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[ CAS No. 181284-14-0 ] {[proInfo.proName]}

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Chemical Structure| 181284-14-0
Chemical Structure| 181284-14-0
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Product Details of [ 181284-14-0 ]

CAS No. :181284-14-0 MDL No. :MFCD10697772
Formula : C6H4ClN3 Boiling Point : -
Linear Structure Formula :- InChI Key :SMGGFRMRMZFJEV-UHFFFAOYSA-N
M.W : 153.57 Pubchem ID :292467
Synonyms :

Calculated chemistry of [ 181284-14-0 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 36.72
TPSA : 49.57 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) : -6.38 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.45
Log Po/w (XLOGP3) : 1.2
Log Po/w (WLOGP) : 1.31
Log Po/w (MLOGP) : -0.48
Log Po/w (SILICOS-IT) : 1.93
Consensus Log Po/w : 1.08

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.99
Solubility : 1.56 mg/ml ; 0.0102 mol/l
Class : Very soluble
Log S (Ali) : -1.84
Solubility : 2.23 mg/ml ; 0.0145 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.73
Solubility : 0.289 mg/ml ; 0.00188 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.21

Safety of [ 181284-14-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 181284-14-0 ]

* 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.

  • Downstream synthetic route of [ 181284-14-0 ]

[ 181284-14-0 ] Synthesis Path-Downstream   1~46

  • 1
  • [ 623-51-8 ]
  • [ 181284-14-0 ]
  • [ 181284-15-1 ]
  • 2
  • [ 88394-05-2 ]
  • [ 181284-14-0 ]
YieldReaction ConditionsOperation in experiment
35% With triethylamine; trichlorophosphate; at 0℃; for 4.0h;Reflux; To a mixture of 3-hydroxy-5-methylpyrazine-2-carboxamide (155 g, 1 .01 mol) and TEA (205 g, 2.03 mol) was added dropwise POCb (500 niL) at 0 C. The reaction mixture was reflux ed for 4 h and then cooled to room temperature. The mixture was concentrated under vacuum and then ethyl acetate (500 mL) and saturated aqueous NaHCOs (1000 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 500 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (95:5) to afford 3-chloro-5-methylpyrazine-2-carbonitrile (55 g, 35% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3): 5 8.51 (s, IH), 2.69 (s, 3H)
  • 3
  • [ 181284-14-0 ]
  • 7-isocyanato-3-methyl-thieno[2,3-<i>b</i>]pyrazine-6-carboxylic acid ethyl ester [ No CAS ]
  • 4
  • [ 181284-14-0 ]
  • 3-[2-((3aR,9bR)-6-Methoxy-1,3,3a,4,5,9b-hexahydro-benzo[e]isoindol-2-yl)-ethyl]-7-methyl-1H-pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% EXAMPLE 92A 3-Cyano-2-chloro-6-methyl-pyrazine 3-Carboxamido-2-hydroxy-6-methylpyrazine (4.09 g, 26.70 mmol), prepared by the method of Dick and Wood, J. Chem. Soc.,1379 (1955), was treated as described in Example 91A with triethylamine (5.41 g, 53.41 mmol) and 70 ml POCl3 to yield the title compound (3.16 g, 77%) as a fluffy yellow solid. mp: 63-65 C. 1 H NMR (300 MHz, CDCl3) delta2.70 (s, 3H), 8.50 (s, 1H). MS (DCI/NH3) m/e 171 (M+NH4)+.
  • 6
  • [ 7732-18-5 ]
  • [ 497-19-8 ]
  • [ 623-51-8 ]
  • [ 181284-14-0 ]
  • ethyl-3-amino-6-methyl-thieno[2,3-b]pyrazine-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% In ethanol; EXAMPLE 92B Ethyl-3-amino-6-methyl-thieno[2,3-b]pyrazine-2-carboxylate The compound resulting from Example 92A (1.00 g, 6.51 mmol) was treated as described in Example 41A with ethyl thioglycolate (0.782 g, 6.51 mmol) and Na2 CO3 (0.69 g, 6.51 mmol) in 20 ml EtOH. Recrystallization of the crude product from EtOH/H2 O gave the title compound (1.12 g, 72%) as a bright yellow solid. mp: 121-123 C. 1 H NMR (300 MHz, CDCl3) delta1.41 (t, 3H), 2.71 (s, 3H), 4.38 (q, 2H), 6.15 (br s, 2H), 8.45 (s, 1H). MS (DCI/NH3) m/e 238 (M+H)+, 255 (M+NH4)+. Analysis calc'd. for C10 H11 N3 O2 S: C, 50.62; H, 4.67; N, 17.71; Found: C, 50.75; H, 4.45; N, 17.70.
  • 7
  • [ 181284-14-0 ]
  • benzyl 4-(4-(2-(7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamido)ethyl)phenyl)piperazine-1-carboxylate [ No CAS ]
  • 8
  • [ 181284-14-0 ]
  • 7-amino-3-methyl-N-(4-(piperazin-1-yl)phenethyl)thieno[2,3-b]pyrazine-6-carboxamide [ No CAS ]
  • 9
  • [ 181284-14-0 ]
  • tert-butyl 3-(4-(2-(7-amino-3-methylthieno[2,3b]pyrazine-6-carboxamido)ethyl)-2-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
  • 10
  • [ 181284-14-0 ]
  • N-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-chlorophenethyl)-7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide [ No CAS ]
  • 11
  • [ 181284-14-0 ]
  • tert-butyl 3-(4-(2-(7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamido)ethyl)-2,5-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
  • 12
  • [ 181284-14-0 ]
  • N-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2,5-difluorophenethyl)-7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide [ No CAS ]
  • 13
  • [ 181284-14-0 ]
  • C28H35FN6O3S [ No CAS ]
  • 14
  • [ 181284-14-0 ]
  • tert-butyl 3-(4-((S)-1-(7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamido)propan-2-yl)-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
  • tert-butyl 3-(4-((R)-1-(7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamido)propan-2-yl)-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
  • 15
  • [ 181284-14-0 ]
  • N-((2S)-2-(4-(3,8-diazabicyclo[3.2.1]octan3-yl)-3-fluorophenyl)propyl)-7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide [ No CAS ]
  • 16
  • [ 181284-14-0 ]
  • 7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxylic acid [ No CAS ]
  • 17
  • [ 2365-48-2 ]
  • [ 181284-14-0 ]
  • methyl 7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; To a solution of <strong>[181284-14-0]3-chloro-5-methylpyrazine-2-carbonitrile</strong> (19 g, 0.12 mol) and methyl 2-mercaptoacetate (14 g, 0.13 mol) in THF (200 mL) was added NaH (60% dispersion in mineral oil; 7.5 g, 0.19 mol) in small portions at 0 C. The reaction mixture was stirred overnight at RT and then water (200 mL) was carefully added to quench the reaction. The resulting mixture was extracted with ethyl acetate (2 x 300 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via silica gel column chromatography eluting with petroleum ether / EtOAc (90: 10 to 70:30) to afford methyl 7-amino-3-methylthieno[2,3-6]pyrazine-6-carboxylate (20 g, 72%> yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-fifc): delta 8.68 (s, IH), 7.10 (br s, 2H), 3.83 (s, 3H), 2.65 (s, 3H)
  • 18
  • [ 163271-08-7 ]
  • [ 181284-14-0 ]
  • tert-butyl N-[1-(3-cyano-6- methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% [00683] 3-Chloro-5-methylpyrazine-2-carbonitrile (1.1 g, 0.007 mol) was dissolved in anhydrous DMF (11 mL) and DIPEA (3.74 mL, 0.021 mol) was added. After stirring for 30 min at room temperature <strong>[163271-08-7]tert-butyl (4-methylpiperidin-4-yl)carbamate</strong> (1.84 g, 0.008 mol) was added in one portion. The reaction mixture was stirred overnight at room temperature, then diluted with EtOAc and extracted with 2% NaCl (aq.). The organic layer was dried over Na2SC4 and concentrated under reduced pressure. The desired product was purified via column chromatography (DCM/acetone 97:3) to yield tert-butyl N-[l-(3-cyano-6- methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate as a pale yellow solid (2.14 g, 90%). 1H MR (400 MHz, DMSO-i) delta 7.97 (s, 1H), 6.67 (bs, 1H), 3.96 (dt, J = 13.7, 4.3 Hz, 2H), 3.39 (dd, J = 13.4, 10.3 Hz, 2H), 2.42 (s, 3H), 2.15 (d, J = 13.4 Hz, 2H), 1.51 (ddd, J = 14.1, 10.6, 3.9 Hz, 2H), 1.40 (s, 9H), 1.27 (s, 3H).
  • 19
  • [ 88394-05-2 ]
  • [ 181284-14-0 ]
YieldReaction ConditionsOperation in experiment
75% With triethylamine; trichlorophosphate; at 0℃; for 2.0h;Reflux; [00682] 5-Methyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (2.0 g, 0.013 mol), was suspended in Et3N (3.63 mL, 0.026 mol), cooled to 0 C and reacted with 36.5 mL POCb. The mixture was heated to reflux for 2 hr and concentrated under reduced pressure. The resulting black oil was extracted with ether (5x50 mL), and the combined extracts were treated with 10% Na2C03 (150 mL). The organic layers were separated, washed with water and brine, dried (Na2S04), and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford 3-chloro-5-methylpyrazine-2-carbonitrile (1.5 g, 75%) as a fluffy solid. NMR (400 MHz, DMSO- d6) delta 8.77 (s, 1H), 2.63 (s, 3H).
  • 20
  • [ 181284-14-0 ]
  • tert-butyl N-[1-(5-bromo-3-cyano-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate [ No CAS ]
  • 21
  • [ 181284-14-0 ]
  • tert-butyl N-{1-[3-cyano-5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate [ No CAS ]
  • 22
  • [ 181284-14-0 ]
  • tert-butyl N-{1-[3-(aminomethyl)-5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate [ No CAS ]
  • 23
  • [ 181284-14-0 ]
  • N-[3-(4-amino-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methyl}formamide [ No CAS ]
  • 24
  • [ 181284-14-0 ]
  • 1-(5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl)-4-methylpiperidin-4-amine [ No CAS ]
  • 25
  • [ 181284-14-0 ]
  • tert-butyl N-{1-[3-(aminomethyl)-6-methylpyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate [ No CAS ]
  • 26
  • [ 181284-14-0 ]
  • C13H21N5O [ No CAS ]
  • 27
  • [ 181284-14-0 ]
  • 4-methyl-1-(6-methylimidazo[1,5-a]pyrazin-8-yl)piperidin-4-amine [ No CAS ]
  • 28
  • [ 181284-14-0 ]
  • [ 5521-57-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 5%-palladium/activated carbon; hydrogen; triethylamine / methanol / 10 h / 20 - 100 °C / 15001.5 Torr / Autoclave 2: dihydrogen peroxide; sodium hydroxide monohydrate / water / 1 h / 55 - 60 °C / pH 8 - 9
  • 29
  • [ 181284-14-0 ]
  • [ 5521-58-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 5%-palladium/activated carbon; hydrogen; triethylamine / methanol / 10 h / 20 - 100 °C / 15001.5 Torr / Autoclave 2: dihydrogen peroxide; sodium hydroxide monohydrate / water / 1 h / 55 - 60 °C / pH 8 - 9 3: sodium hydroxide; bromine / water / 4 h / 0 - 80 °C
  • 30
  • [ 181284-14-0 ]
  • [ 98006-91-8 ]
YieldReaction ConditionsOperation in experiment
With 5%-palladium/activated carbon; hydrogen; triethylamine In methanol at 20 - 100℃; for 10h; Autoclave; 1-3 Preparation of 5-methyl-2-cyanopyrazine Take the 106g crude product obtained in the previous step,Add to the 1L autoclave,Add 74g of triethylamine as acid binding agent,500ml methanol, 5g palladium-carbon catalyst (5%),At room temperature, replace with nitrogen three times and replace with hydrogen three times,Set the initial pressure to 2.0MPa,The temperature is raised to 100 degrees to carry out the hydrogenation reaction.The reaction is over after about 10 hours, the temperature is lowered, the pressure is relieved, and the filter isThe filtrate was concentrated to obtain 68 g of brown-yellow crude product with a yield of 85%.
  • 31
  • [ 181284-14-0 ]
  • (3-chloro-5-methylpyrazin-2-yl)methanamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With hydrogen; acetic acid at 20℃; for 20h; Inert atmosphere; Step-1: Synthesis of (3-Chloro-5-methylpyrazin-2-yl)methanamine (E-2.1) To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (E-1.1, 1.00 g, 6.51 mmol) in acetic acid (20.0 mL) was added Raney Nickel (0.055 g, 0.65 mmol) under inert atmosphere. This reaction mixture was stirred for 20 h under hydrogen bladder pressure at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth and washed with ethyl acetate (2 × 20 mL). The organic layer was concentrated under vacuum and diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 15 mL). The aqueous layer was concentrated to give the crude product, which was triturated with acetonitrile (5 mL) to afford (3-chloro-5-methylpyrazin-2- yl)methanamine (E-2.1, 1.0 g, yield: 78%) as a light brown solid: ESI (m/z) 158 [C6H8ClN3+H]+.
78% With hydrogen; acetic acid at 20℃; for 20h; 1 Step 1: (3-Chloro-5-methylpyrazin-2-yl)methanamine (Compound C-2.1): To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (C-1.1, 1.00 g, 6.51 mmol) in acetic acid (20.0 mL) was added Raney Nickel (0.055 g, 0.65 mmol) under inert atmosphere. This reaction mixture was stirred for 20 h under hydrogen bladder pressure at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth and washed with ethyl acetate (2 20 mL). The organic layer was concentrated under vacuum and diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 15 mL). The aqueous layer was concentrated to give the crude product, which was triturated with acetonitrile (5 mL) to afford (3-chloro-5-methylpyrazin-2-yl)methanamine (C-2.1, 1.0 g, yield: 78%) as a light brown solid: ESI (m/z) 158 [C6H8ClN3+H]+.
78% With hydrogen; acetic acid at 20℃; for 20h; Inert atmosphere; To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (E-1.1, 1.00 g, 6.51 mmol) in acetic acid (20.0 mL) was added Raney Nickel (0.055 g, 0.65 mmol) under inert atmosphere. This reaction mixture was stirred for 20 h under hydrogen bladder pressure at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth and washed with ethyl acetate (2 × 20 mL). The organic layer was concentrated under vacuum and diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 15 mL). The aqueous layer was concentrated to give the crude product, which was triturated with acetonitrile (5 mL) to afford (3- chloro-5-methylpyrazin-2-yl)methanamine (E-2.1, 1.0 g, yield: 78%) as a light brown solid: ESI (m/z) 158 [C6H8ClN3+H]+.
78% With hydrogen; acetic acid at 20℃; for 20h; Inert atmosphere; To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (E-1.1, 1.00 g, 6.51 mmol) in acetic acid (20.0 mL) was added Raney Nickel (0.055 g, 0.65 mmol) under inert atmosphere. This reaction mixture was stirred for 20 h under hydrogen bladder pressure at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth and washed with ethyl acetate (2 × 20 mL). The organic layer was concentrated under vacuum and diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 15 mL). The aqueous layer was concentrated to give the crude product, which was triturated with acetonitrile (5 mL) to afford (3- chloro-5-methylpyrazin-2-yl)methanamine (E-2.1, 1.0 g, yield: 78%) as a light brown solid: ESI (m/z) 158 [C6H8ClN3+H]+.

  • 32
  • [ 181284-14-0 ]
  • N-((3-chloro-5-methylpyrazin-2-yl)methyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C
Multi-step reaction with 2 steps 1: acetic acid; hydrogen / 20 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C
  • 33
  • [ 181284-14-0 ]
  • 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C
Multi-step reaction with 3 steps 1: acetic acid; hydrogen / 20 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C
Multi-step reaction with 3 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / acetonitrile; N,N-dimethyl-formamide / 2 h / 0 - 80 °C
  • 34
  • [ 181284-14-0 ]
  • 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 20 - 60 °C
Multi-step reaction with 4 steps 1: acetic acid; hydrogen / 20 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 60 °C
Multi-step reaction with 4 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / acetonitrile; N,N-dimethyl-formamide / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 60 °C
  • 35
  • [ 181284-14-0 ]
  • 1-iodo-3,6-dimethylimidazo[1,5-a]pyrazin-8-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 20 - 60 °C 5: ammonia / isopropanol / 48 h / 120 °C / Autoclave
Multi-step reaction with 5 steps 1: acetic acid; hydrogen / 20 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 60 °C 5: ammonia / isopropanol / 48 h / 120 °C / Autoclave
Multi-step reaction with 5 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / acetonitrile; N,N-dimethyl-formamide / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 60 °C 5: ammonia / isopropanol / 48 h / 120 °C / Autoclave
  • 36
  • [ 181284-14-0 ]
  • (3-chloro-5-methylpyrazin-2-yl)methanamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% Stage #1: 3-chloro-5-methylpyrazine-2-carbonitrile With hydrogen; acetic acid at 20℃; for 20h; Inert atmosphere; Stage #2: With hydrogenchloride Step-1: Synthesis of (3-chloro-5-methylpyrazin-2-yl)methanamine (J-2) To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (J-1, 5.00 g, 3.26 mmol) in acetic acid (80.0 mL) was added Raney Nickel (1.55 g, 6.65 mmol.) under inert atmosphere. After completion of addition, resulting reaction mixture was stirred for 20 h under hydrogen atmosphere (~30 psi) at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth, washed with EtOAc (2 × 100 mL). The organic layer was concentrated to obtain crude material, which was diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 100 mL). The aqueous layer was concentrated to obtain viscous mass was triturated with acetonitrile (5 mL) to afford (3- chloro-5-methylpyrazin-2-yl)methanamine hydrochloride (J-2, 6.10 g, yield: 88%) as a light brown solid: ESI (m/z) 158 [C6H8ClN3+H]+.
88% Stage #1: 3-chloro-5-methylpyrazine-2-carbonitrile With hydrogen; acetic acid at 20℃; for 20h; Stage #2: With hydrogenchloride In water 1 Step 1: Synthesis of (3-chloro-5-methylpyrazin-2-yl)methanamine (G-2): To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (G-1, 5.00 g, 3.26 mmol) in acetic acid (80.0 mL) was added Raney Nickel (1.55 g, 6.65 mmol.) under inert atmosphere. After completion of addition, resulting reaction mixture was stirred for 20 h under hydrogen atmosphere (~30 psi) at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth, washed with EtOAc (2 100 mL). The organic layer was concentrated to obtain crude material, which was diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 100 mL). The aqueous layer was concentrated to obtain viscous mass was triturated with acetonitrile (5 mL) to afford (3-chloro-5-methylpyrazin-2-yl)methanamine hydrochloride (G-2, 6.10 g, yield: 88%) as a light brown solid: ESI (m/z) 158 [C6H8ClN3+H]+.
  • 37
  • [ 181284-14-0 ]
  • N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3-oxocyclobutanecarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C
Multi-step reaction with 2 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C
Multi-step reaction with 2 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C
  • 38
  • [ 181284-14-0 ]
  • 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3-yl)cyclobutanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C
Multi-step reaction with 3 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C
Multi-step reaction with 3 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C
  • 39
  • [ 181284-14-0 ]
  • 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3-yl)cyclobutanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C
Multi-step reaction with 4 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C
Multi-step reaction with 4 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C
  • 40
  • [ 181284-14-0 ]
  • 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C 5: tetrahydrofuran / 4.75 h / -78 - -20 °C / Inert atmosphere
Multi-step reaction with 5 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C 5: tetrahydrofuran / 2.25 h / -78 °C / Inert atmosphere
Multi-step reaction with 5 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C 5: tetrahydrofuran / 2.25 h / -78 °C / Inert atmosphere
  • 41
  • [ 181284-14-0 ]
  • 3-(8-amino-1-bromo-6-methylimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C 5: tetrahydrofuran / 4.75 h / -78 - -20 °C / Inert atmosphere 6: ammonia / isopropanol / 18 h / 120 °C / Autoclave
Multi-step reaction with 6 steps 1: acetic acid; hydrogen / 20 h / 20 °C / 1551.49 Torr 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C 5: tetrahydrofuran / 2.25 h / -78 °C / Inert atmosphere 6: ammonia / isopropanol / 18 h / 120 °C / Autoclave
Multi-step reaction with 6 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / dichloromethane; ethyl acetate / 1 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; ethyl acetate / 1 h / 0 - 20 °C 4: N-Bromosuccinimide / N,N-dimethyl-formamide / 0.67 h / 20 °C 5: tetrahydrofuran / 2.25 h / -78 °C / Inert atmosphere 6: ammonia / isopropanol / 18 h / 120 °C
  • 42
  • [ 181284-14-0 ]
  • N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 20 - 60 °C 5: ammonia / isopropanol / 48 h / 120 °C / Autoclave 6: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / N,N-dimethyl-formamide; water monomer / 1.33 h / 120 °C / Inert atmosphere; Microwave irradiation
Multi-step reaction with 6 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / acetonitrile; N,N-dimethyl-formamide / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 60 °C 5: ammonia / isopropanol / 48 h / 120 °C / Autoclave 6: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / N,N-dimethyl-formamide; water monomer / 1.33 h / 120 °C / Inert atmosphere; Microwave irradiation
  • 43
  • [ 181284-14-0 ]
  • N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide [ No CAS ]
  • N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3-fluorophenyl)-2-hydroxyacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 20 - 60 °C 5: ammonia / isopropanol / 48 h / 120 °C / Autoclave 6: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / N,N-dimethyl-formamide; water monomer / 1.33 h / 120 °C / Inert atmosphere; Microwave irradiation 7: chiralcel OX-H column / methanol; carbon dioxide / 40 °C / Resolution of racemate; Supercritical conditions; liquid CO2
Multi-step reaction with 7 steps 1: acetic acid; hydrogen / 20 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / acetonitrile; N,N-dimethyl-formamide / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 60 °C 5: ammonia / isopropanol / 48 h / 120 °C / Autoclave 6: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / N,N-dimethyl-formamide; water monomer / 1.33 h / 120 °C / Inert atmosphere; Microwave irradiation 7: carbon dioxide / methanol / 40 °C / Supercritical conditions; Resolution of racemate
  • 44
  • [ 181284-14-0 ]
  • 1-(5-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-4-fluoroindolin-1-yl)-2-(6-methylpyridin-2-yl)ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: acetic acid; hydrogen / 20 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 14 h / 0 °C 3: trichlorophosphate / N,N-dimethyl-formamide; acetonitrile / 2 h / 0 - 80 °C 4: N-iodo-succinimide / N,N-dimethyl-formamide / 3 h / 60 °C 5: ammonia / isopropyl alcohol / 48 h / 120 °C / Autoclave 6: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 1.5 h / 110 °C / Microwave irradiation; Inert atmosphere
  • 45
  • [ 53242-78-7 ]
  • [ 181284-14-0 ]
  • 6-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In butan-1-ol at 90 - 120℃; for 20h; Intermediate 90 (±)-6-cyclopropyl-1-[4-(dimethylamino)butan-2-yl]-1H-pyrazolo[3,4-b]pyrazin-3-amine General procedure: To a solution of 3-chloro-5-cyclopropylpyrazine-2-carbonitrile (1.00 g, 5.57 mmol, intermediate 1) in 15 mL 1 -butanol was added potassium carbonate (3.08 g, 22.3 mmol) and (±)-3-hydrazinyl-N,N-dimethylbutan-1-amine - hydrogen chloride (1/1) (1.40 g, 8.35 mmol). The mixture was stirred for 4 hours at 120°C and over night at room temperature. The reaction mixture was diluted with 150 mL ethyl acetate, extracted with water twice, brine, dried using a hydrophobic filter and evaporated to dryness. The residue was purified by column chromatographiy using a Biotage chromatography system (55g snap NH column, hexane / 0-100% ethyl acetate then ethyl acetate / 0-100% ethanol) to give 668 mg (80 % purity, 35 % yield) of desired compound. LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 276 [M+H]+ -NMR (400 MHz, DMSO-d6) d [ppm]: 0.840 (0.51), 0.858 (1.29), 0.876 (0.67), 0.998 (1.09), 1.002 (0.79), 1.011 (0.83), 1.018 (1.11), 1.023 (0.89), 1.032 (0.60), 1.035 (0.60), 1.067 (0.87), 1.077 (0.72), 1.088 (0.94), 1.096 (0.60), 1.152 (1.64), 1.170 (3.54), 1.187 (1.80), 1.344 (3.18), 1.361 (3.16), 1.389 (1.36), 1.405 (1.28), 1.885 (0.41), 1.893 (0.58), 1.904 (0.41), 1.917 (0.67), 1.928 (0.52), 1.949 (0.76), 1.951 (0.76), 1.954 (0.75), 1.971 (0.75), 1.986 (6.39), 1.993 (0.51), 2.010 (16.00), 2.038 (0.82), 2.071 (6.10), 2.076 (1.10), 2.292 (0.53), 3.682 (0.44), 3.944 (0.42), 3.997 (0.41), 4.015 (1.27), 4.033 (1.28), 4.051 (0.42), 5.730 (1.84), 6.498 (0.64), 8.129 (1.71), 8.310 (3.91).
  • 46
  • [ 13061-96-6 ]
  • [ 313339-92-3 ]
  • [ 181284-14-0 ]
YieldReaction ConditionsOperation in experiment
11% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; cesium fluoride In toluene at 90℃; for 16h; Intermediate 111 3-chloro-5-methylpyrazine-2-carbonitrile To a mixture of 3,5-dichloropyrazine-2-carbonitrile (1.00 g, 5.75 mmol) and methylboronic acid (413 mg, 6.90 mmol) in 10 ml_ toluene cesium fluoride (2.62 g, 17.2 mmol) and 1,1'- bis(diphenylphosphino)ferrocenepalladium(ll) chloride (210 mg, 287 pmol; CAS- RN:[72287-26-4]). The mixture was stirred for 16 hours at 90°C. After cooling to room temperature the mixture was filtered under suction and the filter cake was washed with ethyl acetate. The filtrate was concentrated and the residue was purified using a Biotage chromatography system to give 105 mg (95 % purity, 11 % yield) of the disered title compound. -NMR (400 MHz, DMSO-d6) d [ppm]: 2.616 (16.00), 4.023 (1.20), 8.773 (3.94).
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