Triethylamine → methyl 2-((2S,4R)-2-(azidomethyl)-4-(5-cyclopropylpyrazin-2-yloxy)-pyrrolidin-1-yl)acetate

HRID 1184617Notes

Reaction equation

HRID 1184617 reaction equation
[N:1]([CH2:4][C@H:5]1[NH:9][CH2:8][C@H:7]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:6]1)=[N+:2]=[N-:3].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CO>[N:1]([CH2:4][C@@H:5]1[CH2:6][C@@H:7]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:18][CH2:19]3)=[CH:13][N:12]=2)[CH2:8][N:9]1[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[N+:2]=[N-:3]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 60984Methyl bromoacetateHCID 866805342-((3R,5S)-5-(azidomethyl)pyrrolidin-3-yloxy)-5-cyclopropylpyrazine

Product 1

HCID 86680535methyl 2-((2S,4R)-2-(azidomethyl)-4-(5-cyclopropylpyrazin-2-yloxy)-pyrrolidin-1-yl)acetateYield 54.8%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
65 °C

Procedure

To a solution of the product from Example 201A (290 mg, 1.114 mmol) in triethylamine (388 μl, 2.79 mmol) and methanol (0.3 mL) was added methyl bromoacetate (175 μL, 1.894 mmol), and the resulting mixture was stirred at 65° C. for 18 hours. The cooled mixture was concentrated in vacuo and partitioned between 1 N sodium bicarbonate and ethyl acetate. The organic extract was dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to give the title compound as an oil (203 mg, 54.8%). 1H NMR (500 MHz, pyridine-d5) δ ppm 6.74 (s, 1H), 4.63 (s, 1H), 4.36 (d, J=61.9 Hz, 1H), 4.08 (dt, J=14.2, 6.0 Hz, 1H), 3.81 (dd, J=42.1, 9.2 Hz, 1H), 3.62 (dd, J=11.3, 4.3 Hz, 1H), 3.46-3.27 (m, 1H), 2.23 (dd, J=21.4, 10.3 Hz, 1H), 2.17-2.04 (m, 1H), 1.49 (d, J=8.4 Hz, 11H); MS (ESI) m/z 333 (M+H)+.

Workup

  1. concentrationThe cooled mixture was concentrated in vacuo
  2. custompartitioned between 1 N sodium bicarbonate and ethyl acetate
  3. extractionThe organic extract
  4. dry with materialwas dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by chromatography on a 12 g silica gel column
  8. washeluting with 5% ethyl acetate/hexanes for 3 minutes

Sources & evidence

ORD record
ord-d51cd7adca6a409e88fe7556f461c9eb
Source dataset
uspto-grants-2014_03
Patent number
US08669255B2

Reaction notes

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