Tetrahydrofuran → HCID 89994505, compound

HRID 718865Notes

Reaction equation

HRID 718865 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]12[CH2:28][CH2:27][C:22]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:21][CH:9]1[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([CH:19]=O)[N:16]=[CH:15][C:14]=12.C1COCC1.[Li+].C[Si]([N-:39][Si](C)(C)C)(C)C.[F:44][C:45]1[CH:50]=[CH:49][C:48]([Mg]Br)=[CH:47][CH:46]=1>CCOC(C)=O.O>[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH:19]([C:17]2[N:16]=[CH:15][C:14]3[C@:8]4([CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:28][CH2:27][C:22]5([O:26][CH2:25][CH2:24][O:23]5)[CH2:21][C@H:9]4[CH2:10][CH2:11][CH2:12][C:13]=3[CH:18]=2)[NH2:39])=[CH:47][CH:46]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 2733832Lithium HexamethyldisilazideHCID 86722481HCID 86722481, compoundHCID 178418676HCID 178418676, compound

Product 1

HCID 89994505HCID 89994505, compoundYield 105.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-5 °C

Procedure

A flask with thermometer, septum, nitrogen line and stir bar was charged with rac-(7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolane]-3-carb aldehyde (146, R2=Pyridin-2-ylmethyl) (0.5 g, 1.321 mmol) and THF (15 mL). The mixture was cooled to about −5° C. then LiHMDS (1 M in THF) (1.717 mL, 1.717 mmol) was added. The mixture was stirred at about −5° C. for about 30 min then (4-fluorophenyl)magnesium bromide (2 M in Et2O) (1.321 mL, 2.64 mmol) was added. After about 1 h and 15 min water (2 mL) was added and the mixture stirred for about 15 min. The reaction mixture was diluted with EtOAc (25 mL) and water (˜10 mL). The layers were separated then EtOAc (15 mL) and sat. aq. NH4Cl (˜7 mL) were added to the aqueous layer. The layers were separated then the combined organic solutions were dried over Na2SO4, filtered and concentrated under reduced pressure to yield crude rac-(4-fluorophenyl)((7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-yl)methanamine (147, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.66 g, 105%) which was used directly in the Step 13 without further manipulation; LC/MS, method 3, Rt=1.67 min, MS m/z 474 (M+H)+.

Workup

  1. stirringThe mixture was stirred at about −5° C. for about 30 min
  2. stirringthe mixture stirred for about 15 min
  3. customThe layers were separated
  4. additionEtOAc (15 mL) and sat. aq. NH4Cl (˜7 mL) were added to the aqueous layer
  5. customThe layers were separated
  6. dry with materialthe combined organic solutions were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-115cb34d2fa3463ea5fb89df2f8bb709
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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