Triethylamine → HCID 178476877, compound

HRID 1948091Notes

Reaction equation

HRID 1948091 reaction equation
[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]4[CH:45]=[CH:44][C:34]([CH2:35][P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:33][C:32]=4[O:46][CH3:47])[N:21]=3)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:55][S:56]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]4[CH:45]=[CH:44][C:34]([CH2:35][P:36]([O:37][CH2:38][CH3:39])([O:40][CH2:41][CH3:42])=[O:43])=[CH:33][C:32]=4[O:46][CH3:47])[N:21]=3)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:4][CH2:3]1)(=[O:58])=[O:57]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 178476865HCID 178476865, compound

Product 1

HCID 178476877HCID 178476877, compoundYield 44%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a stirring solution of diethyl (4-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.45 g, 0.66 m mol) in DCM (1.68 mL), cooled to 0° C., was slowly added triethylamine (0.185 mL, 1.33 mol) followed by methanesulfonyl chloride (0.13 mL, 1.66 mmol) and 4-dimethylaminopyridine (0.81 mg, 6.60 μmol). The mixture was stirred at rt overnight. After 16 hrs, a precipitate formed. The organic layer was re-dissolved in DCM and washed with water (2×), dried over sodium sulfated, filtered and concentrated in vacuo to a solid. The crude product was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded, 3×12 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0→4% 7N NH3 (MeOH) in DCM] to afford 220 mg (44%) of the desired product. 1H NMR (400 MHz, MeOD) δ 8.48 (br. s., 1H), 8.33 (s, 1H), 7.82 (d, J=8.08 Hz, 1H), 7.40 (d, J=8.59 Hz, 1H), 7.06 (d, J=2.02 Hz, 1H), 6.96 (d, J=7.58 Hz, 1H), 4.74-4.80 (m, 1H), 4.51 (s, 2H), 4.09 (quin, J=7.20 Hz, 4H), 3.89 (s, 3H), 3.34 (s, 1H), 3.29 (br. s., 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.64 (br. s., 1H), 2.29 (d, J=11.37 Hz, 2H), 1.69-2.00 (m, 6H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 756.19/757.23 (100/90) [MH+]. HPLC: tR=1.53 min (Micromass TOF: polar—3 min).

Workup

  1. waitAfter 16 hrs
  2. customa precipitate formed
  3. washwashed with water (2×)
  4. dry with materialdried over sodium
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo to a solid
  7. customThe crude product was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded, 3×12 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0→4% 7N NH3 (MeOH) in DCM]

Sources & evidence

ORD record
ord-24b5ec431b89413ea27589fa45420ce0
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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