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Chemical Structure| 2460022-74-4 Chemical Structure| 2460022-74-4

Structure of 2460022-74-4

Chemical Structure| 2460022-74-4

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Product Details of [ 2460022-74-4 ]

CAS No. :2460022-74-4
Formula : C16H25FN2O5
M.W : 344.38
SMILES Code : O=C(C1(CC1)F)N[C@@H](C(C)(C)C)C(N2[C@@H](C[C@H](C2)O)C(OC)=O)=O
English Name :Methyl (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

Safety of [ 2460022-74-4 ]

Application In Synthesis of [ 2460022-74-4 ]

* 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 [ 2460022-74-4 ]

[ 2460022-74-4 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 1329698-72-7 ]
  • [ 137081-41-5 ]
  • [ 2460022-74-4 ]
YieldReaction ConditionsOperation in experiment
38% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Methyl (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (BH) In an oven-dried round-bottom flask, under nitrogen atmosphere, to a stirred solution of 1-fluorocyclopropane-1-carboxylic acid (commercially available from, for example, Fluorochem) (0.60 g, 5.765 mmol), methyl (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (BG) (1.545 g, 5.241 mmol), and DIPEA (4.564 mL, 26.207 mmol) in dry DMF (5.0 mL) was added HATU (2.391 g, 6.289 mmol). Stirring was continued at rt overnight. The reaction mixture was diluted with water (30 mL) and extracted with EA (20 mL*4). The reunited organic layers were washed with water (30 mL*2), brine (30 mL), dried over anhydrous Na2SO4 and then evaporated under reduced pressure to give an oil residue, which was purified by double flash column chromatography on SiO2 (first: DCM/MeOH, 98:2; second: DCM/Acetone, 95:5 to 8:2) affording the titled compound as white solid (0.687 g, 38% yield). 1H NMR (400 MHz, CDCl3): δ 7.10 (d, J=5.9 Hz, 1H), 4.72-4.64 (m, 1H), 4.57 (d, J=9.1 Hz, 1H), 4.53 (s, 1H), 4.02 (d, J=11.2 Hz, 1H), 3.79-3.69 (m, 4H), 2.41-2.29 (m, 1H), 2.07-2.97 (m, 2H), 1.37-1.20 (m, 4H), 1.08 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 172.54, 170.26, 170.02, 78.27 (d, J=205.7 Hz), 70.39, 57.67, 57.34, 56.47, 52.26, 37.65, 35.75, 26.33 (3C), 13.68 (d, J=10.3 Hz).
78 % With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Step 3: 8-b (1.6g, 5.6mmol) and 1-fluorocyclopropane carboxylic acid (640mg, 6.16mmol) were dissolved in DMF (15mL), HATU (2.5g, 6.7mmol) and DIPEA (4.3g, 33.6mmol) were added, the reaction was carried out at room temperature for 4 hours, and the TLC monitoring reaction was completed. Water (20mL) was added to the reaction solution, extracted with ethyl acetate (20mL×3), the combined organic phase was washed with saturated sodium chloride solution (40mL), anhydrous sodium sulfate was dried, filtered, the organic phase was concentrated, and the concentrate was purified by column chromatography (MeOH/DCM=1:50-1:20) to obtain 8-c (1.5g, yellow oil), yield: 78%.
  • 2
  • [ 2460022-74-4 ]
  • [ 2316837-29-1 ]
YieldReaction ConditionsOperation in experiment
94% With water; lithium hydroxide In tetrahydrofuran at 20℃;
80% With lithium hydroxide monohydrate In tetrahydrofuran; water at 0 - 20℃; for 18h; (2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic Acid (E3LB-4(B)) To the solution of methyl (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (BH) (0.65 g, 1.887 mmol) in THF (5.0 mL) at 0° C. was added the solution of lithium hydroxide monohydrate (0.792 g, 18.874 mmol) in water (2.5 mL). The resulting mixture was stirred at rt for 18 h. The organic solvent was removed under vacuo, the residue was diluted with ice-water (15 mL) and the pH was slowly adjusted to 2-3 with 2N HCl. The mixture was then extracted with EA (5 mL*4). The reunited organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and then evaporated under reduced pressure to give a residue which was tritured with DEE, filtered off, and dried to give the titled compound as a white solid (0.497 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.55 (bs, 1H), 7.27 (d, J=6.9 Hz, 1H), 5.21 (d, J=3.7 Hz, 1H), 4.60 (d, J=9.1 Hz, 1H), 4.3-4.25 (m, 2H), 3.70-3.54 (m, 2H), 2.21-2.06 (m, 1H), 1.96-1.84 (m, 1H), 1.44-1.10 (m, 4H), 0.96 (s, 9H); 13C NMR (101 MHz, DMSO-d6): δ 173.56, 169.56, 168.53 (d, J=20.3 Hz), 78.55 (d, J=232.5 Hz), 69.28, 58.27, 56.88, 56.78, 37.69, 36.48, 26.57 (3C), 13.33 (dd, J=23.7, 10.3 Hz).
71.4% With lithium hydroxide monohydrate; water In methanol at 20℃; for 3h;
70% With lithium hydroxide monohydrate; water In tetrahydrofuran at 25℃; for 1h; I.E Step E: (2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid To a solution of methyl (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (5.0 g, 15.0 mmol) in THF (40.0 mL) and H2O (10.0 mL) was added lithium hydroxide (1.08 g, 45.3 mmol) and the reaction was stirred at 25 °C for 1 hour. The reaction mixture was adjusted to pH = 6 with 1 N HCl and extracted with DCM for 3 times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford (2S,4R)-1-((S)-2-(1- 111fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.30 g, 70%) as a white solid. MS(ES) [M+H]+331.1.
720 mg With lithium hydroxide monohydrate; water In tetrahydrofuran at 25℃; Inert atmosphere; 1.2 (2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid To a solution of (2S,4R)-methyl 1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (1.00 g, 2.90 mmol) in THF (10 mL) was added LiOH.H2O (366 mg, 8.71 mmol) in H2O (5 mL). The mixture was stirred at 25 °C for 2 h. On completion, the pH of the reaction mixture was adjusted to 4~3 by addition 2 M HCl, then the mixture was extracted with EtOAc (10 mL x 10). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (720 mg) as a white oil.
720 mg With lithium hydroxide monohydrate; water In tetrahydrofuran at 25℃; Inert atmosphere; 1.2 (2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid To a solution of (2S,4R)-methyl 1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (1.00 g, 2.90 mmol) in THF (10 mL) was added LiOH.H2O (366 mg, 8.71 mmol) in H2O (5 mL). The mixture was stirred at 25 °C for 2 h. On completion, the pH of the reaction mixture was adjusted to 4~3 by addition 2 M HCl, then the mixture was extracted with EtOAc (10 mL x 10). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (720 mg) as a white oil.
70 % With lithium hydroxide monohydrate In tetrahydrofuran; water at 20℃; Step 4: Dissolve 8-c (1.5g, 4.3mmol) in THF (30mL) and water (10mL) and add LiOH ·H2O(900mg, 22.0mmol), 2 hours at room temperature, TLC monitoring reaction was completed. Concentrate to remove THF, add sodium hydroxide solid to adjust pH=12, add ethyl acetate (100mL) to extract, collect the aqueous phase, adjust the pH to 3-4 with hydrochloric acid solution (6mol/L) in the aqueous phase, extract with ethyl acetate (100mL×3), combine organic phase, anhydrous sodium sulfate drying, filtration, concentrate organic phase to obtain intermediate 8 (1.0g, white solid), yield: 70%.
4.4 g With water; sodium hydroxide In methanol for 3h; Preparation of 6. To a solution of crude product 5 (5.00 g, 14.52 mmol, 1 equiv.) in MeOH/H2O (50 mL/5mL) was added NaOH (1.16 g, 28.28 mmol, 2.0 equiv.) The mixture was stirred for 3 h. MeOH was removed under rotatory evaporator. The aqueous phase was added TFA until the pH reach 4. The crude product aqueous solution was purified by C-18 reversal column (elution solvents: CH3CN/H2O from 10% to 100%, 0.1%TFA) to get pure product (4.4 g, 92%). ESI MS m/z: 331.15 [M+H]+. 1H NMR (400 MHz, DMSO) δ 12.81 (s, 1H), 7.26 (dd, J = 9.3, 3.0 Hz, 1H), 4.60 (dd, J = 9.4, 1.3 Hz, 1H), 4.44 - 4.27 (m, 2H), 3.66 (dd, J = 10.8, 3.9 Hz, 1H), 3.63 - 3.56 (m, 1H), 2.14 (ddt, J = 11.8, 7.9, 1.8 Hz, 1H), 1.91 (ddd, J = 13.3, 9.3, 4.5 Hz, 1H), 1.42 - 1.37 (m, 1H), 1.37 - 1.31 (m, 1H), 1.26 - 1.14 (m, 2H), 0.99 (s, 9H).

  • 3
  • [ 1024616-23-6 ]
  • [ 137081-41-5 ]
  • [ 2460022-74-4 ]
YieldReaction ConditionsOperation in experiment
83.3% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2h;
59% With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide at 20℃;
99 % With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; Inert atmosphere; 1.1 Sten 1 -(2S,4R)-methyl 1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate To a solution of methyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy- pyrrolidine-2-carboxylate (129 g, 437 mmol, CAS 1024616-23-6) in DMF (1500 mL) was added DIEA (169.68 g, 1.31 mol, 228.67 mL), HATU (216.32 g, 568.91 mmol), and 1-fluorocyclopropanecarboxylic acid (50.10 g, 481.39 mmol, CAS 137081-41-5). The mixture was then stirred at 25 °C for 2 hrs. On completion, the reaction mixture was quenched by addition of H2O (500 mL) at 25 °C, and then diluted with ethyl acetate (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with sat. NaCl (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=2/1) to give title compound (152 g, 99% yield) as a yellow oil. LC-MS (ESI+) m/z 345.0 (M+H)+.
99 % With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; Inert atmosphere; 1.1 Sten 1 -(2S,4R)-methyl 1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate To a solution of methyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy- pyrrolidine-2-carboxylate (129 g, 437 mmol, CAS 1024616-23-6) in DMF (1500 mL) was added DIEA (169.68 g, 1.31 mol, 228.67 mL), HATU (216.32 g, 568.91 mmol), and 1-fluorocyclopropanecarboxylic acid (50.10 g, 481.39 mmol, CAS 137081-41-5). The mixture was then stirred at 25 °C for 2 hrs. On completion, the reaction mixture was quenched by addition of H2O (500 mL) at 25 °C, and then diluted with ethyl acetate (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with sat. NaCl (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=2/1) to give title compound (152 g, 99% yield) as a yellow oil. LC-MS (ESI+) m/z 345.0 (M+H)+.
5 g With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere; I.D Step D: Methyl (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate To a solution of methyl (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (9.0 g, 15.0 mmol), DIPEA (12.2 g, 94.8 mmol) and 1-fluorocyclopropane-1-carboxylic acid (2.47 g, 23.7 mmol) in DMF (100 mL) wasadded HATU (11.7 g, 30.8 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with sat. NH4Cl and extracted with DCM. The combined organic layers were directly concentrated to give a residue which was purified by silica gel column chromatography (0~50 % EtOAc in PE) to afford methyl (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (5.0 g) as a yellow oil. MS(ES) [M+H]+345.1[M+H]+.

 

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