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[ CAS No. 114457-94-2 ]

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Chemical Structure| 114457-94-2
Chemical Structure| 114457-94-2
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Product Details of [ 114457-94-2 ]

CAS No. :114457-94-2 MDL No. :MFCD09800536
Formula : C14H13N3O3 Boiling Point : 573.8°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :271.27 g/mol Pubchem ID :15042559
Synonyms :

Safety of [ 114457-94-2 ]

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 [ 114457-94-2 ]

  • Upstream synthesis route of [ 114457-94-2 ]
  • Downstream synthetic route of [ 114457-94-2 ]

[ 114457-94-2 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 73058-37-4 ]
  • [ 114457-94-2 ]
YieldReaction ConditionsOperation in experiment
93.6% With sodium hydroxide In acetoneCooling with ice The product N-pyrazineformyl-L-phenylalanine methyl ester (1.0g, 3.51mmol) in Preparation example 2 was dissolved with 10ml of acetone, 2N NaOH was added dropwise slowly until a pH value of 12∼13 was obtained, and the solution was kept reacting under the condition of ice water bath, the reaction was monitored by TLC and completed after 2h.
Hydrochloric acid was add dropwise under the condition of ice water bath until a pH value of 2∼3 was obtained, a large amount of white solid was produced, the generated precipitate was filtered, washed with water and diethyl ether followed by airing to dry and gave 0.89g of white product with a yield of 93.6percent, m.p.: 166-169°C. 1H-NMR (DMSO-d6, 300MHz): δ 3.23 (-CH2, m, 2H), 4.74 (-CH, m, 1H), 7.16∼7.25 (-Ph, m, 5H), 8.74 (-CONH, t, 1H), 8.86∼8.89 (-Pyz, t, 2H), 9.14 (-Pyz, d, 1H), 13.06 (-COOH, s, 1H).
93% With lithium hydroxide In tetrahydrofuran; water at 0℃; for 1 h; The product 6a (1mmol) was dissolved in 10mL THF and was added 3N LiOH dropwise at 0°C until TLC showed methyl ester 6a was disappeared completely (1h). The reaction solution was acidified to pH 2. The precipitate was filtered and washed with water until pH value reached 6–7. After dryness, the acid 7a was obtained with high yield and used exactly without further purification, 93percent yield; mp: 166–169°C. 1H NMR (400MHz, CDCl3) δ 9.37 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.22 (d, J=8.1Hz, 1H), 7.25 (dt, J=16.6, 7.2Hz, 5H), 5.12 (dd, J=13.8, 6.2Hz, 1H), 3.31 (dd, J=20.6, 14.1, 6.0Hz, 2H)
1.22 g With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; for 2 h; To a solution of 8a (1.44 g, 5.05 mmol) in THF (5 mL) were added 1 M aq LiOH(6 mL) dropwise with the aid of ice-water bath followed by stirring to r.t. over 2 h.The reaction mixture were diluted with water (20 mL) and extracted with EtOAc (3×5mL). The alkaline water layer were acidized to pH = 2-3 with 1 M aq HCl to give awhite suspension, which were filtrated, washed to pH = 6-7 by water, and dried togive the title compound 9a (1.22 g, 89percent) as a white solid;
Reference: [1] Patent: EP2444411, 2016, B1, . Location in patent: Paragraph 0038
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 15, p. 4031 - 4044
[3] Organic and Biomolecular Chemistry, 2007, vol. 5, # 9, p. 1416 - 1426
[4] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 19, p. 6851 - 6861
[5] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4192 - 4199
[6] Patent: WO2009/36281, 2009, A2, . Location in patent: Page/Page column 37-38
[7] Patent: WO2009/36281, 2009, A2, . Location in patent: Page/Page column 39
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4365 - 4377
[9] Patent: WO2012/48745, 2012, A1, . Location in patent: Page/Page column 14-15
[10] Synthesis (Germany), 2013, vol. 45, # 20, p. 2843 - 2852
[11] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1958 - 1962
  • 2
  • [ 19847-10-0 ]
  • [ 63-91-2 ]
  • [ 114457-94-2 ]
YieldReaction ConditionsOperation in experiment
36%
Stage #1: With sodium carbonate In water; toluene at 10 - 25℃; for 3 h;
Stage #2: With hydrogenchloride In methanol; water at 15 - 20℃;
Step B. Preparation of (S)-3-Phenyl-2-[(pyrazine-2-carbonyl)-amino] -propionic acid (i.e., acid of Formula II, wherein R]is 2-pyrazinyl and R2 is benzyl). A second 500 ml three neck round bottomed flask was equipped with a stir bar, thermocouple, pressure equalizing dropping funnel, nitrogen inlet/outlet and ice/water cooling bath. L- Phenylalanine, 20.2 g (0.122 mol) was added, followed by 28.2 g (0.266 mol) of sodium carbonate and 225 mL of deionized water. The aqueous solution was cooled to 10.0 °C. During this time the addition funnel was charged with the acid chloride/toluene solution prepared in Step A (-125 mL). This toluene solution was added dropwise to the aqueous reaction over approximately 10 minutes at -10 °C. Once the addition was complete, the reaction was warmed to room temperature (-22-25 °C) and vigorously stirred for 3 h. The reaction mixture was then transferred to a separatory funnel and the two layers were separated. The lower aqueous phase was then recharged to the reaction flask. Methanol (125 mL) was then added to the red solution followed by pH adjustment (target pH=l-2) with 3.0 M HC1 (-175 mL), keeping the temperature at 15-20 °C. Some off-gassing occurred at - pH=5, followed by precipitation of the product at pH=3. The slurry was allowed to stir at room temperature for 30 minutes at ambient temperature post pH adjustment. The resulting pink solid precipitate was collected by vacuum filtration,(mother liquor losses <2 mg/mL), washed with deionized water (1X50 ml) then dried in a vacuum oven at 40 °C with a nitrogen sweep to a constant weight to provide 11.92 g (0.43.9 mmol, 36percent) of the title compound with an HPLC purity of 99Apercent. 1H NMR (d6- DMSO, 400MHz) δ 13.04 (s, IH), 9.14 (d, IH, J=1.44 Hz), 8.88 (dd, 2H, J=2.48, 6.16 Hz), 8.75 (dd, IH, J=1.52, 2.4 Hz), 7.25 (m, 4H), 7.18 (m, IH), 4.75 (dt, IH, J=5.48, 8.08 Hz), 3.2 (dd, 2H, J=1.79, 5.32 Hz).
36% With sodium carbonate In water; toluene at 10 - 25℃; A second 500 ml three neck round bottomed flask is equipped with a stir bar, thermocouple, pressure equalizing dropping funnel, nitrogen inlet/ outlet and ice/water cooling bath. E-Phenylalanine, 20.2 g (0.122 mol) is added, followed by 28.2 g (0.266 mol) ofsodium carbonate and 225 mE of deionized watet The aqueous solution is cooled to 10.0°C. During this time the addition flannel is charged with the acid chloride/toluene solution prepared in Step A (.-125 mE). This toluene solution is added dropwise to the aqueous reaction over approximately 10 mm-utes at .—10° C. Once the addition is complete, the reaction is warmed to room temperature (.-22-25° C.) and vigorously stirred for 3 h. The reaction mixture is then transferred to a reparatory flannel and the two layers are separated. The lower aqueous phase is then recharged to the reaction flask. Metha40 nol (125 mE) is then added to the red solution followed by pHadjustment (target pH=1 -2) with 3.0 M HC1 (.-175 mE), keeping the temperature at 15-20° C. Some off-gassing occurs at .-pH=5, followed by precipitation of the product at pH=3. The slurry is allowed to stir at room temperature for 30 minutes atambient temperature post pH adjustment. The resulting pink solid precipitate is collected by vacuum filtration, (mother liquor losses <2 mg/mE), washed with deionized water (1 x50 ml) then dried in a vacuum oven at 40° C. with a nitrogen sweep to a constant weight to provide 11.92 g (0.43.9 mmol,36percent) of the title compound with an HPEC purity of 99 A percent. ‘HNMR(d6-DMSO, 400 MHz)ö 13.04(s, 1H), 9.14(d, 1H, J=1.44 Hz), 8.88 (dd, 2H, J=2.48, 6.16 Hz), 8.75 (dd, 1H, J=1.52, 2.4 Hz), 7.25 (m, 4H), 7.18 (m, 1H), 4.75 (dt, 1H, J=5.48, 8.08 Hz), 3.2 (dd, 2H, J=1.79, 5.32 Hz).
Reference: [1] Patent: WO2011/87822, 2011, A1, . Location in patent: Page/Page column 120-121
[2] Patent: US9340559, 2016, B2, . Location in patent: Page/Page column 20
  • 3
  • [ 7364-51-4 ]
  • [ 103435-88-7 ]
  • [ 114457-94-2 ]
YieldReaction ConditionsOperation in experiment
0.96 g at -40 - 20℃; for 16.5 h; N,O-Bis(trimethylsilyl)acetamide (BSA, 2.49 mL, 10.05 mmol) was added to a solution of L-phenylalanine (0.83 g, 5.02 mmol) and dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 16 h. In another 100 mL reaction flask, 1,1'-carbonyldiimidazole (1.7 g, 10.48 mmol) was added to a solution of pyrazinecarboxylic acid (1 g, 8.06 mmol) and dichloromethane (17 mL). After stirring at room temperature for 16 h, the reaction mixture was cooled in a −40 °C bath and the above solution of L-phenylalanine-BSA was added dropwise over 30 min. The reaction mixture was stirred at room temperature for another 16 h, citric acid(aq) (0.78 M, 17 mL) was added, and extracted with dichloromethane (10 mL × 3). The organic layers were separated, combined, dried over anhydrous Na2SO4 and concentrated. The crude product was recrystallized in dichloromethane/hexanes to give N-(2-pyrazinylcarbonyl)-L-phenylalanine (8, R = benzyl; R' = pyrazinyl, 0.96 g, 3.54 mmol, 70percent) as a colorless solid.
Reference: [1] Tetrahedron, 2009, vol. 65, # 34, p. 7105 - 7108
[2] Molecules, 2013, vol. 18, # 12, p. 15398 - 15411
  • 4
  • [ 18414-58-9 ]
  • [ 32111-21-0 ]
  • [ 114457-94-2 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 11, p. 2873 - 2876
  • 5
  • [ 98-97-5 ]
  • [ 114457-94-2 ]
Reference: [1] Organic and Biomolecular Chemistry, 2007, vol. 5, # 9, p. 1416 - 1426
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4365 - 4377
[3] Patent: WO2012/48745, 2012, A1,
[4] Synthesis (Germany), 2013, vol. 45, # 20, p. 2843 - 2852
[5] Molecules, 2013, vol. 18, # 12, p. 15398 - 15411
[6] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1958 - 1962
[7] Patent: US9340559, 2016, B2,
[8] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 15, p. 4031 - 4044
[9] Patent: EP2444411, 2016, B1,
[10] Patent: EP3312273, 2018, A1,
  • 6
  • [ 7524-50-7 ]
  • [ 114457-94-2 ]
Reference: [1] Organic and Biomolecular Chemistry, 2007, vol. 5, # 9, p. 1416 - 1426
[2] Patent: WO2012/48745, 2012, A1,
[3] Synthesis (Germany), 2013, vol. 45, # 20, p. 2843 - 2852
[4] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1958 - 1962
[5] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 15, p. 4031 - 4044
  • 7
  • [ 98-97-5 ]
  • [ 16480-57-2 ]
  • [ 114457-94-2 ]
Reference: [1] Patent: WO2009/36281, 2009, A2, . Location in patent: Page/Page column 38-39
  • 8
  • [ 2577-90-4 ]
  • [ 114457-94-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4365 - 4377
  • 9
  • [ 15100-75-1 ]
  • [ 114457-94-2 ]
Reference: [1] Patent: EP3312273, 2018, A1,
  • 10
  • [ 179324-69-7 ]
  • [ 114457-94-2 ]
Reference: [1] Journal of Pharmaceutical Sciences, 2000, vol. 89, # 6, p. 758 - 765
[2] Journal of Pharmaceutical Sciences, 2000, vol. 89, # 6, p. 758 - 765
  • 11
  • [ 179324-69-7 ]
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Reference: [1] Journal of Pharmaceutical Sciences, 2000, vol. 89, # 6, p. 758 - 765
[2] Journal of Pharmaceutical Sciences, 2000, vol. 89, # 6, p. 758 - 765
  • 12
  • [ 63-91-2 ]
  • [ 114457-94-2 ]
Reference: [1] Molecules, 2013, vol. 18, # 12, p. 15398 - 15411
  • 13
  • [ 179324-69-7 ]
  • [ 114457-94-2 ]
  • [ 289472-78-2 ]
Reference: [1] Journal of Pharmaceutical Sciences, 2000, vol. 89, # 6, p. 758 - 765
  • 14
  • [ 114457-94-2 ]
  • [ 179324-69-7 ]
Reference: [1] Patent: US2015/259364, 2015, A1,
[2] Patent: US9340559, 2016, B2,
  • 15
  • [ 114457-94-2 ]
  • [ 205393-22-2 ]
YieldReaction ConditionsOperation in experiment
86% With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dichloromethane; acetonitrile at -15 - 25℃; for 1.5 h; Example 3: Compound of formula (4)Mix the (S)-3-phenyl-2-(pyrazine-2-carboxamido)propanoic acid (10.85 g,40.0 mmol) with the trifluoroacetate salt of the compound of formula (2) (16.27g, 40.0 mmol) in 215 ml of anhydrous dichloromethane at 20-25°C. Cool the formed white suspension under stirring to -15°C and add N-methylmorpholine (17.7 ml, 160 mmol) while keeping the internal temperature at -10°C. Add the T3P reagent (2,4,6-triprop-l-yl-l,3,5-trioxa-2,4,6- triphosphinane-2,4,6-trioxide, 38.2 g of 50percent solution in acetonitrile, 60 mmol)at the same temperature. Stir the reaction mixture at -10 to -15°C for 1.5 hours.Warm the reaction mixture to 20-25°C and add 215 ml of water. Separate the layers and was the organic layer with 210 ml of brine. Dry the organic extract with anhydrous sodium sulphate and evaporate the volatiles (5 mbar, 40°C) to an oily residue. Transfer the residue to silic gel pad (54.3 g, Silica gel 60 Merck, 40-63 μιη, 230-400 Mesh) and elute crude product with a mixture of n-heptane/MTBE (460 ml). Evaporate volatiles (5mbar, 40°C) and yield 18.12 g of a yellow residue (86percent).HPLC: Chemical purity 98.69percent (IN), Chiral purity 99.7percent.
Reference: [1] Patent: WO2012/48745, 2012, A1, . Location in patent: Page/Page column 15
[2] Tetrahedron, 2009, vol. 65, # 34, p. 7105 - 7108
[3] Patent: WO2009/36281, 2009, A2, . Location in patent: Page/Page column 39-40
[4] Patent: WO2009/36281, 2009, A2, . Location in patent: Page/Page column 40
  • 16
  • [ 114457-94-2 ]
  • [ 205393-22-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4192 - 4199
  • 17
  • [ 114457-94-2 ]
  • [ 205393-22-2 ]
Reference: [1] Patent: US9340559, 2016, B2, . Location in patent: Page/Page column 20; 21
  • 18
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  • [ 205393-22-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4365 - 4377
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