Trimethyl phosphonoacetate → HCID 90408793, compound

HRID 1855089Notes

Reaction equation

HRID 1855089 reaction equation
[CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C1CCN2C(=NCCC2)CC1.[Li+].[Cl-].[F:25][C:26]1[CH:27]=[C:28]([C:39]23[CH2:46][CH2:45][C:42]([CH2:47][CH2:48][CH:49]=O)([CH2:43][CH2:44]2)[CH2:41][O:40]3)[CH:29]=[C:30]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:31]=1>CC#N>[F:25][C:26]1[CH:27]=[C:28]([C:39]23[CH2:44][CH2:43][C:42]([CH2:47][CH2:48]/[CH:49]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])([CH2:45][CH2:46]2)[CH2:41][O:40]3)[CH:29]=[C:30]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:31]=1

Participants

6

Reactant 4

HCID 80029Trimethyl phosphonoacetateHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 433294Lithium ChlorideHCID 90409025HCID 90409025, compound

Product 1

HCID 90408793HCID 90408793, compoundYield 74.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

A 0° C. mixture of trimethyl phosphonoacetate (0.209 mL, 1.45 mmol), DBU (0.218 mL, 1.45 mmol) and LiCl (0.061 g, 1.45 mmol) in MeCN (5 mL) was stirred for 30 min under N2, after which 3-(1-(3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (0.35 g, 0.966 mmol) in MeCN (5 mL) was added. The reaction was stirred for 2 h at rt, then was concentrated in vacuo. The residue was diluted with Et2O, and then washed successively with 1N aq. HCl, sat. aq. NaHCO3, and brine, dried (MgSO4), and concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient from 0% to 50% EtOAc/hexane over 20 min) to give the title compound (0.30 g, 0.717 mmol, 74.2% yield) as a white solid. 1H NMR (CDCl3) δ: 6.97 (dt, J=15.6, 6.8 Hz, 1H), 6.87 (t, J=1.8 Hz, 1H), 6.75 (ddd, J=10.1, 2.3, 1.4 Hz, 1H), 6.68 (dt, J=10.5, 2.3 Hz, 1H), 5.85 (dt, J=15.6, 1.6 Hz, 1H), 5.40 (t, J=3.2 Hz, 1H), 3.89 (ddd, J=11.3, 10.0, 3.1 Hz, 1H), 3.84-3.81 (m, 2H), 3.75 (s, 3H), 3.62 (dtd, J=11.4, 4.1, 1.4 Hz, 1H), 2.22-2.14 (m, 2H), 2.05-1.98 (m, 4H), 1.88-1.82 (m, 2H), 1.75-1.59 (m, 8H), 1.36-1.30 (m, 2H); 19F NMR (CDCl3) δ: −112.1.

Workup

  1. stirringThe reaction was stirred for 2 h at rt
  2. concentrationwas concentrated in vacuo
  3. additionThe residue was diluted with Et2O
  4. washwashed successively with 1N aq. HCl, sat. aq. NaHCO3, and brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe residual crude oil was chromatographed (SiO2; gradient from 0% to 50% EtOAc/hexane over 20 min)

Sources & evidence

ORD record
ord-36efb5b65c944b10ae97b1c8430638e1
Source dataset
uspto-grants-2015_02
Patent number
US08962660B2

Reaction notes

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