1,8-Diazabicyclo(5.4.0)undec-7-ene → N-(2-((4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide

HRID 629821Notes

Reaction equation

HRID 629821 reaction equation
C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:19][C@H:18]([CH3:20])[O:17][CH2:16][C@:14]2([C:21]2[S:22][CH:23]=[C:24]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[CH:31][N:30]=3)=[O:28])[N:25]=2)[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:19][C@H:18]([CH3:20])[O:17][CH2:16][C@:14]2([C:21]2[S:22][CH:23]=[C:24]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:37])[F:38])=[CH:31][N:30]=3)=[O:28])[N:25]=2)[N:15]=1

Participants

4

Reactant 2

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 118435422HCID 118435422, compound

Product 1

HCID 118435360N-(2-((4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A solution of C9 (390 mg, 0.762 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 95%, 132 μL, 0.838 mmol) in methanol (15 mL) was heated at 70° C. for 90 minutes. After removal of solvent in vacuo, the residue was purified via silica gel chromatography (Gradient: 0% to 8% methanol in dichloromethane) to provide the product as a solid. Yield: 191 mg, 0.419 mmol, 55%. LCMS m/z 456.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.40 (br s, 1H), 8.48 (br dd, J=2.7, 0.6 Hz, 1H), 8.31 (dd, J=8.6, 0.6 Hz, 1H), 7.72 (s, 1H), 7.68 (ddt, J=8.6, 2.7, 0.7 Hz, 1H), 6.65 (t, JHF=72.0 Hz, 1H), 3.93 (AB quartet, downfield doublet is broadened, JAB=11.2 Hz, ΔνAB=45.8 Hz, 2H), 3.75 (dqd, J=11.2, 6.1, 2.3 Hz, 1H), 3.19 (dd, J=12.6, 4.0 Hz, 1H), 2.83-2.90 (m, 1H), 2.61 (dd, J=12.6, 2.8 Hz, 1H), 1.81 (ddd, J=13.2, 12.9, 11.4 Hz, 1H), 1.56 (ddd, J=13.4, 4.2, 2.3 Hz, 1H), 1.30 (d, J=6.1 Hz, 3H).

Workup

  1. customAfter removal of solvent in vacuo
  2. customthe residue was purified via silica gel chromatography (Gradient: 0% to 8% methanol in dichloromethane)

Sources & evidence

ORD record
ord-b5eba5f51ca142c999ac1b03cb3b7816
Source dataset
uspto-grants-2016_04
Patent number
US09315520B2

Reaction notes

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