the American Chemical Society, 1990, vol. 112, # 17, p. 6248 - 6254
[3] Patent: WO2004/48369, 2004, A1, . Location in patent: Page 8
[4] Tetrahedron Letters, 2009, vol. 50, # 28, p. 4030 - 4032
[5] Patent: WO2016/207914, 2016, A2, . Location in patent: Page/Page column 3; 13; 14
[6] European Journal of Inorganic Chemistry, 2009, # 9, p. 1162 - 1171
[7] Patent: US2011/237584, 2011, A1, . Location in patent: Page/Page column 132
[8] European Journal of Pharmaceutical Sciences, 2014, vol. 53, # 1, p. 1 - 9
[9] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 5, p. 505
[10] European Journal of Medicinal Chemistry, 2009, vol. 44, # 12, p. 4954 - 4959
[11] Letters in Drug Design and Discovery, 2010, vol. 7, # 4, p. 275 - 280
[12] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 627 - 643
[13] Chemical Communications, 2007, # 38, p. 3957 - 3959
[14] Patent: WO2013/142269, 2013, A1, . Location in patent: Paragraph 0535; 0536
[15] Patent: WO2017/214359, 2017, A1, . Location in patent: Page/Page column 72-73
[16] Zhurnal Obshchei Khimii, 1955, vol. 25, p. 2313,2314, 2315; engl. Ausg. S. 2285, 2286
[17] Journal of the American Chemical Society, 1940, vol. 62, p. 664
[18] Journal of the American Chemical Society, 1952, vol. 74, p. 1345
[19] Patent: CH187538, 1935, ,
[20] Zeitschrift fuer Naturforschung, B: Chemical Sciences, 1987, vol. 42, # 4, p. 425 - 430
[21] Journal of Chemical Thermodynamics, 2005, vol. 37, # 1, p. 49 - 53
[22] Patent: US2009/306096, 2009, A1, . Location in patent: Page/Page column 19
[23] Patent: WO2005/92304, 2005, A2, . Location in patent: Page/Page column 39
[24] Molecules, 2009, vol. 14, # 10, p. 4197 - 4212
[25] Magnetic Resonance in Chemistry, 2009, vol. 47, # 7, p. 617 - 624
[26] European Journal of Medicinal Chemistry, 2010, vol. 45, # 8, p. 3384 - 3388
[27] European Journal of Inorganic Chemistry, 2011, # 32, p. 5036 - 5042
[28] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6356 - 6365
[29] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 6, p. 1317 - 1322
[30] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 90 - 95
[31] Dalton Transactions, 2017, vol. 46, # 30, p. 9875 - 9885
[32] Pharmaceutical Chemistry Journal, 2018, vol. 51, # 10, p. 907 - 917
5
[ 98-97-5 ]
[ 6164-79-0 ]
Yield
Reaction Conditions
Operation in experiment
63.63%
Stage #1: With sulfuric acid In methanol at 20℃; for 5 h; Reflux Stage #2: With sodium hydrogencarbonate In methanol
Synthesis of methyl pyrazine-2-carboxylate: To a stirred solution of pyrazine-2-carboxylic acid (5 g, 40.29 mmol) in MeOH (20 mL) was added concentrated H2S04 (1 mL) drop wise and stirred under reflux for 5 h. The reaction mixture was cooled to RT; volatiles were evaporated under reduced pressure. The residue was diluted with water and basified to pH~ 8.5 using NaHC03 and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford methyl pyrazine-2-carboxylate (3.5 g, 63.63percent) as an off- white solid. 1H-NMR (DMSO d6, 400 MHz): δ 9.21 (s, 1H), 8.91 (d, 1H), 8.82 (d, 1H), 3.92 (s, 3H); TLC: 50percent EtOAc/Hexane (Rf: 0.4).
Reference：
[1] Patent: WO2012/40230, 2012, A1, . Location in patent: Page/Page column 89-90
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 20, p. 3902 - 3907
[3] Patent: US5945534, 1999, A,
[4] Patent: US2004/53989, 2004, A1,
With potassium carbonate In N,N-dimethyl-formamide for 72 h;
Example 19.1Pyrazine-2-carboxylic acid methyl ester To pyrazine-2-carboxylic acid (15.0 g, 121 mmol) in DMF (150 mL) were added K2CO3 (50 g, 363 mmol) and MeI (9.0 mL, 145 mmol). After stirring for 3 days, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30percent ethyl acetate in hexanes gave the title product (1.28 g, 8percent).1H NMR (300 MHz, CDCl3): δ (ppm) 9.35 (s, 1H), 8.80 (s, 1H), 8.75 (s, 1H), 4.07 (s, 3H).
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 20, p. 3902 - 3907
13
[ 89-01-0 ]
[ 6164-79-0 ]
Reference：
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 664
14
[ 13925-00-3 ]
[ 6164-79-0 ]
Reference：
[1] Journal of Chemical Thermodynamics, 2005, vol. 37, # 1, p. 49 - 53
15
[ 73763-86-7 ]
[ 6164-79-0 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 679
[2] Yakugaku Zasshi, 1956, vol. 76, p. 470[3] Chem.Abstr., 1956, p. 14777
16
[ 4744-50-7 ]
[ 6164-79-0 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 679
[2] Yakugaku Zasshi, 1956, vol. 76, p. 470[3] Chem.Abstr., 1956, p. 14777
17
[ 6164-79-0 ]
[ 768-05-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrazine In ethanol for 2 h; Heating / reflux
Pyrazine-2-carboxylic acid hydrazide. To a stirred solution of pyrazine-2-carboxylic acid methyl ester (11.1 g, 80 mmol) in 140 mL OF ETOH was added hydrazine hydrate (15.6 ML, 320 mmol). The resultant solution was heated to reflux for 2h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100percent) as a white solid. The product was used in subsequent steps without purification.
100%
With hydrazine In ethanol for 2 h; Heating / reflux
Example 261; 5-Phenyl-2-(3-pyrazin-2-yl-ureido)-thiophene-3-carboxylic acid (S)-azepan-3-ylamide pyrazine-2-carbohydrazide. ; To a stirred solution of methyl pyrazine-2-carboxylate (11.1 g, 80 mmol) in 140 mL of EtOH was added hydrazine hydrate (15.6 mL, 320 mmol). The resultant solution was heated to reflux for 2h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100percent) as a white solid. The product was used in subsequent steps without purification.'H NMR (d6-DMSO 8 10.1, br s, 1H; 8 9.12, d, 1H ; 8 8. 83, d, 1H ; 8 8.70, dd, 1H; 8 4.64, br s, 2H), LC/MS (APCI, ES, M+H=139).
75%
With hydrazine hydrate In methanol for 5 h; Reflux
General procedure: To a solution of an appropriate methyl esters17(a–j) (1.0 mmol) in 50 mL of methanol was added 99 percenthydrazine hydrate (4.0 mmol) and the mixture was refluxedfor 5 h up to reaction completed (TLC). After completionof reaction, it was allowed to cool and the obtained solidwas washed with methanol. The crude products wererecrystallized from ethanol.
68%
at 78℃;
Example 21.1Pyrazine-2-carbohydrazide To the title compound of Example 19.1 (1.28 mg, 9.3 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.54 mL, 11.1 mmol) and then heated at 78° C. overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with ethyl acetate, filtered and dried to give the title product as a yellow solid (870 mg, 68percent).1H NMR (300 MHz, (CD3)2SO): δ (ppm) 10.16 (broad s, 1H), 9.13 (s, 1H), 8.84 (s, 1H), 8.70 (s, 1H), 4.65 (broad s, 2H).
56%
With hydrazine In tetrahydrofuran for 3 h; Reflux
Methyl pyrazine-2-carboxylate (0.5g; 3.6mmol) was dissolved in THF (5mL), and 98percent hydrazine (0.53mL; 11mmol) was added. The mixture was refluxed for 3h and cooled to rt. The resulting solid was filtered off, washed with THF and dried over P2O5 to give 0.28g (56percent) of a white solid. Rf=0.53 (CHCl3/MeOH 10:1). mp 166–169°C (lit. 167–169°C) [64]. 1H NMR (300MHz, DMSO): δ 10.11 (s, 1H, NH), 9.12 (s, 1H, Ar), 8.82 (d, J=2.4Hz, 1H, Ar), 8.68 (d, J=2.4Hz, 1H, Ar), 4.65 (s, 2H, NH2). 13C NMR (75MHz, DMSO): δ 161.7, 147.4, 145.1, 143.7, 143.4.
Reference：
[1] Patent: WO2005/16909, 2005, A1, . Location in patent: Page/Page column 73
[2] Patent: WO2005/66163, 2005, A2, . Location in patent: Page/Page column 128
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 14, p. 5007 - 5015
[4] European Journal of Inorganic Chemistry, 2011, # 32, p. 5036 - 5042
[5] European Journal of Medicinal Chemistry, 2009, vol. 44, # 12, p. 4954 - 4959
[6] Letters in Drug Design and Discovery, 2010, vol. 7, # 4, p. 275 - 280
[7] Medicinal Chemistry, 2011, vol. 7, # 3, p. 245 - 249
[8] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 627 - 643
[9] Patent: US2007/259862, 2007, A1, . Location in patent: Page/Page column 26
[10] Chemistry - A European Journal, 2018, vol. 24, # 39, p. 9928 - 9939
[11] Chemical Communications, 2012, vol. 48, # 5, p. 708 - 710
[12] Chemistry - A European Journal, 2012, vol. 18, # 2, p. 442 - 445
[13] European Journal of Medicinal Chemistry, 2016, vol. 120, p. 97 - 110
[14] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 22, p. 622
[15] Patent: US2149279, 1935, ,
[16] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[17] Patent: US6297235, 2001, B1,
[18] European Journal of Medicinal Chemistry, 2010, vol. 45, # 8, p. 3384 - 3388
[19] Patent: WO2010/125102, 2010, A1, . Location in patent: Page/Page column 125-126
[20] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6356 - 6365
[21] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 90 - 95
[22] Dalton Transactions, 2017, vol. 46, # 30, p. 9875 - 9885
[23] Pharmaceutical Chemistry Journal, 2018, vol. 51, # 10, p. 907 - 917
[24] Chemical Research in Toxicology, 2018, vol. 31, # 6, p. 435 - 446
[25] Patent: US2149279, 1935, ,
18
[ 6164-79-0 ]
[ 27825-21-4 ]
[ 33332-25-1 ]
Reference：
[1] Magnetic Resonance in Chemistry, 2009, vol. 47, # 7, p. 617 - 624
19
[ 6164-79-0 ]
[ 5780-66-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at -78 - 72℃; for 0.333333 h;
Method 54; Pvrazine-2-carboxaldehyde oxime A IN solution of lithium aluminium hydride in THF (73. 8ml, 73.8mmol) was added to a suspension of methyl pyrazine-2-carboxylate (20g, 145mmol) in anhydrous THF (300. 0ml) at-78°C keeping the reaction temperature below-72°C. On completion of addition the reaction mixture was left to stir at-78°C for a further 20 minutes and then quenched with glacial acetic acid (20. 0ml). The resulting mixture was warmed to room temperature and the volatiles removed by evaporation. The residue was dissolved in 3N hydrochloric acid (116ml) and extracted with DCM. The extracts were combined, washed with saturated aqueous sodium hydrogen carbonate solution and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with DCM/diethylether (100: 0 then 80: 20 and then 0: 100) to give pyrazine-2-carboxaldehyde (15.67g, 100percent). This was immediately dissolved in chloroform (200ml) cooled to 0°C and hydroxylamine mono-hydrochloride (11. 02g, 159. 5mmol) and triethylamine (24. 2ml, 117. 4mmol) were added. The reaction mixture was then stirred at ambient temperature for 0.5 hour, and the solvent removed by evaporation. The residue suspended in diethylether (500ml) and the insolubles removed by filtration. The filtrate was evaporated and the residue purified by chromatography eluting with DCM/diethylether (100: 0 then 80: 20 and then 0: 100) to give the title compound (5. 5g, 31percent) as a solid. NMR (DMSO-d6) : 8.15 (s, 1H), 8.62 (dd, 2H), 8. 99 (s, 1H).
Reference：
[1] Patent: WO2005/40159, 2005, A1, . Location in patent: Page/Page column 212-213
[2] Tetrahedron Letters, 2009, vol. 50, # 28, p. 4030 - 4032
[3] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
[4] Chemical Communications, 2007, # 38, p. 3957 - 3959
[5] Journal of the American Chemical Society, 1990, vol. 112, # 17, p. 6248 - 6254
[6] Bulletin des Societes Chimiques Belges, 1982, vol. 91, # 2, p. 153 - 162
[7] Journal of the Chemical Society, Faraday Transactions, 1993, vol. 89, # 1, p. 43 - 48
[8] Bulletin des Societes Chimiques Belges, 1982, vol. 91, # 2, p. 153 - 162
[9] Patent: US2009/306096, 2009, A1, . Location in patent: Page/Page column 19-20
[10] Patent: WO2005/92304, 2005, A2, . Location in patent: Page/Page column 39
[11] Organic Letters, 2012, vol. 14, # 23, p. 6104 - 6107
20
[ 6164-79-0 ]
[ 23688-89-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 21, p. 7678 - 7692
<strong>[98-97-5]Pyrazine-2-carboxylic acid</strong> (5 g, 40.3 mmol) was dissolved inMeOH (150 ml), and a few drops of H2SO4 were added. The resultingreaction mixture was refluxed for 2 h. Methanol was evaporated and the resulting reaction mixture was extracted withEtOAc, washed with saturated NaHCO3 solution, then with brineand dried over anhydrous Na2SO4. The solvent was removed invacuo to give the methyl pyrazine-2-carboxylate (5.5 g, yield98%). 1H NMR (CDCl3, 400 MHz) d 9.32 (d, 1H, J = 1.5 Hz), 8.78(d, 1H, J = 2.4 Hz), 8.73 (dd, 1H, J = 2.4, 1.5 Hz), 4.04 (s, 3H).
94.8%
With sulfuric acid; at 80 - 85℃; for 5h;
Example 1; Methyl pyrazine-2-carboxylate (Formula 3). 20.0 g (805.8 mmole) of pyrazine-2-carboxylic acid was added to 160 mL of methanol, and 1.0 mL of a concentrated sulfuric acid was gradually dropwise added thereto with stirring. A reaction solution was refluxed at a temperature of 80 to 85C for 5 hours. The reaction solution was cooled to a temperature of 20 to 22 C and concentrated to a volume of 25mL. Then, 80 mL of methylenechloride and 40 mL of water were added to the resultant concentrate. The resultant solution was then neutralized by gradual addition of 40 mL of a saturated sodium hydrogen carbonate solution to get a pH of 8.5. An organic layer was separated and a water layer was extracted again with 40 mL of methylenechloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and washed with 20 mL of methylenechloride. A filtrate was concentrated to give 21.1 g of the titled compound as a pale brown solid (yield 94.8%). Melting point: 60-61 C
91%
With sulfuric acid; at 55 - 65℃; for 19h;Industrial scale;
? Charged MeOH (8.8 L) and OT-1 (1758 g) at RT. (0129) ? Charged H2S04 (69.5 g) in one portion (21-22 C exotherm). Heated to (60-65 C) and stirred at 55-65 C for 19 hours. (0130) 19 h, 96.0% OT-2 and 4.0% OT-1 by HPLC (0131) ? Reaction was cooled to 15/30 C. No precipitate formed. (0132) ? NaHC03 (180 g) was charged in lots. The solution bubbled slightly and quickly went from yellow to pink. The mixture was stirred for 5 min at 15/30 C. (0133) ? The mixture was then concentrated to 1.5-2.5 vol at (0134) ? Charged NaCl (.700 g) in water (2.5 vol). Upon stirring, solution became clear. (0135) ? Stirred for 15 min at 15/30 C. After stirring, the aqueous layer became slightly cloudy. The solids were filtered off and the layers were separated. (0136) ? The aqueous layer was extracted with DCM (3x2 vol.). TLC indicated that extraction was complete after 3rd extraction. (0137) ? Organic layers were dried over anhydrous Na2S04 (.4g/g SM) . (0138) ? Concentrated to 1.5-2.5 vol under vacuum at (0139) ? Charged heptanes (8 vol) over a minimum of 30 min. Pale white slurry. Let stir overnight. ? Stirred at -5/- 15 C for a minimum of 1 hr. Solids were filtered off and rinsed with cold heptanes (0140) ? (2x1 vol.) Pulled solids dry on filter for 10 min. Dried in vacuum oven at (0141) Color changed, but no degradation was observed . (0142) Output material: ST-601 (0143) Lot No.: 2463-24- 1 (0144) Appearance: light Brown Solids (0145) Yield: 1721 g (91.0%) (0146) HPLC purity: 98.9% (0147) 1 NMR- Conforms to structure
87%
REFERENCE EXAMPLE 8-42-pyrazinemethanol (Compound CD)Step 1; To methanol (8.0 mL), thionyl chloride (2.08 mL) was added dropwise under a nitrogen atmosphere at -10 C. and the mixture was stirred at the same temperature for 30 minutes. To this, 2-<strong>[98-97-5]pyrazinecarboxylic acid</strong> (1.00 g, 8.06 mmol) was added at the same temperature and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated, a saturated aqueous sodium bicarbonate solution was added to the residue, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol 19/1) to give methyl 2-pyrazinecarboxylate (969 mg, yield: 87%).1H-NMR (270 MHz, CDCl3, delta); 4.06 (s, 3H), 8.74 (dd, J=1.3, 2.3 Hz, 1H), 8.79 (d, J=1.3 Hz, 1H), 9.34 (d, J=2.3 Hz, 1H).
72%
With sulfuric acid; for 6h;Reflux;
General procedure: A catalytic amount of concentrated H2SO4 wasadded to a solution of carboxylic acids 16(a-j) (1.0 mmol)in 50 mL of methanol, and the mixture was refluxed for 6 h. It was allowed to cool. The saturated solution ofNaHCO3 was added to the reaction mixture, and it wasextracted with EtOAc (2 X 50 mL). The combined organiclayer was dried Na2SO4 and concentrated to obtain puremethyl esters 17(a-j).
63.63%
With sulfuric acid; for 5h;Reflux;
[0535] Synthesis of methyl pyrazine-2-carboxylate: [0536] To a stirred solution of pyrazine-2-carboxylic acid (5 g, 40.29 mmol) in MeOH (20 mL) was added concentrated H2S04 (1 mL) drop-wise and stirred under reflux for 5 h. The reaction mixture was cooled to RT; volatiles were evaporated under reduced pressure. The residue was diluted with water and basified to pH~ 8.5 using NaHC03 and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford methyl pyrazine-2- carboxylate (3.5 g, 63.63%) as an off-white solid. 1H-NMR (DMSO d6, 400 MHz): delta 9.21 (s, 1H), 8.91 (d, 1H), 8.82 (d, 1H), 3.92 (s, 3H); TLC: 50% EtOAc/Hexane (Rf: 0.4).
53%
To <strong>[98-97-5]pyrazinecarboxylic acid</strong> (5.80 g, 46.5 mmol) in dichloromethane (100 mL) was added oxalyl chloride (5.10 mL, 60.4 mmol) followed by catalytic DMF. The reaction mixture was stirred at 23C for 6 h. Methanol (30 mL) was then added, and the mixture was stirred for an additional 30 min. The reaction mixture was concentrated in vacuo. The residue was taken up in EtOAc (200 mL), and washed with sat. NaHCO3 (aq) (1X100 mL) and brine (1X100mL). The organic layer was dried (MgSO4), and concentrated in vacuo to provide 3.38 g (53%) of methyl pyrazine-2-carboxylate which was used without further purification in the next step.1H NMR (400 MHz, CDCl3): d ppm 9.34 (d, 1H), 8.79 (d, 1H), 8.74 (dd, 1H), 4.06 (s, 3H); LCMS (Method A): tR= 0.48 min, m/z 139.3 (M+H)+.
With sulfuric acid; for 6h;Reflux;
A solution of pyrazine-2-carboxylic acid (Aldrich, 12.41 g, 0.1 mol) in MeOH (Aldrich, anhydrous, 100 mL) was stirred with H2SO4 (Aldrich, concentrated, 2 mL) at reflux for 6 hours. The reaction mixture was then concentrated and treated with saturated aqueous Na2CO3 solution (20 mL) till pH=8-9. The mixture was extracted with EtOAc (3*100 mL), and the combined extracts were washed with brine (2*20 mL) and dried over MgSO4. The drying agent was removed by filtration. The organic solution was concentrated and dried to give the title compound 1H NMR (300 MHz, CDCl3) delta 4.06 (s, 3H), 8.73 (dd, J=2.4, 1.6 Hz, 1H), 8.79 (d, J=2.4 Hz, 1H), 9.33 (d, J=1.6 Hz, 1H) ppm. MS (DCI/NH3) m/z 139 (M+H)+.
With sulfuric acid; In methanol; for 6h;Heating / reflux;
Pyrazine-2-carb aldehyde A round bottom flask was charged with <strong>[98-97-5]pyrazine carboxylic acid</strong> (17.7 g, 140 mMol), methanol (200 mL) and conc. sulphuric acid (2 mL) and the mixture was stirred at reflux for 4 hrs then left to stand overnight. The next day the mixture was refluxed for 2 more hours. The solvent was then evaporated in vacuo, the residue was diluted with dichloromethane and neutralised with 20% sodium bicarbonate solution. The dichloromethane phase was dried over MgS04 and evaporated to give the crude product as an off-white solid. Purification by column chromatography (silica gel, dichloromethane) gave <strong>[98-97-5]pyrazinecarboxylic acid</strong> methyl ester 13.5 g as a white solid.
With sulfuric acid; for 12h;Reflux;
Concentrated sulfuric acid (1.20 mL) was added slowly with vigorous agitation to a mixture of 2.48 g (20 mmol) of <strong>[98-97-5]2-<strong>[98-97-5]pyrazine carboxylic acid</strong></strong> (1) and 32 mL (1 mol) of methanol. The mixture was then reux for 12 h. Excess methanol was removed by evaporation and the residue was washed with water. The organic layer was again treated with water and concentrated sodium bicarbonate solution to an alkaline reaction, and then again with water. The product was dried over anhydrous MgSO4, collected by ltration, and distilled.
With sulfuric acid; for 5h;Reflux;
(1) <strong>[98-97-5]Pyrazine-2-carboxylic acid</strong> is fully dissolved in anhydrous methanol,Then add an appropriate amount of concentrated sulfuric acid and heat to reflux for 5 h.After the reaction is cooled, adjust the pH to neutral with saturated NaHCO3,Extract with dichloromethane and keep the dichloromethane layer,The solvent was removed by rotary evaporation to obtain an oily pyrazine-2-carboxylic acid methyl ester;After dissolving it in anhydrous methanol, hydrazine hydrate was added dropwise, and after heating under reflux for 21 h,Cool to room temperature, remove methanol by rotary evaporation to obtain pyrazine-2-hydrazide as a red solid product;The ratio of the amount of pyrazine-2-carboxylic acid methyl ester to the amount of hydrazine hydrate is 1: 2.
General procedure for hydroxamic synthesis
General procedure: To a solution of methyl heteroaryl-carboxylate derivative(3.62 mmol) in methanol (10 mL) at room temperature andunder stirring, 3.9 mL of hydroxylamine 50% (65.2 mmol)was slowly added. The solution was stirred for 72 h. Thesolvent was evaporated under vacuum and the solid wasresuspended in dichloromethane, filtered, and thus washedfrom traces of pyrazine-2-carboxylate. Then, the solid wasresuspended in water (4 mL) to remove traces of hydroxylamine:the pyrazine-2-hydroxamic acid being poorly solublein water, the mixture was cooled down in an ice bath for3 h to assist the product precipitation. Then, the solid wasfiltered, washed with cold acetone, and dried under vacuum.
With hydrazine; In ethanol; for 2h;Heating / reflux;
Pyrazine-2-carboxylic acid hydrazide. To a stirred solution of pyrazine-2-carboxylic acid methyl ester (11.1 g, 80 mmol) in 140 mL OF ETOH was added hydrazine hydrate (15.6 ML, 320 mmol). The resultant solution was heated to reflux for 2h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100%) as a white solid. The product was used in subsequent steps without purification.
100%
With hydrazine; In ethanol; for 2h;Heating / reflux;
Example 261; 5-Phenyl-2-(3-pyrazin-2-yl-ureido)-thiophene-3-carboxylic acid (S)-azepan-3-ylamide pyrazine-2-carbohydrazide. ; To a stirred solution of methyl pyrazine-2-carboxylate (11.1 g, 80 mmol) in 140 mL of EtOH was added hydrazine hydrate (15.6 mL, 320 mmol). The resultant solution was heated to reflux for 2h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100%) as a white solid. The product was used in subsequent steps without purification.'H NMR (d6-DMSO 8 10.1, br s, 1H; 8 9.12, d, 1H ; 8 8. 83, d, 1H ; 8 8.70, dd, 1H; 8 4.64, br s, 2H), LC/MS (APCI, ES, M+H=139).
75%
With hydrazine hydrate; In methanol; for 5h;Reflux;
General procedure: To a solution of an appropriate methyl esters17(a-j) (1.0 mmol) in 50 mL of methanol was added 99 %hydrazine hydrate (4.0 mmol) and the mixture was refluxedfor 5 h up to reaction completed (TLC). After completionof reaction, it was allowed to cool and the obtained solidwas washed with methanol. The crude products wererecrystallized from ethanol.
68%
With ethanol; hydrazine; at 78℃;
Example 21.1Pyrazine-2-carbohydrazide To the title compound of Example 19.1 (1.28 mg, 9.3 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.54 mL, 11.1 mmol) and then heated at 78 C. overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with ethyl acetate, filtered and dried to give the title product as a yellow solid (870 mg, 68%).1H NMR (300 MHz, (CD3)2SO): delta (ppm) 10.16 (broad s, 1H), 9.13 (s, 1H), 8.84 (s, 1H), 8.70 (s, 1H), 4.65 (broad s, 2H).
56%
With hydrazine; In tetrahydrofuran; for 3h;Reflux;
Methyl pyrazine-2-carboxylate (0.5g; 3.6mmol) was dissolved in THF (5mL), and 98% hydrazine (0.53mL; 11mmol) was added. The mixture was refluxed for 3h and cooled to rt. The resulting solid was filtered off, washed with THF and dried over P2O5 to give 0.28g (56%) of a white solid. Rf=0.53 (CHCl3/MeOH 10:1). mp 166-169C (lit. 167-169C) [64]. 1H NMR (300MHz, DMSO): delta 10.11 (s, 1H, NH), 9.12 (s, 1H, Ar), 8.82 (d, J=2.4Hz, 1H, Ar), 8.68 (d, J=2.4Hz, 1H, Ar), 4.65 (s, 2H, NH2). 13C NMR (75MHz, DMSO): delta 161.7, 147.4, 145.1, 143.7, 143.4.
With hydrazine; In methanol;
d Pyrazine-2-hydrazide To a solution of the product from Example 1 step c) (22 g, 159 mmol) in methanol (250 ml) was slowly added hydrazine monhydrate (36.6 ml, 710 mmol). The reaction mixture was stirred for 1.5 h. The precipitate produced was filtered, washed with diethyl ether and dried in the oven at 80 C. to give the required product (30 g). 1H NMR (250 MHz, DMSO) delta 4.66 (2H, broad peak), 8.66 (1H, m), 8.84 (1H, d, J=2.5 Hz), 9.13 (1H, d, J=2.5 Hz), 10.15 (1H, broad peak); MS (ES+) m/e 139 [MH+].
With hydrazine hydrate; In ethanol; at 20 - 80℃; for 5.0833h;
Methyl 2-pyrazinecarboxylate (1132) (42 g, 304 mmol) was dissolved in ethanol (750 mL) and treated with hydrazine hydrate (22.17 mL, 456 mmol). The solution was stirred at room temperature for 5 minutes whereupon a precipitate started to form. The mixture was cautiously heated to 80 0C for 5 h and cooled to room temperature. Approximately 50% of the solvent was then removed in vacuo, the slurry was heated to reflux and the solution cooled to room temperature overnight. The resulting solid was filtered, washed with a little ethanol, diethyl ether and dried in a vacuum oven to afford product in 39.77 g as beige needles. LC/MS = 139 (M+H)+, retention time = 0.32 minutes (2 minute method (high pH)).
With hydrazine hydrate; In ethanol; at 80℃;
Equimolar quantities (15 mmol) of (2) and the 85% hydrazine monohydrate were dissolved in anhydrous ethanol (25 mL) and vigorously stirred at 80 under oil bath for 4-5 h . The crude was precipitated from the solvent, collected using suction filtration and dried, and followed by recrystallization in ethanol.
With hydrazine hydrate; In methanol; for 21h;Reflux;
(1) Pyrazine-2-carboxylic acid is fully dissolved in anhydrous methanol,Then add an appropriate amount of concentrated sulfuric acid and heat to reflux for 5 h.After the reaction is cooled, adjust the pH to neutral with saturated NaHCO3,Extract with dichloromethane and keep the dichloromethane layer,The solvent was removed by rotary evaporation to obtain an oily pyrazine-2-carboxylic acid methyl ester;After dissolving it in anhydrous methanol, hydrazine hydrate was added dropwise, and after heating under reflux for 21 h,Cool to room temperature, remove methanol by rotary evaporation to obtain pyrazine-2-hydrazide as a red solid product;The ratio of the amount of pyrazine-2-carboxylic acid methyl ester to the amount of hydrazine hydrate is 1: 2.
With sodium methylate; In methanol; toluene; at 110℃; for 3h;
Methyl 3-oxo-3-(pyrazin-2-yl)propanoate: To a stirred solution of sodium methoxide (25% in MeOH, 27.54 mL, 72.4 mmol, 1 eq) in 90 mL of toluene at 110 C. in a 3-neck flask attached with a mechanical stirrer, condenser and dropping funnel was added a solution of methylpyrazine-2-carboxylate (10 g, 72.4 mmol, 1 eq) in 115 mL of methyl acetate, dropwise, over a period of ?35-40 min. A yellow precipitate was formed. Stirring was continued at 110 C. for 3 hrs. The reaction was cooled and the yellow precipitate was filtered and washed with a small quantity of toluene. This solid was taken into 200 mL of saturated ammonium chloride and 400 mL of EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 6.52 g (50%) of methyl 3-oxo-3-(pyrazin-2-yl)propanoate as a yellow solid.
50%
With methanol; sodium methylate; In toluene; at 110℃; for 3h;
Methyl 3-oxo-3-(pyrazin-2-yl)propanoate: To a stirred solution of sodium methoxide (25% in MeOH, 27.54 mL, 72.4 mmol, 1 eq) in 90 mL of toluene at 110 C. in a 3-neck flask attached with a mechanical stirrer, condenser and dropping funnel was added a solution of methylpyrazine-2-carboxylate (10 g, 72.4 mmol, 1 eq) in 115 mL of methyl acetate, dropwise, over a period of ?35-40 min. A yellow precipitate was formed. Stirring was continued at 110 C. for 3 hrs. The reaction was cooled and the yellow precipitate was filtered and washed with a small quantity of toluene. This solid was taken into 200 mL of saturated ammonium chloride and 400 mL of EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 6.52 g (50%) of methyl 3-oxo-3-(pyrazin-2-yl)propanoate as a yellow solid.
50%
With sodium methylate; In methanol; acetic acid methyl ester; toluene; at 110℃;
To a stirred solution of sodium methoxide (25% in MeOH, 27.54 mL, 72.4 mmol, 1 eq) in 90 mL of toluene at 110 C. in a 3-neck flask attached with a mechanical stirrer, condenser and dropping funnel was added a solution of methylpyrazine-2-carboxylate (10 g, 72.4 mmol, 1 eq) in 115 mL of methyl acetate, dropwise, over a period of ?35-40 min. A yellow precipitate was formed. Stirring was continued at 110 C. for 3 hrs. The reaction was cooled and the yellow precipitate was filtered and washed with a small quantity of toluene. This solid was taken into 200 mL of saturated ammonium chloride and 400 mL of EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 6.52 g (50%) of methyl 3-oxo-3-(pyrazin-2-yl)propanoate as a yellow solid.
50%
With sodium methylate; In methanol; toluene; at 100℃;
To a stirred solution of sodium methoxide (25% in MeOH, 27.54 mL, 72.4 mmol, 1 eq) in 90 mL of toluene at 110 C. in a 3-neck flask attached with a mechanical stirrer, condenser and dropping funnel was added a solution of methylpyrazine-2-carboxylate (10 g, 72.4 mmol, 1 eq) in 115 mL of methyl acetate, dropwise, over a period of ?35-40 min. A yellow precipitate was formed. Stirring was continued at 110 C. for 3 hrs. The reaction was cooled and the yellow precipitate was filtered and washed with a small quantity of toluene. This solid was taken into 200 mL of saturated ammonium chloride and 400 mL of EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 6.52 g (50%) of methyl 3-oxo-3-(pyrazin-2-yl)propanoate as a yellow solid.
50%
With sodium methylate; In methanol; toluene; at 110℃;
To a stirred solution of sodium methoxide (25% in MeOH, 27.54 mL, 72.4 mmol, 1 eq) in 90 mL of toluene at 110 C. in a 3-neck flask attached with a mechanical stirrer, condenser and dropping funnel was added a solution of methylpyrazine-2-carboxylate (10 g, 72.4 mmol, 1 eq) in 115 mL of methyl acetate, dropwise, over a period of ?35-40 min. A yellow precipitate was formed. Stirring was continued at 110 C. for 3 hrs. The reaction was cooled and the yellow precipitate was filtered and washed with a small quantity of toluene. This solid was taken into 200 mL of saturated ammonium chloride and 400 mL of EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 6.52 g (50%) of methyl 3-oxo-3-(pyrazin-2-yl)propanoate as a yellow solid.
50%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;Inert atmosphere;
To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),<strong>[6164-79-0]methyl pyrazine-2-carboxylate</strong> (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid(1.95 g, 50%). 1H NMR (CDCl3, 400 MHz) d keto form: 9.28 (d, 1H,J = 1.5 Hz), 8.80 (d, 1H, J = 2.4 Hz), 8.66 (overlapped, 1H), 4.18 (s,2H), 3.74 (s, 3H); enol form: 12.30 (s, 1H), 9.15 (d, 1H, J = 1.5 Hz),8.66 (overlapped, 1H), 8.60 (dd, 1H, J = 2.3, 1.5 Hz), 6.34 (s, 1H),3.85 (s, 3H).
In a dropwise fashion, add 2-pyrazine methylester (1.0 g, 1.0 eq. ) and methyl acetate (1. 14 mL, 2.0 eq. ) as a solution in toluene (10 mL) to a hot (90 C) mixture of sodium methoxide (600 mg, 1.5 eq. ) in toluene (100 mL). Heat the mixture for 20 h. at 90 C, then cool to RT and concentrate in vacuo. Dissolve the residue in excess methyl acetate, heat at reflux for another 20 h. Cool the mixture to RT, add H20, and extract with EtOAc. Dry the organic layer over NA2SO4, filter, and concentrate in vacuo to give the title compound that was used without further purification. Rf = 0.58 (1: 1 EtOAc/hexanes).
The 4- (3-CHLORO-4- (2-PYAZINYLMETHOXY) anilino) -5-fluoroquinazoline used as starting material was obtained as follows: Methylpyrazine carboxylate (8.5g) was stirred in water (200 ml) and sodium borohydride (11.65 g) was added in one portion, resulting in a vigorous exotherm. The reaction mixture was stirred vigorously for 30 minutes, and then ethanol (80 ML) and saturated potassium carbonate (150 ml) were added. The mixture was stirred for 30 minutes and then extracted with ethyl acetate (5 x 150 ml) and DCM (5 x 150 ml). The combined extracts were dried and concentrated to give pyrazin-2-ylmethanol as a yellow oil (5.43 g, 80%), which was used without purification; NMR spectrum (DMSO-D6) 4.65 (s, 2H), 5.57 (br s, 1H), 8.54 (d, 2H), 8.71 (s, 1H).
75%
With sodium tetrahydroborate; calcium chloride; In ethanol; at 25℃; for 5h;
To methyl pyrazine-2-carboxylate (3.35 g, 24.3 mmol) in EtOH (60 mL) was added calcium chloride (4.03 g, 36.4 mmol) followed by sodium borohydride (1.38 g, 36.4 mmol). The reaction mixture was stirred at 23C for 5 h. The mixture was quenched with a mixture of acetic acid (4.20 mL, 72.8 mmol) and water (1.31 mL, 72.8 mmol), and stirred for 30 min. The mixture was filtered through a pad a silica gel, and the pad was washed with 5-10% MeOH/DCM containing 0.3% conc. NH3 (aq). The combined filtrates were concentrated in vacuo, and the crude residue was purified by FCC (SiO2, elution with 0-10% MeOH/DCM)to provide 2.01 g (75%) of pyrazin-2-ylmethanol. 1H NMR (400 MHz, d6-DMSO): d ppm 8.71 (m, 1H), 8.56 (dd, 1H), 8.54 (d, 1H), 5.61 (t, 1H), 4.63 (d, 2H); LCMS (Method E): tR= 0.56 min, m/z 111.3 (M+H)+. Step 3: 2-(Chloromethyl)pyrazine
36%
Step 2; Lithium aluminum hydride (40.0 mg, 1.06 mmol) was suspended in tetrahydrofuran (1.0 mL). To this, a solution of methyl 2-pyrazinecarboxylate (66.0 mg, 0.478 mmol) in tetrahydrofuran (0.5 mL) was added dropwise under a nitrogen atmosphere at 0 C. and the mixture was stirred at the same temperature for 15 minutes. Then, water (40 muL), a 15% aqueous sodium hydroxide solution (40 muL) and water (120 muL) were successively added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through Celite and the mother liquid was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give 2-pyrazinemethanol (Compound CD) (19.0 yield: 36%).1H-NMR (270 MHz, CDCl3, delta): 3.11 (brd, J=5.6 Hz, 1H), 4.85 (d, J=5.6 Hz, 1H), 8.52-8.55 (m, 2H), 8.64 (s, 1H).
Synthesis of pyrazin-2-ylmethanol:To a stirred solution of methyl pyrazine-2-carboxylate (0.5 g, 3.62 mmol) in H20 (10 mL) was added NaBH4 (685 g, 18.02 mmol) portion wise at 0 C, and the reaction mixture was allowed to warm to RT and stirred for 30 min under inert atmosphere. To this saturated K2C03 (10 mL) and EtOH (5 mL) was added and stirring was continued for another 1 h at RT. The progress of the reaction was monitored by TLC; the reaction mixture was extracted with EtOAc. The combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford crude pyrazin-2-ylmethanol (0.3 g). LC-MS: 99.91%; 111.9 (M++l) (column; X-bridge C-18, (50x3.0 mm, 3.5mu); RT 0.72 min. 0.1% TFA in water: ACN; 0.8 ml/min); TLC: 100% EtOAc (Rf: 0.2).
0.3 g
[0537] Synthesis of pyrazin-2-ylmethanol: [0538] To a stirred solution of methyl pyrazine-2-carboxylate (0.5 g, 3.62 mmol) in H20 (10 mL) was added NaBH4 (685 g, 18.02 mmol) portion wise at 0 C, and the reaction mixture was allowed to warm to RT and stirred for 30 min under inert atmosphere. To this saturated K2C03 (10 mL) and EtOH (5 mL) was added and stirring was continued for another 1 h at RT. The progress of the reaction was monitored by TLC; the reaction mixture was extracted with EtOAc. The combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford crude pyrazin-2-ylmethanol (0.3 g). LC-MS: 99.91%; 111.9 (M++l) (column; X-bridge C-18, (50x3.0 mm, 3.5mu); RT 0.72 min. 0.1% TFA in water: ACN; 0.8 ml/min); TLC: 100% EtOAc (Rf: 0.2).
With sodium tetrahydroborate; water; at 15℃; for 16h;
Step 1 - Pyrazin-2-ylmethanol (0522) [00340] To a solution of methyl pyrazine-2-carboxylate (15.0 g, 108 mmol) in water (250 mL) was added sodium borohydride (20.5 g, 543 mmol) in one portion and the reaction mixture was stirred vigorously at 15 C for 16 hrs. On completion, methanol (100 mL) was added dropwise into the reaction mixture. After stirring at 15 C for 0.5 hr, the mixture was concentrated in vacuo to remove methanol and the aqueous phase was extracted with dichloromethane (6 x 80 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.
With sodium tetrahydroborate; In methanol; at 20℃;
A stirred solution of methyl 2-pyrazinecarboxylate(4.94 g, 35.8 mmol) in methanol (350 mL)was slowly added sodium borohydride (5.410 g, 143 mmol)in 1 g portions over 10 min. Caution: The solution becameyellow and evolved heat and gas, add the sodium borohydridecautiously. The solution was stirred overnightat room temperature. H2O (20 mL) was added and thereaction was shaken vigorously. The suspension was thenevaporated to dryness under reduced pressure to an oilyyellow powder. Ethyl acetate (350 mL) was then added andthe resulting suspension was stirred vigorously overnight.The suspension was filtered and evaporated to drynessunder vacuum to give the crude product as a yellow oilwhich was used without further purification (2.80 g, ca.71%). 1H NMR (300 MHz, CDCl3): delta (ppm) 8.64 (br, 1H, H-3),8.53 (m, 1H, H-2), 8.50 (m, 1H, H-1), 4.84 (s, 2H, CH2).
Method 54; Pvrazine-2-carboxaldehyde oxime A IN solution of lithium aluminium hydride in THF (73. 8ml, 73.8mmol) was added to a suspension of methyl pyrazine-2-carboxylate (20g, 145mmol) in anhydrous THF (300. 0ml) at-78°C keeping the reaction temperature below-72°C. On completion of addition the reaction mixture was left to stir at-78°C for a further 20 minutes and then quenched with glacial acetic acid (20. 0ml). The resulting mixture was warmed to room temperature and the volatiles removed by evaporation. The residue was dissolved in 3N hydrochloric acid (116ml) and extracted with DCM. The extracts were combined, washed with saturated aqueous sodium hydrogen carbonate solution and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with DCM/diethylether (100: 0 then 80: 20 and then 0: 100) to give pyrazine-2-carboxaldehyde (15.67g, 100percent). This was immediately dissolved in chloroform (200ml) cooled to 0°C and hydroxylamine mono-hydrochloride (11. 02g, 159. 5mmol) and triethylamine (24. 2ml, 117. 4mmol) were added. The reaction mixture was then stirred at ambient temperature for 0.5 hour, and the solvent removed by evaporation. The residue suspended in diethylether (500ml) and the insolubles removed by filtration. The filtrate was evaporated and the residue purified by chromatography eluting with DCM/diethylether (100: 0 then 80: 20 and then 0: 100) to give the title compound (5. 5g, 31percent) as a solid. NMR (DMSO-d6) : 8.15 (s, 1H), 8.62 (dd, 2H), 8. 99 (s, 1H).
With lithium aluminium tetrahydride; In tetrahydrofuran; at -78℃; for 1h;Inert atmosphere;
A solution of the product of Example 83A (6.91 g, 50 mmol) in THF (Aldrich, anhydrous, 150 mL) was cooled down to -78° C. and a solution of LiAlH4 (Aldrich, 1.898 g, 50.0 mmol) in THF (50 mL) was added slowly via an additional funnel. The mixture was stirred at -78° C. under N2 for 1 hour, and then it was then carefully and slowly quenched with HOAc (Aldrich, 10 mL) at -70° C. The mixture was slowly warmed up to ambient temperature and stirred for 10 hours. After being concentrated, the residue was stirred with HCl (2N, 15 mL) in CH2Cl2 (300 mL) for 20 minutes and then filtered through diatomaceous earth to remove solid inorganic salt. The organic filtrate solution was concentrated and the residue was dissolved in EtOAc (100 mL) and filtered through diatomaceous earth again. The organic filtrate solution was concentrated to give the titled compound. 1H NMR (300 MHz, DMSO-d6) delta 8.91 (dd, 1H), 8.94 (d, 1H), 9.12 (d, J=1.6 Hz, 1H), 10.08 (s, 1H) ppm; MS (DCI/NH3) m/z 109 (M+H)+.
With lithium aluminium tetrahydride; In tetrahydrofuran; at -70℃; for 0.666667h;
LiAlH4 (4g, 100 mMol) was slowly added to a solution of pyrazinecarboxylic acid methyl ester (12. 8g, 100 mMol) in tetrahydrofuran (400 mL) at-70° C. The mixture was stirred at this temperature for 40 min, followed by neutralisation with 20 mL of glacial acetic acid. The solvent was evaporated in vacuo and the residue was partitioned between 30 mL of 2N HCL and dichloromethane. A large amount of brown solid precipitated which was filtered off. The dichloromethane layer was passed through a pad of silica, the solvent was evaporated to give the pyrazine 2-carboxaldehyde (1.4g) as a yellow oil.
[Referential Example 184] 1-[(6-Chloronaphthalen-2-yl)sulfonyl]-6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine
[Referential Example 184] 1-[(6-Chloronaphthalen-2-yl)sulfonyl]-6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine At room temperature, 2-methoxycarbonylpyrazine (1.00 g) was dissolved in methanol. The resulting solution was subjected to catalytic reduction by the addition of 10% palladium-carbon (100 mg) for 2 hours under normal pressure. After the removal of the catalyst by filtration, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (5% methanol-dichloromethane), whereby 6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine(880 mg, 86%) was obtained as a yellow oil.
Stage #1: acetone oxime With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 0.5h;
Stage #2: methyl pyrazine-2-carboxylate In tetrahydrofuran; hexane at 20℃; for 1h;
Stage #3: With sulfuric acid In tetrahydrofuran; hexane at 0 - 20℃; for 1h;
With potassium carbonate In N,N-dimethyl-formamide for 72h;
19.1
Example 19.1Pyrazine-2-carboxylic acid methyl ester To pyrazine-2-carboxylic acid (15.0 g, 121 mmol) in DMF (150 mL) were added K2CO3 (50 g, 363 mmol) and MeI (9.0 mL, 145 mmol). After stirring for 3 days, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30% ethyl acetate in hexanes gave the title product (1.28 g, 8%).1H NMR (300 MHz, CDCl3): δ (ppm) 9.35 (s, 1H), 8.80 (s, 1H), 8.75 (s, 1H), 4.07 (s, 3H).
ethyl 8-methoxy-2-methyl-1-oxo-6-(pyrazin-2-ylcarbonyl)-1,2,3,4-tetrahydropyffolo[1,2-a]-pyrazine-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: ethyl 6-bromo-8-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h;
Stage #2: methyl pyrazine-2-carboxylate In tetrahydrofuran; hexane at 20℃;
183.1
To a cold (-78 °C) solution of ethyl 6-bromo-8-methoxy-2-methyl-1-oxo-1,2,3,4- tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (0.5 g, 1.51 mmol; Example 7, steps 1 to 6, substituting benzyl bromide with iodomethane in step 5) in anhydrous THF (15 mL) under an atmosphere of dry nitrogen, a solution of n-BuLi in hexane (1.81 mL, 1.81 mmol, 1 M) was added. The resultant mixture was stirred at-78 °C for 15 minutes, and treated with methyl pyrazine-2-carboxylate (0.21 g, 1.51 mmol). The reaction mixture was allowed to warm up to room temperature, treated with dilute hydrochloric acid, and concentrated under vacuum. The residue was extracted with ethyl acetate. The organic extracts were combined, washed with aqueous sodium carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 0 to 10% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound. ¹H NMR (400 MHz, CDCI3) No. 9.25 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 2.6 Hz, 1H), 8.57 (d, J = 2.6, 1.5 Hz, 1H), 4.43 (m, 2H), 4.07 (s, 3H), 3.81 (q, J = 7.1 Hz, 1H), 3.67 (m, 2H), 3.15 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). ES MS M+l = 359
Synthesis of methyl pyrazine-2-carboxylate: To a stirred solution of pyrazine-2-carboxylic acid (5 g, 40.29 mmol) in MeOH (20 mL) was added concentrated H2S04 (1 mL) drop wise and stirred under reflux for 5 h. The reaction mixture was cooled to RT; volatiles were evaporated under reduced pressure. The residue was diluted with water and basified to pH~ 8.5 using NaHC03 and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to afford methyl pyrazine-2-carboxylate (3.5 g, 63.63%) as an off- white solid. 1H-NMR (DMSO d6, 400 MHz): delta 9.21 (s, 1H), 8.91 (d, 1H), 8.82 (d, 1H), 3.92 (s, 3H); TLC: 50% EtOAc/Hexane (Rf: 0.4).
With thionyl chloride; sodium bicarbonate; In methanol; di-isopropyl ether; water;
EXAMPLE 1 Methyl pyrazinecarboxylate 106.6 g of thionyl chloride was added dropwise over 1 hour at 4 to 6 C. to 1200 ml of methanol under argon. 100.1 g of pyrazinecarboxylic acid was added at 9 C. and the mixture was heated for 2 hours at 61 C., with the acid passing completely into solution. After cooling to room temperature, a solution of 145 g of sodium hydrogen carbonate in 1.4 l of water was added slowly. The methanol was distilled off on a rotary evaporator at 50 to 120 mbar and a bath temperature of 45 C., and the residue was extracted three times with dichloromethane (400 ml, 100 ml, 100 ml). Concentration of the organic phase provided 83.15 g of crude product, which was recrystallized from ca. 250 g of diisopropyl ether. The yield of the title compound was 70.6 g, plus 10.28 g from the mother liquor (total: 72.5 percent). Other data concerning the title compound was: 1 H NMR (CDCl3, 400 MHz): delta 4.08 (s, 3H); 8.75 (d, J=0.5 Hz, 1H); 8.80 (d, J=0.5 Hz, 1H); 9.30 (s, 1H).
With sulfuric acid; sodium hydrogencarbonate; In methanol; toluene;
Step 1 (esterification of pyrazine-2-carboxylic acid to yield methyl-pyrazine-2-carboxylate): To a 1L single-neck round-bottomed flask fitted with condenser and drying tube filled with silica gel was charged methanol (400 mL) with agitation at room temperature. Pyrazine-2-carboxylic acid (50.00 g, 402.90 mmol) was charged to the flask in one portion and the resulting slurry was vigorously stirred. Conc. sulfuric acid (0.25 mL) was charged to the slurry. The slurry was heated to reflux temperature and stirred at this temperature for 2 days. The resulting pale yellow solution was allowed to cool to room temperature. This process takes 90 minutes. Solid sodium bicarbonate (4.00 g, 47.62 mmol) was added to the solution in one portion and the slurry was stirred vigorously for 30 minutes. The suspension was filtered and the filtrate was transferred to a 2L single-neck round-bottomed flask and concentrated to about half volume in vacuo a 35 C. Toluene (1200 mL) was added to the methanol solution and a Dean-Stark trap fitted with drying tube was attached. The solution was heated at atmospheric pressure (external oil bath a120 C.) and the first 300 mL solvent fraction was run off and discarded. The Dean-Stark trap was removed and the reaction solution was concentrated in vacuo a45 C. to a volume of 300 mL. The organic phase containing the desired methyl-pyrazine-2-carboxylate was filtered to remove solid particulates and used directly in the next step as a solution in toluene (a small analytical sample was removed and concentrated in vacuo a 35 C. to yield a pale brown solid, m.p. 60-61 C., structure confirmed by 1H NMR and 13C NMR).
With sodium methylate In water; toluene at 110℃; for 3h;
12A.1
A mixture of 25% (wt) solution of NaOCH3 in CH3OH (10.4 ml, 0.051 mol) and toluene (36 ml) was heated at 110° C. while a solution of 2-methoxycarbonylpyrazine (4 g, 0.0289 mol) in EtOAc (45 ml) was added dropwise. The mixture was heated for an additional 3 h and then cooled to rt. The solid precipitate was collected by filtration. The solid was dissolved in NH4Cl (sat) and the mixture extracted with EtOAc. The organic extracts were dried and concentrated under vacuum to give 4.3 g of the title compounds which were used without purification.
With hydrogenchloride; CH3ONa; In methanol; water; ethyl acetate; acetonitrile;
EXAMPLE 4 Production of N-[3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-5-yl]pyrazine-2-carboxamide Into a mixture of 0.5 g (1.6 mmol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-3-carbonitrile, 0.24 g (1.7 mmol) of methyl pyrazinecarboxylate, and 0.5 ml of acetonitrile was gradually added 0.3 g (1.6 mmol) of 28% CH3ONa/CH3OH at room temperature. After 2 hours of stirring at room temperature, 5 ml of water and then concentrated hydrochloric acid were added thereto to make the mixture pH 2, whereby crystals were precipitated. Thereto was added 10 ml of ethyl acetate, followed by extraction. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the layer was concentrated and the resulting crystals were filtrated. The crystals were washed with a small amount of hexane and ethyl acetate and the dried to obtain 0.5 g (yield 77%) of N-[3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole-5-yl]pyrazine-2-carboxamide.
1 Exemplary Synthesis of n-Butyl Pyrazinamde
Exemplary Synthesis of n-Butyl Pyrazinamde Synthesis of n-butylpyrazinamide is performed as described by Kushner et al. (1952, J Amer. Chem. Soc. 74: 3617-3621). Briefly, to a 50 mL round bottomed flask containing a magnetic stirbar, was added 5.0 g (36.2 mmol) methyl pyrazinoate and 25 mL of anhydrous ethanol, under an inert atmosphere of argon. Anhydrous n-butyl amine (7.71 g, 108.6 mmol) was added dropwise over 30 min. The mixture was stirred and warmed to room temperature for 24 hr, which was sufficient time for the reaction to go to completion as determined by thin-layer chromatography. The solvent and excess n-butyl amine were removed under high vacuum, leaving 5.83 g (32.5 mmol) of n-butyl pyrazinamde as a viscous syrup. This material was recrystallized to yield 4.53 g of n-butyl pyrazinamde as white crystals.
In ethanol
Exemplary Synthesis of n-Buteyl Pyrazinamde
Exemplary Synthesis of n-Buteyl Pyrazinamde Synthesis of n-butylpyrazinamide is performed as described by Kushner et al. (1952, J. Amer. Chem. Soc. 74: 3617-3621). Briefly, to a 50 mL round bottomed flask containing a magnetic stirbar, was added 5.0 g (36.2 mmol) methyl pyrazinoate and 25 mL of anhydrous ethanol, under an inert atmosphere of argon. Anhydrous n-butyl amine (7.71 g, 108.6 mmol) was added dropwise over 30 min. The mixture was stirred and warmed to room temperature for 24 hr, which was sufficient time for the reaction to go to completion as determined by thin-layer chromatography. The solvent and excess n-butyl amine were removed under high vacuum, leaving 5.83 g (32.5 mmol) of n-butyl pyrazinamde as a viscous syrup. This material was recrystallized to yield 4.53 g of n-butyl pyrazinamde as white crystals.
Preparation of 2-Methoxycarbonyltetrahydropyrazine XXV
Preparation of 2-Methoxycarbonyltetrahydropyrazine XXV 5 g of pyrazine carboxylic acid methyl ester (36.2 mmol, from Lancaster, Inc.) was dissolved in 200 ml of 95% ethanol with 500mg 10% palladium on active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered and removed. The filtrate was concentrated to afford methoxycarbonyltetrahydropyrazine XXV, which was sufficiently pure enough for subsequent reactions. 2-Methoxycarbonyltetrahydropyrazine XXV: 1H NMR (300 MHz, CD3OD) δ 7.10(s, 1H), 4.84 (b, 2H), 3.66 (s, 3H), 3.29 (t, J=6.0 Hz, 2H), 3.08 (t, J=6.0 Hz, 2H); 13C NMR (75 MHz, CD3OD) δ 166.1, 130.8, 105.4, 48.4, 40.6, 40.0; MS m/z: (M+H)+calcd for C6H11N2O2: 143.08, found 143.09. HPLC retention time 0.11 (Method C).
1.c c
c Methyl 2-pyrazine carboxylate Acetyl chloride (50 ml) was added very slowly to methanol (500 ml), and the mixture was allowed to cool before pyrazine-2-carboxylic acid (15 g, 124 mmol) in methanol (15 ml) was added. The reaction mixture was left to stand at room temperature overnight. The methanol was removed in vacuo to give the required product (22 g). 1H NMR (250 MHz, DMSO) δ 3.95 (3H, s), 8.82 (1H, m), 8.90 (1H, d, J=2.5 Hz), 9.21 (1H, d, J=2.5 Hz); MS (ES+) m/e 153 [MH+].
bicyclo[2.2.1]hepta-2,5-dienerhodium(I) chloride dimer[ No CAS ]
1-[1(R)-(di-tert-butylphosphino)ethyl]-2(S)- (diphenylphosphino)ferrocene[ No CAS ]
[ 198992-49-3 ]
Yield
Reaction Conditions
Operation in experiment
In methanol
9 Methyl (S)-piperazine-2-carboxylate
EXAMPLE 9 Methyl (S)-piperazine-2-carboxylate Analogously to Example 4, 0.52 g (3.5 mmol) of methyl pyrazinecarboxylate (prepared according to Example 1), 33.6 mg (72.8 μmol) of bicyclo[2.2.1]hepta-2,5-dienerhodium(I) chloride dimer and 92.9 mg (171 μmol) of 1-[1(R)-(di-tert-butylphosphino)ethyl]-2(S)-(diphenylphosphino)ferrocene were hydrogenated for 20 hours in 10 ml of methanol at 70° C. and 50 bar. A conversion of 85 percent was determined by NMR. The ee value was determined by hydrolyzing the ester according to Example 8. The ee value was 3.6 percent.
XII Example XII
Example XII A mixture of 55.2 parts of methyl 2-pyrazinecarboxylate, 48.9 parts of 2-aminoethanol and 360 parts of ethyl acetate was allowed to stand overnight at room temperature. The precipitated product was filtered off, washed with ethyl acetate and dried, yielding 54.5 parts (80%) of N-(2-hydroxyethyl)-2-pyrazinecarboxamide; mp. 125° C. (intermediate 22).
27 Preparation of 1-Cyclopropyl-3-(2-pyrazinyl)-1,3-propanedione
EXAMPLE 27 Preparation of 1-Cyclopropyl-3-(2-pyrazinyl)-1,3-propanedione A stirred mixture of 14.0 g. of methyl pyrazinoate, 16.8 g. of cyclopropylmethyl ketone, 6.0 g. of sodium methoxide and 200 ml. of benzene is heated under reflux for 5 hours. A 400 ml. volume of water is added to the mixture. The benzene phase is separated and the aqueous solution is made weakly acidic with dilute hydrochloric acid. A yellow solid precipitates, which is collected and recrystallized from hexane to give white crystals, m.p. 111°-112°C.
With sodium methylate In water; benzene
22 Preparation of 1-cyclopropyl-3-(2-pyrazinyl)-1,3-propanedione
EXAMPLE 22 Preparation of 1-cyclopropyl-3-(2-pyrazinyl)-1,3-propanedione A stirred mixture of 14.0 g. of methyl pyrazinoate, 16.8 g. of cyclopropylmethyl ketone, 6.0 g. of sodium methoxide and 200 ml. of benzene is heated under reflux for 5 hours. A 400 ml. volume of water is added to the mixture. The benzene phase is separated and the aqueous solution is made weakly acidic with dilute hydrochloric acid. A yellow solid precipitates, which is collected and recrystallized from hexane to give white crystals, m.p. 111°-112° C.
8 Preparation of 2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)pyrazine
EXAMPLE 8 Preparation of 2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)pyrazine To a mixture of 2.8 g. of cyclopropanecarboxamidoxime hydrochloride and 2.8 g. of methyl pyrazinoate in 50 ml. of toluene is added 2.2 g. of sodium methoxide. The mixture is heated under reflux for 30 minutes and then poured into 100 ml. of water. The toluene phase is separated and the aqueous phase is extracted with chloroform. The combined organic solutions are dried over magnesium sulfate and concentrated under reduced pressure to give a solid. This solid is recrystallized from cyclohexane to give cream-colored crystals, melting point 66°-68°C. The compound forms a slightly water soluble phosphate salt, when treated with phsophoric acid.
PREPARATION K Pyrazine-2-carboxaldehyde Pyrazine-2-carboxylic acid was esterified with methanolic sulfuric acid at reflux for five hours. The methanol was evaporated in vacuo , diluted with methylene chloride and neutralized with sodium bicarbonate (pH 7.5). The dried organic layer was concentrated to afford methyl pyrazine-2-carboxylate as an off-white solid in 84percent yield which was recrystallized from isopropanol, ethyl ether to give yellow needles. 1H-NMR(CDCl3)ppm (delta): 4.1 (s, 3H), 8.93 (m, 2H), 9.47 (m, 1H).
84%
PREPARATION K Pyrazine-2-carboxaldehyde Pyrazine-2-carboxylic acid was esterified with methanolic sulfuric acid at reflux for five hours. The methanol was evaporated in vacuo, diluted with methylene chloride and neutralized with sodium bicarbonate (pH 7.5). The dried organic layer was concentrated to afford methyl pyrazine-2-carboxylate as an off-white solid in 84percent yield which was recrystallized from isopropanol, ethyl ether to give yellow needles. 1 H--NMR(CDCl3)ppm (delta): 4.1 (s, 3H), 8.93 (m, 2H), 9.47 (m, 1H).
40
[ 6164-79-0 ]
[ 144-55-8 ]
[ 87-69-4 ]
[ 6705-33-5 ]
Yield
Reaction Conditions
Operation in experiment
With diisobutylaluminium hydride; In tetrahydrofuran; dichloromethane;
a 2-Hydroxymethylpyrazine To methyl 2-pyrazinecarboxylate (1.80 g) in THF (60 ml) was added diisobutylaluminium hydride (1 M solution in THF; 39 ml) at -78 C. with stirring. The solution was allowed to warm to room temperature, and stirred for 24 h. The reaction was quenched with solid tartaric acid, then aqueous sodium potassium tartrate, and stirred for 30 min at room temperature. Saturated aqueous sodium hydrogen carbonate was added until the pH of the solution was >7. The solution was washed with ethyl acetate (3*200 ml), and the organic layers combined, washed with saturated sodium chloride solution (1*200 ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, eluent =5% methanol in dichloromethane) to yield 2-hydroxymethylpyrazine as a dark brown oil (0.16 g). 1H NMR (250 MHz, CDCs) delta3.42 (1 H, br s), 4.85 (2 H, s), 8.55 (2 H, m), 8.68 (1 H, s); MS (ES+) m/e 111 [MH+].
Procedure: · Charged ST-601 (1 kg), NaH, 60 wt.% (579 g) and toluene (10 vol) and stirred at 15/25 C. No reaction (no gas evolution, exotherm or appearance change). (0157) ? Charged methyl propionate (64 g). No immediate reaction (no gas evolution, exotherm or appearance change) at 15/25 C. ? Charged MeOH (85 g) at 15/25 C. Immediately started to react (gas evolution, exotherm). Heated to 30/40 C. (0158) ? Charged methyl propionate (893 g) at 30/40 C over 5 h. The reaction was slower in the beginning, but became faster (more exotherm and gas evolution) after 1-2 h when -0.3 eq of methyl propionate was charged. Stirred at 30/40 C for 88 h. (0159) 64 h, 30/35 C, brown slurry, practically no gas evolution observed, IPC HPLCl: 74.4% + 14.1 % = 88.5% o/ ST-602 at 4.81 min and 5.62 min; 1.2% of ST -601 at 1.97 min; 5.8% of "Int" at 3.21 min. (0160) 72 h, 35 C, IPC HPLC2: 47.8% + 42.9%c=90 % o/ST-602; 0.9% ofST-601; 4.3% of "Int" 88 h, 38 C, IPC HPLC3: 60.3% + 32.6%=92.9% o/ST-602; 0.64% ofST-601; 1.8% of "Int" (0161) ? Reaction was cooled to 15/20 C. (0162) ? Charged AcOH (2.5 eq) over a minimum of 1 hr. Exothermic. Slightly thick, brown suspension. (0163) ? Charged 10% NaCl solution (8 vol) over a minimum of 1 h at 15/30 C. Slight exotherm. Brown, biphasic solution. Let stir at 15/30 C for a minimum of 30 min to dissolve all solids. (0164) ? The phases were separated. Both the aqueous and the organic phases were brown. (0165) ? The organic phase was washed with a 10% NaCl solution (5 vol). (0166) ? The organic phase was washed with NaHC03 (0.1 g/g SM) in 10% aq. NaCl solution (5 vol.) (0167) ? The organic phase was dried over anhydrous sodium sulfate (0.2 g/g SM) for a minimum of 2 hrs. (0168) ? Solids were filtered off and rinsed with Toluene (l x l vol) (0169) ? Concentrated to 3-4 vol at (0170) Isolated material: ST- 602 (0171) Lot No.: 2463-52-2 (0172) Appearance: light brown liquid (0173) Yield: Assumed 100% (1406 g net directly used in next step) HPLC: 94.3% of ST-602
89.0%
Example 2; Methyl 2-methyl-3-(pyrazin-2-yl)-3-oxopropionate (formula 4). 1.2 L of tetrahydrofuran and 87.8 g (0.78 mole) of potassium t-butoxide were added to a reactor and cooled to 0C. 71.5 mL (0.74 mol) of methyl propionate was dropwise added to the reactor and stirred at 0C for 30 minutes. 60 g (0.434 mole) of the <strong>[6164-79-0]methyl pyrazine-2-carboxylate</strong> of Example 1 dissolved in 500 mL of tetrahydrofuran was dropwise added to the reactor for 30 minutes and stirred at a temperature of 20 to 25 C for 3 hours. 0.5 L of distilled water and 0.5 L of saturated ammonium chloride solution were added to the reaction solution and stirred for 30 minutes. The resultant reaction solution was concentrated to a volume of 1.0 L and then extracted with 1.0 L of methylenechloride. The resultant extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give 75.0 g of the titled compound as a dark brown viscous oil (yield 89.0%). NMR (S, CDCl3) : 1.50 (d, 3H), 3.65 (s, 3H), 4.70 (q, 1H), 8.60 (d, 1 H), 8.80 (d, 1 H), 9.21 (s, 1 H)
79%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;Inert atmosphere;
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),<strong>[6164-79-0]methyl pyrazine-2-carboxylate</strong> (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
With NaH; ammonium chloride; In toluene;
To a 2L 3-neck round-bottomed flask under a nitrogen atmosphere was charged NaH (22.11 g, 552.77 mmol) (60% dispersion in oil). Toluene (250 mL) was charged to the flask and the resulting slurry was stirred for 15 minutes at 20 C. The slurry was allowed to settle and the toluene removed by decantation. Additional toluene (250 mL) was added and the slurry was stirred for at 20 C. Methyl propionate (53.23 mL, 552.77 mmol) suspended in anhydrous toluene (250 mL) was added dropwise over 30 minutes. The resulting slurry was then heated to reflux temperature (external oil bath a140 C.). To the refluxing suspension was charged <strong>[6164-79-0]methyl pyrazine-2-carboxylate</strong> (54.72 g, 394.83 mmol) in anhydrous toluene (300 mL) (from step 1 of the process) dropwise over a period of 45 minutes. The reaction contents were heated at reflux temperature for 2.5 hours. The resultant dark brown slurry was allowed to cool to 20 C. Saturated ammonium chloride solution (500 mL) was charged to the slurry in one portion and the biphasic solution was vigorously stirred for 120 minutes, then agitation was stopped and the phases were allowed to separate. The dark brown-coloured lower aqueous phase (approx. 500 mL) was removed and the remaining yellow/orange-coloured upper organic phase (approx. 900 mL) was retained and combined with toluene extracts (2*175 mL) of the aqueous phase. The organic phase was filtered to remove solid particulates and concentrated in vacuo a45 C. to a volume of 400 mL to yield the desired methyl-2-methyl-3-(pyrazin-2-yl)-3-oxopropionate, which was used directly in the next reaction step. A small analytical sample was concentrated in vacuo a35 C. to yield a viscous oil. Structure was confirmed by 1H NMR and 13C NMR.
Stage #1: methyl pyrazine-2-carboxylate; (trifluoromethyl)trimethylsilane With cesium fluoride In 1,2-dimethoxyethane at 20℃; for 18h;
Stage #2: With tetrabutyl ammonium fluoride; acetic acid In tetrahydrofuran at 20℃; for 3h;
12
EXAMPLE 12; Preparation of a Compound of Formula (18) Preparation of 2,2,2-trifluoro- 1 -(p yrazin-2- vDethanone<18); [0141] Pyrazine carboxylate methyl ester (7 g) was dissolved in dimethoxy ethane (monoglyme) (2OmL) and treated at room temperature with trimethylsilyltrifluoro-methane (1OmL; 1.44eq) and caesium fluoride (0.77 g; O.leq) that had been freshly dried at for 10 minutes under vacuum while being heated with a heat gun. After 18 hours at room temperature the reaction mixture was concentrated under reduced pressure at room temperature, and the residue was dissolved in tetrahydrofuran (5OmL) and acetic acid (2OmL) and treated with tert-butylammonium fluoride (5OmL; IM THF solution) for 3 hours at room temperature. The reaction was diluted with ethyl acetate, and washed with dilute aqueous sodium bicarbonate solution (3 times), brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to an oil. Trituration of the oil with dichloromethane/hexane gave 2,2,2-trifluoro-l-(pyrazin-2-yl)ethanone (18) as a brown solid (2.9 g).
Stage #1: methyl pyrazine-2-carboxylate; Ethyl 2-phenylethanoate With sodium ethanolate In tetrahydrofuran; ethanol Reflux;
Stage #2: With sulfuric acid; water
With 3-chloro-benzenecarboperoxoic acid; In 1,2-dichloro-ethane; at 60℃; for 16h;
Example 1D; Methyl 4-oxy-2-pyrazinecarboxylate; <strong>[6164-79-0]Methyl 2-pyrazinecarboxylate</strong> (Pyrazine Specialists, 10.04 g, 72.2 mmol) was suspended in 1,2-dichloroethane (100 mL). To the reaction mixture was added mCPBA (32.35 g, 77%, 144 mmol). The reaction was stirred at 60 C. for 16 h. The reaction was then allowed to cool to ambient temperature and diluted with CH2Cl2 (300 mL). The precipitate was filtered off and washed with additional CH2Cl2 (3×35 mL). The filtrates were combined, dried over K2CO3, filtered and concentrated under vacuum. The residue was suspended in hexane (50 mL). The title compound was isolated by filtration, washed with additional hexane (2×50 mL) to afford a slightly yellow solid (7.22 g, 64%). 1H NMR (DMSO-d6, 300 MHz) delta ppm 3.91 (s, 3H), 8.54 (dd, J=4.07, 1.69 Hz, 1H), 8.64-8.67 (m, 2H). MS (DCI/NH3) m/z 155 (M+H)+.
Thionyl chloride (0.146 L, 1998 mmol) was added to methanol (1.5 L) dropwise at -5 ° to 0 0C over a period of 1 hour and was stirred at this temperature for 30 minutes. The solution was allowed to warm to room temperature whereupon 2-pyrazine carboxylic acid (62 g, 500 mmol) was added. The mixture was cautiously heated at reflux for 6 h and allowed to cool to room temperature overnight. LCMS indicated that the reaction was complete. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (500 mL) and saturated sodium bicarbonate solution (500 mL). The aqueous phase was extracted with ethyl acetate (3 x 500 mL), the combined organic extracts were washed with water (250 mL), brine (250 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid. The solid was recrystalised from -500 ml of 1 :1 pentane:cyclohexane, decanting the hot solution twice off a dark viscous oil. Care was taken to minimise the amount of product oiling out upon cooling affording as cream needles. The mothor liquors were concentrated in vacuo and the residue recrystalised from the same solvent (-200 mL) affording a second crop, as buff needles. Analysis by LCMS and NMR indicates that both materials are consistant with desired product and of comaparable purity.Both batches were combined to afford product in 42.8 g as beige needles.LC/MS = 139 (M+H)+, retention time = 0.40 minutes (2 minute method).
1.45
This solid was taken into 200 mL of saturated ammonium chloride and 400 mL of EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 6.52 g (50%) of methyl 3-oxo-3-(pyrazin-2-yl)propanoate as a yellow solid.
Multi-step reaction with 3 steps
1.1: acetic acid methyl ester; toluene / 110 °C
2.1: ethanol / 10 h / Reflux
3.1: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C
3.2: 1.5 h / 20 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / toluene; methanol / 3 h / 110 °C
2.1: acetic acid / ethanol / 10 h / Reflux
3.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 - 20 °C
3.2: 1.5 h / 20 °C
Multi-step reaction with 3 steps
1.1: sodium methylate; methanol / toluene / 3 h / 110 °C
2.1: ethanol / 0.17 h
2.2: 10 h / Reflux
3.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 1 h / 0 - 20 °C
3.2: 1.5 h / 20 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / methanol; toluene; acetic acid methyl ester / 110 °C
2.1: ethanol / 10 h / Reflux
3.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 1 h / 0 - 20 °C
3.2: 1.5 h / 20 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / methanol; toluene / 100 °C
2.1: ethanol / 10 h / Reflux
3.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 1 h / 0 - 20 °C
3.2: 1.5 h / 20 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / methanol; toluene / 110 °C
2.1: ethanol / 0.17 h
2.2: 10 h / Reflux
3.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 - 20 °C
3.2: 1.5 h / 20 °C
Stage #1: acetonitrile With potassium <i>tert</i>-butylate In tetrahydrofuran at 60℃; for 0.0833333h;
Stage #2: methyl pyrazine-2-carboxylate In tetrahydrofuran at 60℃; for 0.5h;
Stage #3: With hydrogenchloride; hydrazinecarboxylic acid methyl ester In ethanol; water for 14h; Cooling with ice;
90.1
To a solution of 18-crown-6 (0.57 g, 2.2 mM) in tetrahydrofuran (10 mL), there was added a 1.0M potassium tert-butoxide/tetrahydrofuran solution (24 mL, 24 mM) and then the mixture was heated up to 60° C. Acetonitrile (1.3 mL, 24 mM) was then added to the mixture at that temperature, followed by the stirring of the same for 5 minutes and the subsequent addition of 2-methoxycarbonyl-pyrazine (3 g, 22 mM). After stirring the mixture at 60° C. for 30 minutes, it was cooled to room temperature, the precipitated solid was recovered through filtration and washed with tetrahydrofuran. The resulting solid was dried in vacio, suspended in ethanol (60 mL) and then methyl carbazinate (2.7 g, 30 mM) was added thereto. Concentrated hydrochloric acid (2.2 mL) was added to the suspension with ice-cooling and the mixture was stirred for 14 hours at that temperature. There were added, to the mixture, potassium carbonate (2.4 g, 17 mM) and water (10 mL) and the mixture was stirred at 90° C. for one hour. After cooling the mixture to room temperature, it was concentrated under reduced pressure and then water was added thereto. The mixture was extracted with ethyl acetate, the organic phase thus obtained was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to thus give a crude product of the title compound (627 mg, yield: 18%). MS (ESI) m/z (M+H)+ 162
methyl 7,7-dimethyl-6-oxo-1,4-bis(trifluoromethanesulfonyl)-1,4,4a,6,7,7a-hexahydrofuro[2,3-b]pyrazine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: methyl pyrazine-2-carboxylate; trifluoromethylsulfonic anhydride In dichloromethane at -30℃; Inert atmosphere;
Stage #2: 1,1-bis(trimethylsiloxy)-2-methylprop-1-ene In dichloromethane at -30 - 20℃; for 12h; Inert atmosphere;
Stage #1: methyl pyrazine-2-carboxylate; trifluoromethylsulfonic anhydride In dichloromethane at -30℃; Inert atmosphere;
Stage #2: (Bis-trimethylsilanyloxy-methylene)-cyclohexane In dichloromethane at -30 - 20℃; for 12h; Inert atmosphere;
sodium 2-cyano-1-(pyrazin-2-yl)ethenolate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydride In tetrahydrofuran; mineral oil for 20h; Reflux;
59A.1 Step 1: Sodium 2-cyano-1-(pyrazin-2-yl)ethenolate
Step 1: Sodium 2-cyano-1-(pyrazin-2-yl)ethenolate A solution of 1.5 g (10.9 mmol) of methylpyrazine-2-carboxylate and 446 mg (10.9 mmol) of acetonitrile in 16.5 ml of THF was added dropwise to a suspension, heated under reflux, of 434 mg of sodium hydride (60% strength suspension in mineral oil) in 10 ml of THF. The reaction mixture was heated under reflux for 20 h. After cooling, 50 ml of methyl tert-butyl ether were added and the mixture was stirred for 30 minutes. The precipitate formed was filtered off with suction over a frit and dried under oil pump vacuum. This gave 1.77 g (96% of theory) of the title compound which was used without further characterization for the next step.
Stage #1: methyl pyrazine-2-carboxylate 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 = 80 %;
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.
Stage #1: methyl pyrazine-2-carboxylate; 4-methoxyphenylboronic acid With ferrous(II) sulfate heptahydrate; dipotassium peroxodisulfate In water; chlorobenzene at 20℃; for 2h;
Stage #2: With sodium hydroxide In water
With sodium hydride In 1,4-dioxane; mineral oil for 2.5h; Reflux;
Intermediate P132
Intermediate P1321007301 Step A: Preparation of 3-oxo-3-(pyrazin-2-yl)propanenitrile: To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) in dioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol), followed by methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reaction heated to reflux for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with 1120 (25 mL) and extracted with Et20 (25 mE). The aqueous phase was neutralized with 2M aqueous HC1 (0.7 mL), then extracted with 10% MeOHJDCM (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgSO4, filtered, and concentrated to yield the crude product as an orange syrup (134 mg, 62.9% yield). ‘H NMR (CDC13) ö 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd, 111), 4.34 (s, 2H).
With sodium hydride In 1,4-dioxane; mineral oil for 2.5h; Reflux;
A [00417] Step A: Preparation of 3-oxo-3-(pyrazin-2-yl)propanenitrile
[00417] Step A: Preparation of 3-oxo-3-(pyrazin-2-yl)propanenitrile: To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) in dioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol), followed by methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reaction heated to reflux for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with H20 (25 mL) and extracted with Et20 (25 mL). The aqueous phase was neutralized with 2M aqueous HC1 (0.7 mL), then extracted with 10% MeOH/DCM (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgS04, filtered, and concentrated to yield the crude product as an orange syrup (134 mg, 62.9% yield). 1H NMR (CDC13) δ 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd, 1H), 4.34 (s, 2H).
With sodium hydride In 1,4-dioxane; mineral oil for 2.5h; Reflux;
A (00601] Step A: Preparation of 3-oxo-3-(pyrazin-2-yl)propanenitrile:
(00601] Step A: Preparation of 3-oxo-3-(pyrazin-2-yl)propanenitrile: To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) in dioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol), followed by methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reaction heated to reflux for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with H20 (25 mE) and extracted with Et20 (25 mL). The aqueous phase was neutralized with 2M aqueous HC1 (0.7 mL), then extracted with 10% MeOHJDCM (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgSO4, filtered, and concentrated to yield the crude product as an orange syrup (134 mg, 62.9% yield). 1 NMR (CDC13) 6 9.32 (d, 1H), 8.87 (d, 111), 8.68 (dd, 1H), 4.34 (s, 2H).
With sodium hydride In 1,4-dioxane; mineral oil for 2.5h; Reflux;
A Step A: Preparation of 3-oxo-3-(pyrazin-2-vDpropanenitrile:
Intermediate P132 l-methyl-3-(pyrazin-2-yl)-lH-pyrazol-5-amine [00532] Step A: Preparation of 3-oxo-3-(pyrazin-2-vDpropanenitrile: To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) in dioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol), followed by methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reaction heated to reflux for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with H20 (25 mL) and extracted with Et20 (25 mL). The aqueous phase was neutralized with 2M aqueous HC1 (0.7 mL), then extracted with 10% MeOH/DCM (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgS04, filtered, and concentrated to yield the crude product as an orange syrup (134 mg, 62.9% yield). NMR (CDC13) δ 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd, 1H), 4.34 (s, 2H).
With sodium hydride In 1,4-dioxane; mineral oil for 2.5h; Reflux;
A Step A: Preparation of 3-oxo-3-(pyrazin-2-yl)propanenitrile:
To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) in dioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol), followed by methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reaction heated to reflux for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with H20 (25 mL) and extracted with Et20 (25 mL). The aqueous phase was neutralized with 2M aqueous HC1 (0.7 mL), then extracted with 10% MeOH/DCM (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgS04, filtered, and concentrated to yield the crude product as an orange syrup (134 mg, 62.9% yield). 1H NMR (CDC13) δ 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd, 1H), 4.34 (s, 2H).
With sodium hydride In 1,4-dioxane; mineral oil for 2.5h; Reflux;
A Step A: Preparation of 3-oxo-3-(pyrazin-2-yl)propanenitrile
To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) in dioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol), followed by methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reaction heated to reflux for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with H20 (25 mL) and extracted with Et20 (25 mL). The aqueous phase was neutralized with 2M aqueous HCl (0.7 mL), then extracted with 10% MeOH/DCM (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with MgS04, filtered, and concentrated to yield the crude product as an orange syrup (134 mg, 62.9% yield). 1H NMR (CDC13) δ 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd, 1H), 4.34 (s, 2H).
With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane at 60℃;
22.1 Step 1: Preparation of 2-(methoxycarbonyl)pyrazine 1-oxide
Step 1: Preparation of 2-(methoxycarbonyl)pyrazine 1-oxide To a solution of methylpyrazine-2-carboxylate (10.0 g, 70 mmol) in 1,2-dichloroethane (120 mL) was added 3-chloroperoxybenzoic acid (25.0 g, 140 mmol). The reaction mixture was stirred at 60° C. overnight. The resulting mixture was cooled to r.t. and filtered. The filtrate was dried over anhydrous K2CO3 and concentrated under reduced pressure. The residue was triturated with hexane and filtered and dried to afford 2-(methoxycarbonyl)pyrazine 1-oxide. LC-MS: m/z 155.0 (M+H)+.
With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane at 60℃;
22.1 Step 1: Preparation of 2-(methoxycarbonyl)pyrazine 1-oxide.
Step 1: Preparation of 2-(methoxycarbonyl)pyrazine 1-oxide. To a solution of methyl pyrazine2-carboxylate (10.0 g, 70 mmol) in 1,2-dichloroethane (120 mL) was added 3- chloroperoxybenzoic acid (25.0 g, 140 mmol). The reaction mixture was stirred at 60°C overnight. The resulting mixture was cooled to r.t. and filtered. The filtrate was dried over anhydrous K2CO3and concentrated under reduced pressure. The residue was triturated with hexane and filtered and dried to afford 2-(methoxycarbonyl)pyrazine 1-oxide.LC-MS: m/z 155.0 (M+H).
Stage #1: methyl pyrazine-2-carboxylate; acetaldehyde With tert.-butylhydroperoxide; ferrous(II) sulfate heptahydrate; sulfuric acid; acetic acid at -5 - 20℃; for 4h;
Stage #2: With sodium sulfite at 20℃;
Methyl 3-acetylpyrazine-2-carboxylate (3)
Acetaldehyde (15.35g, 348.42 mmol), H2SO4 (50%, 232 ml) and AcOH (99%, 232 ml) were added to methyl pyrazine-2-carboxylate (16.04 g, 116.14 mmol). The mixture was stirred and cooled to -5°C and 70% tert-BuO2H (31.40 g, 348.42 mmol) and FeSO4·7H2O(96.86 g, 348.42 mmol) were added simultaneously. During the addition the temperature was not allowed to exceed 10°C. The resulting mixture was stirred for additional 2h, during which the temperature was allowed to rise to 20°C. After two hours, Na2SO3 was added to the mixture until a test with starch-iodide paper was negative. Thereafter, the reaction mixture was extracted with EtOAc, the collected organic layers were dried over MgSO4 and evaporated to dryness prior to purification via column chromatography (silica gel 60, petrolether/ethyl acetate 6:4). Yield:4.60 g (22%), yellow crystals, mp. 136°C-137°C1H-NMR (200 MHz, CDCl3):δ (ppm) 2.79 (s, 3H, COCH3),4.11 (s, 3H, COOCH3),9.35 (d, J = 8.1 Hz,2H, 5-CH, 6-CH),13C-NMR (50 MHz, CDCl3): δ(ppm) 25.9 (COCH3),53.3 (COOCH3),142.8 (6-CH). 144.9(5-CH), 145.1 (2-C),148.9 (3-C), 163.6 (COOCH3),198.5 (COCH3), MS: m/z (%) 194 (M+,1), 180 (5), 165 (1), 150 (7), 138 (10), 122 (11), 106 (4), 94 (4),80 (12), 59 (7), 43 (100), 41 (5)
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.4
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
methyl 2-(pyrazine-2-carbonyl)pentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.5
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.6
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
methyl 3-oxo-2-phenyl-3-(pyrazin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.7
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
methyl 2-benzyl-3-oxo-3-(pyrazin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.8
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
methyl 2-(4-methylbenzyl)-3-oxo-3-(pyrazin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.9
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
methyl 2-(4-methoxybenzyl)-3-oxo-3-(pyrazin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.10
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
methyl 2-(4-chlorobenzyl)-3-oxo-3-(pyrazin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.11
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
methyl 4-phenyl-2-(pyrazine-2-carbonyl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 5h; Inert atmosphere;
2.12
General procedure: To a mixture of NaH (60% in mineral oil, 0.68 g, 28.2 mmol),methyl pyrazine-2-carboxylate (3 g, 21.7 mmol) and dry DMF(30 mL), methyl acetate (2.09 g, 28.2 mmol) was added dropwiseunder N2 atmosphere. After being stirred at rt for 5 h, the reactionmixture was concentrated in vacuo, and the residue treated withsaturated aqueous NaHCO3 solution followed by extraction withEtOAc. The combined organic phase were dried with MgSO4,filtered, and concentrated in vacuo. Column chromatographicpurification (n-hexane/EtOAc = 8:1) yielded 5a as white solid
Stage #1: methyl pyrazine-2-carboxylate With potassium phosphate; 2,2,2-trifluoroethanol In 1,4-dioxane at 125℃; for 0.5h; Sealed tube; Schlenk technique; Inert atmosphere;
Stage #2: benzyl-methyl-amine In 1,4-dioxane at 125℃; for 22h; Sealed tube; Schlenk technique; Inert atmosphere;
methyl pyrazine-2-carboxylate hydrochloride[ No CAS ]
[ 6164-79-0 ]
Yield
Reaction Conditions
Operation in experiment
37 g
With potassium carbonate In dichloromethane for 5h;
Methyl 2-pyrazinecarboxylate:
To a stirred suspensionof methyl 2-pyrazinecarboxylate hydrochloride (49.6 g,0.284 mol) in dichloromethane (300 mL) was added potassiumcarbonate (48.6 g, 0.352 mol) and the suspension wasstirred for five hours, during which time the suspended solid became flocculent. The suspension was then filteredand the filtrate evaporated to dryness under reducedpressure at 40 °C to yield methyl 2-pyrazinecarboxylateas colourless oil which rapidly crystallised into an off-whitesolid at room temperature (37.0 g, 94%). Found: C, 51.94;H, 4.55; N, 20.55. Calc. for C6H6N2O2: C, 52.17; H, 4.38; N,20.28. 1H NMR (300 MHz, CDCl3): δ (ppm) 9.33 (d, J = 1.0Hz, 1H, H-3), 8.79 (d, J = 2 Hz, 1H, H-1), 8.74-8.73 (m, 1H,H-2), 4.06 (s, 3H, OCH3).
methyl 5-((1,3-dioxoisoindolin-2-yl)methyl)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With dilauryl peroxide In 1,2-dichloro-ethane for 7h; Inert atmosphere; Reflux; regioselective reaction;
1 General procedures for the xanthate-mediated alkylation
General procedure: A magnetically stirred solution of xanthate (2.0 equiv) and pyrazine (1.0 equiv) in 1, 2-dichloroethane (1.0mmol/mL according to the xanthate) was refluxed for 15min under a flow of nitrogen. Then dilauroyl peroxide (DLP) was added portionwise (20mol % according to the xanthate) every hour until total consumption of one substrate. The reaction mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. Unless otherwise specified, the crude product was purified by flash chromatography on silica gel.
(2-(dimethylamino)phenyl)(pyrazin-2-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30 mg
Stage #1: 2-bromo-N,N-dimethylaniline With magnesium; lithium chloride In tetrahydrofuran at 0℃; Inert atmosphere;
Stage #2: methyl pyrazine-2-carboxylate In tetrahydrofuran at 0℃; for 0.166667h; Flow reactor; Inert atmosphere;
Stage #1: 1-bromo-3-chlorobenzene With magnesium; lithium chloride In tetrahydrofuran at 0℃; Inert atmosphere;
Stage #2: methyl pyrazine-2-carboxylate In tetrahydrofuran at 25℃; for 0.166667h; Flow reactor; Inert atmosphere;
With Eosin Y; di-tert-butyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate In acetonitrile at 20℃; for 5h; Inert atmosphere; Irradiation; chemoselective reaction;
With sodium tertiary butoxide In neat (no solvent) at 20℃; for 1h; Inert atmosphere; Schlenk technique; Green chemistry;
90%
With sodium tertiary butoxide at 20℃;
35 Example 35
Sodium tert-butoxide (309.9 mg, 3.2 mmol), aniline (200 mg, 2.15 mmol) and methyl pyrazine-2-carboxylate (445.5 mg, 3.2 mmol) were sequentially added to a 25 ml reaction tube, and the reaction was stirred at room temperature for 0.5 -2.0h (TLC monitoring).After the reaction, 20 ml of water was directly added to quench the reaction, the solid precipitated in the system was crushed, filtered under reduced pressure, and dried to obtain a white solid product.The product weighed 385 mg, 90% yield, mp 126.8-128.1°C.
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