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Product Details of [ 5049-61-6 ]

CAS No. :5049-61-6 MDL No. :MFCD00006137
Formula : C4H5N3 Boiling Point : -
Linear Structure Formula :- InChI Key :XFTQRUTUGRCSGO-UHFFFAOYSA-N
M.W : 95.10 Pubchem ID :78747
Synonyms :
2-Aminopyrazine;NSC 13147

Calculated chemistry of [ 5049-61-6 ]

Physicochemical Properties

Num. heavy atoms : 7
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 : 26.44
TPSA : 51.8 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.93 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.63
Log Po/w (XLOGP3) : -0.07
Log Po/w (WLOGP) : 0.07
Log Po/w (MLOGP) : -1.13
Log Po/w (SILICOS-IT) : 0.38
Consensus Log Po/w : -0.03

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.02
Solubility : 9.09 mg/ml ; 0.0955 mol/l
Class : Very soluble
Log S (Ali) : -0.57
Solubility : 25.8 mg/ml ; 0.271 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.21
Solubility : 5.93 mg/ml ; 0.0624 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.69

Safety of [ 5049-61-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5049-61-6 ]

* 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 [ 5049-61-6 ]
  • Downstream synthetic route of [ 5049-61-6 ]

[ 5049-61-6 ] Synthesis Path-Upstream   1~56

  • 1
  • [ 5049-61-6 ]
  • [ 6270-63-9 ]
Reference: [1] Journal of the Chemical Society, 1947, p. 371
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 400
[3] Journal of Biological Chemistry, 1947, vol. 171, p. 321,324
  • 2
  • [ 19847-12-2 ]
  • [ 5049-61-6 ]
YieldReaction ConditionsOperation in experiment
82.6% at 20 - 60℃; for 5 h; A 500ml three-neck flask, was added at a concentration of 20percent sodium hydroxide (30g) solution, and sodium hypochlorite solution (100ml), was added 2-cyano-pyrazine (21g, 0.2mol) at room temperature, the reaction was stirred for 1h. Then for 4h at 50 ~ 60 , with dichloromethane (4 × 200ml) was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid 15.7g, yield 82.6percent.
Reference: [1] Patent: CN105622526, 2016, A, . Location in patent: Paragraph 0020; 0021; 0022
[2] Patent: CN108570011, 2018, A, . Location in patent: Paragraph 0012; 0013; 0014
  • 3
  • [ 14508-49-7 ]
  • [ 5049-61-6 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 14, p. 3734 - 3737
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 400
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1137 - 1140
  • 4
  • [ 136918-14-4 ]
  • [ 5049-61-6 ]
  • [ 457099-33-1 ]
YieldReaction ConditionsOperation in experiment
73% With sodium carbonate In CH2Cl2/MeOH; dichloromethane; trifluoroacetic acid Step 3:
2-(5-Amino-pyrazin-2-ylmethyl)-isoindole-1,3-dione.
To a stirred solution of the phthalimide (495 mg, 1.4 mmol) in 7 mL CH2Cl2 at room temperature in a capped flask was added trifluoroacetic acid (7 mL).
After stirring overnight, the reaction was concentrated to remove excess trifluoroacetic acid and was then dissolved in 200 mL 10/1 CH2Cl2/MeOH, stirred rapidly, and treated with a solution of 10percent Na2CO3 (200 mL).
The organics were isolated, dried (MgSO4), filtered and concentrated to give the free aminopyrazine as a yellow solid (260 mg, 73percent).
1H-NMR (400 MHz, CDCl3) δ8.25 (s, 1H), 7.85 (m, 2H), 7.77 (s, 1H), 7.74 (m, 2H), 4.83 (s, 2H)
Reference: [1] Patent: US2003/69284, 2003, A1,
  • 5
  • [ 4949-13-7 ]
  • [ 5049-61-6 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567
  • 6
  • [ 14508-49-7 ]
  • [ 5049-61-6 ]
  • [ 533930-18-6 ]
Reference: [1] Organometallics, 2017, vol. 36, # 2, p. 251 - 254
  • 7
  • [ 24241-18-7 ]
  • [ 5049-61-6 ]
  • [ 59489-71-3 ]
Reference: [1] Organic Process Research and Development, 2006, vol. 10, # 4, p. 822 - 828
  • 8
  • [ 487-21-8 ]
  • [ 5049-61-6 ]
Reference: [1] Journal of the American Chemical Society, 1945, vol. 67, p. 802,804
  • 9
  • [ 290-37-9 ]
  • [ 5049-61-6 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 1285 - 1287
  • 10
  • [ 475641-51-1 ]
  • [ 5049-61-6 ]
Reference: [1] Synlett, 2002, # 7, p. 1093 - 1096
  • 11
  • [ 475641-51-1 ]
  • [ 71-43-2 ]
  • [ 5049-61-6 ]
Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 22, p. 8800 - 8807
  • 12
  • [ 5424-01-1 ]
  • [ 5049-61-6 ]
Reference: [1] Journal of the American Chemical Society, 1945, vol. 67, p. 802,804
[2] Journal of the Chemical Society, 1947, p. 371
[3] Chemische Berichte, 1907, vol. 40, p. 4852
[4] Patent: US2479442, 1946, ,
[5] Patent: US2479442, 1946, ,
[6] Patent: US2479442, 1946, ,
[7] Patent: US2479442, 1946, ,
  • 13
  • [ 98-96-4 ]
  • [ 5049-61-6 ]
Reference: [1] Journal of the American Chemical Society, 1940, vol. 62, p. 664
  • 14
  • [ 88002-29-3 ]
  • [ 5049-61-6 ]
  • [ 88002-33-9 ]
Reference: [1] Monatshefte fuer Chemie, 1983, vol. 114, p. 789 - 798
  • 15
  • [ 2423-65-6 ]
  • [ 14508-49-7 ]
  • [ 5049-61-6 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1984, vol. 57, # 10, p. 3015 - 3016
  • 16
  • [ 98-97-5 ]
  • [ 5049-61-6 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 9, p. 1721 - 1724
  • 17
  • [ 487-21-8 ]
  • [ 7664-93-9 ]
  • [ 5049-61-6 ]
Reference: [1] Journal of the American Chemical Society, 1945, vol. 67, p. 802,804
  • 18
  • [ 17114-78-2 ]
  • [ 5049-61-6 ]
  • [ 106358-48-9 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14
  • 19
  • [ 5049-61-6 ]
  • [ 59489-71-3 ]
YieldReaction ConditionsOperation in experiment
81.5% With N-Bromosuccinimide In dichloromethane at 0℃; for 3.5 h; EXAMPLE 1A
5-bromo-2-pyrazinamine
A 0° C. solution of 2-aminopyrazine (15.0 g, 157 mmol) in dichloromethane (900 mL) was treated with N-bromosuccinimide (28.2 g, 159 mmol), stirred for 3.5 hours, and filtered through diatomaceous earth (Celite.(R).).
The filtrate was treated with silica gel (300 g) and concentrated.
The concentrate was purified by flash column chromatography with 30percent ethyl acetate/hexanes to provide 22.09 g (81.5percent) of the desired product. MS (APCI(+)) m/z 174 (M+H)+; 1H NMR(300 MHz, CDCl3) δ 8.09 (d, J=1.4 Hz, 1H), 7.77 (d, J=1.7 Hz, 1H), 4.30-4.78 (br s, 2H).
81.5% With N-Bromosuccinimide In dichloromethane at 0℃; for 3.5 h; EXAMPLE 1A
5-bromo-2-pyrazinamine
A 0° C. solution of 2-aminopyrazine (15.0 g, 157 mmol) in dichloromethane (900 mL) was treated with N-bromosuccinimide (28.2 g, 159 mmol), stirred for 3.5 hours, and filtered through diatomaceous earth (Celite.(R).).
The filtrate was treated with silica gel (300 g) and concentrated.
The concentrate was purified by flash column chromatography with 30percent ethyl acetate/hexanes to provide 22.09 g (81.5percent) of the desired product. MS (APCI(+)) m/z 174 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=1.4 Hz, 1H), 7.77 (d, J=1.7 Hz, 1H), 4.30-4.78 (br s, 2H).
77% With N-Bromosuccinimide In dichloromethane at 0℃; for 2 h; 2-Amino-5-bromopyrazine (15).; To a cooled solution of 2-aminopyrazine 11 (2.00 g, 21.00 mmol) in dichloromethane (50 mL) N-bromosuccinimide (NBS) (3.73 g, 21.00 mmol) was added in portion. The mixture was stirred at 0 0C for 2h and washed with Na2CO3 s.s. and water, the organic layer was dried over Na2SO4, filtered and the solvent removed under reduced pressure to get 2.80 g of the title compound 15 (77percent yield) as an orange solid without further purification (mp 105-110 0C). 1H-NMR (CDCl3): 4.61 (br s, 2H), 7.75 (s, IH), 8.07 (s, IH). MS (GC-MS): m/z 174 .
74% With N-Bromosuccinimide In dichloromethane at 0 - 20℃; for 4 h; /-Bromosuccinimide (8.98 g, 50 mmol) was added portionwise over 15 minutes to a solution of 2-aminopyrazine (4.75 g, 50 mmol) in dichloromethane (300 mL) at O0C. After 45 minutes at O0C, and 3 hours at room temperature, the mixture was filtered through Celite and the filtrate was concentrated. The brown residue was purified by silica chromatography, eluting with 35percent then 50percent ethyl acetate in hexane, to give 2-amino-5- bromopyrazine (6.41 g, 74percent) as a yellow solid.1H NMR (CDCI3, 400MHz) δ 8.02 (s, 1 H), 7.71 (s, 1 H), 4.58 (br s, 1 H). LCMS (1 ) Rt = 1.05 min; m/z (ESI+) 174, 176 (MH+).
72% With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide; acetonitrile at -5℃; for 0.5 h; Inert atmosphere A light yellow solution of 19.0 g (0.20 mol) of 2-aminopyrazine in 40 ml of DMF and 120 ml of acetonitrile, and a light yellow solution of 30.0 g (0.10 mol) of 1 ,3-dibromo-5,5- dimethylhydantoin (DBH) in 20 ml of DMF and 180 ml of acetonitrile are simultaneously added during 30 minutes under argon from two dropping funnels at -5°C to pre-cooled 20 ml of acetonitrile. After addition the resulting brown solution is treated with 40 ml of a 10percent-solution of sodium thiosulfate at -5°C providing a brown suspension and stirring continued until room temperature is reached. The reaction mixture is concentrated under vacuum and 180 ml of aqueous 2percent-solution of sodium carbonate added, followed by the addition of 10 g of Hyflo® filter aid. The mixture is stirred for 30 minutes, filtered, and four times extracted with a 3:2-mixture of ethyl acetate and hexane. The combined organic phases are dried over sodium sulfate and concentrated under vacuum, providing a dark oil which is further suspended in hexane and filtered giving a tacky solid. After drying under vacuum at 60°C a viscous oil is obtained which is dissolved in 100 ml of ethyl acetate and the resulting suspension filtered through a 5 cm layer of silica gel followed by rinsing the silica gel with 200 ml of ethyl acetate. The reddish brown solution is treated with activated charcoal DARCO® KB-G and stirred at room temperature during 24 hours followed by filtration and concentration under vacuum, giving the title product as light yellow viscous oil (yield: 25.0 g (72percent)). 1H-NMR (400 MHz, d6-DMSO): δ = 6.64 (s, 1 H), 7.68 (s, 1 H), 8.03 (s, 1 H)
70% With N-Bromosuccinimide In dichloromethane Preparation c-119
5-Bromo-pyrazin-2-ylamine
To a solution of pyrazin-2-ylamine (2.0 g, 21.03 mmol) in dry dichloromethane (120 mL) at 0° C., was added N-bromosuccinimide (3.74 g, 21.03 mmol) slowly to maintain the internal temperature below 0° C.
The mixture was stirred at the same temperature for 24 hours, and then washed with saturated aqueous sodium bicarbonate (30 mL) and water (30 mL).
The combined aqueous extracts were extracted with dichloromethane (3*100 mL).
The combined organic extracts were. dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo to afford the crude product.
The residue was purified by flash column chromatography (10percent to 50percent ethyl acetate/hexanes) to yield the title compound (2.57 g, 70percent) as a yellow solid. LRMS (m/z): 174 (M)-. 1H NMR (CDCl3, 300 MHz): δ 8.08 (1H, d, J=1,3 Hz), 7.76 (1H, d, J=1,3 Hz).
70% With N-Bromosuccinimide In dichloromethane at 0℃; for 24 h; To a solution of pyrazin-2-ylamine (2. 0 g, 21. 03 mmol) in dry DICHLOROMETHANE (120 mL) at 0 °C, was added N-BROMOSUCCINIMIDE (3. 74 g, 21. 03 mmol) slowly to maintain the internal temperature below 0 °C. The mixture was stirred at the same temperature for 24 hours, and then washed with saturated aqueous sodium bicarbonate (30 mL) and water (30 mL). The combined aqueous extracts were extracted with DICHLOROMETHANE (3 x 100 mL). The combined organic extracts were dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo to afford the crude product. The residue was purified by flash column chromatography (10percent to 50percent ethyl acetate/hexanes) to yield the title compound (2. 57 g, 70percent) as a yellow solid. LRMS (m/z) : 174 (M)-. 'H NMR (CDCI3, 300 MHz) : 8. 08 (1H, d, J= 1. 3 Hz), 7. 76 (1H, D, J= 1. 3 Hz).
70% With N-Bromosuccinimide In dichloromethane at 20℃; for 3 h; To a solution of pyrazin-2-amine (30 g, 0.32 mmol) in DCM (900 mL) at 0 °C was added NBS (56 g, 0.32 mmol). The reaction mixture was stirred at ambient temperature for 3 h and then washed with sat. NaHCO3 and brine. The organic layer was dried over anhydrous Na2504, filtered and concentrated to afford 5 -bromopyrazin-2-amine (38 g, 70 percent) as a white solid whichwas used directly in the next step.
65% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; for 20 h; Darkness Under absence of light and at 0° C., N-bromosuccinimide (7.84 g, 44.05 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 5.90 g of a light brown solid.
Column chromatography, using silica and a dichloromethane/ethyl acetate (3/1) mixture as the eluent, yielded pure 2-bromo-5-aminopyrazine as 5.00 g (65percent) of a light yellow solid.
1H-NMR (CDCl3, 400 Mhz): 8.09 (s, 1H, H-6), 7.77 (s, 1H, H-3), 4.65 (bs, 2H, NH) ppm.
13C-NMR (CDCl3, 100 Mhz): 153.5 (C-2), 144.3 (C-6), 131.9 (C-3), 126.8 (C-5) ppm.
62.9% With N-Bromosuccinimide In dichloromethane at 0℃; for 1 h; Inert atmosphere Step 1:
Synthesis of 5-bromopyrazin-2-amine
To a stirred solution of pyrazin-2-amine (3 g, 31.545 mmol) in anhydrous DCM (30 mL) was added NBS (5.6 g, 31.54 mmol) under nitrogen and stirred at 0° C. for 1 h.
Progress of reaction was monitored by TLC.
After reaction completion DCM was added and washed with water.
The organic layer was dried over sodium sulphate and concentrated under reduced pressure.
Crude was purified by silica gel (100-200 mesh) column chromatography using 70percent DCM/hexane to 10percent ethyl acetate in hexane as eluent to yield 5-bromopyrazin-2-amine (3.4 g, 62.9percent) as white solid.
MS: 175.1 [M++1]
56% With N-Bromosuccinimide In dichloromethane; ethyl acetate Step 1:
2-amino-5-bromopyrazine.
To a stirred, cooled (0° C) solution of amino pyrazine (5.0 g, 52.6 mmol) in methylene chloride (200 mL) was added N-bromosuccinimide (9.39 g, 52.8 mmol).
After stirring for 24 hours, the reaction was washed with aqueous 10percent sodium carbonate (3*50 mL), water (50 mL), then dried (MgSO4), and filtered.
The filtered material was concentrated under reduced pressure, taken up in minimal ethyl acetate (5 mL) followed by hexanes (200 mL).
Yellow crystals formed which were filtered and dried. (56 percent yield).
54% at 0℃; for 1 h; To a [CH2C12] (150 mL) solution of aminopyrazine (1) (5.90 g, 62 mmol) in an ice bath was added N-bromosuccinimide ("NBS", 11.1 g, 62 mmol) as a solid. The resulting mixture was stirred for 1 hr to form a brown slurry. The slurry was poured into 2 N [NA2C03] (150 mL), and extracted with [CH2C12] [(3X100] mL). The combined organic extracts were washed with brine, dried over [MGS04,] and evaporated to afford a brown solid. The crude material was purified on silica gel (eluting with 20-40percent ethyl acetate in hexane) to afford 5.80 g (54percent yield) of the desired compound (2) as an off-white solid. LCMS: [M/Z =] 174.0, 176.0 [(M+H).]
54.42% With N-Bromosuccinimide In dichloromethane at 20℃; for 6 h; Cooling To a solution of 2-aminopyrazine (i) (2 g, 21.02 mmol) in dry DCM (10 ml) was added NBS (3.78 g, 21.23 mmol) portion-wise under cold condition and the resulting mixture was allowed to stir at RT for 6h. 5 ml of water was added and the layers were separated. Aqueous layer was extracted with DCM (10 ml X 2). Combined organic layers were washed with Brine solution (5 ml), dried over anhydrous Na2S04 and concentrated under vacuum. Crude material was purified by column chromatography over silica gel 230-400 mesh by using 18percent of ethyl acetate in petroleum ether as an eluent to afford compound (ii) (1.98 g, 54.42percent) as white solid.
53% With N-Bromosuccinimide In dichloromethane at 0℃; for 1.66667 h; 2-Aminopyrazine (Aldrich, 20 g, 0.21 mol) was dissolved in 600 mL of CH2Cl2 and then cooled to 0° C. in an ice bath.
To the resulting slurry was added N-Bromosuccinimide (Aldrich, 37.6 g, 0.211 mol) portion-wise over approximately 10 min.
The slurry was allowed to mix in the ice bath for 1.5 hr.
The slurry was then filtered through a bed of Celite.(R)..
The bed of Celtite.(R). was washed with ~150 mL CH2Cl2.
The filtrate was then concentrated in vacuo to solids.
The resulting solids were purified by chromatography (silica, ethyl acetate/hexanes), producing 19.4 g (53percent) of product.
1H NMR confirmed the structure of the desired product.
52.7% With N-Bromosuccinimide In dichloromethane at 20℃; for 1.5 h; Cooling; Inert atmosphere To a suspension of 2-aminopyrazine (1) (20.0 g, 210.28 mmol) in dry DCM (200 mL) was added N-bromosuccinimide (37.42 g, 210.28 mmol) in portion wise at cold condition under nitrogen atmosphere and stirred at RT for 1.5 h. Reaction mixture was concentrated under vacuum, added 30 mL of water and filtered the crude solid. Filtrate was extracted with DCM:MeOH (9: 1, 50 mL X 4). Combined organic layers was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. Combined crude solids were purified by column chromatography over silica gel 230-400 mesh using 0-1 percent of methanol in dichloromethane as an eluent to afford product 2 (19.0 g, 52.7percent) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.03 (d, J = 1.28 Hz, 1H), 7.68 (d, J = 1.32 Hz, 1H), 6.66 (s, 2H). LC-MS APCI: Calculated for C4H4BrN3: 174.00; Observed m/z [M+H]+ 176.00.
39% With N-Bromosuccinimide In dichloromethane at 0℃; Example 17-1
Synthesis of 2-amino-5-bromopyrazine
To a solution of 2-aminopyrazine (200 g, 2.1 mol) in dichloromethane (2.5 L) cooled to between 0 °C and -5 °C, was added N-bromosuccimide (375 g, 2.1 mol) over a 4 hour period, during which time the temperature was kept below 0 °C.
The reaction mixture was kept below 0 °C overnight, stirred vigorously and quenched with water (1 L).
The mixture was filtered and washed with 10percent aqueous K2CO3.
The organic phase was dried over MgSO4 and concentrated in vacuo.
The resultant solid was triturated with hexane and ethyl acetate.
The yellow/brown solid was filtered and dried to give 2-amino-5-bromopyrazine 12* (142 g, 39 percent).
1H-NMR (270MHz, CDCl3): δ = 4.79 (2H, br.s, NH2), 6.98-7.77 (1H, s, Ar), 8.08(1 H, s, Ar).
35% With pyridine; pyridinium hydrobromide perbromide In chloroform at 20℃; for 2.16667 h; 5-bromopvrazin-2-amine (M); To a solution of 2-aminopyrazine (1.00 g, 10.0 mmol) in chloroform (50 mL) and pyridine (0.8 mL, 10.0 mmol), solid pyridineNo.HBr3 (3.37 g, 10.0 mmol) was added in portions over 10 min. The reaction mixture was stirred at room temperature for 2 h. Saturated NaHCOs aqueous solution (25 mL) was added to this reaction mixture carefully (pH 7 to 8) and stirred for 10 min. Organic layer was separated, washed with water (15 mL x 3) (filtered if necessary), dried with Na2S04, filtered, and evaporated to dryness. The residue was purified using column chromatography (silica gel, 1:1:8 hexane/CH2CI2/EtOAc). The fractions containing product were evaporated to dryness under vacuum to yield compound M as a pale yellow solid (601 mg, 3.45 mmol, 35percent). 1H NMR (DMSO-d6, 300 MHz) No. 6.63 (bs, 2H), 7.67 (d, 1H, J, 1.4), 8.02 (d, 1 H, J, 1.4).
33% With N-Bromosuccinimide In dichloromethane for 2 h; NBS (45 g, 253 mmol) was added in portions to a suspention of 2- aminopyrazine (25 g, 263 mmol) in dichloromethane (500 ml) over a period of 2h. The mixture was filtered and evaporated. The residue was suspended in dichloromethane (60 ml) and stirred for 10 minutes before hexane (60 ml) was added. The mixture was stirred vigorously for 15 minutes and filtrated. The yellow powder was washed with CH2CI2/ hexane 1 : 1 (3x). The solid was dis- solved in diethylether and washed with water (3x), dried (mgso4) and evaporated, yield: 15.0 g (33percent). Light yellow solid. HPLC 95percent Rt=I .04 (system A. 10- 97percent MeCN over 3 minutes). HPLC 95percent Rt=O.78 (system B. 10-97percent MeCN over 3 minutes). MS (elecronspray; [M+H}+ 174.4. IH NMR (400 MHz, CHLORO- FORM-D) δ ppm 4.60 (s, 2 H) 7.76 (d, J= I .51 Hz, 1 H) 8.08 (d, J= I .51 Hz, 1 H).

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[26] Patent: US2003/207920, 2003, A1,
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[28] Patent: US2008/45539, 2008, A1, . Location in patent: Page/Page column 25
[29] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4336 - 4344
[30] Chemistry - A European Journal, 2010, vol. 16, # 19, p. 5645 - 5660
[31] Patent: WO2010/100144, 2010, A1, . Location in patent: Page/Page column 106
[32] Patent: WO2010/122151, 2010, A1, . Location in patent: Page/Page column 60-61
[33] Patent: WO2012/56478, 2012, A1, . Location in patent: Page/Page column 62-63
[34] Organic Process Research and Development, 2006, vol. 10, # 4, p. 822 - 828
[35] Physical Chemistry Chemical Physics, 2014, vol. 16, # 8, p. 3617 - 3622
[36] Patent: WO2015/96035, 2015, A1, . Location in patent: Page/Page column 68
[37] Patent: WO2015/100147, 2015, A1, . Location in patent: Page/Page column 69
[38] Patent: WO2018/152405, 2018, A1, . Location in patent: Paragraph 00202
[39] Patent: WO2006/105262, 2006, A1, . Location in patent: Page/Page column 76; 77
[40] Patent: WO2004/56369, 2004, A1, . Location in patent: Page/Page column 24
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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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Reference: [1] Journal of Heterocyclic Chemistry, 1982, vol. 19, # 3, p. 673 - 674
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Reference: [1] Patent: WO2004/96797, 2004, A1, . Location in patent: Page 33-34
[2] Patent: US2004/53982, 2004, A1,
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Reference: [1] Patent: WO2004/78754, 2004, A1, . Location in patent: Page 24
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Reference: [1] Journal of the American Chemical Society, 1952, vol. 74, p. 3617,3618,3620
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Reference: [1] Collection of Czechoslovak Chemical Communications, 1989, vol. 54, # 5, p. 1306 - 1310
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14622 - 14626
  • 29
  • [ 5049-61-6 ]
  • [ 33332-29-5 ]
YieldReaction ConditionsOperation in experiment
45% With N-chloro-succinimide In chloroform (pre-treated over basic Al2O3) at 70℃; for 0.166667 h; Microwave irradiation (60W) in a sealed tube Method b:; 2-Amino-pyrazine (0.10 g, 1.05 mmol) and NCS (80 mg, 0.60 mmol) were added in a microwave tube with 1.5 mL of the anhydrous CHCl3 and sealed. The tube was placed in the microwave cavity and heated at 70°C for 10 min. (70C10M60W300Psi). After the workup, the crude (0.15 g) was purified by FCC (Hexane/DCM/ AcOEt = 1 :1 :1) to afford 35 mg (yield 45percent) of the product as yellow solid. 1H NMR (270 MHz; d6-DMSO), δ 7.99 (IH, s, H-6), 7.67 (IH, s, H-3), 6.65 (2H, bs, NH2). m/z (EI-MS): 129 (M+), 99, 94 ([M-Cl]+).; When the distilled chloroform used for the reaction was pre-treated over basic Al2O3, the black polymers formed in the reaction decreased dramatically. When NCS was added slowly into the refluxing 2-aminopyrazine, the product was isolated at 26percent. Moreover, when microwave irradiation was used at 70°C for 10 min., the yield reached 45percent (Figure 4)
26% With N-chloro-succinimide In chloroform (pre-treated over basic Al2O3) at 60℃; for 2 h; 5-chloropyrazin-2-amine (P13).; Method a:; In a double necked dry flask equipped with condenser and dropping funnel, under nitrogen flow, were added 2-amino-pyrazine (0.50 g, 5.25 mmol) and 13 mL of anhydrous CHCl3 previously passed on basic Al2O3. This solution was heated at 600C under stirring. A solution of NCS (0.35 g, 2.12 mmol) in 7 mL of the anhydrous CHCl3 was added to the mixture through dropping funnel during 1.5 hr. After another 30 minutes, the reaction was stopped and the solvent evaporated. The residue was <n="14"/>dissolved in methanol and absorbed on silica (2 g). This crude product was purified by FCC (Hexane/DCM/AcOEt = 1 :1:1) to afford 73 mg (yield 26percent) of product as yellow solid.; When the distilled chloroform used for the reaction was pre-treated over basic Al2O3, the black polymers formed in the reaction decreased dramatically. When NCS was added slowly into the refluxing 2-aminopyrazine, the product was isolated at 26percent. Moreover, when microwave irradiation was used at 70°C for 10 min., the yield reached 45percent (Figure 4)
22% With N-chloro-succinimide In dichloromethane for 5 h; Heating / reflux A 250ml round bottom flask was charged with 2-aminopyrazine (1Og, O.lmol), N-chlorosuccinimide (14g, O.lmol) and dichloromethane (100ml) under nitrogen. The reaction mixture was refluxed for 5h, then allowed to cool to room temperature. The reaction mixture was filtered though a 1 cm thick celite pad, which was then thoroughly washed with dichloromethane. The EPO <DP n="21"/>organic was concentrated in vacuo and the compound was purified by flash chromatography, using as eluent pentane/EtOAc 0percent to 50percent, to give the title compound (3g, 22percent). IHNMR (CDCl3) 4.5-4.8 (2H, brs), 7.8 (IH, s), 8.0 (IH, s).
15% With N-chloro-succinimide In dichloromethane at 40℃; for 2 h; Inert atmosphere Step 1:
Synthesis of 5-chloropyrazin-2-amine
To a stirred solution of pyrazin-2-amine (3 g, 31.545 mmol) in anhydrous DCM (30 mL) was added NCS (4.2 g, 30.545 mmol) under nitrogen and stirred at 40° C. for 2 h.
Progress of reaction was monitored by TLC.
After reaction completion DCM was added and washed with water.
The organic layer was dried over sodium sulphate and concentrated under reduced pressure.
Crude was purified by silica gel (100-200 mesh) column chromatography using 20percent ethyl acetate in hexane as eluent to yield 5-chloropyrazin-2-amine (0.59 g, 15percent) as yellow solid.
MS: 242.08 [M++1]
8.2% With N-chloro-succinimide In dichloromethane at 0℃; for 24 h; [0383] A solution of 2-aminopyrazine (23.86 g, 0.2509 mol) in methylene chloride (420 mL) was cooled to 0° C. and then treated with N-chlorosuccinimide (33.50 g, 0.2509 mol). The reaction mixture was stirred at 0° C. for 24 h. The resulting dark reaction mixture was diluted with water (500 mL) and then concentrated in vacuo to remove methylene chloride. The aqueous layer was continuously extracted with ethyl acetate until product was absence from the aqueous layer as determined by thin layer chromatography. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 25percent ethyl acetate/hexanes) afforded 2-amino-5-chloropyrazine (2.66 g, 8.2percent) as a yellow solid: mp 126-128° C.; EI-HRMS m/e calcd for C4H4ClN3 (M+) 129.0094, found 129.0090. [0384] A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 200 mg, 0.56 mmol) and triphenylphosphine (192 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyrazine (145 mg, 1.12 mmol) and 2,6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10percent aqueous hydrochloric acid solution (1.x.20 mL), a saturated aqueous sodium bicarbonate solution (1.x.20 mL) and water (1.x.20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (137 mg, 52percent) as a light yellow foam: [α]23589=-27.35° (c=0.49, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 470.0703, found 470.0705.

Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 36, p. 5937 - 5940
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 19, p. 4746 - 4758
[3] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 12; 27
[4] Journal of Heterocyclic Chemistry, 1982, vol. 19, # 3, p. 673 - 674
[5] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 11-12; 27
[6] Patent: WO2006/58074, 2006, A1, . Location in patent: Page/Page column 19-20
[7] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0562-0564
[8] Patent: US2003/225283, 2003, A1, . Location in patent: Page 49-50
[9] Australian Journal of Chemistry, 1992, vol. 45, # 5, p. 877 - 888
[10] Patent: WO2008/85316, 2008, A1, . Location in patent: Page/Page column 53
[11] Patent: WO2005/97778, 2005, A1, . Location in patent: Page/Page column 15
[12] Patent: WO2004/56369, 2004, A1, . Location in patent: Page/Page column 24
[13] Patent: WO2005/123723, 2005, A1, . Location in patent: Page/Page column 11
  • 30
  • [ 5049-61-6 ]
  • [ 33332-29-5 ]
  • [ 873-42-7 ]
YieldReaction ConditionsOperation in experiment
4% With N-chloro-succinimide In chloroform for 2 h; Heating / reflux Initial attempt showed that the reaction gave a lot of black polymers after a few <n="29"/>min., with the main product being 3,5-dichloro-2-amino pyrazine. Only small amount of 5- chloro-2-aminopyrazine was isolated (eq 7). This reaction could not be scaled up because it was not reproducible.
Reference: [1] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 26-27
  • 31
  • [ 5049-61-6 ]
  • [ 107-20-0 ]
  • [ 274-79-3 ]
YieldReaction ConditionsOperation in experiment
50% at 100℃; for 48 h; Inert atmosphere Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40percent 2-chloroacetaldehyde solution (15 mL, 78 mmol), followed by addition of sodium bicarbonate (6.60 g, 78 mmol).
After stirring for 48 hours at 100 °C, the reaction mixture was cooled to room temperature, added with 100 mL of a saturated potassium carbonate solution, and extracted with dichloromethane (100 mL*3).
The organic phase was combined, dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain imidazo[1,2-a]pyrazine 4b (3 g, yield 50.0percent) as a brown solid.
MS m/z (ESI): 120.1 [M+1]
50% at 100℃; for 48 h; Step 1
imidazo[1,2-c]pyrazine
Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40percent 2-chloroacetaldehyde solution (15 mL, 78 mmol), followed by addition of sodium bicarbonate (6.60 g, 78 mmol).
After stirring for 48 hours at 100° C., the reaction mixture was cooled to room temperature, added with 100 mL of a saturated potassium carbonate solution, and extracted with dichloromethane (100 mL*3).
The organic phase was combined, dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain imidazo[1,2-a]pyrazine 4b (3 g, yield 50.0percent) as a brown solid.
MS m/z (ESI): 120.1 [M+1]
35% With sodium hydrogencarbonate In water at 100℃; for 48 h; A mixture of 2-aminopyrazin (25 g, 262.9 mmole), chloroacetaldehyde (50percent in water, 50 ml, 394 mmole) and NaHCO3 (33.1 g, 394 mmole) was heated for 2 days at 100° C. The reaction mixture was then cooled to RT, satd. K2CO3 solution (100 ml) was added, and the mixture was washed with DCM. The organic phase was dried over Na2SO4 and then concentrated by evaporation to dryness. Purification was carried out by column chromatography on silica gel (DCM/methanol, 95:5+5percent NH4OH [35percent].
35% With sodium hydrogencarbonate In water at 100℃; for 48 h; 5, 6 , 7 , 8-tetrahydroimidazo [1, 2-a] pyrazine A29Stage 1. was added to a mixture of 2-aminopyrazin (25 g, 262.9 mmole), chloroacetaldehyde (50percent in water, 50 ml, 394 mmole) and NaHCO3 (33.1 g, 394 mmole) and heated for 2 days at 1000C. The reaction mixture was then cooled to RT, saturated K2CO3 solution (100 ml) was added, and the mixture was washed with DCM. The organic phase was dried over sodium sulfate and then concentrated by evaporation to dryness . Purification was carried out by column <n="108"/>chromatography on silica gel (DCM / methanol, 95:5 + 5percent NH4OH [35percent] .
24% With sodium hydrogencarbonate In water at 100℃; for 48 h; A mixture of 2-aminopyrazine (25 g, 262.9 mmol) and chloroacetaldehyde (50percent solution in water, 50 ml, 394 mmol) was heated for 2 d at 100° C. in the presence of sodium hydrogen carbonate (33.1 g, 394 mmol). The reaction mixture was cooled to room temperature, and saturated potassium carbonate solution (100 ml) was added thereto. Extraction with dichloromethane was then carried out, and the organic phase was dried (Na2SO4) and concentrated. Purification was carried out by column chromatography (dichloromethane/methanol 95:5+5percent NH4OH [35percent]). Yield: 7.6 g (24percent)
0.8 g at 90℃; for 5 h; Sealed tube Imidazo[1,2-aJpyrazine: A solution of aminopyrazine (1 g, 10.5 mmol) and chloroacetaldehyde (50percent wt in H,O; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated at 90°C5 in a sealed tube for 5 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and diluted with dichlorornethane (DCM). The organic layer washed with saturated aqueous NaHCO3 then dried over MgSO4 and concentrated. The crude product was purifiedsilica gel flash chromatography (eluted with 10percent MeOH/DCM) to provide 0.8 g of product.

Reference: [1] Patent: EP2604610, 2013, A1, . Location in patent: Paragraph 0089; 0090
[2] Patent: US2013/131068, 2013, A1, . Location in patent: Paragraph 0115; 0116
[3] Patent: US2009/186899, 2009, A1, . Location in patent: Page/Page column 36
[4] Patent: WO2009/90055, 2009, A1, . Location in patent: Page/Page column 106; 107
[5] Patent: US2008/153843, 2008, A1, . Location in patent: Page/Page column 67
[6] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
[7] Patent: WO2007/75869, 2007, A2, . Location in patent: Page/Page column 50
[8] Patent: WO2013/162727, 2013, A1, . Location in patent: Page/Page column 53
[9] Patent: US2014/336182, 2014, A1, . Location in patent: Paragraph 0532
  • 32
  • [ 5049-61-6 ]
  • [ 2032-35-1 ]
  • [ 274-79-3 ]
YieldReaction ConditionsOperation in experiment
94% With hydrogen bromide In ethanol; water at 70 - 80℃; for 17 h; To a solution of aminopyrazine (5 g, 53 mol, 1 eq.) in ethanol (212 ml) was added bromoacetaldehyde diethylacetal (12 ml, 80 mol, 1.5 eq.) and HBr (48percent, 26.5 ml).
The mixture was heated at 70-80° C. for 17 hours.
The mixture was then cooled to rt (room temperature), then a mixture of 1N NaOH (200 ml) and 20percent IPA/DCM (isopropyl alcohol/Dichloromethane) was added to the reaction mixture.
The combined organic layer was dried over sodium sulfate and concentrated to afford 5.9 g of brown solid of imidazo[1,2-a]pyrazine (yield 94percent).
1H-NMR (400 MHz, DMSO-d6) δ 9.05 (m, 1H), 8.60 (dd, 1H), 8.13 (d, 1H), 7.87 (d, 1H), 7.81 (d, 1H).
MS m/z 120 [M++1].
24.01% With hydrogen bromide In ethanol for 24 h; Reflux 2-Pyrazinamine (9.51 g, 100 mmol) was dissolved in ethanol (300 ml) and 2-bromo- 1 ,1-bis(ethyloxy)ethane (21.06 ml, 140 mmol) was added. 48percent hydrobromic acid (33.3 ml) was added and the mixture heated at reflux for 24 hr. The solution was concentrated in vacuo to a crude solid that was basified with 10percent ammonia-ice (300ml). The solution was extracted in to ethyl acetate (3 x 300ml), the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid, (4.76g). The solid was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100percent [25percent 2M ammonmia/methanol in dichloromethane] in dichloromethane gradient) to afford imidazo[1 ,2-a]pyrazine (2.86 g, 24.01 mmol, 24.01 percent yield).).1H NMR (CDCI3, 400 MHZ) d 9.11 (s, 1 H), 8.10 (d, 1 H, J = 4.8 Hz, 7.88 (d, 1 H. 4.8 Hz, 7.83 (s, 1 H), 7.71 (s, 1 H)
Reference: [1] Patent: US2004/220189, 2004, A1, . Location in patent: Page 21
[2] Patent: WO2010/125101, 2010, A1, . Location in patent: Page/Page column 50
  • 33
  • [ 5049-61-6 ]
  • [ 97-97-2 ]
  • [ 274-79-3 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride In ethanol; water at 70 - 80℃; for 12 h; 2-amino-pyrazine (10g, 0.1mmol) was dissolved in 150ml of absolute ethanol, and slowly added dropwise to the above solution chloroacetaldehyde dimethylacetal (18.7g, 0.15mmol), then added dropwise 37percent of concentrated hydrochloric acid, the pH of the reaction system is 3-4, after completion of the dropwise addition, the reaction system was heated to 70-80 , TLC detection progress of the reaction, 12 hours after the completion of the reaction, the reaction solution was cooled to room temperature, is added 1N sodium hydroxide solution to adjust the pH value of the reaction system to 8-9, then adding a mixed solvent of 200ml of isopropanol and methylene chloride (wherein the isopropanol / dichloromethane 1/5 volume ratio) was extracted, and extracted twice , the combined organic phases were dried over anhydrous sodium sulfate, filtered, dried organic solvent was spin-indole [1,2-A] pyrazine 11g, yield of about 90percent
Reference: [1] Patent: CN103864799, 2016, B, . Location in patent: Paragraph 0028 - 0031
  • 34
  • [ 5049-61-6 ]
  • [ 7252-83-7 ]
  • [ 274-79-3 ]
YieldReaction ConditionsOperation in experiment
72% With hydrogen bromide In ethanol; water for 18 h; Heating / reflux 2-Aminopyrazine (100 mg, 1.1 mmol) and bromoacetaldehyde dimethylacetal (253 mg, 1.6 mmol) were dissolved in ethanol (4.5 ml), hydrobromic acid (48percent, 0.5 ml) added and the mixture was heated under reflux for 18 h.
The solution was allowed to cool to room temperature then pre-adsorbed directly onto silica.
Purification by silica gel chromatography eluding with dichloromethane and 1percent conc. ammonia on a gradient of methanol (1-4percent) gave imidazo[1,2-α]pyrazine (90 mg, 72percent) as a white crystalline solid: δH (360 MHz, CDCl3) 6.70 (1H, s), 7.82 (1H, s), 7.88 (1H, d, J 4), 8.29 (1H, d, J 4), 9.12 (1H, s).
536 mg With hydrogenchloride In ethanol for 14 h; Reflux To a solution of 2-aminopyrazine (2.0 g, 21.03 mmol) in ethanol (40 mL) was added 2-bromo-1,1-dimethoxyethane (2.5 mL, 21.03 mmol) followed by 5 drops of concentrated hydrochloric acid. After refluxing for 14 hours, the solvent was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (100percent ethyl acetate, 10percent methanol in ethyl acetate, then 10percent methanol in dichloromethane) to give 536 mg of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.70 (bs, 1H), 7.82 (bs, 1H), 7.89 (d, 1H, J=4.4 Hz), 8.10 (d, 1H, J=4.6 Hz), 9.12 (s, 1H)
420 mg With hydrogen bromide In ethanolReflux 2-Aminopyrazine (500 mg, 5.26 mmol) was dissolved in ethanol (25 mL), and bromoacetaldehyde dimethyl acetal (0.93 mL, 7.89 mmol) and 40percent hydrobromic acid (3 mL) were added thereto. Heat to reflux overnight.After completion of the reaction, it was cooled to room temperature, and a 1N aqueous sodium hydroxide solution (20 mL) was added thereto.Extracted with 20percent isopropanol / dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was purified by silica gel column chromatography to give a white solid420mg.
Reference: [1] Patent: US2004/19057, 2004, A1, . Location in patent: Page/Page column 9
[2] Patent: US5028605, 1991, A,
[3] Patent: US2015/359793, 2015, A1, . Location in patent: Paragraph 0198
[4] Patent: CN104341425, 2018, B, . Location in patent: Paragraph 0169; 0171; 0172; 0173
  • 35
  • [ 5049-61-6 ]
  • [ 24241-18-7 ]
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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  • [ 5049-61-6 ]
  • [ 873-42-7 ]
YieldReaction ConditionsOperation in experiment
57% With N-chloro-succinimide In tetrahydrofuran at 100℃; for 10 h; Inert atmosphere 2-Aminopyrazine (0.50 g, 5.26 mmol) was dissolved in THF (50 mL), and N-chlorosuccinimide (1.62 g, 12.1 mmol) was added to the solution with stirring. The mixture was refluxed at 100 °C for 10 h. After cooling, solvent was evaporated. The residue was directly purified by column chromatography. Finally, the obtained product was washed with pentane/diethyl ether (5:1) to 2-Amino-3,5-dichloropyrazine 1b (492 mg, 57percent) as a slightly yellow solid. 1H NMR (200 MHz, CDCl3) δ 7.99 (s, 1H), 5.10 (br, 2H)
Reference: [1] Organic Letters, 2016, vol. 18, # 9, p. 1976 - 1979
[2] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 12, p. 4271 - 4274
[3] Organic Letters, 2013, vol. 15, # 9, p. 2156 - 2159
[4] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 27
  • 40
  • [ 5049-61-6 ]
  • [ 33332-29-5 ]
  • [ 873-42-7 ]
YieldReaction ConditionsOperation in experiment
4% With N-chloro-succinimide In chloroform for 2 h; Heating / reflux Initial attempt showed that the reaction gave a lot of black polymers after a few <n="29"/>min., with the main product being 3,5-dichloro-2-amino pyrazine. Only small amount of 5- chloro-2-aminopyrazine was isolated (eq 7). This reaction could not be scaled up because it was not reproducible.
Reference: [1] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 26-27
  • 41
  • [ 5049-61-6 ]
  • [ 121-44-8 ]
  • [ 65032-08-8 ]
YieldReaction ConditionsOperation in experiment
78% With [(phenylbenzothiazole)2Ir(nBu)3]OTf In 5,5-dimethyl-1,3-cyclohexadiene at 155℃; for 10 h; Inert atmosphere; Schlenk technique A novel process for the reaction of a secondary amine by reaction of 2-aminopyrazine with triethylamine, comprising the steps of:Under nitrogen protection,Under nitrogen protection,2-aminopyrazine (95 mg, 1 mmol) was added to a 50 mL Schlenk tube,Triethylamine (304 mg, 3 mmol),[(Bt) 2 * Ir * P (nBu) 3] OTf (9.6 mg, 0.01 mmol, 1.0 molpercent),Add 2.0mL xylene;The reaction solution was reacted at 155 ° C for 10 h,The resulting solution was separated on a silica gel column from 200 to 300 mesh (eluent 1:10 ethyl acetate / petroleum ether)After removal of the solvent,To get the product.Yield: 78percent.
Reference: [1] Patent: CN104710257, 2017, B, . Location in patent: Paragraph 0042; 0043; 0044
  • 42
  • [ 5049-61-6 ]
  • [ 75-03-6 ]
  • [ 65032-08-8 ]
Reference: [1] Tetrahedron, 2012, vol. 68, # 44, p. 9009 - 9015
  • 43
  • [ 5049-61-6 ]
  • [ 59489-71-3 ]
  • [ 21943-12-4 ]
  • [ 24241-18-7 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1982, vol. 19, # 3, p. 673 - 674
  • 44
  • [ 5049-61-6 ]
  • [ 87005-15-0 ]
  • [ 78109-26-9 ]
Reference: [1] Patent: US2003/203897, 2003, A1,
  • 45
  • [ 5049-61-6 ]
  • [ 2579-22-8 ]
  • [ 90734-76-2 ]
YieldReaction ConditionsOperation in experiment
52% With iron(III) chloride In toluene at 60℃; for 18 h; General procedure: A mixture of 2-aminopyridine (0.2 mmol), 3-phenylpropiolaldehyde (0.2 mmol) and ferric chloride (5 molpercent) in toluene (1 mL) was placed in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 60 °C for 18 h. After the reaction was finished, water (5 mL) was added and the solution was extracted with ethyl acetate (3×5 mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 22, p. 11209 - 11214
[2] Tetrahedron Letters, 2018, p. 667 - 670
  • 46
  • [ 5049-61-6 ]
  • [ 70-23-5 ]
  • [ 77112-52-8 ]
YieldReaction ConditionsOperation in experiment
27%
Stage #1: at 20℃; for 2.5 h;
Stage #2: for 2 h; Reflux
[0077] Method A- oxylate [0078] To a stirred solution of 2-aminopyrazine (1.0 g, 10.5 mmol) in dimethoxyethane, ethyl bromopyruvate (2.36 g, 13.0 mmol) was added at room temperature and stirred for 2.5 hours. The reaction mixture was cooled to 0°C and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with ethyl acetate to give a pale brown solid. The precipitate was suspended in 50 mL ethyl alcohol and heated at reflux temperature to turn to a clear solution. After refluxing for 2 hours, the reaction mixture was concentrated under reduced pressure and then mixed with CH2CI2 and saturated aqueous NaHCC>3 solution. The mixture was filtered through a pad of Celite, and the separated organic layer was dried by Na2S04 and filtered. The residue was applied to silica gel column chromatography, and the column was eluted with (CH2Cl2:MeOH = 99:1 to 97:3), and the collected fractions were concentrated under reduced pressure. The title compound was obtained as pale yellow crystals (0.546 g, 27percent). *H NMR (400 MHz, CDC13) δ 9.21 (s, 1H), 8.26 (s, 1H), 8.09 (dd, 7 = 4.7, 1.6 Hz, 1H), 7.96 (d, 7 = 4.7 Hz, 1H), 4.49 (q, 7 = 7.1 Hz, 2H), 1.45 (t, 7 = 7.1 Hz, 3H).
22%
Stage #2: for 2 h; Heating / reflux
Step 1: Imidazo [1, 2-a] pyrazine-2-carboxylic acid ethyl ester:; Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2- aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with Et20 to give pale brown crystals. The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution. After refluxing for 2h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCI3 and saturated NaHCO3aq. The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCis-MeOH (99/1-97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHCI3- Et20. The titled compound was obtained as pale pink crystals. Yield : 10.9 g, 22percent). 'H NMR (CDCI3) 8 d 1.46 (t, 3H, J = 7.2 Hz), 4.49 (q, 2H, J = 7.2 Hz), 7.96 (d, 1H, J=4. 7Hz), 8.08 (dd, 1 H, J = 1. 2,4. 7 Hz), 8.26 (s, 1 H), 9.21 (d, 1 H, J = 1. 2 Hz).
22% at 0 - 20℃; for 3 h; Example 9; Preparation of (5R), (6Z)-6- (7-Methyl-5. 6, 7, 8-tetrahydroimidazor1, 2-alpyrazin-2- vlmethylene)-7-oxo-4-thia-1-aza-bicyclor3. 2. Olhept-2-ene-2-carboxylic acid, sodium salt Step 1 : Imidazo [1, 2-a] pyrazine-2-carboxylic acid ethyl ester: Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2- aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0 °C and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with Et20 to give pale brown crystals. The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution. After refluxing for 2h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCI3 and saturated NaHCO3aq. The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCI3- MeOH (99/1-97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHC13-Et20. The titled compound was obtained as pale pink crystals. Yield : 10.9 g, 22percent). 'H NMR (CDCI3) d 1.46 (t, 3H, J = 7.2 Hz), 4.49 (q, 2H, J = 7.2 Hz), 7.96 (d, 1 H, J = 4.7 Hz), 8.08 (dd, 1H, J= 1.2, 4.7 Hz), 8.26 (s, 1H), 9.21 (d, 1 H, J = 1.2 Hz).
22%
Stage #1: at 20℃; for 2.5 h;
Stage #2: at 0℃; for 2.5 h; Heating / reflux
Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2-aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h.
The reaction mixture was cooled to 0° C. and stirred for 30 min to afford a pale brown precipitate.
The precipitate was filtered and washed with Et2O to give pale brown crystals.
The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution.
After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCl3 and saturated NaHCO3aq.
The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgSO4) and filtered.
The filtrate was concentrated under reduced pressure.
The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-MeOH (99/1~97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHCl3-Et2O.
The titled compound was obtained as pale pink crystals. Yield: 10.9 g, 22percent).
1H NMR(CDCl3)δ d 1.46(t, 3H, J=7.2 Hz), 4.49(q, 2H, J=7.2 Hz), 7.96(d, 1H, J=4.7 Hz), 8.08(dd, 1H, J=1.2, 4.7 Hz), 8.26(s, 1H), 9.21 (d, 1H, J=1.2 Hz).
20%
Stage #1: at 0 - 25℃; for 4.5 h;
Stage #2: for 4 h; Heating / reflux
To a solution of 2-amino pyrazine (20 g, 210 mmol) in dimethoxy ethane (400 ml) was added ethyl bromopyruvate (32.8 ml) at 25° C. and the resulting reaction mixture was allowed to stir at the same temperature for 4 hrs. It was then cooled to 0° C. and stirred for 30 minutes. The separated solid was filtered and washed with ether. Solid residue was taken in ethanol (1000 ml) and refluxed for 4 hrs. Solvent was removed completely, residue taken in chloroform (1000 ml), saturated sodium bicarbonate solution (700 ml) was added to it and the mixture was allowed to stir for 45 minutes. The mixture was filtered through celite bed, washed several times with chloroform and filtrate was dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude mass, which was purified by crystallization using ether-methanol mixture.Yield: 20percent
20%
Stage #1: at 0 - 25℃; for 4.5 h;
Stage #2: for 4 h; Heating / reflux
To a solution of 2-amino pyrazine (20 g, 210 mmol) in dimethoxy ethane (400 ml) was added ethyl bromopyruvate (32.8 ml) at 25° C. and the resulting reaction mixture was allowed to stir at the same temperature for 4 hrs. It was then cooled to 0° C. and stirred for 30 minutes. The separated solid was filtered and washed with ether. Solid residue was taken in ethanol (1000 ml) and refluxed for 4 hrs. Solvent was removed completely, residue taken in chloroform (1000 ml), saturated sodium bicarbonate solution (700 ml) was added to it and the mixture was allowed to stir for 45 minutes. The mixture was filtered through celite bed, washed several times with chloroform and filtrate was dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude mass, which was purified by crystallization using ether-methanol mixture. Yield: 20percent
20%
Stage #1: at 0 - 25℃; for 4.5 h;
Stage #2: for 4 h; Reflux
Stage #3: With sodium hydrogencarbonate In chloroform; water for 0.75 h;
To a solution of 2-amino pyrazine (2Og, 210 mmol) in dimethoxy ethane (400 ml) was added ethyl bromopyruvate (32.8 ml) at 25°C and the resulting reaction mixture was allowed to stir at the same temperature for 4 hrs . It was then cooled to O0C and stirred for 30 minutes. The separated solid was filtered and washed with ether. Solid residue was taken in ethanol (1000ml) and refluxed for 4hrs. Solvent was removed completely, residue taken in chloroform (1000ml), saturated sodium bicarbonate solution (700 ml) was added to it and the mixture was allowed to stir for 45 minutes . The mixture was filtered through celite bed, washed several times with chloroform and filtrate was dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude mass, which was purified by crystallization using ether-methanol mixture. Yield : 20percent
20% at 20℃; for 5 h; Synthesis of 206-A. A mixture of ethyl 3-bromo-2-oxopropanoate (10.8 g, 55.3 mmol) and pyrazin-2-amine (5.0 g, 52.6 mmol) in DME (150 mL) was stirred at room temperature for 5 h. The precipitate was collected by filtered. Then the cake was dissolved in EtOH (100 mL) and stirred at 80 oC for 2 h. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 2 : 1~ 1 : 2) to give 206-A (2.0 g, 20percent) as a yellow solid.
450 mg
Stage #1: at 20 - 35℃; for 2 h;
Stage #2: With ethanol In 1,2-dimethoxyethane for 2 h; Reflux
Ethyl bromopyruvate (2.15 g, 11.04 mmol) was added to stirred solution of 2-aminopyrazine (1 g, 10.5 mmol) in 1,2-Dimethoxy ethane (10 mL). The reaction mixture was stirred at 20-35° C. for 2 h. The mixture was then filtered to obtain a solid precipitate which was dried well, dissolved in EtOH (10 mL) and refluxed for 2 h. This mixture was concentrated, diluted with aqueous saturated sodium bicarbonate solution, extracted with chloroform.-The chloroform layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using 60-120 silica gel and 60percent EtOAc in Hexane as eluent) to afford 450 mg of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 9.22 (1H, s), 8.28 (1H, s), 8.12-8.08 (1H, m), 8 (1H, d, J=4.8 Hz), 4.52-4.47 (2H, m), 1.5 (3H, t).

Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3687 - 3706
[2] Farmaco, Edizione Scientifica, 1981, vol. 36, # 1, p. 61 - 80
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2300 - 2304
[4] Patent: WO2014/113191, 2014, A1, . Location in patent: Paragraph 0077; 0078
[5] European Journal of Medicinal Chemistry, 1983, vol. 18, # 5, p. 413 - 417
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4623 - 4637
[7] Patent: WO2003/93279, 2003, A1, . Location in patent: Page/Page column 50
[8] Patent: WO2003/93277, 2003, A1, . Location in patent: Page/Page column 68-69
[9] Patent: US2006/276445, 2006, A1, . Location in patent: Page/Page column 12
[10] Patent: US2009/186899, 2009, A1, . Location in patent: Page/Page column 45-46
[11] Patent: US2009/186899, 2009, A1, . Location in patent: Page/Page column 46-47
[12] Patent: WO2009/90055, 2009, A1, . Location in patent: Page/Page column 134
[13] Patent: WO2017/7756, 2017, A1, . Location in patent: Paragraph 496
[14] Journal of Chemical Research, Miniprint, 1984, # 2, p. 468 - 480
[15] Patent: US2004/132708, 2004, A1,
[16] Patent: WO2013/134226, 2013, A1, . Location in patent: Page/Page column 96
[17] Patent: US2015/5280, 2015, A1, . Location in patent: Paragraph 0771 - 0773
[18] Patent: WO2004/58266, 2004, A1, . Location in patent: Page/Page column 57
[19] Patent: WO2005/110410, 2005, A2, . Location in patent: Page/Page column 322
  • 47
  • [ 5049-61-6 ]
  • [ 92234-23-6 ]
  • [ 77112-52-8 ]
Reference: [1] Patent: US2013/236468, 2013, A1, . Location in patent: Paragraph 0344
  • 48
  • [ 5049-61-6 ]
  • [ 65868-37-3 ]
  • [ 77112-52-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
  • 49
  • [ 5049-61-6 ]
  • [ 70-23-5 ]
  • [ 77112-53-9 ]
Reference: [1] Patent: US2015/5280, 2015, A1, . Location in patent: Paragraph 0605 - 0607
  • 50
  • [ 5049-61-6 ]
  • [ 16182-04-0 ]
  • [ 88002-33-9 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: at 20℃; for 18 h; Cooling with ice
Stage #2: With hydroxylamine hydrochloride; triethylamine In 1,4-dioxane; methanol; ethanol at 20℃; for 5 h; Reflux
Step 1. [l,2,4]triazolo[l,5-a]pyrazin-2-amine [0190] To a stirred solution of pyrazin-2-amine (25.0 g, 0.26 mol) in dioxane (300 mL) was added O- ethyl carbonisothiocyanatidate (37.90 g, 0.29 mol) dropwise under ice-water bath. After stirring for 18 hrs at rt, the mixture was concentrated. A mixture of TEA (109 mL, 0.78 mol) and hydroxylamine hydrochloride (72.50 g, 1.04 mol) in MeOH/EtOH (200 mL : 200 mL) was then added to the suspension The resulting mixture was stirred for 1 hr at rt, then the heated to reflux to afford a clear solution. After refluxing for additional 4 hs, the mixture was cooled to rt and concentrated to afford the crude which was recrystallized with 95percent ethanol to afford the title compound as a pale yellow solid (32.03 g, 91percent). MS (ESI) calcd for C5H5N5: 135.1; found: 136.3 [M+H]. *H NM (400 MHz, d6- DMSO) δ 8.83 (d, J = 1.2 Hz, 1H), 8.68 (dd, J = 4.4 and 1.2 Hz, 1H), 7.97 (d, J = 4.4 Hz, 1H), 6.45 (brs, 2H).
33%
Stage #1: at 20℃; for 18 h;
Stage #2: With hydroxylamine hydrochloride; triethylamine In methanol; ethanol at 20℃; for 6 h; Reflux
To a solution of pyrazin-2-amine (2S g, 260 mmol)in dioxane (300 ml) at room temperature was added ethoxycarbonyl-isothiocyanate (37.9 g, 289 mmol) slowly. The mixturewas stirred for 18 hours and the solvent was evaporatedunder vacuum. The residual solid was dissolved in a mixtureof methanol (1SO ml) and ethanol (1SO ml). To this solutionwas added TEA (109 ml, 780 mmol) and hydroxylaminehydrochloride (72.S g, 1040 mmol). The mixture was stirredat room temperature for 2 hours and was heated to reflux for4 hours. The crude mixture was cooled to room temperatureand the solvent was evaporated. The residual solid was purifiedby colunm chromatography (0-20percent methanol/ClLx.'L)to obtain a white solid (60 g). The solid was taken into EtOAcand water. The aqueous layer was extracted with EtOActwice. The combined organic layer was washed with brineand dried over sodium sulfate to obtain [I ,2,4]triazolo[1 ,S-a]pyrazin-2-amine as a white solid (12 g, 88 mmol, 33percent).
Reference: [1] Patent: WO2016/100349, 2016, A2, . Location in patent: Paragraph 0190
[2] Patent: JP5714745, 2015, B2, . Location in patent: Paragraph 0535; 0536
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3687 - 3706
  • 51
  • [ 88002-29-3 ]
  • [ 5049-61-6 ]
  • [ 88002-33-9 ]
Reference: [1] Monatshefte fuer Chemie, 1983, vol. 114, p. 789 - 798
  • 52
  • [ 887144-97-0 ]
  • [ 5049-61-6 ]
  • [ 213019-67-1 ]
Reference: [1] Journal of Fluorine Chemistry, 2010, vol. 131, # 9, p. 951 - 957
  • 53
  • [ 5049-61-6 ]
  • [ 2314-97-8 ]
  • [ 213019-67-1 ]
Reference: [1] Journal of Fluorine Chemistry, 2010, vol. 131, # 1, p. 98 - 105
  • 54
  • [ 5049-61-6 ]
  • [ 70-23-5 ]
  • [ 1286754-14-0 ]
YieldReaction ConditionsOperation in experiment
28.9% at 0 - 30℃; for 4.5 h; Inert atmosphere Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol).
After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0 °C and stirred for 30 minutes until a solid precipitated.
The reaction mixture was filtered, and the filter cake was washed with ether (10 mLx3).
The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours.
The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid.
MS m/z (ESI): 192.1 [M+1]
Reference: [1] Patent: EP2604610, 2013, A1, . Location in patent: Paragraph 0121; 0122
  • 55
  • [ 5049-61-6 ]
  • [ 64-17-5 ]
  • [ 1113-59-3 ]
  • [ 1286754-14-0 ]
YieldReaction ConditionsOperation in experiment
28.9%
Stage #1: at 20 - 30℃; for 4 h;
Stage #2: for 4 h; Reflux
Step 1
ethyl imidazo[1,2-c]pyrazine-3-carboxylate
Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol).
After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0° C. and stirred for 30 minutes until a solid precipitated.
The reaction mixture was filtered, and the filter cake was washed with ether (10 mL*3).
The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours.
The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid.
MS m/z (ESI): 192.1 [M+1]
Reference: [1] Patent: US2013/131068, 2013, A1, . Location in patent: Paragraph 0176; 0177
  • 56
  • [ 5049-61-6 ]
  • [ 886860-50-0 ]
YieldReaction ConditionsOperation in experiment
70.5% With N-iodo-succinimide In methanol at 80℃; for 10 h; A 1000 mL single-neck round bottom flask was charged with 2-aminopyrazine (28.50 g, 300 mmol), N-iodosuccinimide(134.99 g, 600 mmol), methanol 340 ml,The mixture in the reaction flask was stirred at 80 ° C for 10 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 give pure product2-Amino-5-iodopyrazine, after drying,Calculated yield 70.50percentPurity 99.58percent (HPLC).
40% With N-iodo-succinimide In water; dimethyl sulfoxide at 20℃; for 12.5 h; Cooling with ice 2-amino pyrazine (20 g, 0.21 mmol) and DMSO (300 mL), was dissolved in water (10 mL), and the at ice bath N- iodosuccinimide ( 49.7 g, 0.22mmol) was added, after stirring for 30 minutes, stirred at room temperature for 12 hours. Ethyl acetate - extracted from the water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) as eluant to afford the title compound (18.5 g, 40percent) as a yellow solid
Reference: [1] Patent: CN106674137, 2017, A, . Location in patent: Paragraph 0009-0011; 0012-0014; 0015-0016
[2] Heterocycles, 2012, vol. 86, # 2, p. 1323 - 1339
[3] Patent: JP2015/54838, 2015, A, . Location in patent: Paragraph 0083; 0084
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