Phthalimide → 2-[[2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methyl]isoindoline-1,3-dione

HRID 1517612Notes

Reaction equation

HRID 1517612 reaction equation
N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[S:20][C:19]2[C:21]3([O:42][CH2:43][C:44]([F:46])([F:45])[C:18]=2[CH:17]=1)[CH2:26][CH2:25][N:24]([CH2:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[C:38]([CH2:39]O)=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:32]=1)[CH2:23][CH2:22]3.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[S:20][C:19]2[C:21]3([O:42][CH2:43][C:44]([F:45])([F:46])[C:18]=2[CH:17]=1)[CH2:22][CH2:23][N:24]([CH2:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[C:38]([CH2:39][N:51]4[C:47](=[O:57])[C:48]5[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=5)[C:50]4=[O:52])=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:32]=1)[CH2:25][CH2:26]3

Participants

6

Reactant 4

HCID 6809PhthalimideHCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 52914971Ly-2940094

Product 1

HCID 671693782-[[2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methyl]isoindoline-1,3-dioneYield 91.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

Diisopropyl azodicarboxylate (0.105 mL, 0.54 mmol) is added to a solution of [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol (0.173 g, 0.36 mmol), phthalimide (0.079 mg, 0.54 mmol) and triphenylphosphine (0.142 g, 0.54 mmol) in toluene (3 mL) at 0° C. The mixture is stirred at room temperature overnight. The solvent is removed and the residue is purified first using a 2 g SCX cartridge and after evaporation of the 2 N ammonia in methanol fraction by normal phase Isco chromatography eluting with hexane/ethanol (3%-30%) to give 0.201 g of 2-[[2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methyl]isoindoline-1,3-dione. MS (m/z): 610 (M+1).

Workup

  1. customThe solvent is removed
  2. customthe residue is purified first
  3. customafter evaporation of the 2 N ammonia in methanol fraction by normal phase Isco chromatography
  4. washeluting with hexane/ethanol (3%-30%)

Sources & evidence

ORD record
ord-09feae51527049caa3a407f20b95a803
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

Loading…