Lithium Hexamethyldisilazide → HCID 68279566, compound

HRID 529410Notes

Reaction equation

HRID 529410 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:11][CH:10]=3.Cl.[F:31][C:32]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].[Cl-].[NH4+]>[F:31][C:32]1([F:37])[CH2:36][CH2:35][N:34]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:23]2[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=4)[CH2:33]1

Participants

6

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 249034823,3-Difluoropyrrolidine hydrochlorideHCID 86709322HCID 86709322, compound

Product 1

HCID 68279566HCID 68279566, compound

Reagents, catalysts & solvents 2

HCID 66572931HCID 66572931, compoundCatalystHCID 25517Ammonium ChlorideSolvent

Procedure

A vial was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine (50.0 mg, 0.122 mmol), 3,3-difluoropyrrolidine hydrochloride (36.0 mg, 0.243 mmol), and RuPhos precatalyst (8.87 mg, 0.012 mmol). The vial was flushed with N2 gas, then lithium bis(trimethylsilyl)amide (1M in THF) (608 μl, 0.608 mmol) was added slowly to the mixture. After about 10 mins, the mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified on a 12 g Redi-Sep Gold silica-gel column eluting with a 90:10:1 mixture of DCM/MeOH/NH4OH in EtOAc to provide (S)-3-(3,3-difluoropyrrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno [2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.06 (br. s., 1 H) 2.14 (br. s., 1 H) 2.51-2.61 (m, 2 H) 3.33-3.41 (m, 2 H) 3.58 (t, J=7.59 Hz, 2 H) 3.81 (t, J=13.04 Hz, 2 H) 4.34-4.46 (m, 2 H) 6.00 (br. s., 2 H) 6.57 (s, 1 H) 7.28 (d, J=8.33 Hz, 1 H) 7.48 (t, J=5.34 Hz, 1 H) 7.53 (d, J=8.76 Hz, 1 H) 7.62 (s, 1 H) 8.00-8.07 (m, 1 H) 8.10 (s, 1 H) 8.22 (d, J=4.06 Hz, 1 H).

Workup

  1. customThe vial was flushed with N2 gas
  2. extractionextracted with EtOAc
  3. dry with materialThe combined organic extracts were dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified on a 12 g Redi-Sep Gold silica-gel column
  7. washeluting with a 90:10:1 mixture of DCM/MeOH/NH4OH in EtOAc

Sources & evidence

ORD record
ord-03cdcfecdf054aae87c8e4be84b33b33
Source dataset
uspto-grants-2016_05
Patent number
US09346827B2

Reaction notes

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