Tetrahydrofuran → HCID 118061924, compound

HRID 920804Notes

Reaction equation

HRID 920804 reaction equation
[F:1][C:2]1([F:11])[C:4]2([CH2:7][CH:6](C(O)=O)[CH2:5]2)[CH2:3]1.C1C=CC(P([N:26]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[C:45]([C:46]([NH2:48])=[O:47])=[C:40]3[CH2:41][NH:42][CH2:43][CH2:44][N:39]3[N:38]=2)[CH:33]=[CH:34][C:35]=1[F:36].C1[CH2:53][O:52]CC1>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[C:45]([C:46]([NH2:48])=[O:47])=[C:40]3[CH2:41][N:42]([C:53]([NH:26][CH:6]4[CH2:5][C:4]5([C:2]([F:1])([F:11])[CH2:3]5)[CH2:7]4)=[O:52])[CH2:43][CH2:44][N:39]3[N:38]=2)[CH:33]=[CH:34][C:35]=1[F:36]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 199401P,P-Diphenylphosphinic azideHCID 1180616272-(3-Chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamideHCID 1180629661,1-Difluorospiro[2.3]hexane-5-carboxylic acid

Product 1

HCID 118061924HCID 118061924, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A solution of Intermediate 320B (83 mg, 0.509 mmol), TEA (0.142 mL, 1.018 mmol) and DPPA (0.11 mL, 0.509 mmol) in toluene (10 mL) was heated to 90° C. and stirred for 2 h. The reaction mixture was cooled to RT and to it was added a solution of Intermediate 185B (100 mg, 0.339 mmol) in THF (3 mL) and stirred for 4 h. The reaction mixture was quenched with water and the aq layer was extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with a 10% aq. solution of NaHCO3 and then water, dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC and was loaded on a 0.5 mm silica gel plate and developed using 6% MeOH in CHCl3. The band containing the desired product was separated and extracted into 10% MeOH in DCM, then was filtered and concentrated to afford mixture of 320 and 321 as an off-white solid. The individual isomers were separated by preparative chiral SFC.

Workup

  1. stirringstirred for 4 h
  2. customThe reaction mixture was quenched with water
  3. extractionthe aq layer was extracted with ethyl acetate (3×5 mL)
  4. washThe combined organic layer was washed with a 10% aq. solution of NaHCO3
  5. dry with materialwater, dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified by preparative TLC
  9. additionThe band containing the desired product
  10. customwas separated
  11. extractionextracted into 10% MeOH in DCM
  12. filtrationwas filtered
  13. concentrationconcentrated
  14. customto afford
  15. customThe individual isomers were separated by preparative chiral SFC

Sources & evidence

ORD record
ord-2f8c514611a442de84c73485fc44a574
Source dataset
uspto-grants-2016_03
Patent number
US09273058B2

Reaction notes

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