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Structure of 51171-02-9

Chemical Structure| 51171-02-9

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Product Details of [ 51171-02-9 ]

CAS No. :51171-02-9
Formula : C6H5BrN2O2
M.W : 217.02
SMILES Code : BrC1=NC=CN=C1C(=O)OC
MDL No. :MFCD08753935
InChI Key :CMITUAXQMWSHLL-UHFFFAOYSA-N
Pubchem ID :13318551

Safety of [ 51171-02-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 51171-02-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 2
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 41.01
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

52.08 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.69
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.82
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.03
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

-0.09
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.41
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.97

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.97
Solubility 2.31 mg/ml ; 0.0106 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.5
Solubility 6.93 mg/ml ; 0.0319 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.59
Solubility 0.56 mg/ml ; 0.00258 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.04 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.08

Application In Synthesis of [ 51171-02-9 ]

* 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 [ 51171-02-9 ]

[ 51171-02-9 ] Synthesis Path-Downstream   1~29

  • 1
  • [ 16298-03-6 ]
  • [ 51171-02-9 ]
YieldReaction ConditionsOperation in experiment
63% With hydrogen bromide; bromine; sodium nitrite; In water; at 0℃; for 0.25h; Bromine (3.91 g, 24.46 mmol) was added dropwise to a stirred mixture of 3- aminopyrazine-2-carboxylic acid methyl ester (1.27 g, 8.29 mmol) and hydrobromic acid (4.70 mL, 41.5 mmol) at 00C. A solution of sodium nitrite (1.44 g, 20.9 mmol) in water (6 mL) was then added dropwise. The reaction mixture was stirred for 15 min, brought to pH 8 with NaHCO3 (saturated, aqueous), and extracted with ethyl acetate (80 mL) and chloroform (50 mL). The combined organics were dried over MgSO4 and concentrated in vacuoto give 1.13 g (63%) of an orange oil which solidified on standing.
63% With hydrogen bromide; bromine; sodium nitrite; In water; at 0℃; for 0.25h; Bromine (3.91 g, 24.46 mmol) was added dropwise to a stirred mixture of 3- aminopyrazine-2-carboxylic acid methyl ester (1.27 g, 8.29 mmol) and hydrobromic acid (4.70 mL, 41.5 mmol) at 00C. A solution of sodium nitrite (1.44 g, 20.9 mmol) in water (6 mL) was then added dropwise. The reaction mixture was stirred for 15 min, brought to pH 8 with NaHCO3 (saturated, aqueous), and extracted with ethyl acetate (80 mL) and chloroform (50 mL). The <n="47"/>combined organics were dried over MgSO4 and concentrated in vacuo to give 1.13 g (63%) of an orange oil which solidified on standing. LC-MS m/z 217 (M+H+); RT 1.15 mm.
63% With hydrogen bromide; bromine; sodium nitrite; In water; at 0℃; for 0.25h; Bromine (3.91 g, 24.46 mmol) was added dropwise to a stirred mixture of 3- aminopyrazine-2-carboxylic acid methyl ester (1.27 g, 8.29 mmol) and hydrobromic acid (4.70 mL, 41.5 mmol) at 00C. A solution of sodium nitrite (1.44 g, 20.9 mmol) in water (6 mL) was then added dropwise. The reaction mixture was stirred for 15 min, brought to pH 8 with NaHCO3 (saturated, aqueous), and extracted with ethyl acetate (80 mL) and chloroform (50 mL). The combined organics were dried over MgSO4 and concentrated in vacuoto give 1.13 g (63%) of an orange oil which solidified on standing.
46% With bromine; sodium nitrite; In chloroform; water; hydrogen bromide; EXAMPLE 157A Methyl 3-bromopyrazine-2-carboxylate To a rapidly stirring heterogeneous mixture of 3-aminopyrazine-2-carboxylic acid methyl ester (2.00 g, 13.1 mmol) in 48% hydrobromic acid (7.9 mL) cooled to 0 C. was added bromine (2.00 mL, 6.2 g, 38.8 mmol) dropwise over 5 minutes. Then a solution of sodium nitrite (2.27 g, 32.8 mmol) in 9.5 mL of water was added dropwise over 10 minutes. The reaction mixture was stirred at 0 C. for 15-30 minutes and then basified with 60 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate followed by chloroform. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was flash chromatographed on silica gel eluding with mixtures of hexane and ethyl acetate to afford the title compound (1.265 g, 46%). m.p. 43.5-44 C. 1 H NMR (CDCl3, 300 MHz) delta 4.04 (s, 3H), 8.50 (bs, 1H), 8.60 (bs, 1H). MS (DCl/NH3) m/e 217/219 (M+H)+, 234/236 (M+H+NH3)+.
12% With tert.-butylnitrite; copper(I) bromide; In acetonitrile; at 60℃; for 0.25h; Example 81; Synthesis of (3,5-bis-trifluoromethyl-benzyl)- [3-(cycIopentylmethyl-ethyl-amino)- pyrazin-2-ylmethyl]-carbamic acid methyl ester; Step (i): Synthesis of 3-bromo-pyrazine-2-carboxylic acid methyl ester; Copper bromide (1.36 g, 6.1 mmol) and £-butyl nitrite (0.78 g, 7.6 mmol) were added to a 50 mL round bottom flask along with acetonitrile (2 niL), and this mixture was heated at 60 0C for 5 min. After this time, 3-amino-pyrazine-2-carboxylic acid methyl ester (0.8 g, 5.09 mmol) was added portion- wise, with stirring, and stirring was continued at the same temperature for another 10 min. The reaction mixture was then cooled to RT, poured into 100 mL of dilute HCL (2N), and then extracted with diethyl ether (3 x 50 mL). The combined organic layer was washed with dilute HCl, dried over sodium sulfate, and then concentrated under vacuum to afford the title compound (0.139 g), yield: 12 %.1H NMR (CDCl3, 400 MHz): d 8.58 (m, 2H), 4.04 (s, 3H)) ; m/z (CI-MS) 217 (M+) ; IR (neat, cm-1): 3385, 2955, 1742
With hydrogen bromide; bromine; sodium nitrite; In water; (A) Methyl 2-bromo-3-pyrazine carboxylate To a stirred mixture of 12.7 g. of methyl 2-amino pyrazine carboxylate and 47 ml. of 48% hydrobromic acid there was added, dropwise, 12.6 ml. of bromine keeping the temperature at 0. A solution of 14.4 g. of sodium nitrite in 60 ml. of water was then added, dropwise, at 0 and the reaction mixture stirred for 15 minutes. The reaction mixture was basified to pH 8 with sodium bicarbonate and extracted with ethyl acetate and again with chloroform. The organic layers were dried over magnesium sulfate, filtered and concentrated to a yellow oil. Recrystallization from ether-hexane yielded the product, m.p. 43-45 C.
With hydrogen bromide; bromine; sodium nitrite; In water; (A) Methyl 2-bromo-3-pyrazine carboxylate: To a stirred mixture of 12.7 g. of methyl 2-amino pyrazine carboxylate and 47 ml. of 48% hydrobromic acid there was added, dropwise, 12.6 ml. of bromine keeping the temperature at 0. A solution of 14.4 g. of sodium nitrite in 60 ml. of water was then added, dropwise, at 0 and the reaction mixture stirred for 15 minutes. The reaction mixture was basified to pH 8 with sodium bicarbonate and extracted with ethyl acetate and again with chloroform. The organic layers were dried over magnesium sulfate, filtered and concentrated to a yellow oil. Recrystallization from ether-hexane yielded the product, m.p. 43-45 C.
With hydrogen bromide; bromine; sodium nitrite; In water; (A) Methyl 2-bromo-3-pyrazine carboxylate To a stirred mixture of 12.7 g. of methyl 2-amino pyrazine 3-carboxylate and 47 ml. of 48% hydrobromic acid there is added, dropwise, 12.6 ml. of bromine keeping the temperature at 0. A solution of 14.4 g. of sodium nitrite in 60 ml. of water is then added, dropwise, at 0 and the reaction mixture stirred for 15 minutes. The reaction mixture is basified to pH 8 with sodium bicarbonate and extracted with ethyl acetate and again with chloroform. The organic layers are dried over magnesium sulfate, filtered and concentrated to a yellow oil. Recrystallization from ether-hexane yields the product, m.p. 43-45 C.
With hydrogen bromide; bromine; sodium nitrite; In water; (A) Methyl 2-bromo-3-pyrazine carboxylate: To a stirred mixture of 12.7 g. of methyl 2-aminopyrazine 3-carboxylate and 47 ml. of 48% hydrobromic acid there is added, dropwise, 12.6 ml. of bromine keeping the temperature at 0. A solution of 14.4 g. of sodium nitrite in 60 ml. of water is then added, dropwise, at 0 and the reaction mixture stirred for 15 minutes. The reaction mixture is basified to pH 8 with sodium bicarbonate and extracted with ethyl acetate and again with chloroform. The organic layers are dried over magnesium sulfate, filtered and concentrated to a yellow oil. Recrystallization from ether-hexane yields the product, m.p. 43-45 C.
With hydrogen bromide; bromine; sodium nitrite; In water; at 0℃; for 2h; Step 1: synthesis of methyl 3-bromopyrazine-2-carboxylate (99)To a solution of methyl 3-amino-2-pyrazinecarboxylate (13.06 mmol, 2 g) in hydrobromic acid (13.06 mmol, 7.4 ml, 1.057 g) at 0C was added bromine (38.9 mmol, 2 mL, 6.22 g) drop wise and then a solution of sodium nitrite (33.3 mmol, 2.3 g) in water (4 mL). The reaction was stirred for 2h at 0C and the reaction mixture was extracted with CH2CI2. Organic layer was dried and evaporated to give crude methyl 3- bromopyrazine-2-carboxylate 101 (1.2gr, 43%). (m/z) = 217 and 219 (M+H)+.
With hydrogen bromide; bromine; sodium nitrite; In water; at 0℃; for 2h; Step 1: synthesis of methyl 3-bromopyrazine-2-carboxylate (99)[0305]To a solution of methyl 3-amino-2-pyrazinecarboxylate (13.06 mmol, 2 g) in hydrobromic acid (13.06 mmol, 7.4 ml, 1.057 g) at 0 C. was added bromine (38.9 mmol, 2 mL, 6.22 g) drop wise and then a solution of sodium nitrite (33.3 mmol, 2.3 g) in water (4 mL). The reaction was stirred for 2 h at 0 C. and the reaction mixture was extracted with CH2Cl2. Organic layer was dried and evaporated to give crude methyl 3-bromopyrazine-2-carboxylate 101 (1.2 gr, 43%). (m/z)=217 and 219 (M+H)+.

  • 2
  • [ 51171-02-9 ]
  • [ 143618-46-6 ]
  • [ 151322-82-6 ]
YieldReaction ConditionsOperation in experiment
(A) Methyl 2-bromo-3-pyrazine carboxylate: To a stirred mixture of 12.7 g. of methyl-2-amino pyrazine carboxylate and 47 ml. of 48% hydrobromic acid there was added, dropwise, 12.6 ml. of bromine keeping the temperature at 0. A solution of 14.4 g. of sodium nitrite in 60 ml. of water was then added, dropwise, at 0 and the reaction mixture stirred for 15 minutes. The reaction mixture was basified to pH 8 with sodium bicarbonate and extracted with ethyl acetate and again with chloroform. The organic layers were dried over magnesium sulfate, filtered and concentrated to a yellow oil. Recrystallization from ether-hexane yielded the product, m.p. 43-45 C.
  • 5
  • [ 51171-02-9 ]
  • [ 151-50-8 ]
  • CuCN [ No CAS ]
  • [ 6164-77-8 ]
  • 6
  • [ 51171-02-9 ]
  • 3-{Butyl-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-pyrazine-2-carboxylic acid [ No CAS ]
  • 7
  • [ 51171-02-9 ]
  • 3-{Butyl-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-pyrazine-2-carboxylic acid methyl ester [ No CAS ]
  • 8
  • [ 51171-02-9 ]
  • [ 50541-93-0 ]
  • [ 784155-40-4 ]
YieldReaction ConditionsOperation in experiment
In isopropyl alcohol;Heating / reflux; A mixture of methyl 2-bromopyrazine-3-carboxylate (J. Med. Chem. , 1969, 12, 285) (2.2 g, 10.1 mmol) and 4-AMINO-1-BENZYLPIPERIDINE (2.0 g, 10.5 mmol) was refluxed in 2- propanol overnight. Thin layer chromatography (10% methanol in ethyl acetate) showed the reaction was complete. The solvent was evaporated, and the crude product dissolved in chloroform (100 mL), which was washed with saturated sodium carbonate solution (20 ML), and dried over magnesium sulfate. The title compound was obtained as a gum (3.8 g). MS 327 (M+1).
  • 9
  • [ 51171-02-9 ]
  • [ 4492-37-9 ]
  • [ 898911-70-1 ]
YieldReaction ConditionsOperation in experiment
43% With potassium carbonate; In N,N-dimethyl-formamide;Heating / reflux; Step (ii): Synthesis of 2-(cyclopentylmethyl-ethyl-amino)-pyrazine-2-carboxylic acid methyl ester; 3-Bromo-pyrazine-2-carboxylic acid methyl ester (0.893 g, 4.11 mmol), obtained from a scale-up reaction of step (i), and potassium carbonate (1.7 g, 12.3 mmol) were added to a 50 mL two neck round bottom flask. To this flask, 10 mL of DMF was added, followed by the dropwise addition of a DMF solution of N-cyclopentylmethyl ethyl amine (0.627 g, 4.93 mmol). This mixture was refluxed overnight, after which it was allowed to cool to RT, poured onto crushed ice (10 mL), and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under vacuum to give the title compound (0.468 g), yield: 43%. 1H NMR (CDCl3, 400 MHz): d 8.11 (m, IH), 7.87 (m, IH), 3.96 (s, 3H), 3.46-3.39 (m, 4H), 2.29-2.25 (m, IH), 1.71-1.60 (m, 3H), 1.19-1.15 (m, 3H), 0.88-0.83 (m, 5H) m/z (CI-MS): 264 (M+H-I, 100%); IR (cm-1): 3749, 3421, 2951.
  • 10
  • [ 51171-02-9 ]
  • [ 455267-21-7 ]
  • [ 455265-99-3 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; Example 97 (3-Methyl-pyrazin-2-yl)-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amine EXAMPLE 97 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and <strong>[51171-02-9]3-bromo-pyrazine-2-carboxylic acid methyl ester</strong> followed by reduction with lithium tri-sec-butylborohydride at 0 C. in THF: MS (m+1)=375.5.
  • 11
  • [ 51171-02-9 ]
  • ethyl acetate n-hexane [ No CAS ]
  • [ 89109-19-3 ]
YieldReaction ConditionsOperation in experiment
With toluene-4-sulfonic acid; aniline; In water; (B) Methyl 2-phenylamino-3-pyrazine carboxylate A mixture of 9.5 g. of <strong>[51171-02-9]methyl 2-bromo-3-pyrazine carboxylate</strong>, 8.2 g. of aniline, 0.5 g. of p-toluene sulfonic acid and 100 ml. of water was stirred and refluxed for two hours. The reaction mixture was poured on ice, extracted with ethyl acetate, the organic extracts were dried and concentrated to yield an oil. The crude residue was eluted on a silica gel column with ethyl acetate-hexane (1:2) yielding the product of this example as a yellow solid, m.p. 72-75 C.
With toluene-4-sulfonic acid; aniline; In water; (B) Methyl 2-phenylamino-3-pyrazine carboxylate: A mixture of 9.5 g. of <strong>[51171-02-9]methyl 2-bromo-3-pyrazine carboxylate</strong>, 8.2 g. of aniline, 0.5 g. of p-toluene sulfonic acid and 100 ml. of water was stirred and refluxed for two hours. The reaction mixture was poured on ice, extracted with ethyl acetate, the organic extracts were dried and concentrated to yield an oil. The crude residue was eluted on a silica gel column with ethyl acetate-hexane (1:2) yielding the product of this example as a yellow solid, m.p. 72-75 C.
With toluene-4-sulfonic acid; aniline; In water; (B) Methyl 2-phenylamino-3-pyrazine carboxylate A mixture of 9.5 g. of <strong>[51171-02-9]methyl 2-bromo-3-pyrazine carboxylate</strong>, 8.2 g. of aniline, 0.5 g. of p-toluene sulfonic acid and 100 ml. of water is stirred and refluxed for two hours. The reaction mixture is poured on ice, extracted with ethyl acetate, the organic extracts are dried and concentrated to yield an oil. The crude residue is eluted on a silica gel column with ethylacetate-hexane (1:2) yielding the product of this example as a yellow solid, m.p. 72-75 C.
With toluene-4-sulfonic acid; aniline; In water; (B) Methyl 2-phenylamino-3-pyrazine carboxylate: A mixture of 9.5 g. of <strong>[51171-02-9]methyl 2-bromo-3-pyrazine carboxylate</strong>, 8.2 g. of aniline, 0.5 g. of p-toluene sulfonic acid and 100 ml. of water is stirred and refluxed for two hours. The reaction mixture is poured on ice, extracted with ethyl acetate, the organic extracts are dried and concentrated to yield an oil. The crude residue is eluted on a silica gel column with ethylacetate-hexane (1:2) yielding the product of this example as a yellow solid, m.p. 72-75 C.

  • 12
  • [ 51171-02-9 ]
  • [ 106-47-8 ]
  • 3-(4-chlorophenylamino)-pyrazine-2-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethyl acetate; (a) 3-(4-chlorophenylamino)-pyrazine-2-carboxylic acid methyl ester A mixture of 21.7 g <strong>[51171-02-9]3-bromo-pyrazine-2-carboxylic acid methyl ester</strong> and 25.5 g 4-chloroaniline in 150 ml ethyl acetate is boiled 4 days at reflux. The solution is washed with 4 N hydrochloric acid, water and then with 2 N sodium carbonate. The organic phase is dried over sodium sulphate and evaporated to give the heading compound (recrystallized from isopropanol) m.p. 135-136.
  • 13
  • [ 51171-02-9 ]
  • [ 76885-01-3 ]
  • [ 865-47-4 ]
  • [ 95-54-5 ]
  • pyrazino [2,3-b][1,5]benzodiazepin-11(10H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; ethyl acetate; triethylamine; N,N-dimethyl-formamide; To a solution of 6.5 g 3-(2-amino-4-chloro-N-methyl-phenylamino)-pyrazine-2-carboxylic acid methyl ester in 100 ml N,N-dimethyl-formamide are added 5.0 g potassium tert. butylate at 0 C. The mixture is stirred at room temperature for 2 hours, poured into ice water and acidified to pH 4 with glacial acetic acid, whereupon the heading compound is precipitated, m.p. 305-307 (recrystallized from methanol). In analogous manner to that described in Example 1, the following compounds of formula I are obtained: The starting materials of formula III for Examples 10-16, 20-23 and 25 are prepared in analogous manner to that described in Example 1, steps (a) to (e). The starting material of formula III for Examples 2 to 5 and 17 may be obtained as follows: 2.2 g of <strong>[51171-02-9]3-bromo-pyrazine-2-carboxylic acid methyl ester</strong> and 2.2 g 1,2-phenylene diamine suspended in 50 ml triethylamine are boiled for 17 hours under reflux. After the mixture has been cooled, water and ethyl acetate are added to precipitate out pyrazino [2,3-b][1,5]benzodiazepin-11(10H)-one, m.p. 298-300.
  • 14
  • [ 51171-02-9 ]
  • [ 1095-85-8 ]
  • 3-(2-tritylsulfanylethylamino)pyrazine-2-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With triethylamine; In acetonitrile; for 18h;Heating / reflux; A solution of <strong>[51171-02-9]3-bromopyrazine-2-carboxylic acid methyl ester</strong> (0.10 g, 0.45 mmol), 2- tritylsulfanylethylamine (0.29 g, 0.90 mmol) and triethylamine (0.06 mL, 0.44 mmol) in acetonitrile (5 mL) was heated to reflux for 18 h under argon. The mixture was concentrated under reduced pressure and purified by column chromatography (3:1 Hex:EtOAc), yielding 0.058 g (28%) of the desired product.
28% With triethylamine; In acetonitrile; for 18h;Heating / reflux; A solution of <strong>[51171-02-9]3-bromopyrazine-2-carboxylic acid methyl ester</strong> (0.10 g, 0 45 mmol), 2- t?tylsulfanylethylamine (0 29 g, 0 90 mmol), and triethylamine (0.OS mL, 0.44 mmol) in acetonitrile (5 mL) was heated to reflux for 18 h under argon. The mixture was concentrated under reduced pressure and purified by column chromatography (3:1 Hex. EtOAc), yielding 0.058 g (28%) of the desired product. 1H NMR (400 MHz1 CD2CI2) delta 7.95 (s, 1H), 8.44 (s, 1 H), 8.31 (s, 1H), 7 57.18 (m, 15H), 4 20 (s, 3H), 3.36(t, 2H), 2.50 (t, 2H).
28% With triethylamine; In acetonitrile; for 18h;Heating / reflux; A solution of <strong>[51171-02-9]3-bromopyrazine-2-carboxylic acid methyl ester</strong> (0.10 g, 0.45 mmol), 2- tritylsulfanylethylamine (0.29 g, 0.90 mmol) and triethylamine (0.06 mL, 0.44 mmol) in acetonitrile (5 mL) was heated to reflux for 18 h under argon. The mixture was concentrated under reduced pressure and purified by column chromatography (3:1 Hex:EtOAc), yielding 0.058 g (28%) of the desired product.
28% With triethylamine; In acetonitrile; for 18h;Heating / reflux; A solution of <strong>[51171-02-9]3-bromopyrazine-2-carboxylic acid methyl ester</strong> (0.10 g, 0.45 mmol), 2- tritylsulfanylethylamine (0.29 g, 0.90 mmol) and triethylamine (0.06 mL, 0.44 mmol) in acetonitrile (5 mL) was heated to reflux for 18 h under argon. The mixture was concentrated under reduced pressure and purified by column chromatography (3:1 Hex:EtOAc), yielding 0.058 g (28%) of the desired product.

  • 15
  • [ 67-56-1 ]
  • [ 51171-02-9 ]
  • [ 124-41-4 ]
  • [ 40155-20-2 ]
YieldReaction ConditionsOperation in experiment
for 0.5h; To a solution of 2 g of <strong>[51171-02-9]methyl 3-bromopyrazine-2-carboxylate</strong> (prepared as described by J. H.Jones, W. H. Holtz, E. J. C. Cragoe, J. Med. Chem., 1969, 12, 285-287) in 50 mL of methanol was added 4 mL of 30% NaOMe in methanol. After stirring 30 min the reaction was quenched with 6 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 50 mL ethyl acetate and 50 mL saturated NaHCO3, the extract dried over MgSO,*. Concentration under reduced pressure gave a white crystalline solid: MS (m+1) = 169.1; 1H NMR (400 MHz, CDC13) 8.3 (m, 2H), 4.1 (s, 3H), 4.0 (s, 3H).
  • 16
  • [ 51171-02-9 ]
  • [ 1351238-14-6 ]
  • [ 1351237-96-1 ]
YieldReaction ConditionsOperation in experiment
42.9% With sodium carbonate; In ethanol; at 70℃; Step 2: synthesis of N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7- oxo-6,7-dihydrothieno[2,3-b]pyrazine-6-carboxamide (100)A solution of 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetamido)-4- methylphenyl)benzamide 16 (0.054mmol, 20mg), methyl 3-bromopyrazine-2- carboxylate 101 ( 0.054mmol, 11.8mg) and Na2C03 (1.2 eq, 7 mg) in ethanol (1 mL) was stirred overnight at 70C. The reaction mixture was quenched in cold 1 N HC1 solution and extracted with CH2CI2. Organic layer was dried and evaporated.Purification by chromatography (0-10% methanol in CH2CI2) gave N-(5-(3-(2- cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-oxo-6,7-dihydrothieno[2,3- b]pyrazine-6-carboxamide 102 (l lmg, 42.9 %). NMR (400 MHz, DMSO-d6) 1.77 (s, 6H), 2.35 (s, 3H), 7.15 (d, J= 8.6 Hz, IH), 7.48 (dd, J= 8.2 Hz and 2.3 Hz, IH), 7.59 (t, J= 7.8 Hz, IH), 7.74 (d, J = 7.8 Hz, IH), 7.97 (d, J= 7.8 Hz, IH), 8.07 (t, J = 2.0 Hz, 1H), 8.54 (br s, 1H), 8.62 (br s, 1H), 8.66 (d, J = 1.6 Hz, 1H), 10.29 (s, 1H). (m/z) 473 (M+H)+.
With sodium carbonate; In ethanol; at 70℃; Step 2: synthesis of N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-oxo-6,7-dihydrothieno[2,3-b]pyrazine-6-carboxamide (100)[0306]A solution of 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetamido)-4-methylphenyl)benzamide 16 (0.054 mmol, 20 mg), <strong>[51171-02-9]methyl 3-bromopyrazine-2-carboxylate</strong> 101 (0.054 mmol, 11.8 mg) and Na2CO3 (1.2 eq, 7 mg) in ethanol (1 mL) was stirred overnight at 70 C. The reaction mixture was quenched in cold 1N HCl solution and extracted with CH2Cl2. Organic layer was dried and evaporated. Purification by chromatography (0-10% methanol in CH2Cl2) gave N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-oxo-6,7-dihydrothieno[2,3-b]pyrazine-6-carboxamide 102 (11 mg, 42.9%). NMR (400 MHz, DMSO-d6) 1.77 (s, 6H), 2.35 (s, 3H), 7.15 (d, J=8.6 Hz, 1H), 7.48 (dd, J=8.2 Hz and 2.3 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.07 (t, J=2.0 Hz, 1H), 8.54 (br s, 1H), 8.62 (br s, 1H), 8.66 (d, J=1.6 Hz, 1H), 10.29 (s, 1H). (m/z)=473 (M+H)+.
  • 17
  • [ 5424-01-1 ]
  • [ 51171-02-9 ]
  • 18
  • [ 51171-02-9 ]
  • [ 1415407-07-6 ]
  • 19
  • [ 51171-02-9 ]
  • [ 1415407-08-7 ]
  • 20
  • [ 51171-02-9 ]
  • [ 937669-80-2 ]
  • 21
  • [ 51171-02-9 ]
  • (N-heterocyclic carbene)Ag(SCF2H) [ No CAS ]
  • C7H6F2N2O2S [ No CAS ]
  • 22
  • [ 51171-02-9 ]
  • (1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl)(difluoromethyl)silver [ No CAS ]
  • C7H6F2N2O2 [ No CAS ]
  • 23
  • [ 36947-68-9 ]
  • [ 51171-02-9 ]
  • C12H14N4O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
28.2% To a solution of Example 72a (1.55 g, 7.1 mmol) was dissolved in DMSO (15 mL) followed by 2-isopropyl-lH-imidazole (866 mg, 7.9 mmol) and Cs2C03 (5.8 g, 17.9 mmol), and then heated to 100C for lh. (detected by TLC PE:EA=2: 1, showed reaction completed). After cooled to r.t., filtered and the filtrate was used to next step without purification. The filtrate was added K2C03 (1.5 g 10.6 mmol) and CH3I (1.5 g 10.6 mmol), then stirred at 50C for lh. The residue was extracted with EtOAc (50 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 72b (480 mg, yield 28.2 %) as a yellow oil.
  • 24
  • [ 51171-02-9 ]
  • C6H10(2)HBN2O2 [ No CAS ]
  • C12H13(2)HN4O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; XPhos; In 1,4-dioxane; water; at 105℃; for 1h;Inert atmosphere; To a solution of Example 51a (0.56 g, 2.6 mmol, 1.0 eq.) was dissolved in Dioxane (10 mL) and water (lmL) was added Example 48d (600 mg, 3.9 mmol, 1.5 eq.), Na2C03 (0.51 g, 5.2 mmol, 2.1 eq.), Pd2(dba)3 (50 mg) and x-phos (50 mg), and then heated to 105C under N2 for lh. The reaction was purified by flash (PE:EA=20%) to give the title Example 5 lb (600 mg, yield 93 %) as yellow oil.
  • 25
  • [ 51171-02-9 ]
  • C11H12N4O2 [ No CAS ]
  • 26
  • [ 51171-02-9 ]
  • C11H12(2)H2N4O [ No CAS ]
  • 27
  • [ 51171-02-9 ]
  • C11H11(2)H2ClN4 [ No CAS ]
  • 28
  • [ 51171-02-9 ]
  • 2-hydroxy-6-((3-(2-isopropyl-1H-imidazol-1-yl)pyrazin-2-yl)methoxy-d<SUB>2</SUB>)benzaldehyde [ No CAS ]
  • 29
  • [ 51171-02-9 ]
  • [ 1095-85-8 ]
  • [ 885685-66-5 ]
 

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Technical Information

Categories

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