Formaldehyde → 2-((3aS,5S,6aR)-3a-(6-(trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine-3-carbonyl)hexahydro-2H-cyclopenta[b]furan-5-yl)isoindoline-1,3-dione

HRID 1747154Notes

Reaction equation

HRID 1747154 reaction equation
[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]1[CH2:19][C@H:15]2[O:16][CH2:17][CH2:18][C@@:14]2([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[OH:34])=[O:21])[CH2:13]1.C=O.O.[C:38]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[CH:26][C:25]2[O:34][CH2:38][N:22]([C:20]([C@:14]34[CH2:13][C@H:12]([N:3]5[C:4](=[O:11])[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[C:2]5=[O:1])[CH2:19][C@H:15]3[O:16][CH2:17][CH2:18]4)=[O:21])[CH2:23][C:24]=2[CH:29]=1

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 521998p-Toluenesulfonic acid monohydrateHCID 86708154(3aS,5S,6aR)-5-(1,3-dioxoisoindolin-2-yl)-N-(2-hydroxy-5-(trifluoromethyl)benzyl)hexahydro-2H-cyclopenta[b]furan-3a-carboxamide

Product 1

HCID 867081552-((3aS,5S,6aR)-3a-(6-(trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine-3-carbonyl)hexahydro-2H-cyclopenta[b]furan-5-yl)isoindoline-1,3-dione

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A solution of the product of Step C (7.97 g, 15.5 mmol, 1 eq), paraformaldehyde (9.28 g, 310 mmol, 20 eq) and p-toluenesulfonic acid hydrate (2.94 g, 15.5 mmol, 1 eq) in toluene (300 mL) was heated to 130° C. for 18 hours in a flask equipped with a Dean-Stark trap. The solution was cooled to rt and concentrated. Purification by chromatography (200 g column) eluting with 25 to 60 to 100% ethyl acetate/heptane afforded the product of Step D. Calculated for C25H21F3N2O5: 487.1 (M+1). found: 487.2.

Workup

  1. customequipped with a Dean-Stark trap
  2. concentrationconcentrated
  3. customPurification by chromatography (200 g column)
  4. washeluting with 25 to 60 to 100% ethyl acetate/heptane

Sources & evidence

ORD record
ord-e9a8d07db17649ff8cbfc59d63bfd125
Source dataset
uspto-grants-2015_10
Patent number
US09150532B2

Reaction notes

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