Tetrahydrofuran → HCID 178484162, compound

HRID 1879663Notes

Reaction equation

HRID 1879663 reaction equation
[Cl-].[Cl-].[Cl-].[In+3].[CH3:5][N:6]([C@@H:8]1[C:26](=[O:27])[C:25]([C:28]([NH2:30])=[O:29])=[C:24]([OH:31])[C@:23]2([OH:32])[C@H:9]1[CH2:10][C@H:11]1[C:20]([C:21]2=[O:22])=[C:19]([OH:33])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][C:17]=2[OH:34])[CH2:12]1)[CH3:7].[CH2:36]1[CH2:40]OC[CH2:37]1>>[CH:37]1([C:14]2[CH:15]=[CH:16][C:17]([OH:34])=[C:18]3[C:13]=2[CH2:12][C@@H:11]2[C:20]([C:19]3=[O:33])=[C:21]([OH:22])[C@@:23]3([OH:32])[C@H:9]([C@H:8]([N:6]([CH3:7])[CH3:5])[C:26]([OH:27])=[C:25]([C:28]([NH2:30])=[O:29])[C:24]3=[O:31])[CH2:10]2)[CH2:36][CH2:40]1

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 159675indium(III)chlorideHCID 54687146HCID 54687146, compound

Product 1

HCID 178484162HCID 178484162, compoundYield 72%

Procedure

A 1000 mL 2 or 3 neck round-bottomed flask with reflux condenser was charged with anhydrous InCl3 (12.1 g, 40.5 mmol) and dried under vacuum with a heat gun. After the flask cooled to ambient temperature and was flushed with argon, anhydrous THF (240 mL) was added. The solution was cooled to −78° C. and c-PrMgBr (244 mL, 122 mmol) as a 0.5 M solution in THF was added. After 15 minutes, the solution was allowed to slowly warm to room temperature to form a clear heterogeneous solution. To the reaction flask was added 7-iodosancycline (19.4 g, 36.0 mmol) and Pd(t-Bu3)2 (0.920 g, 1.80 mmol). The solution was heated to reflux under argon until complete (approximately 1 hour). After cooling to ambient temperature, the solution was quenched with MeOH (1 mL) and poured into a stirring cold solution of 1M HCl (3 L). After 1 hour, the solution was filtered through a pad of Celite, while rinsing with water. The water solution was loaded onto a DVB column for solid phase extraction and the product was isolated by eluting with 1% TFA/CH3CN. The crude product was further purified by preparatory HPLC (C18, linear gradient 20-60% acetonitrile in water with 0.1% TFA, to afford 11.8 g in 72% yield as a yellow solid. 1H NMR (CD3OD) δ 7.18 (d, J=7.4 Hz, 1H), 6.61 (d, J=7.4 Hz, 1H), 3.99 (s, 1H), 3.34 (dd, J=9.1, 2.8 Hz, 1H), 3.05-2.84 (m, 10H), 2.32-2.09 (m, 2H), 0.86-0.75 (m, 2H), 0.51-0.37 (m, 2H). LC/MS (MH+) 455.

Workup

  1. customdried under vacuum with a heat gun
  2. customwas flushed with argon, anhydrous THF (240 mL)
  3. additionwas added
  4. temperatureThe solution was cooled to −78° C.
  5. temperatureto slowly warm to room temperature
  6. customto form a clear heterogeneous solution
  7. temperatureThe solution was heated
  8. temperatureto reflux under argon until complete (approximately 1 hour)
  9. temperatureAfter cooling to ambient temperature
  10. customthe solution was quenched with MeOH (1 mL)
  11. additionpoured into a stirring cold solution of 1M HCl (3 L)
  12. waitAfter 1 hour
  13. filtrationthe solution was filtered through a pad of Celite
  14. washwhile rinsing with water
  15. extractionThe water solution was loaded onto a DVB column for solid phase extraction
  16. customthe product was isolated
  17. washby eluting with 1% TFA/CH3CN
  18. customThe crude product was further purified by preparatory HPLC (C18, linear gradient 20-60% acetonitrile in water with 0.1% TFA
  19. customto afford 11.8 g in 72% yield as a yellow solid

Sources & evidence

ORD record
ord-1118ee8365fa485d900e255592ff557b
Source dataset
uspto-grants-2012_11
Patent number
US08318706B2

Reaction notes

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