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[ CAS No. 82454-61-3 ] {[proInfo.proName]}

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Chemical Structure| 82454-61-3
Chemical Structure| 82454-61-3
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Product Details of [ 82454-61-3 ]

CAS No. :82454-61-3 MDL No. :MFCD13175209
Formula : C7H6N2 Boiling Point : -
Linear Structure Formula :- InChI Key :ZVGIVKMNLUTRPN-UHFFFAOYSA-N
M.W : 118.14 Pubchem ID :21954827
Synonyms :

Calculated chemistry of [ 82454-61-3 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 36.58
TPSA : 38.91 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
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) : 0.9
Log Po/w (WLOGP) : 0.73
Log Po/w (MLOGP) : 0.8
Log Po/w (SILICOS-IT) : 1.24
Consensus Log Po/w : 1.03

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.63
Solubility : 2.75 mg/ml ; 0.0233 mol/l
Class : Very soluble
Log S (Ali) : -1.3
Solubility : 5.89 mg/ml ; 0.0499 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.7
Solubility : 2.37 mg/ml ; 0.0201 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.83

Safety of [ 82454-61-3 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H320-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 82454-61-3 ]

* 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 [ 82454-61-3 ]
  • Downstream synthetic route of [ 82454-61-3 ]

[ 82454-61-3 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 457628-40-9 ]
  • [ 82454-61-3 ]
YieldReaction ConditionsOperation in experiment
99% With methanol; potassium carbonate In tetrahydrofuran at 20℃; for 1 h; Manufacturing Example 28-1-3 Ethynyl-pyridin-2-ylamine; To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg, 137 μmol) described in Manufacturing Example 28-1-2 in tetrahydrofuran (1 mL) and methanol (1 mL) was added potassium carbonate (37.9 mg, 274 μmol) at room temperature, which was stirred for 1 hour at room temperature. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (16 mg, 99percent).1H-NMR Spectrum (CDCl3) δ (ppm): 3.07 (1H, s), 4.73 (2H, brs), 6.46 (1H, d, J=8.6 Hz), 7.53 (1H, dd, J=2.2, 8.6 Hz), 8.21 (1H, s).
99% With potassium carbonate In tetrahydrofuran; methanol at 20℃; for 1 h; To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg, 137 μmol) described in Manufacturing Example 28-1-2 in tetrahydrofuran (1 mL) and methanol (1 mL) was added potassium carbonate (37.9 mg, 274 μmol) at room temperature, which was stirred for 1 hour at room temperature. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (16 mg, 99percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 3.07 (1H, s), 4.73 (2H, brs), 6.46 (1H, d, J=8.6 Hz), 7.53 (1H, dd, J=2.2, 8.6 Hz), 8.21 (1H, s).
91%
Stage #1: With tetrabutyl ammonium fluoride In tetrahydrofuran for 2 h;
Stage #2: With water In diethyl ether
The above trimethylsilylalkyne (340 mg, 1.79 mmol) was dissolved in 3.6 mL of cold THF and 3.6 mL of 1.0 M TBAF in THF was slowly added to the stirring mixture. After 2h, the mixture was concentrated and partitioned between Et2O and water. The ether layer was washed with brine, and the washes were extracted once with Et2O. The extracts were combined, dried with MgS04, filtered, and concentrated to provide 191 mg of 2-amino-5-ethynyl pyridine (1.61 mmol, 91percent).
73% With methanol; potassium carbonate In tetrahydrofuran at 0℃; for 5 h; b)
5-Ethynyl-pyridin-2-ylamine
To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (32.1 g, 169 mmol) in THF (150 mL) and methanol (350 mL) at 0° C. was added potassium carbonate (2.33 g, 16.9 mmol) and the mixture was stirred at 0° C. for 5 h.
It was diluted with ice water (500 mL), extracted with tert-butylmethylether (3*500 mL), washed the combined organic layers with brine and dried over magnesium sulfate.
Concentration left a dark brown solid, which was dissolved in hot ethyl acetate and precipitated with n-heptane trituration to give the 5-ethynyl-pyridin-2-ylamine (14.61 g, 73percent) as a light brown solid. MS: m/e=118.1 [M+H]+.
49 g With potassium hydroxide In ethanol; water at 20℃; for 1 h; Inert atmosphere A 1.5 L 4-necked round bottom flask equipped with a thermometer, a mechanical stirrer and an inert gas supply, were charged with 80 g (420.3 mmol) of compound 12, 700 mL ethanol, and a solution of 2.7 g (41.1 mmol, 0.1 eq.) potassium hydroxide in 10 ml water. The mixture was stirred at room temperature for 1 h. The mixture was concentrated at 50° C. under 260-230 mbar to remove ca. 500 solvent. 750 mL Water were added and the remaining EtOH was evaporated at 60° C. under 65 mbar. The mixture was extracted once with 750 mL, twice with 250 mL, a total of 1250 ethyl acetate. The combined organic phases containing some insoluble material were dried over 80 g sodium sulfate, filtered and the wet cake was rinsed with 50 mL ethyl acetate. The filtrate was evaporated under reduced pressure (240 mbar) at 50° C. to a volume of 350 mE. A quantity of 700 mL n-Heptane was added with constant volume exchange at 50° C. under 240- 210 mbat An additional 100 ml n-heptane was added and crystallization was completed at room temperature for 1 h. The product was filtered, washed with 350 ml n-heptane and dried at room temperature under <10 Mbar for 3 h to provide 49 g of compound 9.

Reference: [1] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 76-77
[2] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 74
[3] Dalton Transactions, 2006, vol. 6, # 13, p. 1627 - 1635
[4] Patent: WO2005/90333, 2005, A1, . Location in patent: Page/Page column 71
[5] Patent: US2007/287739, 2007, A1, . Location in patent: Page/Page column 7
[6] Patent: EP2065377, 2009, A1, . Location in patent: Page/Page column 63-64
[7] Letters in Drug Design and Discovery, 2011, vol. 8, # 5, p. 401 - 405
[8] Patent: WO2012/85127, 2012, A1, . Location in patent: Page/Page column 55
[9] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3033 - 3047
[10] Patent: US2013/85278, 2013, A1, . Location in patent: Paragraph 0129; 0130
  • 2
  • [ 911114-11-9 ]
  • [ 82454-61-3 ]
YieldReaction ConditionsOperation in experiment
88% With sodium hydroxide In toluene at 95 - 102℃; A suspension of compound 13 (17.10 g) and sodium hydroxide (12.2 g) toluene (170 mE) was heated under reduced pressure (approx. 750 Mbar) to 95 to 102° C. within 30 to 60 minutes (approx. 110° C. jacket temperature). The mixture was subsequently stirred at this temperature for 4 to 7 hours. Upon complete conversion (<2percent starting material), the mixture was cooled to 80-86° C. and washed at this temperature three times with water (45 mE and 2x30 mL). The combined aqueous layers were back extracted at room temperature with MeTHF (80 mL). The combined toluene and MeTHF layers were concentrated to almost dryness. The residue was dissolved in 120 mL of MeTHF and subsequently polish filtered. The filter cake was rinsed with MeTHF (2x25 mL) thmishing 157.16 g solution of compound 9 with an assay of 6.4percent (w/w), corresponding to a corrected yield of 88percent.
Reference: [1] Patent: US2013/85278, 2013, A1, . Location in patent: Paragraph 0131; 0133
  • 3
  • [ 1072-97-5 ]
  • [ 82454-61-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[3] Dalton Transactions, 2006, vol. 6, # 13, p. 1627 - 1635
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 5, p. 401 - 405
[5] Patent: US2013/85278, 2013, A1,
  • 4
  • [ 141354-32-7 ]
  • [ 82454-61-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
  • 5
  • [ 926009-62-3 ]
  • [ 82454-61-3 ]
  • [ 926009-43-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
  • 6
  • [ 20511-12-0 ]
  • [ 82454-61-3 ]
Reference: [1] Patent: US2013/85278, 2013, A1,
  • 7
  • [ 82454-61-3 ]
  • [ 911112-17-9 ]
  • [ 911115-16-7 ]
YieldReaction ConditionsOperation in experiment
84% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In 2-methyltetrahydrofuran at 70 - 75℃; A solution of 7 (36.0 g), copper(I) iodide (334 mg), bis-(triphenylphosphine)-palladium(II)-dichloride (557 mg), triphenylphosphine (414 mg) and triethylamine (25.5 mE) in MeTHF (145 mE) was treated at 70-75°C. within 2 to 3 hours with a MeTHF solution of 1.1 equiv. of 5-ethynylpyridin-2- ylamine (9) (prepared according to Example 11) and the resulting suspension was subsequently stirred at 70-75°C. for additional 5-10 hours. The mixture was cooled to 30° C. and treated with water (150 mE) and 25percent aqueous ammonium hydroxide solution (30 mE). The biphasic mixture was stirred for 30 minutes and the layers were then allowed to separate for 20 minutes. The aqueous layer was removed and the MeTHF layer was washed twice with a mixture of water (150 mE) and 25percent aqueous ammonium hydroxide solution (30 The MeTHF layer was subsequently washed with water (3x 150 mE). The organic layer was polish filtered, and the filtrate was treated with n-tributylphosphine (1.00 mE). MeTHF was then distilled off and completely replaced by isopropanol (500 mE in total) at atmospheric pressure. The resulting suspension (ca. 250 mE) was heated to reflux and stirred at reflux for 2 hours then cooled to room temperature overnight. The product was filtered and washed with two portions of isopropanol (50 mE). The wet crystals were dried at 50° C. and <30 mbar until constant weight affording 29.45 g (84percent yield based on 7) of compound A as red crystals with a purity of 99.7percent (HPEC, area-percent).
Reference: [1] Patent: US2013/85278, 2013, A1, . Location in patent: Paragraph 0120; 0121
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