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[ CAS No. 18591-57-6 ] {[proInfo.proName]}

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Chemical Structure| 18591-57-6
Chemical Structure| 18591-57-6
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Product Details of [ 18591-57-6 ]

CAS No. :18591-57-6 MDL No. :MFCD00234902
Formula : C16H12N2O Boiling Point : -
Linear Structure Formula :- InChI Key :LTWBZUZTTUVPIM-UHFFFAOYSA-N
M.W : 248.28 Pubchem ID :619180
Synonyms :

Calculated chemistry of [ 18591-57-6 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 74.93
TPSA : 46.01 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.5
Log Po/w (XLOGP3) : 3.07
Log Po/w (WLOGP) : 3.52
Log Po/w (MLOGP) : 2.09
Log Po/w (SILICOS-IT) : 3.51
Consensus Log Po/w : 2.94

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.88
Solubility : 0.0325 mg/ml ; 0.000131 mol/l
Class : Soluble
Log S (Ali) : -3.7
Solubility : 0.0492 mg/ml ; 0.000198 mol/l
Class : Soluble
Log S (SILICOS-IT) : -6.12
Solubility : 0.00019 mg/ml ; 0.000000764 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.67

Safety of [ 18591-57-6 ]

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 [ 18591-57-6 ]

* 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 [ 18591-57-6 ]
  • Downstream synthetic route of [ 18591-57-6 ]

[ 18591-57-6 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 18591-57-6 ]
  • [ 41270-66-0 ]
YieldReaction ConditionsOperation in experiment
90.7% With trichlorophosphate In N,N-dimethyl-formamide at 100℃; for 1.5 h; Inert atmosphere; Cooling with ice 3-methyl-2-hydroxyquinoxaline (2.48 g, 0.01 mol) was added to 25 mL of anhydrous N,N-dimethylmethyl under ice bathIn the amide, N2 is protected, and phosphorus trichloride (1.37 g, 0.01 mol) is added thereto, and after reacting for 0.5 h,Heat to 100 ° C, and then react for 1 h, cool to room temperature, spin off most of the solvent, then add ethyl acetate (50 mL), add ice water (20 mL), with acetic acidEthyl ester (50 mL * 3) was extracted, the organic phase was collected, dried over sodium sulfate and filtered to give a white solid 3-methyl-2-chloro-quinoxalineThe crude product was then beaten with ethyl acetate, filtered, and dried in vacuo to give 2.41 g of white solid 3-methyl-2-chloro-quinoxaline.Rate: 90.7percent
77% at 100 - 110℃; 50 gm of 2-hydroxy-5,6-diphenylpyrazine obtained was treated with 250 ml of POCI3 and then heated the reaction mixture at 100-110 °C with stirring for 5-6 hrs. the reaction mixture was cooled to room temperature and poured in 1000 ml of ice water at 0-5 °C and maintained with stirring for 60 minutes. The solid obtained was filtered, washed with water and dried to obtain 41.3 gm of desired compound. Yield: 77.00 percent.
Reference: [1] Patent: CN108623541, 2018, A, . Location in patent: Paragraph 0052-0054; 0073-0075; 0088; 0092-0094
[2] Patent: WO2017/60827, 2017, A1, . Location in patent: Page/Page column 11
[3] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 3, p. 783 - 786
[4] Patent: US2003/69284, 2003, A1,
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 253 - 263
  • 2
  • [ 18591-57-6 ]
  • [ 41270-66-0 ]
YieldReaction ConditionsOperation in experiment
520 g at 20℃; Reflux To 5,6-diphenylpyrazin-2(lH)-one (500 gm), added POCl3 (2500 ml) at 20 - 25 deg C and stirred for 10 hours to 12 hours at reflux. Cooled and then the pH was adjusted to neutral. Filtered the solid thus separated, washed with methanol and dried to yield 5-Chloro-2,3- diphenylpyrazine.
Yield: 520 gm
Chromatographic Purity (by HPLC): 99.43percent
Reference: [1] Journal of the American Chemical Society, 1952, vol. 74, p. 1580,1582
[2] Patent: WO2017/168401, 2017, A1, . Location in patent: Page/Page column 12
  • 3
  • [ 18591-57-6 ]
  • [ 243472-70-0 ]
YieldReaction ConditionsOperation in experiment
93% With phosphorus tribromide In N,N-dimethyl-formamide for 2.5 h; Inert atmosphere; Cooling with ice; Reflux 3-methyl-2-hydroxyquinoxaline (2.48 g, 0.01 mol) was added to 20 mL of anhydrous toluene under ice bath, N2Protected, added phosphorus tribromide (3.24g, 0.012mol), reacted for 0.5h, heated to reflux for 2h, cooled to room temperature,Spin off most of the solvent, add ethyl acetate (50 mL), add ice water (20 mL) and extract with ethyl acetate (50mL*3)The organic phase was collected and washed successively with cooled sodium bicarbonate solution (100 mL), water, saturated brine (200 mL*2), sodium sulfateDry, filter and rotary to give a crude solid of 3-methyl-2-bromo-quinoxaline as a gray solid, then ethyl acetate, filtered, vacuumDrying 2.89 g of white solid 3-methyl-2-bromo-quinoxaline, yield: 93percent
88% With phosphorus(V) oxybromide In toluene at 85℃; for 2 h; 5-Hydroxy-2,3-diphenylpyrazine (1.0 g, 4.0 mmol) was dissolved in 10 mL of toluene and treated with 5 mol of 5-hydroxy-2,3-diphenylpyrazine and 1 mol of phosphorus oxybromide (6.22g, 20.0mmol). The reaction was carried out at 85 ° C for 2.0 hours. After completion of the reaction by TLC, the reaction solution was slowly poured into a mixture of 30g of ice and water while still hot. After stirring was continued for another 20 minutes, Sodium bicarbonate solution to adjust the pH value to 8.0, ethyl acetate extract 30mL * 3 times, saturated brine 20mL washed, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation to give crude 2-bromo-5,6-diphenylpyrazine The crude product was recrystallized from methanol to give 1.10 g of pure product of 2-bromo-5,6-diphenylpyrazine. The yield of the product was 88percent and the purity of the product was 98percent.
Reference: [1] Patent: CN108623541, 2018, A, . Location in patent: Paragraph 0111-0113; 0126; 0130-0132
[2] Patent: CN106632093, 2017, A, . Location in patent: Paragraph 0009; 0010; 0011; 0012
[3] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 3, p. 783 - 786
  • 4
  • [ 18591-57-6 ]
  • [ 243472-70-0 ]
Reference: [1] Journal of the American Chemical Society, 1956, vol. 78, p. 2141,2144
  • 5
  • [ 1668-10-6 ]
  • [ 134-81-6 ]
  • [ 18591-57-6 ]
YieldReaction ConditionsOperation in experiment
91.1%
Stage #1: With sodium hydroxide In methanolReflux; Inert atmosphere
Stage #2: With hydrogenchloride In methanol; water at 0 - 25℃; for 0.5 h;
Benzil (62.0 g, 0.29 mol), aminoacetamide hydrochloride (35.37 g, under nitrogen)0.32 mol) and NaOH (23.2 g, 0.58 mol) were sequentially added to 500 mL of methanol solvent, and heated under reflux for 3 to 4 h, passed through LC-The MS monitors the reaction and the starting material reacts completely. The reaction solution was cooled to 0-5 ° C, then 12 N HCl (38 mL) solution was added dropwise, and in the roomAfter stirring the reaction solution for 30 minutes under temperature, 30 g of sodium hydrogencarbonate and 350 mL of water were added, and the reaction solution was filtered, water (20 mL) and methanol.(20 mL) The solid was washed separately and dried in vacuo to give 65.5 g of 3-methyl-2-hydroxyquinoxaline as a white solid.91.1percent,
89% With hydrogenchloride; sodium hydroxide; potassium carbonate In methanol; chloroform; water; ethyl acetate Step 1:
Synthesis of 5,6-diphenylpyrazin-2-ol
First, 4.2 g (20 mmol) of benzil, 2.21 g (20 mmol) of glycinamide hydrochloride, and 40 mL of methanol were put into a three-neck flask equipped with a reflux pipe, the air in the flask was replaced with nitrogen, the mixture was refluxed, an aqueous solution of 1.6 g (40 mmol) of sodium hydroxide in 3.2 mL of water was added, and the reflux was continued for 3 hours.
Then, stirring was performed until the temperature of the flask was returned to room temperature.
After that, 2.5 mL of 12M concentrated hydrochloric acid, 2 g of potassium bicarbonate, and 25 mL of water were added to this mixture, and filtration was performed.
The obtained residue was dried at 100° C. under reduced pressure and purified by silica gel column chromatography using chloroform and ethyl acetate in a 5:2 ratio as a developing solvent.
The solvent in the solution was distilled off and the resulting residue was recrystallized with hexane; thus, 3.04 g of a yellow solid, which was an objective substance, was obtained in a yield of 89percent.
The synthesis scheme of Step 1 is shown in (c-1) below.
82.7%
Stage #1: at 0 - 5℃; for 0.75 h;
A solution of 95 gm methanol is 500 ml water was added slowly at 0-5 °C to a solution of (0084) 52.5 gm glycinamide hydrochloride in 600 ml methanol and then stirred at same temperature for 45 minutes. To the reaction mixture was then added 100 gm benzil and maintained under stirring for 4-5 hrs and then neutralized with 185 ml cone, hydrochloric acid to obtain solid. The solid obtained was washed with 400 ml water and dried to obtain (0085) 97.6 gm 2-hydroxy-5,6-diphenylpyrazine. Yield: 82.70 percent.
79% With hydrogenchloride; sodium hydroxide; potassium carbonate In methanol; water; toluene Step 1:
Synthesis of 5,6-diphenylpyrazin-2-ol
First, 21.0 g (100 mmol) of benzil, 13.3 g (120 mmol) of glycinamide hydrochloride, 9.6 g (240 mmol) of sodium hydroxide, and 500 mL of methanol were put into a 1-L three-neck flask, and the air in the flask was replaced with nitrogen.
This mixture was heated for reflux for approximately 3 hours.
Then, the temperature of the flask was returned to room temperature, 12.5 mL of 12 M concentrated hydrochloric acid was added to this mixture, and stirring was performed for approximately 30 minutes.
Then, 10 g of potassium bicarbonate and 125 mL of water were added.
Filtration was performed to give a solid, and the solid was washed with water and methanol in this order.
The resulting residue was dried at 100° C. under reduced pressure and recrystallized with 50 mL of toluene to give 19.5 g of a yellow solid, which was an objective substance, in a yield of 79percent.
The synthesis scheme of Step 1 is shown in (b-1).
79% With sodium hydroxide In methanol for 3 h; Reflux; Inert atmosphere First, 21.0 g (100 mmol) of benzil, 13.3 g (120 mmol) of glycinamide hydrochloride, 9.6 g (240 mmol) of sodium hydroxide, and 500 mL of methanol were put into a 1-L three-neck flask, and the air in the flask was replaced with nitrogen. This mixture was heated for reflux for approximately 3 hours. Then, the temperature of the flask was returned to room temperature, 12.5 mL of 12 M concentrated hydrochloric acid was added to this mixture, and stirring was performed for approximately 30 minutes. Then, 10 g of potassium bicarbonate and 125 mL of water were added. Filtration was performed to give a solid, and the solid was washed with water and methanol in this order. The resulting residue was dried at 100° C. under reduced pressure and recrystallized with 50 mL of toluene to give 19.5 g of a yellow solid, which was an objective substance, in a yield of 79percent. The synthesis scheme of Step 1 is shown in (b-1).

Reference: [1] Patent: CN108623541, 2018, A, . Location in patent: Paragraph 0049-0051; 0069-0072; 0089-0091; 0108-0110; 0127
[2] Patent: US2015/147840, 2015, A1, . Location in patent: Page/Page column
[3] Patent: WO2017/60827, 2017, A1, . Location in patent: Page/Page column 11
[4] Patent: US2015/147840, 2015, A1, . Location in patent: Page/Page column
[5] Patent: US2016/108006, 2016, A1, . Location in patent: Paragraph 0173-0175
[6] European Journal of Organic Chemistry, 2005, # 5, p. 847 - 853
  • 6
  • [ 1668-10-6 ]
  • [ 134-81-6 ]
  • [ 457099-23-9 ]
  • [ 18591-57-6 ]
YieldReaction ConditionsOperation in experiment
80% With sodium hydroxide In methanol Step 1:
2-Hydroxy-5,6-diphenylpyrazine.
To a stirred suspension of glycinamide hydrochloride (1.1 gm, 10 mmol) in 20 mL MeOH at 0° C. was added 20percent NaOH (10 mL, 50 mmol).
A clear solution formed and was treated slowly portionwise with benzil (2.1 gm, 10 mmol) as a solid.
The yellow solution was stirred at 0° C. for 2 hours and then neutralized to approximately pH=7 with concentrated HCl.
The bright yellow color disappeared and a tan precipitate formed.
The material was isolated by filtration with MeOH and triturated with EtOAc to give 2-hydroxy-5,6-diphenylpyrazine (2 gm, 80percent).
1H-NMR (400 MHz, CDCl3) δ8.24 (s, 1H), 7.42-7.31 (m, 4H), 7.39-7.21 (m, 6H).
Reference: [1] Patent: US2003/69284, 2003, A1,
  • 7
  • [ 134-81-6 ]
  • [ 598-41-4 ]
  • [ 18591-57-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 253 - 263
  • 8
  • [ 67-56-1 ]
  • [ 623-11-0 ]
  • [ 134-81-6 ]
  • [ 598-41-4 ]
  • [ 18591-57-6 ]
Reference: [1] Journal of the American Chemical Society, 1949, vol. 71, p. 78,79, 80
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