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Chemical Structure| 24241-18-7
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Product Details of [ 24241-18-7 ]

CAS No. :24241-18-7 MDL No. :MFCD00673150
Formula : C4H3Br2N3 Boiling Point : -
Linear Structure Formula :- InChI Key :DTLBKXRFWUERQN-UHFFFAOYSA-N
M.W : 252.89 Pubchem ID :620004
Synonyms :
3,5-Dibromo-2-pyrazinamine;3,5-Dibromopyrazin-2-ylamine

Calculated chemistry of [ 24241-18-7 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 41.84
TPSA : 51.8 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.79 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.54
Log Po/w (XLOGP3) : 1.48
Log Po/w (WLOGP) : 1.59
Log Po/w (MLOGP) : 0.55
Log Po/w (SILICOS-IT) : 1.71
Consensus Log Po/w : 1.37

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.83
Solubility : 0.371 mg/ml ; 0.00147 mol/l
Class : Soluble
Log S (Ali) : -2.17
Solubility : 1.69 mg/ml ; 0.00669 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.0
Solubility : 0.251 mg/ml ; 0.000993 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.46

Safety of [ 24241-18-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P330-P362-P403+P233-P501 UN#:N/A
Hazard Statements:H315-H319-H335-H302+H312+H332 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 24241-18-7 ]

* 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.

  • Upstream synthesis route of [ 24241-18-7 ]
  • Downstream synthetic route of [ 24241-18-7 ]

[ 24241-18-7 ] Synthesis Path-Upstream   1~38

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  • [ 5049-61-6 ]
  • [ 59489-71-3 ]
Reference: [1] Organic Process Research and Development, 2006, vol. 10, # 4, p. 822 - 828
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Reference: [1] Chemical Communications, 2011, vol. 47, # 16, p. 4688 - 4690
[2] CrystEngComm, 2012, vol. 14, # 18, p. 5845 - 5853
[3] Journal of Heterocyclic Chemistry, 1982, vol. 19, # 3, p. 673 - 674
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Reference: [1] Organic Process Research and Development, 2006, vol. 10, # 4, p. 822 - 828
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  • [ 59489-71-3 ]
Reference: [1] Organic Process Research and Development, 2006, vol. 10, # 4, p. 822 - 828
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  • [ 5049-61-6 ]
  • [ 59489-71-3 ]
  • [ 21943-12-4 ]
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Reference: [1] Journal of Heterocyclic Chemistry, 1982, vol. 19, # 3, p. 673 - 674
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YieldReaction ConditionsOperation in experiment
99%
Stage #1: at 20℃; for 2 h; Reflux
Stage #2: With sodium hydrogencarbonate In water for 0.25 h;
To an aqueous (10 kg) solution of 3,5-dibromopyrazine-2-amine (1018 g, 4.03 mol), 2-bromo-1,1-dimethoxyethane (1.79 kg, 4.14 mol) was added at room temperature and stirred for 2 hours while heating under reflux. To the reaction solution, water (15.3 kg) and sodium hydrogen carbonate (744 g) were added and further stirred for 15 minutes. The resultant solid substance was obtained by filtration to obtain the titled compound (1106 g, 3.99 mmol, 99percent) as a brown solid substance.1H-NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 8.23 (s, 1H), 9.02 (s, 1H).
95%
Stage #1: With hydrogen bromide In ethanol; water at 20℃; for 21 h; Heating / reflux
Stage #2: With sodium carbonate In dichloromethane; water
General Procedures; 6,8-Dibromo-imidao[1,2-a]pyrazine; A mixture of 2-Amino-3, 5-dibromopyrazine (72.0 g, 285 mmol) in ethanol (1.1 L) was stirred at room temperature and treated with bromoacetaldehyde diethylacetal (97 mL, 640 mmol), water (72 mL) and concentrated hydrobromic acid (72 mL). The reaction was heated at reflux for five hours, then cooled slowly to room temperature over 16 hours. The resulting white precipitate was then filtered, resuspended in dichloromethane (2 L) and basified with aqueous sodium carbonate solution. After vigorous mixing, the organic phase was separated, dried over MgS04 and concentrated in vacuo, to give a pale yellow solid. Purification of the crude solid was achieved by suspending it in diisopropyl ether (500 mL) and stirring vigorously for one hour. The resulting suspension was filtered to give the title compound (A) as a pale yellow solid (74.5 g, 95 percent).
12.0 g
Stage #1: With hydrogen bromide In water at 55℃; for 2 h;
Stage #2: at 78℃; for 16 h;
A 100-mL, three-neck flask was charged with 2-bromo-l,l-dimethoxyethane 4 (23.2 g (16 mL, 137.2 mmol) and aqueous HBr (47.6percent HBr by wt, 8.8 mmol/mL, 6.6 mL, 58.8 mmol), and the reaction mixture was heated to reflux (55°C) for 2 hours. The mixture was allowed to cool to 40°C, and solid NaHCC3 was added in small portions, until evolution of gas ceased. The resulting suspension was filtered, under vacuum, into a 500-mL, three-neck flask, and the filter cake was washed with isopropanol (200 mL). Solid 3,5-dibromopyrazin-2-amine (3) (12.0 g, 47.2 mmol) was added into the isopropanol filtrate, and the reaction mixture was heated at reflux (78°C) for 16 hours. The resulting suspension was cooled to room temperature, filtered, the cake was washed with cold isopropanol (100 mL), and then the cake was dried under vacuum. The cake was transferred into a three-neck flask, into which, water (200 mL) was added, followed by solid K2CC3, in small portions, until gas evolution ceased, after which the reaction was stirred for 30 minutes. The resulting precipitate was isolated by filtration, and washed with water (200 mL). The solid was dried at 50°C, to constant weight, then dissolved in THF, filtered through a plug (celite, silica gel, and charcoal). The solvent was removed under vacuum, to give 12.0 g of the desired product (5) as a white solid at 99percent purity, as determined by NMR and LC-MS. IH NMR (500 MHz, CDC13) δ 8.26 (s, IH), 7.84 (d, J = 1.0 Hz, IH), 7.78 (d, J = 1.1 Hz, IH); 13C NMR (126 MHz, CDC13) δ 136.93, 134.06, 120.29, 119.26, 115.78.
Reference: [1] Patent: US2012/59162, 2012, A1, . Location in patent: Page/Page column 53-54
[2] Patent: WO2005/85252, 2005, A1, . Location in patent: Page/Page column 37-38; 40-41
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 512 - 516
[4] Patent: WO2016/209895, 2016, A1, . Location in patent: Paragraph 15; 16
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YieldReaction ConditionsOperation in experiment
100% at 20℃; for 19 h; Reflux Intermediate Example 1 -1 : Preparation of 6,8-dibromo-imidazo[ 1 ,2-a]pyrazineTo a stirred suspension of 2-amino-3,5-dibrompyrazine (427 g, 1688mmol) in water (6.4 L) / THF (482 mL), at rt was added bromacetaldehyde-diethylacetal (998 g, 5065 mmol) in one portion. After stirring under reflux for 4 h, the clear orange solution was stirred for an additional 15 h at rt. The suspension was filtered, and the remaining solid was washed with MeOH (2 L) and dried in vaccuo at 60° C to yield 6,8-dibromo-imidazo[1 ,2-a]pyrazine as an off-white solid (500 g, 107percent with residual MeOH): 1 H-NMR (300 MHz, d6-DMSO): δ =9.02 (s, 1 H), 8.23 (d, 1 H), 7.89 (d, 1 H) ppm. UPLC-MS: RT = 0.80 min; m/z 277.9 [MH+]; required MW = 276.9.
76% at 120℃; for 16 h; 3,5-dibromo-pyrazin-2-ylamine (10.4g, 41.12 mmol), and bromoacetaldehyde diethyl acetal (9.8 ml, 62.51mmol) then dissolved in a mixed solvent of tetrahydrofuran (14 ml) and distilled water (140 ml), and the mixture was stirred for 4 hours at 120°C , in addition stirred at room temperature for 12 hours to.Saturated aqueous sodium hydrogen carbonate solution to the reaction solution was neutralized by addition.The resulting solid was filtered, washed with distilled water and dried to give the title compound (8.7g, 76percent).
500 g at 20℃; for 19 h; Inert atmosphere; Reflux To a stirred suspension of 2-amino-3,5-dibrompyrazine (427 g, 1688mmol) in water (6.4 L) / THF (482 mL), at rt was added bromacetaldehyde-diethylacetal (998 g, 5065 mmol) in one portion. After stirring under reflux for 4 h, the clear orange solution was stirred for an additional 15 h at rt. The suspension was filtered, and the remaining solid was washed with MeOH (2 L) and dried in vaccuo at 60° C to yield 6,8-dibromo-imidazo[1 ,2-a]pyrazine as an off-white solid (500 g, 107percent with residual MeOH): 1H-NMR (300 MHz, d6-DMSO): δ =9.02 (s, 1 H), 8.23 (d, 1 H), 7.89 (d, 1 H) ppm. UPLC-MS: RT = 0.80 min; m/z 277.9 [MH+]; required MW = 276.9.
Reference: [1] Patent: WO2012/80236, 2012, A1, . Location in patent: Page/Page column 63
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 24, p. 6991 - 6995
[3] Patent: KR2015/113801, 2015, A, . Location in patent: Paragraph 0140-0143
[4] Patent: WO2004/72080, 2004, A1, . Location in patent: Page 45
[5] Patent: WO2005/14599, 2005, A1, . Location in patent: Page/Page column 44-45
[6] Patent: WO2012/80228, 2012, A1, . Location in patent: Page/Page column 42
[7] Patent: WO2012/80229, 2012, A1, . Location in patent: Page/Page column 44-45
[8] Patent: WO2012/80230, 2012, A1, . Location in patent: Page/Page column 44
[9] Patent: US2013/281460, 2013, A1, . Location in patent: Paragraph 0267-0268
[10] Patent: US2013/267527, 2013, A1, . Location in patent: Paragraph 0242-0243
[11] Patent: WO2014/20041, 2014, A1, . Location in patent: Page/Page column 130-131
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YieldReaction ConditionsOperation in experiment
83.71% at 80℃; for 8.5 h; To a 1000 mL single-necked round bottom flask was added 2-amino-3,5-dibromopyrazine (43.18 g, 220 mmol), chloroacetaldehyde (77.72 g, 396 mmol) and DMF 550 mL. The mixture in the reaction flask was stirred at 80 ° C for 8.5 hours. TLC and GC confirmed the reaction was complete. After the reaction was completed, the solvent was removed by rotary evaporation to give a crude product, which was purified by silica gel column chromatography to obtain the pure product 6,8-dibromoimidazo [1,2a] pyrazine. After drying, the yield was 83.71percent and the purity was 99.00percent (HPLC
74%
Stage #1: for 24 h; Heating / reflux
Stage #2: With triethylamine In dichloromethane; water; isopropyl alcohol
A mixture of 2-amino-3,5-dibromopyrazine (Aldrich, 6.0 g, 24.0 mmol) and 50percent aqueous solution of chloroacetaldehyde (Aldrich, 4.8 mL) in 2-propanol (30 mL) was stirred and refluxed under N2 for 24 hr. CH2Cl2 (300 mL) and triethylamine (12 mL) were added and the solvent was evaporated. The residue was suspended in 10:1 H2O:2-propanol (200 mL), filtered, and the solid was washed on filter with 10:1 H2O:2-propanol (2.x.100 mL). It was dried in a vacuum to yield pale beige solid (4.81 g, 74percent).
53% at 100℃; for 24 h; Step-(ii): Synthesis of 6, 8-dibromoimidazo [1, 2-a] pyrazine:To a stirred solution of Intermediate-lOa (0.2 g, 0.79 mmol) in IPA (5niL) was added Chloro acetaldehyde (0.12 mL, 0.952 mmol), and stirred at 100°C for 24h. After the reaction was completed, the reaction mixture was cooled RT, pale brown solid was precipitated out, filtered the solid dried under vaccum to get the desired product (150 mg, 53percent); 1H NMR (400 MHz, DMSO-d6): ö 9.02(s, 1H), 8.24(s, 1H), 7.9(s, 1H); MS (ES) m/z 277.9 (M+1).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 17, p. 5170 - 5174
[2] Patent: CN106632354, 2017, A, . Location in patent: Paragraph 0012; 0013; 0014; 0015; 0016; 0017; 0018-0022
[3] RSC Advances, 2015, vol. 5, # 47, p. 37887 - 37895
[4] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 348, p. 102 - 109
[5] RSC Advances, 2018, vol. 8, # 18, p. 9707 - 9717
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5870 - 5875
[7] Patent: US2004/63715, 2004, A1, . Location in patent: Page/Page column 27
[8] Patent: WO2014/125410, 2014, A1, . Location in patent: Page/Page column 28; 29
[9] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
[10] Patent: WO2003/84959, 2003, A1, . Location in patent: Page/Page column 131-132
[11] Patent: US2006/84650, 2006, A1, . Location in patent: Page/Page column 90
[12] RSC Advances, 2014, vol. 4, # 19, p. 9885 - 9892
[13] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 330 - 337
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Reference: [1] Patent: US2010/152159, 2010, A1, . Location in patent: Page/Page column 12-13
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 20, p. 5988 - 5993
[3] Patent: WO2010/68257, 2010, A1, . Location in patent: Page/Page column 91-92
[4] Patent: WO2008/5457, 2008, A2, . Location in patent: Page/Page column 184
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Reference: [1] Patent: WO2012/80234, 2012, A1, . Location in patent: Page/Page column 44-45
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Reference: [1] Patent: US2003/212073, 2003, A1,
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YieldReaction ConditionsOperation in experiment
84% With N-Bromosuccinimide In water; dimethyl sulfoxide at 0 - 20℃; for 7 h; Referring to Scheme 3, pyrazin-2-ylamine (1 g, 10.5 mmol) was dissolved in a solution of DMSO (40 ml)/H2O (1 ml) at 0° C. N-bromosuccinimide (3.93 g, 22 mmol) was added over an hour keeping the temperature below 5° C. Once addition was complete, the mixture was stirred for 6 hours at RT. The mixture was poured over ice water (150 ml) whilst stirring, then extracted with EtOAc (4.x.100 ml). The organic layers were combined, dried and evaporated to leave an orange oil, which solidified overnight under high vacuum. 3,5-dibromopyrazin-2-amine was produced as an orange/brown solid (2.24 g, 84percent). The product was used for the next reaction without further purification. [M+H] calc'd for C4H3Br2N3, 254; found, 254.
83% With N-Bromosuccinimide In dimethyl sulfoxide at 20℃; for 4 h; Pyrazin-2-amine (9, 4.00 g, 42.1 mmol, 1.0 equiv) was completely dissolved in DMSO (80 mL) in an argon-flushed, 500-mL round-bottomflask, and then NBS (18.7 g, 26.3 mmol, 2.5 equiv) was added over 3 h. The mixture was stirred a further 1 h at r.t. The reaction was complete within 4 h (TLC monitoring). The mixture was poured into H2O (200 mL), extracted with EtOAc (3 × 200 mL), and the combined organic layers were washed with H2O (3 × 200 mL), sat. brine (100 mL), and H2O (2 × 200 mL). The organic solution was dried (anhyd MgSO4) and concentrated by rotary evaporation. Finally the product was purified by crystallization (EtOH) to give 5 (8.736 g, 34.94 mmol, 83percent) as a pale yellow, needle-shaped, crystalline compound; Rf = 0.46 (silica gel, hexane–EtOAc, 2:1); mp 115–116 °C. Spectral results are in agreement with literature values.31
77% With N-Bromosuccinimide In water; dimethyl sulfoxide at 0 - 20℃; for 17 h; Inert atmosphere A solution of 2-aminopyrazine 4 (3.81 g, 40.1 mmol) in DMSO (80 mL) and water (2 mL) was stirred at 0 °C for 10 min. NBS (16.4 g, 92.2 mmol) was added portionwise to the solution over 50 min, keeping the temperature below 15 °C. The reaction mixture was warmed to rt and stirred for 16 h. The solution was poured into ice-water (250 mL) and stirred. The orange solid was collected by filtration and dried. The filtrate was extracted with ethyl acetate (200 mL). The organic layer was washed with 5percent aqueous sodium carbonate (50 mL) and water (50 mL), then dried, filtered and concentrated. The combined material was recrystallised from water (200 mL) to give 5 (7.80 g, 77percent) as a brown solid. (Found: C, 19.33; H, 1.10; N, 16.68; C4H3N3Br2 requires C, 19.00; H, 1.20; N, 16.62percent); δH (250 MHz; CDCl3) 5.08 (2H, br s, NH2), 8.07 (1H, s, 6-H); δC (125 MHz; CDCl3) 123.7, 123.9, 143.2, 151.9; LC-MS (15 min) m/z 256, 254, 252 (MH+); HPLC tR 4.45 min; purity 98percent; (HRMS found: MH+ m/z 251.8776; requires 251.8766).
77.8% With pyridine; bromine In dichloromethane at 20℃; for 4 h; A 500ml three-neck flask, was added 2-amino pyrazine (19g, 0.2mol), dichloromethane (200ml) and pyridine (50ml) mixed solution at room temperature was slowly added dropwise bromine (67.2g, 0.42mol) in dichloro methane (100ml) solution, stirred at room temperature 4h, the reaction system was added to 100ml of water, stirred for 2h, the organic layer was washed with water (100ml × 3), the organic phase was moved to a flask with silica gel, and activated charcoal is heated at reflux for 1h, suction , the solvent was distilled off under reduced pressure, the resulting solid was added hexane (45 ml of) and refluxed for 2h and filtered while hot, and dried to give a yellow solid 39.4g, yield 77.8percent.
76.6% With N-Bromosuccinimide In water; dimethyl sulfoxide at 20℃; Cooling with ice; Inert atmosphere At room temperature,2-aminopyrazine (8.00 g, 84.12 mmol) was dissolved in dimethylsulfoxide (160 mL)Add water (4 mL),Ice bath,N-bromosuccinimide (31.50 g, 177.00 mmol) was added portionwise to the reaction solution over 30 min,Feeding is completed,Stirred at room temperature overnight,Add water (500mL) quenching,Ethyl acetate (500 mL x 3)Dried over anhydrous Na2SO4,The solvent was removed and the residue was subjected to column chromatography (eluent: PE / EtOAc (v / v) = 6/1) to give 16.40 g of light yellow Color solid, yield: 76.6percent.
69% With N-Bromosuccinimide In water; dimethyl sulfoxide for 5 h; Cooling with ice To a DMSO-water (4.61 kg-114 g) solution of pyrazine-2-amine (456 g, 4.79 mol), NBS (1.79 kg, 10.1 mol) was added under ice cooling and stirred at the same temperature for 5 hours. To the reaction solution under ice cooling, ice water was added and diluted with ethyl acetate and then the water phase was extracted with ethyl acetate. Organic phases were combined, washed with water, and dried over magnesium sulfate. The organic phase was filtrated and then concentrated under reduced pressure to obtain the titled compound (830 g, 3.28 mmol, 69percent) as a brown solid substance.MS (ESI) m/z=252 (M+H)+.
69% With N-Bromosuccinimide In chloroform at 40℃; for 6 h; Inert atmosphere In an argon atmosphere, aminopyrazine (600.0mg, 6.31mmol, 1.0equiv) was dissolved in chloroform (25mL) and then NBS (3.37g, 18.93mmol, 3.0equiv) was added over 1h at room temperature. When the addition was completed, the mixture was stirred a further 6h at 40°C. The mixture was poured into saturated Na2S2O3 solution (100mL), extracted with EtOAc (3×100mL) and the combined organic layers where washed with saturated brine (100mL). The organic solution was dried with Na2SO4 and concentrated by rotary evaporation. Finally the residue was purified by chromatography on silica gel (gradient elution: PE–EtOAc, 9:1→7:3) to give 10 (1.0856g, 4.29mmol, 69percent) as a pale yellow compound. Rf=0.65 (silica gel, PE–EtOAc, 7:3); mp 114–116°C; 1H NMR (400MHz, CDCl3): δ=8.02 (s, 1H), 5.17 (br s, 2H); 13C NMR (100MHz, CDCl3): δ=152.0, 143.2, 124.1, 123.6; IR (neat): νmax=3447, 3281, 3187, 3154, 2933, 1811, 1714, 1621, 1549, 1506, 1450, 1359, 1333, 1202, 1151, 1133, 1096, 1079, 1040, 908, 877, 801, 755, 696cm−1; HRMS (ESI): calcd for C4H479Br2N3+ 251.8766; found 251.8779; calcd for C4H479Br81BrN3+ 253,8746; found 253.8757; calcd for C4H481Br2N3+ 255.8726; found 255.8735. The spectroscopic data are in good agreement with those reported in the literature.14a
68% With N-Bromosuccinimide In dichloromethane at 20℃; 3,5-Dibromopyrazin-2-amine Pyrazin-2-amine (2.0g, 21 mmol) was dissolved in dichloromethane (50 mL)and the resulting solution was stirred at room temperature. N-bromosuccinimide(9.4g, 53mmol) was added. After completion, the mixture was concentrated underreduced pressure to give brown solid crude which was subsequently purified bychromatography (applied in hexane; eluted 10percent EtOAc/hexane) to give the title compound as a pale yellowsolid (3.6g 14 mmol, 68percent). Mpt: 106-108 oC; Rf = 0.80 (1:1 EtOAc/hexane);IR (νmax/cm-1, thin film): 3447, 3280, 3154, 1621, 1549,1506, 1450; 1H NMR (600 MHz, CDCl3): δH = 5.04(brs, 2H, NH2), 8.04(s, 1H, 6-H); 13C NMR(150 MHz, CDCl3): δC = 123.8 (C-5), 124.0 (C-3),143.3 (C-6), 152.0 (C-2); HRMS m/z (CI+): found251.87731 [M+H]+, C4H4Br2N3requires 251.87720.  
67% With N-Bromosuccinimide In water; dimethyl sulfoxide at 0 - 20℃; for 16 h; [0094] Pyrazin-2-amine (VIII) (1.91 g, 20.08 mmol) was dissolved in dimethylsulfoxide (DMSO) (40 mL) and distilled water (1 mL).
To the resulting solution was slowly added dropwise N-Bromosuccinimide (NBS) (8.20 g, 46.07 mmol) at 0 °C and the solution was stirred at room temperature for 16 hrs.
Ice was added to the solution and the solution was stirred to give a yellow solid which was filtered to give the title compound (3.40 mg, 67 percent).
1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 5.05 (br, 2H).
66% With bromine; sodium acetate In acetic acid at -5 - 20℃; 2-Aminopyrazine (9.5 g, 100 mmol) was placed in a reaction flask containing glacial acetic acid (70 mL) and warmed on a steam bath until it dissolved. Sodium acetate trihydrate (33 g, 243 mmol) was added with constant swirling. The slurry was stirred in an ice-salt bath maintained at -5 °C and bromine (16 mL) was added dropwise over a 4 h period (if the bromine addition was speeded up the reaction became turbulent and potentially hazardous). The mixture was stirred in the ice bath for 2 h and then at room temperature for 24 h. It was then poured into ice (50 g) and neutralized with concentrated ammonia (pH 8). The crude product was collected and recrystallized from methanol (Norit) to give colourless needles of 2-amino-3,5-dibromopyrazine(16.8 g, 66percent), m.p.: 113-114 °C (lit. [13,26] 114-115 °C).
65% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; for 20 h; Darkness Under absence of light and at 0° C., N-bromosuccinimide (15.68 g, 88.1 mmol) was added to a solution of 2-aminopyrazine (4.19 g, 44.06 mmol) in dry dichloromethane (250 ml).
The mixture was stirred for 20 h at 4° C. and then washed with four 40 ml portions of a saturated sodium carbonate solution in water.
The organic layer was dried (MgSO4) and evaporated under reduced pressure, affording the title compound as 12.8 g of a light brown solid.
Column chromatography, using silica and a dichloromethane/ethyl acetate (3/1) mixture as the eluent, yielded pure 2-amino-3,5-dibromopyrazine as 5.00 g (65percent) of a light yellow solid.
1H-NMR (CDCl3, 400 Mhz): 8.09 (s, I H), 4.95 (211, NH) ppm. 13C-NMR (CDCl3): 153.5 (C-2), 144.3, 131.9, 126.8 ppm.
64.9% With N-Bromosuccinimide In water; dimethyl sulfoxide at 20℃; for 23 h; To a solution of aminopyrazine (4l) (10.0 g, 105 mmol) in DMSO (200 mL) and water (5 mL) was added N-bromosuccinimide (39.3 g, 221 mmol) at room temperature, and the mixture was stirred for 23 hours.
To the mixture was added water and the product was extracted with diethyl ether (300 mL*4). The combined organic extract was washed successively with water (400 mL*2) and brine (500 mL*2), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 280 g, n-hexane/dichloromethane/ethyl acetate=5/4/1). The resulting solid was further purified by recrystallization (n-hexane/ethyl acetate) to give Compound 42 (17.3 g, 68.3 mmol, 64.9percent) as a colorless solid. Rf=0.48 (n-hexane/dichloromethane/ethyl acetate=5/4/1); 1H NMR (400 MHz, CDCl3) δ 5.05 (s, 2H), 8.05 (s, 1H).
60% With N-Bromosuccinimide In tetrahydrofuran at 0 - 20℃; for 0.333333 h; Inert atmosphere A compound (1), (2.0 g, 21.0 mmol and 1.0 eq.), and THF (25 ml) were put in and stirred to the 200 ml three necked flask under a nitrogen atmosphere. Next, what dissolved N-bromosuccinimide (8.2 g, 46.1 mmol, 2.2 eq.) in THF (25 ml) was dropped by 0 C, and it agitated for 20 minutes at the room temperature.Cerite filtration of the impurity was carried out after ending reaction. And washed the filtrate by extraction, H2O, and sat.NH4Cl aq. with ethyl acetate, and it was made to dry by Na2SO4, and condensed. a part of obtained residue silica gel column chromatography (7 : n-hexane: eluate : ethyl acetate = 3) separation refinement condensing object compound (2) (3.16 g, yield:60 percent) It obtained as a white solid.
53% With N-Bromosuccinimide In dichloromethane at 0℃; for 2 h; Stage 1. 3, 5-Dibromopyrazin-2-amine To a solution of aminopyrazine (11.36 g, 0.12 mol) in DCM (700 mL) at 0°C was added N-bromosuccinimide (44.64 g, 0.25 mol) portion-wise. The reaction was stirred for 2 hrs. The reaction was washed with sat Na2CO3 (3 x 200 mL), dried over Mg504, filtered and concentrated in vacuo before purification by column chromatography (20percent EtOAc/heptane) to give the title compound as a yellow solid (15.9 g, 53percent). LCMS: m/z 252/254/256 [M+H].
51% With pyridine; bromine In chloroform at 20℃; for 2 h; To a solution of aminopyrazine (P) (1.902 g, 20 mmol, 1 eq.) in chloroform (160 ml) was added pyridine (3.4 ml, 42 mmol, 2.1 eq.) and bromine (2.15 ml, 2.1 eq.).
The mixture was stirred at rt for 2 hours.
The mixture was then diluted with DCM, washed with water, dried over sodium sulfate and concentrated to afford 2.583 g of title compound (yield 51percent) as a light brown solid.
1H-NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 6.98 (br s, 2H).
47% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; To a stirred solution of aminopyrazine (8.21 g, 86.4 mmol) in anhydrous methylene chloride (215 mL) cooled to 00C was added N-bromosuccinimide (32.3 g, 181 mmol) in portions over a six hour period, during which time the temperature of the reaction was kept below 00C. The resulting mixture was stored at 4°C overnight, after which it was stirred vigorously and quenched with H2O (100 mL). The organic layer was separated, after which it was washed with saturated aqueous ΝaHCC>3, washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to yield a residue that was triturated with 20percent EtOAc in hexanes to yield the title compound (10.3 g, 47percent) as a yellow/brown powder. 1H NMR (CDCl3, 300MHz) δ 8.02 (s, IH), 5.05 (bs, 2H); HPLC retention time: 1.99 minutes; MS ESI (m/z): 252.0/254.0/256.2 (M+ 1)+, calc. 251.
47% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; Preparation of 3,5-dibromopyrazin-2-amine Intermediate BA) [0322] To a stirred solution of aminopyrazine (8.21 g, 86.4 mmol) in anhydrous methylene chloride (215 mL) cooled to 0°C was added N-bromosuccinimide (32.3 g, 181 mmol) in portions over a six hour period, during which time the temperature of the reaction was kept below 0°C. The resulting mixture was stored at 4°C overnight, after which it was stirred vigorously and quenched with H20 (100 mL). The organic layer was separated, after which it was washed with saturated aqueous NaHC03, washed with brine, dried over MgS04, filtered, and evaporated in vacuo to yield a residue that was triturated with 20percent EtOAc in hexanes to yield the title compound (10.3 g, 47percent) as a yellow/brown powder. 1H NMR (CDC13, 300MHz) δ 8.02 (s, 1H), 5.05 (bs, 2H); HPLC retention time: 1.99 minutes; MS ESI (m/z): 252.0/254.0/256.2 (M+l)+, calc. 251.
47% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; Making reference to Scheme 6, to a stirred solution of aminopyrazine (8.21 g, 86.4 mmol) in anhydrous methylene chloride (215 mL) cooled to 0°C was added N- bromosuccinimide (32.3 g, 181 mmol) in portions over a six hour period, during which time the temperature of the reaction was kept below 0°C. The resulting mixture was stored at 4°C overnight, after which it was stirred vigorously and quenched with H20 (100 mL). The organic layer was separated, after which it was washed with saturated aqueous aHC03, washed with brine, dried over MgS04, filtered, and evaporated in vacuo to yield a residue that was triturated with 20percent EtOAc in hexanes to yield the title compound (10.3 g, 47percent) as a yellow/brown powder. NMR (CDC13, 300MHz) δ 8.02 (s, 1H), 5.05 (bs, 2H); HPLC retention time: 1.99 minutes; MS ESI (m/z): 252.0/254.0/256.2 (M+l)+, calc. 251.
47.8% With bromine In pyridine; dichloromethane at 40℃; for 1.5 h; Darkness A solution of dichloromethane (200 mL) and pyridine (25.3 mL, 0.315 mol) was added to a three-necked flask containing 2-aminopyrazine (14.27 g, 0.15 mol) and stirred well. In the dark and while refluxing a solution of bromine (16.2 mL, 0.315 mol) in dichloromethane (100 mL) was slowly added dropwise to the three-necked flask. About 1 h later the addition finished and the mixture was refluxed at 40 °C for 30 min more. After TLC monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature and distilled water (50 mL) was added and themixture was stirred vigorously for 10 min. Then the organic layer was collected and washed twice with distilled water. Silica gel (10 g) and activated carbon (1 g) were added to the organic layer and the mixture was decolorized under reflux for 30 min. After hot filtration, the filtrate was collected and vacuum distilled. The residue was refluxed with n-hexane (45 mL) for 2 h, filtered while hot again and the solid product was dried and weighed to give 18.15 g of a pale yellow solid (47.8percent yield). 1H-NMR(DMSO-d6) δ 8.14 (s, 1H), 7.01 (s, 2H).
47.8% With pyridine; bromine In dichloromethane; water at 40℃; for 1.5 h; To a three-necked flask equipped with 2-aminopyrazine (14.27 g, 0.15 mol) was added dichloromethane (200 mL) and pyridine(25.3 mL, 0.315 mol); immersed in water at 40 ° C, slowly added dropwise bromine (16.2 mL,0.315 mol) in dichloromethane (100 mL). After the reaction, the solution changed from orange to orange to orange1h was added dropwise; reflux was continued at 40 ° C for 30 min; cooling to room temperature, adding distilled water (50 mL) to the reaction system,Stirring for 10 min, standing on the stratified layer; collecting the lower liquid, the collected liquid was washed twice with distilled water (100 mL); the organic phaseWas transferred to a flask equipped with silica gel (10 g) and activated carbon (1 g), boiled and refluxed for 30 min. The filtrate was collected by filtration and distilled under reduced pressure,The solid obtained after the distillation was transferred to a flask equipped with n-hexane (45 mL) and refluxed at 80 ° C for 2 h. The filtrate was filtered while hotThe solid product was dried and weighed to give 18.15 g of a pale yellow solid, i.e., 3,5-dibromo-2-aminopyrazine, in a yield of 47.8percent.
41% With N-Bromosuccinimide In water; dimethyl sulfoxide at 20℃; for 4 h; To a solution of the compound 2-aminopyrazine (3.8 g, 40.00 mmol) in dimethyl sulfoxide (30 mL) and water (2 mL) was added N-bromosuccinimide (17.80 g, 0.10) in an ice bath. Mol). After stirring at room temperature for 4 hours, the reaction was poured into ice water (250 mL). Extract with ethyl acetate (50 mL×4). Combine the organic phases, filter, and wash the filtrate with 5percent sodium carbonate solution (200 mL) and saturated aqueous sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, and concentrate. The residue is subjected to silica gel column chromatography. Purification by chromatography (petroleum ether/ethyl acetate=5:1) gave compound 56-b (4.10 g, 41percent).
38% With N-Bromosuccinimide In dichloromethane at 20℃; for 2 h; NBS (100 g, 561.8 mmol) was added in small portions to a stirred solution of 2-aminopyrazine (25 g, 263 mmol) in dichloromethane (600 ml) over a period of 1 hour. The reaction was stirred at r.t. for Ih and washed with water. The organic phase was dried (MgSψ4) and evaporated. The crude product was filtered through a plug of silica using 2.5percent MeOH in dichloromethane as the elu- ent.Yield 25 g (38percent). HPLC 99percent (System A). MS (electronspray) M+H+ m/z 254.4. IH NMR (400 MHz, CHLO ROFORM-D) δ ppm 5.04 (s, 2 H) 8.03 (s, 1 H).
38% With pyridine; bromine In dichloromethane at 0 - 20℃; for 16 h; Step-(i): Synthesis of 3,5 -dibromopyrazin-2-amine: To a stirred solution of pyrazin-2-amine (0.5 g, 5.2 mmol) in DCM (10 mL), was added pyridine (0.95 mL, 11.05 mmol) at 0°C followed by bromine (0.56 mL, 11.05 mmol) which was stirred at RT for 16h. After the reaction was completed, it was cooled to room temperature, quenched with Na2CO3 (30 mL), extracted with DCM (2 x 100 mL). The combined organicphases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude product was purified by colunm chromatography using 100-200 mesh silica gel and 2percent MeOH in DCM as eluent to give the titled product as an off white solid (510 mg, 38percent); MS (ES) mz 254 (M+1).
36% With pyridine; bromine In chloroform at 0 - 20℃; for 16 h; To a mixture of 2-amino pyrazine (50 g, 0.5 mol) in chloroform (1000 ml) cooled to 0°C was added pyridine (100 ml, 1.21 mol) and bromine (54 ml, 1.05 mmol) dropwise. The mixture was stirred at rt for 16h, then water was added. The organic phase was extracted, dried (MgS04), filtered and evaporated to obtain I- 01 , 48 g (Y: 36 percent) of a yellow solid which was dried in vacuo.
36% With pyridine; bromine In chloroform at 0 - 20℃; for 16 h; Preparation of Intermediate I-01. To a mixture of 2-amino pyrazine (50 g, 0.5 mol) in chloroform (1000 ml) cooled to 0° C. was added pyridine (100 ml, 1.21 mol) and bromine (54 ml, 1.05 mmol) dropwise. The mixture was stirred at rt for 16 h, then water was added. The organic phase was extracted, dried (MgSO4), filtered and evaporated to obtain I-01, 48 g (Y: 36percent) of a yellow solid which was dried in vacuo.
36% With pyridine; bromine In chloroform at 0 - 20℃; for 16 h; To a mixture of 2-amino pyrazine (50 g, 0.5 mol) inchloroform (1000 ml) cooled to 0° C. was added pyridine (100 ml, 1.21 mol) and bromine (54 ml, 1.05 mmol) drop- wise. The mixture was stirred at it for 16 h, then water was added. The organic phase was extracted, dried (MgSO4), filtered and evaporated to obtain 1-01, 48 g (Y: 36percent) of ayellow solid which was dried in vacuo.
34% With N-Bromosuccinimide In water; dimethyl sulfoxide at 5 - 20℃; A I L three-necked round bottom flask was charged with pyrazin-2-amine (20 g, 0.21 mol), DMSO (600 mL) and water (15 mL). To the above was added in portions N-Bromosuccinimide (77.9 g, 0.44 mol) while keeping the inner temperature below 5 °C. The resulting mixture was stirred at 20 °C overnight. The solvent was evaporated and the residue was purified by flash columnchromatography on silica gel with a 1 :10 EtOAc/petroleum ether, to afford 18 g (34percent) of the product as a yellows solid. *H NMR (300 MHz, CDC13) δ: 8.02 (s, 1H), 4.72 (br, 2H).
1.51 g With N-Bromosuccinimide In water; dimethyl sulfoxide at 15 - 20℃; for 16 h; 3,5-Dibromo-2-aminopyrazine N-Bromosuccinimide (5.1 g, 28.7 mmol) was added slowly and portion wise to a mixture of aminopyrazine (1.3 g, 13.6 mmol) in dimethylsulfoxide (11 ml) and water (17 ml). During the addition of N-bromosuccinimide, the temperature of the reaction mixture was maintained below 15 °C. After the addition, the reaction mixture was stirred for 16 h at RT. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 10 percent Na2C03 solution followed by washing with water and brine. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo to obtain crude product. The product was purified using column chromatography. Yield: 1.51 g 1H NMR (CDC13): 5.04 (2H, s), 8.03 (1H, s)
4.0 g With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide; acetonitrile at 0℃; for 1 h; A solution of 2-aminopyrazine 1 (4.5 g, 47.4 mmol) in 50 mL DMF/MeCN solvent mixture (1:3) and a solution of l,3-dibromo-5,5-dimethylhydantoin 2 (13.6 g, 47.6 mmol, 2 eq. of "Br") in 40 mL DMF/MeCN solvent mixture (1:3) were simultaneously added (using two syringe needles) to a solution of MeCN (100 mL) at 0°C. The reaction mixture was stirred for one hour, quenched with aqueous sodium thiosulfate (I N, 200 mL) and concentrated under vacuum. The crude product (>99percent conversion, 8 g) was dissolved in EtOAc and filtered through celite/charcoal and recrystallized from acetonitrile (4.0 g, 50percent recovery). The reaction was scaled up to 12.0 g in two batches and the desired product 3 was analyzed by NMR and LC-MS. IH NMR (500 MHz, CDC13) δ 7.99 (s, IH); 13C NMR (126 MHz, CDC13) δ 151.92, 143.16, 142.99, 123.95, 123.56.

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  • [ 124-41-4 ]
  • [ 24241-18-7 ]
  • [ 5900-13-0 ]
YieldReaction ConditionsOperation in experiment
8.1 g for 3 h; Reflux A 30percent w/w solution of NaOMe in MeOH (8.4 mL, 44.8 mmol) was added to a stirring suspension of 3,5-dibromo-2-aminopyrazine (10 g, 39.5 mmol) in dry MeOH (40 mL).
The reaction mixture was heated to reflux and maintained for 3 h.
The reaction was allowed to cool to rt and concentrate to 1/3 volume.
The reaction was then partitioned between DCM and saturated aqueous NaHCO3 solution.
The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution (3*).
The combined aqueous portions were back extracted with DCM (3*).
The combined organic portions were washed with brine, dried (Na2SO4), and concentrated to provide 8.1 g of 5-bromo-3-methoxypyrazin-2-amine: 1H NMR (300 MHz, CDCl3): 7.64 (s, 1H), 4.79 (br s, 2H), 4.01 (s, 3H).
450 mg for 16 h; Reflux 5-Bromo-3-methoxypyrazin-2-amine A mixture of 3,5-dibromo-2-aminopyrazine (750 mg, 2.9 mmol), sodium methoxide (400 mg, 7.4 mmol) and methanol (20 ml) was refluxed for 16 h. The solvent was removed and the residue was purified using column chromatography. Yield: 450 mg 1H NMR (CDCI3): 3.99 (3H, s), 4.76 (2H, s), 7.63 (1H, s)
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  • 19
  • [ 773837-37-9 ]
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  • [ 17231-51-5 ]
YieldReaction ConditionsOperation in experiment
67.2%
Stage #1: at 125℃;
Stage #2: at 125℃; for 5 h;
Step 1: synthesis of 3-amino-6-bromopyrazine-2-carbonitrile (14)A solution of copper(i) cyanide (1.20 g, 13.42 mmol) and sodium cyanide (0.658 g, 13.42 mmol) in DMF (10 mL) was heated to 125°C. 2-amino-3,5-dibromo pyrazine (2.61 g, 10.32 mmol) was added in portions. The reaction was stirred at 125°C, and after 5h quenched in ice cold NaHC03 solution. The black precipitate was filtrated off and the filtrate was extracted (3x) with EtOAc. The organic layer was washed with brine, dried and evaporated. Purification by chromatography (CH2CI2) gave pure 3- amino-6-bromopyrazine-2-carbonitrile 14 (1.38 g, 67.2 percent). 1H-NMR (400 MHz, CDC13) 5.29 (br s, 2H), 8.30 (s, 1H). (m/z) = 199 and 201 (M+H)+.
67.2% at 125℃; for 5 h; Step 1:
synthesis of 3-amino-6-bromopyrazine-2-carbonitrile (14)
A solution of copper(i) cyanide (1.20 g, 13.42 mmol) and sodium cyanide (0.658 g, 13.42 mmol) in DMF (10 mL) was heated to 125° C. 2-amino-3,5-dibromo pyrazine (2.61 g, 10.32 mmol) was added in portions.
The reaction was stirred at 125° C., and after 5 h quenched in ice cold NaHCO3 solution.
The black precipitate was filtrated off and the filtrate was extracted (3*) with EtOAc.
The organic layer was washed with brine, dried and evaporated.
Purification by chromatography (CH2Cl2) gave pure 3-amino-6-bromopyrazine-2-carbonitrile 14 (1.38 g, 67.2percent).
1H-NMR (400 MHz, CDCl3) 5.29 (br s, 2H), 8.30 (s, 1H).
(m/z)=199 and 201 (M+H)+.
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  • 21
  • [ 110-89-4 ]
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  • [ 90674-84-3 ]
YieldReaction ConditionsOperation in experiment
97% at 120℃; for 18 h; Amine (1.58 mmoll) was added to 2-amino-3,5-dibromopyrazine 2 (0.791 mmol) in DMSO or ethanol (0.5 ml) and the mixture was heated to 120° C. in a sealed tube. If the amine was in short supply, one equivalent of amine and one equivalent of iPr2NEt were used. The reaction was allowed to proceed for 18 h. The solution was cooled, partitioned between methylene chloride and water (1:1, 200 ml) and the organic phase removed. The aqueous phase was extracted with methylene chloride (50 ml) and the combined organic layers were dried over Na2SO4 and concentrated giving the product 5. ; Prepared from 2-amino-3,5-dibromopyrazine and piperidine according to general procedure 4 (method 2) providing the diaminopyrazine (199 mg, 97percent) as a yellow solid; 1H NMR (500 MHz, CDCl3) δ 7.72 (s, 1H), 4.53 (s, 2H), 3.12-3.10 (t, J=5.3 Hz, 4H), 1.71-1.67 (m, 4H), 1.65-1.61 (m, 2H).
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  • [ 24241-18-7 ]
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  • 25
  • [ 24241-18-7 ]
  • [ 21943-15-7 ]
YieldReaction ConditionsOperation in experiment
79.4%
Stage #1: at 15 - 25℃;
Stage #2: With sodium nitrite In water at 10 - 15℃; for 2.5 h;
Preparation of compound 36a: 3,5-dibromopyrazin-2-olTo a stirred solution of 3,5-dibromopyrazin-2-amine (30 g, 0.12 mol) in AcOH (300 ml_) was added dropwise cone. H2SO4 (50 ml_) at 15-25 0C. To the resulting solution was then added dropwise a solution of NaNO2 (16.6 g, 0.24 mol) in water (100 ml_) at 10-15 0C during a period of 1.5 h. After the addition, the resulting mixture was stirred at 10-15 0C for 1 h. The reaction mixture was poured into water (3 L) and extracted with EtOAc (1 L x 3). The combined organic layers were washed with saturated NaHCOs (1 L x 3) and brine (1 L) in sequence, dried over Na2SO4 and concentrated in vacuo which gave the title compound 36a as a yellow solid (24 g, 79.4percent). 1H NMR (400 MHz, CDCI3): 7.44 (s, 1 H).
Reference: [1] Patent: WO2010/16005, 2010, A1, . Location in patent: Page/Page column 144
  • 26
  • [ 24241-18-7 ]
  • [ 74-88-4 ]
  • [ 84539-07-1 ]
YieldReaction ConditionsOperation in experiment
61% With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.416667 h; To a stirred solution of amine 1 (1.0 mmol) in dry DMF (3 mL) was added sodium hydride (60percent dispersion in mineral oil, 2.2 mmol) and alkyl iodide (4.0 mmol). The resulting mixture was stirred under nitrogen at room temperature for 25 minutes. The reaction mixture was then quenched with water (6 mL), extracted with diethyl ether (2.x.12 mL) and the combined organics were washed with brine, dried over sodium sulfate and concentrated. Biorg. Med. Chem. 2001, 9, 1149-1154.; Prepared from 2-amino-3,5-dibromopyrazine and iodomethane (568 mg, 4.00 mmol) according to general procedure 1.
Purification by column chromatography (12 g ISCO column eluding with hexanes and ethyl acetate; gradient 100percent hexanes to 70percent hexanes) provided the substituted aminopyrazine (171 mg, 61percent) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 8.11 (s, 1H), 3.07 (s, 6H).
Reference: [1] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 5, p. 1149 - 1154
[2] Patent: US2006/142307, 2006, A1, . Location in patent: Page/Page column 4-5; 19
  • 27
  • [ 24241-18-7 ]
  • [ 89123-58-0 ]
YieldReaction ConditionsOperation in experiment
93% With ammonium hydroxide In water at 110℃; for 16 h; sealed tube Example 54; Step 1; A suspension of 1 (3 g, 11.64 mmol) in 25percent aq. NH4OH (15 mL) in sealed tube was heated at 110° C. for 16 h. After completion of reaction (reaction progress was monitored by TLC), the reaction mixture was partitioned between ethyl acetate-water (3.x.50 mL). The combined extracts were washed with saturated brine, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with 15percent ethyl acetate-hexane to afford 2 as a yellow solid (2.1 g, 93percent). MS m/z (ES): 189 (M+H)+.
68% at 130℃; for 120 h; 3,5-Dibromopyrazin-2-amine (10.0 g, 39.5 mmol) was suspended in 200 ml concentrated (32percent) aqueous ammonia and the mixture was stirred at 130 00 in a pressure tube for 5 days. The mixture was allowed to cool, forming a precipitate. Thesolid was collected by filtration, washed with water and dried in vacuo to give 5.10 g(27.0 mmol, 68percent yield) of the title compound as a pale brown solid. Purity 100percent.1H NMR (300 MHz, DMSO-d6) ö ppm 7.20 (s, 1 H), 6.40 (br s, 2H), 6.05 (br s, 2H).UPLC/MS (3 mm) retention time 0.69 mm.LRMS: mlz 189, 191 (M+1, lxBr).
5 g at 130℃; Autoclave; Inert atmosphere (a) Add 2-amino-3,5-dibromopyrazine (10 g, 39.54 mmol, 1 eq) to a 100 mL autoclaveAnd ammonia (50 mL, commercially available),Raise the temperature to 130 ° C under nitrogen protection conditions and carry out the reaction overnight (10 to 12 hours);Cooling, suction filtration,The obtained solid was vacuum dried to give 5.0 g of Compound II.
Reference: [1] Patent: US2011/59118, 2011, A1, . Location in patent: Page/Page column 81-82
[2] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 6, p. 1059 - 1065
[3] Patent: WO2017/64068, 2017, A1, . Location in patent: Page/Page column 59; 60
[4] Patent: TWI523856, 2016, B, . Location in patent: Paragraph 0078
[5] Patent: CN108395436, 2018, A, . Location in patent: Paragraph 0010
  • 28
  • [ 24241-18-7 ]
  • [ 77112-66-4 ]
Reference: [1] Patent: US5861401, 1999, A,
  • 29
  • [ 64-17-5 ]
  • [ 24241-18-7 ]
  • [ 77112-66-4 ]
Reference: [1] Farmaco, Edizione Scientifica, 1981, vol. 36, # 1, p. 61 - 80
  • 30
  • [ 24241-18-7 ]
  • [ 112342-72-0 ]
Reference: [1] ACS Combinatorial Science, 2016, vol. 18, # 12, p. 702 - 709
  • 31
  • [ 141-97-9 ]
  • [ 24241-18-7 ]
  • [ 125208-06-2 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1989, # 4, p. 467 - 471
  • 32
  • [ 70-23-5 ]
  • [ 24241-18-7 ]
  • [ 87597-21-5 ]
YieldReaction ConditionsOperation in experiment
50.6% at 20 - 110℃; Step A: Preparation of ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10 C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over a2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm.
50.6% at 110℃; for 3 h; Step A: Preparation of ethyl 6,8-dibromoimidazo[ 1 , 2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3, 5-dibrompyrazine (20 g, 79mmol) in dimethyicarbonate (1 33 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDC ): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm.
50.6% at 20 - 110℃; for 3 h; Intermediate Example 1 -2: Preparation of (6,8-dibromoimidazo[1 ,2-a]pyrazin-2- yl)methanolStep A: Preparation of ethyl 6,8-dibromoimidazo[1 , 2-a]pyrazi'ne-2-carboxylateTo a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over a2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCI3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm.
50.6% at 110℃; Step A: Preparation of ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3,5-di brom pyrazi ne (20 g, 79m mol ) i n dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 3/4) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm.
50.6% at 20 - 110℃; To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110° C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6percent) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz,
50.6% at 110℃; for 3 h; To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110° C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6percent) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3: δ=8.30 (s, 1H), 8.27 (s, 1H), 4.48 (q, 2H), 1.43 (tr, 3H) ppm.

Reference: [1] Patent: WO2012/80232, 2012, A1, . Location in patent: Page/Page column 36-37
[2] Patent: WO2012/80228, 2012, A1, . Location in patent: Page/Page column 42-43
[3] Patent: WO2012/80234, 2012, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2012/80236, 2012, A1, . Location in patent: Page/Page column 64
[5] Patent: US2013/281460, 2013, A1, . Location in patent: Paragraph 0270-0271
[6] Patent: US2013/267527, 2013, A1, . Location in patent: Paragraph 0245-0246
  • 33
  • [ 65868-37-3 ]
  • [ 24241-18-7 ]
  • [ 87597-21-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
  • 34
  • [ 110-91-8 ]
  • [ 24241-18-7 ]
  • [ 117719-17-2 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: at 120℃; for 48 h;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
A solution of intermediate 1-01(15 g, 59.3 mmol) in morpholine (15 ml, 178 mmol) was heated at 120°C in a Parr reactor for 48h. A brown solid appears. The solid was suspended in DCM and washed with NaHC03 aq. sat (twice). The organic phase was dried (NaS04), filtered and evaporated to dryness to obtain I-02, 14.8 g of a brown solid (Y: 96 percent).
96% at 120℃; for 48 h; Preparation of Intermediate I-02. A solution of intermediate I-01(15 g, 59.3 mmol) in morpholine (15 ml, 178 mmol) was heated at 120° C. in a Parr reactor for 48 h. A brown solid appears. The solid was suspended in DCM and washed with NaHCO3 aq. sat (twice). The organic phase was dried (NaSO4), filtered and evaporated to dryness to obtain 1-02, 14.8 g of a brown solid (Y: 96percent)
96.1% for 1 h; Reflux A mixture of morpholine (50 mL) and 3,5-dibromo-2-aminopyrazine (12.50 g) was refluxed for 1 h until the reaction was complete by TLC analysis. The solution was cooled to room temperature andadded to a beaker containing ice water (300 mL) with continuous stirring. The solid was precipitated and filtered. After drying, 12.30 g of a yellow solid with a metallic luster was obtained (a yield of 96.1percent). 1H-NMR (DMSO-d6) δ 7.70 (s, 1H), 6.28 (s, 2H), 3.85–3.62 (m, 4H), 3.04 (d, J = 4.0 Hz, 4H).
96.1% at 80℃; for 1 h; Morpholine (50 mL) was added to a three-necked flask containing 12.50 g of 3,5-dibromo-2-aminopyrazine and maintained at 80 ° CThe reaction was completed by the reaction of TLC for 1 h. The refluxed system was cooled to room temperature and added to a mixture containing ice water (300 mL)The mixture was stirred and dried to give 12.30 g of a yellow solid with metallic luster, i.e., 3-morpholine-5-Bromo-2-aminopyrazine in a yield of 96.1percent.
96% at 120℃; for 48 h; A solution of intermediate 1-01(15 g, 59.3 mmol) inmorpholine (15 ml, 178 mmol) was heated at 120° C. in a Parr reactor for 48 h. A brown solid appears. The solid was suspended in DCM and washed with NaHCO3 aq. sat (twice). The organic phase was dried (NaSO4), filtered and evaporated to dryness to obtain 1-02, 14.8 g of a brown solid(Y: 96percent)
86.7% at 80℃; for 6 h; A 500ml three-neck flask, was added morpholine (9.6g, 0.11mol) and 2-amino-3,5-dibromo-pyrazine (25.3g, 0.1mol) and N- methylpyrrolidinone (100ml), and at 80 reaction 6h, TLC tracking, cooled to room temperature, add water 400ml, stirring, suction filtered and dried to give a yellow solid 22.5g, a yield of 86.7percent.
74%
Stage #1: at 120℃; for 24 h;
Stage #2: With sodium carbonate In dichloromethane; water
Preparation of intermediate 11-1; A solution of product 2-amino-3,5-dibromo-4-ylpyrazine (cas: 117719-17-2), (40 g, 158 mmol, 1.0 eq) in morpholine (41.5 ml, 474 mmol 3.0 eq) was heated at 120°C in a parr reactor for 24h. A brown solid appears. The solid was suspended in DCM and washed with Na2C03 aq. sat (twice). The organic phase was dried (MgS04), filtered and solvent removed in vacuo to give a brown solid, which was triturated from Et20 to afford the desired product (30.54 g, 74percent) as a pale brown solid as 11-1.

Reference: [1] Patent: WO2011/36461, 2011, A1, . Location in patent: Page/Page column 77
[2] Tetrahedron Letters, 2012, vol. 53, # 9, p. 1082 - 1084
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 1874 - 1878
[4] Patent: US2012/83492, 2012, A1, . Location in patent: Page/Page column 91
[5] Molecules, 2017, vol. 22, # 2,
[6] Patent: CN106831812, 2017, A, . Location in patent: Paragraph 0137; 0138; 0139
[7] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 21, p. 4794 - 4799
[8] Patent: US9993554, 2018, B2, . Location in patent: Page/Page column 49; 241; 242
[9] Patent: CN105622526, 2016, A, . Location in patent: Paragraph 0026; 0027; 0028
[10] Patent: WO2011/89400, 2011, A1, . Location in patent: Page/Page column 117
[11] Patent: CN108570011, 2018, A, . Location in patent: Paragraph 0012; 0013; 0014
  • 35
  • [ 24241-18-7 ]
  • [ 1066-54-2 ]
  • [ 875781-41-2 ]
YieldReaction ConditionsOperation in experiment
94% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at -5 - 0℃; for 1.5 h; Inert atmosphere To a solution of 3,5-dibromopyrazin-2-amine (2.00 g, 7.91 mmol) in THF (24 mL)were added triethylamine (3.3 mL, 24 mmol), cuprous iodide (151 mg, 0.79 mmol) andPd(PPh3hCh (561 mg, 0.79 mmol). The mixture was cooled to -5 oc under nitrogen protection,then trimethylsilylacetylene (1.07 mL, 7.50 mmol) was dropwised slowly into the mixture. Afterthe addition, the mixture was warmed to 0 oc and stirred for 1.5 h. The mixture was concentratedin vacuo to remove the solvent and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v) = 511) to give the title compound as black oil (42 mg, 94 percent).MS (ESI, pos. ion) m/z: 272.00 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 8.04 (s, lH), 5.14 (s, 2H), 0.30 (s, 9H).
84.4% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; for 1.16667 h; Inert atmosphere; Cooling with ice Ice bath,3,5-dibromopyrazine-2-amine (16.30 g, 64.50 mmol), cuprous iodide (2.45 g, 12.90 mmol)Tetraphenylphenylphosphine palladium (3.70 g, 3.20 mmol)And N, N-dimethylformamide (80 mL) was placed in a single-necked flask,Under N2, triethylamine (44.8 mL, 321 mmol) was added,Trimethylsilylacetylene (8.7 mL, 61.3 mmol) was slowly added dropwise over 10 min,After the dropwise addition, the mixture was stirred at room temperature for 1 h. Filtered, washed with dichloromethane (100 mL) and the filtrate was concentrated, The concentrate was subjected to column chromatography (eluent: PE / EtOAc (v / v) = 20/1) to give 14.70 g of a white solid, yield:84.4percent.
75% With triethylamine In N,N-dimethyl-formamide at 20℃; Step 1 : 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine(Trimethylsilyl)acetylene (1.845 g, 2.655 niL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (5 g, 19.77 mmol), triethylamine (10.00 g, 13.77 mL, 98.85 mmol), Copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4(1.142 g, 0.9885 mmol) in DMF (25.00 mL) and the resulting solution stirred at ambient temperature for 30 minutes. The reaction was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organics washed with water, dried (MgSO4) and concentrated in vacuo. The mixture was purified on silica gel by flash column chromatography (0-15percent EtO Ac/Petrol) to afford the product as a yellow solid (3.99g, 75percent Yield). IH NMR (400.0 MHz, DMSO) d 0.30 (s, 9H), 8.06 (s, IH) ppm; MS (ES+) 271.82
75% With copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5 h; [00195] Step 1 : (Trimethylsilyl)acetylene (1.9 g, 2.7 niL, 18.8 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (5.0 g, 19.8 mmol), triethylamine (10.0 g, 13.8 mL, 98.9 mmol), copper (I) iodide (452 mg, 2.37 mmol) and Pd(PPh3)4 (1.14 g, 0.99 mmol) in DMF (25 mL) and the resulting solution stirred at room temperature for 30 min. The reaction was diluted with ethyl acetate and water and the layers separated. The aqueous layer was extracted further with ethyl acetate and the combined organics washed with water, dried over MgS04, and concentrated in vacuo. The mixture was purified via silica gelchromatography (0-15percent ethyl acetate/hexanes) to afford 5-bromo-3-((trimethylsilyl) ethynyl)pyrazin-2-amine as a yellow solid (3.99g, 75percent yield). 3/4 NMR (400 MHz, DMSO- d6) δ 0.30 (s, 9H), 8.06 (s, 1H); MS (ES+) 271.82
75% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5 h; (Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine 1 (5 g, 19.77 mmol) in DMF (25 mL)Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15percent EtO Ac/Petroleum ether to give the product as a yellow solid (3.99g, 75percent Yield). XH NMR (400.0 MHz, DMSO) ? 0.30 (9H, s), 8.06 (IH, s); MS (ES+) 271.82
75% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5 h; [00178] (Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine 1 (5 g, 19.77 mmol) in DMF (25 mL)Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15percent EtO Ac/Petroleum ether to give the product as a yellow solid (3.99g, 75percent Yield). IH NMR (400.0 MHz, DMSO) d 0.30 (9H, s), 8.06 (IH, s); MS (ES+) 271.82
75% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; (Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (compound i) (5 g, 19.77 mmol) in DMF (25 mL). Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15percent EtOAc/Petroleum ether to give the product as a yellow solid (3.99 g, 75percent Yield). 1H NMR (400.0 MHz, DMSO) ? 0.30 (9H, s), 8.06 (IH, s); MS (ES+) 271.82.
75% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5 h; 5-Bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine 2 [00178] (Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine 1 (5 g, 19.77 mmol) in DMF (25 mL) Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15percent EtO Ac/Petroleum ether to give the product as a yellow solid (3.99g, 75percent Yield). 1H NMR (400.0 MHz, DMSO) d 0.30 (9H, s), 8.06 (IH, s); MS (ES+) 271.82
71% With triethylamine In N,N-dimethyl-formamide at 120℃; for 0.5 h; Step 1: Synthesis of 5-Bromo-3-trimethylsilanylethynyl-pyrazm-2-yIamine.[0282] To a solution of 3,5-Dibromo-pyrazin-2-ylamine (3.00 g, 11.86 mmol) in DMF(35 ml) was added triethylamine (16 ml), then tetraldstriphenylphine palladium (0) (685 mg,0.59 mmol) and copper(i) iodide (271 mg, 1.42 mmol) were added sequentially. Finallytrimethylsilylacetylene (2.0 ml, 14.3 mmol) was added dropwise. The reaction mixture wasstirred at 120 °C for 30 minutes and then directly adsorbed onto silica gel. Purification byflash chromatography on silica gel with a gradient of ethyl acetate/hexane afforded the titlecompound (2.30g, 71percent yield) as yellow oil. MS: m/z 270.0/272.0 [MH+].
70% With copper(l) iodide; triethylamine In tetrahydrofuran at 0 - 10℃; for 7 h; To a solution of 3,5-dibromopyrazin-2-amine (40.0 g, 158 mmol), TEA (66.1 mL, 475 mmol), and copper(I) iodide (0.301 g, 1.58 mmol) in THF (1172 ml) was added PdCl2(PPh3)2 (1.11 g, 1.58 mmol). The reaction mixture was cooled at about 0° C. and a solution of (trimethylsilyl)acetylene (20.8 mL, 150 mmol) in THF (146 mL) was added drop-wise. The reaction mixture was stirred at about 0-10° C. for about 7 h and then concentrated under reduced pressure. The dark brown residue was dissolved in DCM (600 mL) and filtered through a Celite.(R). pad (3 cm in height.x.9 cm in diameter) while eluting with DCM (300 mL). The filtrate was washed with water (2.x.500 mL) and brine (500 mL), dried over anhydrous MgSO4, filtered through a Florisil.(R). pad (1 cm in height by 9 cm in diameter) while washing with DCM/MeOH (9:1, 200 mL), and concentrated under reduced pressure to give a brown solid. The solid was triturated and sonicated with warm petroleum ether (b.p. 30-60° C., 250 mL), cooled and collected, washing with petroleum ether (b.p. 30-60° C.; 2.x.100 mL), and dried in a vacuum oven at about 70° C. to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (34.6 g, 70percent): LC/MS (Table 2, Method d) Rt=1.59 min; MS m/z: 272 (M+H)+.
47% With copper(l) iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 1 h; Inert atmosphere To a solution of 3,5-dibromopyrazin-2-amine (10 g, 40 mmol), copper(I) iodide (0.91 g, 4.7 mmol), diisopropylethylamine (53 mL, 0.55 mol), and tetrakis(triphenylphosphine)-palladium(0) (2.3 g, 1.9 mmol) in DMF (120 mL) that was de-gassed with Ar was added trimethylsilylacetylene (6.7 mL, 48 mmol). The resulting mixture was stirred under an Ar atmosphere for 1 h at 1200C, after which it was evaporated to dryness in vacuo. The residue was subjected to silica gel chromatography eluting with 35percent EtOAc in hexanes to give a brown oil that was triturated with hexanes to give the title compound (5.0 g, 47percent). 1H NMR (CDCl3, 300 MHz): δ 8.04 (s, IH), 5.10 (s, 2 H), 0.28 (s, 9H). HPLC retention time: 2.75 minutes. MS ESI (m/z): 270.0, 272.0 (M+H) +, calc. 269.
47% With copper(l) iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 1 h; Inert atmosphere Preparation of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (Intermediate AQ) [0313] To a solution of 3,5-dibromopyrazin-2-amine (10 g, 40 mmol), copper(I) iodide (0.91 g, 4.7 mmol), diisopropylethylamine (53 mL, 0.55 mol), and tetrakis(triphenylphosphine)- palladium(O) (2.3 g, 1.9 mmol) in DMF (120 mL) that was de-gassed with Ar was added trimethylsilylacetylene (6.7 mL, 48 mmol). The resulting mixture was stirred under an Ar atmosphere for 1 h at 120°C, after which it was evaporated to dryness in vacuo. The residue was subjected to silica gel chromatography eluting with 35percent EtOAc in hexanes to give a brown oil that was triturated with hexanes to give the title compound (5.0 g, 47percent). 1H NMR (CDC13, 300 MHz): δ 8.04 (s, 1H), 5.10 (s, 2 H), 0.28 (s, 9H). HPLC retention time: 2.75 minutes. MS ESI (m/z): 270.0, 272.0 (M+H) +, calc. 269.
47% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 1 h; Inert atmosphere Making reference to Scheme 5, to a solution of 3,5-dibromopyrazin-2-amine (10 g, 40 mmol), copper(I) iodide (0.91 g, 4.7 mmol), diisopropylethylamine (53 mL, 0.55 mol), and tetrakis(triphenylphosphine)-palladium(0) (2.3 g, 1.9 mmol) in DMF (120 mL) that was de-gassed with Ar was added trimethylsilylacetylene (6.7 mL, 48 mmol). The resulting mixture was stirred under an Ar atmosphere for 1 h at 120°C, after which it was evaporated to dryness in vacuo. The residue was subjected to silica gel chromatography eluting with 35percent EtOAc in hexanes to give a brown oil that was triturated with hexanes to give the title compound (5.0 g, 47percent). XH NMR (CDC13, 300 MHz): δ 8.04 (s, 1H), 5.10 (s, 2 H), 0.28 (s, 9H). HPLC retention time: 2.75 minutes. MS ESI (m/z): 270.0, 272.0 (M+H)+, calc. 269
17% With copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 120℃; for 0.5 h; To a solution of intermediate I-82 (10 g, 40 mmol, 1.0 eq) in DMF (115 mL) was added neat triethylamine (53 mL), Pd(PPh3)4 (2.3 g, 2.0 mmol, 0.05 eq) and CuI (0.90 g, 4.7 mmol, 0.12 eq) followed by drop wise addition of ethynyltrimethylsilane (6.7 mL, 48 mmol, 1.2 eq) and the reaction mixture was stirred for 30 minutes at 120° C. The crude reaction mixture was concentrated by evaporation and the crude reaction product was purified by silica gel column chromatography to give intermediate I-83 (3.0 g, 17percent) as yellow oil. MS (ESI): m/z 271 (M+H+).
20 g With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In acetonitrile at 0 - 20℃; for 1.75 h; Inert atmosphere Step 1 A 500 ml three necked round bottom flask was charged with 3,5-dibromopyrazine-2- amine (25.0 g, 0.0988 mole) which was dissolved in acetonitrile (250 ml). The reaction mixture was cooled to 0 ° C and triethylamine (50.0 g, 0.4941 mole), copper (1) iodide (2.26 g, 0.0119 mole), and Pd (PPh3)4 (5.7 g, 0.0049 mole) were added under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0 °C followed by slow addition of trimethylsilylacetylene (10.7g, 0.1089 mole) over 15 min at the same temperature. After completion of the addition, the reaction mixture was warmed up to RT and stirred for 90 min. The reaction mixture was diluted by ethyl acetate and filtered. The filtrate was collected and washed with water. Layers were separated and aqueous layer was re-extracted by ethyl acetate. Combined organic layer was dried over Na2S04, filtered and concentrated to afford crude product which was purified using column purification to afford 20.0 g of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine.

Reference: [1] Patent: WO2018/108125, 2018, A1, . Location in patent: Paragraph 00586
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 693 - 698
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4399 - 4404
[4] Patent: CN106432246, 2017, A, . Location in patent: Paragraph 0540; 0541; 0542
[5] Patent: WO2010/54398, 2010, A1, . Location in patent: Page/Page column 150-151
[6] Patent: WO2011/143426, 2011, A1, . Location in patent: Page/Page column 69
[7] Patent: WO2013/49722, 2013, A1, . Location in patent: Paragraph 00209
[8] Patent: WO2013/49720, 2013, A1, . Location in patent: Paragraph 00178
[9] Patent: WO2013/49726, 2013, A2, . Location in patent: Paragraph 00162
[10] Patent: WO2013/49719, 2013, A1, . Location in patent: Paragraph 00178
[11] Patent: US2014/107093, 2014, A1, . Location in patent: Page/Page column
[12] Patent: WO2006/15124, 2006, A2, . Location in patent: Page/Page column 102
[13] Patent: US2009/312338, 2009, A1, . Location in patent: Page/Page column 61
[14] Patent: WO2010/68483, 2010, A2, . Location in patent: Page/Page column 66-67
[15] Patent: WO2011/149950, 2011, A2, . Location in patent: Page/Page column 65-66
[16] Patent: WO2014/85795, 2014, A1, . Location in patent: Paragraph 0280
[17] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 114
[18] Patent: WO2012/158785, 2012, A1, . Location in patent: Page/Page column 89-90
[19] Patent: WO2014/81732, 2014, A1, . Location in patent: Page/Page column 31-32
[20] Patent: US2015/118229, 2015, A1, . Location in patent: Paragraph 0183
[21] Patent: WO2015/162459, 2015, A1, . Location in patent: Page/Page column 327; 328
[22] Drugs of the Future, 2018, vol. 43, # 10, p. 731 - 743
  • 36
  • [ 24241-18-7 ]
  • [ 1082843-70-6 ]
YieldReaction ConditionsOperation in experiment
83% With tert.-butylnitrite; titanium tetrachloride In dichloromethane at 20℃; for 2 h; [0953] To a solution of3,5-dibromopyrazin-2-amine (234g, 932 mmol) in DCM (700 mL) and titanium (IV) chloride(174 g, 926 mmol), tert-butyl nitrite (572 g, 5.55 mol) wasslowly added. The resulting mixture was stirred for 2 h atroom temperature and treated with water (500 mL). Theresulting mixture was extracted with DCM (3x500 mL). Thecombined organic layers were concentrated under reducedpressure. The resultant residue was purified by flash colunmchromatography on silica gel (EtOAc/petroleum ether (1:50v/v)) to obtain compound 90d as colorless oil (210 g, 83percentyield). Mass Spectrum (LCMS, ESI pos.): Calcd. forC4 HBr2ClN2 : 272.8 (M+H). found 272.6.
82% With tert.-butylnitrite; titanium tetrachloride In DCM at 0 - 20℃; Step 1: Synthesis of Compound (A') as Described in the General Reaction Scheme; 2-chloro-3,5-dibromo-pyrazineTo a well stirred solution of 2-amino-3,5-dibromopyrazine (3.21 g, 12.692 mmol) in DCM (20 1 mL) cooled to 0° C. is added TiCl4 (2.41 g, 12.692 mmol, 1.00 equiv.) in one portion, thus giving a dark red slurry. t-Butylnitrite (2.62 g, 25.385 mmol, 2.00 equiv.) is then added dropwise, causing the solution to turn bright yellow. The ice bath is then removed and the reaction is then allowed to proceed at room temperature. More TiCl4 (1.50 g, 1.2 equiv.) is added and the mixture is stirred further for one hour. At that point an orange solution has formed and LC-MS shows full conversion of the starting material to the desired product which ionises very poorly. Water (100 1 mL) is added to the reaction, forming an emulsion. DCM (50 1 mL) is added, and the DCM layer is separated, and the aqueous layer is further extracted with DCM (3.x.50 mL) until the DCM layer is colorless. The DCM layers are gathered, washed with brine and dried over anhydrous Na2SO4, to yield after solvent removal, compound A' (2.81 g, 82percent) as an orange oil, which is used as such in the following step.
Reference: [1] Patent: US2014/364414, 2014, A1, . Location in patent: Paragraph 0945; 0952-0953
[2] Patent: US2009/286798, 2009, A1, . Location in patent: Page/Page column 26-27
[3] Patent: US2011/118269, 2011, A1, . Location in patent: Page/Page column 14
[4] Patent: WO2014/1377, 2014, A1, . Location in patent: Page/Page column 153; 154
  • 37
  • [ 78-95-5 ]
  • [ 24241-18-7 ]
  • [ 1208082-91-0 ]
YieldReaction ConditionsOperation in experiment
55% for 16 h; Reflux 3,5-Dibromo-pyrazin-2-ylamine (5 g, 19.8 mmol), 2-chloro-acetone (18.3 g, 198 mmol) and dioxane (40 ml) were heated at reflux temperature for 16 h. The r.m was concentrated under reduced pressure, and the residue was triturated with DIPE. Yield: 3.6 g of intermediate 101 (55 percent).
35% at 90℃; for 16 h; Preparation of Intermediate I-05. Intermediate I-01 (2 g, 7.9 mmol) was solved in 2-chloroacetone (3 ml,). The reaction was heated in a sealed tube at 90° C. for 16 h. A precipitate appears. Then Et2O was added. The precipitate was filtered off as a salt. The resulting solid was suspended in DCM and treated with an aqueous saturated solution of Na2CO3. The organic phase was extracted, dried (MgSO4), filtered and evaporated to obtain the intermediate I-05 (1.2 g of a brown solid, Y: 35percent)
35% at 90℃; for 16 h; Sealed tube Intermediate 1-01 (2 g, 7.9 mmol) was solved in 2-chlo- roacetone (3 ml). The reaction was heated in a sealed tubeat 90° C. for 16 h. A precipitate appears. Then Et20 was added. The precipitate was filtered off as a salt. The resulting solid was suspended in DCM and treated with an aqueous saturated solution of Na2CO3. The organic phase was extracted, dried (MgSO4), filtered and evaporated to obtainthe intermediate 1-05 (1.2 g of a brown solid, Y: 35percent)
Reference: [1] Patent: WO2010/89292, 2010, A1, . Location in patent: Page/Page column 93
[2] Patent: US2012/83492, 2012, A1, . Location in patent: Page/Page column 92
[3] Patent: US9993554, 2018, B2, . Location in patent: Page/Page column 243
  • 38
  • [ 24241-18-7 ]
  • [ 1416740-16-3 ]
YieldReaction ConditionsOperation in experiment
88.7% at 10 - 20℃; for 1.5 h; Step 3: 2-bromo-7-nitro-5H-pyrrolo[2,3-b]pyrazine[00199] 2-bromo-5H-pyrrolo[2,3-b]pyrazine (20 g, 101.0 mmol) was dissolved in ice-cold sulfuric acid (140.0 mL) , producing a bright orange solution, and concentrated nitric acid (12.73 g, 8.470 mL, 202.0 mmol) was added drop wise with stirring over 30 min keeping the temperature under 10 °C (turning the solution to a clear red colour). The reaction was removed from the ice bath after 30 min and allowed to warm to ambient temperature and left to stir at ambient temperature for 1 hour. The reaction mixture was poured onto ice to obtain a yellow solid. The solid was filtered, washed with water to give 2-bromo-7-nitro-5H- pyrrolo[2,3-b]pyrazine the desired product as a yellow solid. (21.76 g, 88.7percent). MS (ES+) 244.87.
Reference: [1] Patent: WO2012/178123, 2012, A1, . Location in patent: Page/Page column 64
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