Trimethylphosphine → (6S)-N-[(5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

HRID 589015Notes

Reaction equation

HRID 589015 reaction equation
[N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[CH2:35][C@@:25]4([C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:34])[CH2:24][C:21]3=[N:22][CH:23]=2)=[O:17])[CH2:7][CH2:6][C@H:5]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[F:43])=[N+]=[N-].CP(C)C>C1(C)C=CC=CC=1>[NH2:1][C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[CH2:35][C@@:25]4([C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:34])[CH2:24][C:21]3=[N:22][CH:23]=2)=[O:17])[CH2:7][CH2:6][C@H:5]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[F:43]

Participants

4

Reactant 2

HCID 68983TrimethylphosphineHCID 117992085(6S)-N-[(5S,6S,9R)-5-Azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

Product 1

HCID 71819577(6S)-N-[(5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

(6S)—N-[(5S,6S,9R)-5-Azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide (13 mg, 0.022 mmol) was azeotroped with dry toluene and dried under high vacuum. The azide was dissolved in THF (1 mL), trimethylphosphine (1 M in toluene, 0.25 mL, 0.25 mmol) was added, and the resulting solution was stirred at ambient temperature for 1.5 h. The reaction solution was concentrated to dryness in vacuo, resuspended in THF (2 mL) and water (0.5 mL) and heated at 85° C. in a sealed vial for 4 h. The mixture was allowed to cool, most of the THF was removed by evaporation and the residual solution was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H2O:CH3CN:TFA-95:5:0.1 to 0:100:0.1. Product-containing fractions were combined and neutralized with saturated aqueous sodium bicarbonate and the acetonitrile was removed by evaporation under reduced pressure. The resulting mixture was extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=553.3 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.95 (d, 1H, J=2.0 Hz); 8.48 (dd, 1H, J=4.9, 1.6 Hz); 8.24 (d, 1H, J=2.0 Hz); 8.08 (dd, 1H, J=5.3, 1.6 Hz); 8.00 (d, 1H, J=7.9 Hz); 7.42-7.35 (m, 2H); 7.28 (s, 1H); 7.25-7.15 (m, 2H); 6.96 (dd, 1H, J=7.4, 5.3 Hz); 5.58 (dd, 1H, J=10.1, 3.3 Hz); 4.74 (d, 1H, J=9.4 Hz); 3.65-3.55 (m, 2H); 3.40-3.30 (m, 2H); 3.06 (br s, 1H); 2.41-2.24 (m, 2H); 2.04-1.94 (m, 1H); 1.71-1.53 (m 1H).

Workup

  1. customdried under high vacuum
  2. dissolutionThe azide was dissolved in THF (1 mL)
  3. concentrationThe reaction solution was concentrated to dryness in vacuo
  4. temperaturewater (0.5 mL) and heated at 85° C. in a sealed vial for 4 h
  5. temperatureto cool, most of the THF
  6. customwas removed by evaporation
  7. customthe residual solution was purified by reversed-phase HPLC on a C-18 column
  8. washeluting with a gradient of H2O
  9. customthe acetonitrile was removed by evaporation under reduced pressure
  10. extractionThe resulting mixture was extracted with ethyl acetate (2×50 mL)
  11. dry with materialthe combined organic layers were dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-05d813560dc54a8c98b989d9e90191a8
Source dataset
uspto-grants-2016_01
Patent number
US09227973B2

Reaction notes

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