Diisopropylethylamine → HCID 24788500, compound

HRID 1712685Notes

Reaction equation

HRID 1712685 reaction equation
C(N(CC)C(C)C)(C)C.O([C:17]([NH:19][C:20]1[CH:25]=[C:24]([O:26][C:27]2[C:32]([F:33])=[CH:31][C:30]([NH:34][C:35]([C:37]3([C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])[CH2:39][CH2:38]3)=[O:36])=[C:29]([F:50])[CH:28]=2)[CH:23]=[CH:22][N:21]=1)=[O:18])C1C=CC=CC=1.Cl.[OH:52][C@@H:53]1[CH2:57][CH2:56][NH:55][CH2:54]1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:50][C:29]1[CH:28]=[C:27]([O:26][C:24]2[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:17]([N:55]3[CH2:56][CH2:57][C@@H:53]([OH:52])[CH2:54]3)=[O:18])[CH:25]=2)[C:32]([F:33])=[CH:31][C:30]=1[NH:34][C:35]([C:37]1([C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])[CH2:38][CH2:39]1)=[O:36]

Participants

6

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 516892Sodium BicarbonateHCID 2759336(3R)-pyrrolidin-3-ol hydrochloride2×HCID 24788625Benzyl 1-({[4-([2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate

Product 1

HCID 24788500HCID 24788500, compoundYield 90.2%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

N,N-Diisopropylethylamine (0.249 ml) was added to a mixture of benzyl 1-({[4-({2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (200 mg), (R)-3-hydroxypyrrolidine hydrochloride (88.2 mg) and N-methylpyrrolidinone (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 5 hours. (R)-3-Hydroxypyrrolidine hydrochloride (44.1 mg) and N,N-diisopropylethylamine (0.125 ml) were added at room temperature, and the mixture was stirred for 15 hours and 40 minutes. A saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added to the mixture to quench the reaction, and the mixture was partitioned after the addition of ethyl acetate and tetrahydrofuran (1:1) (50 ml) and (30 ml). The organic layer was washed with brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (178.2 mg, 90%) as a white solid.

Workup

  1. stirringthe mixture was stirred for 15 hours and 40 minutes
  2. customto quench
  3. customthe reaction
  4. customthe mixture was partitioned
  5. additionafter the addition of ethyl acetate and tetrahydrofuran (1:1) (50 ml) and (30 ml)
  6. washThe organic layer was washed with brine (30 ml)
  7. dry with materialdried over anhydrous magnesium sulfate
  8. customThe desiccant was removed by filtration
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  11. additionThe fractions containing the target compound
  12. concentrationwere concentrated under reduced pressure

Sources & evidence

ORD record
ord-a4fa9453bc2246e7acaaafdf9776445f
Source dataset
uspto-grants-2010_09
Patent number
US07790885B2

Reaction notes

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