Trifluoroacetic acid → HCID 178472345, compound

HRID 1947829Notes

Reaction equation

HRID 1947829 reaction equation
Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:42]2[CH2:47][CH2:46][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C@@H:42]4[CH2:43][CH2:44][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]

Participants

4

Reactant 3

HCID 6422Trifluoroacetic acidHCID 86654002Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonateHCID 178472341HCID 178472341, compound

Product 1

HCID 178472345HCID 178472345, compoundYield 38.8%

Procedure

A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (119.5 mg, 0.26 mmol) and ethyl cis-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (100 mg, 0.32 mmol) in TFE (2.39 mL, 32.8 mmol) was treated with TFA (90.1 mg, 0.790 mmol) and irradiated on the microwave at 105° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to a solid. The material was purified on a CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dry loaded, elution gradient: 0→5% MeOH in 1:1 DCM/EtOAc] to afford 74 mg (38%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.46 (br. s., 1H), 8.35 (s, 1H), 7.89 (d, J=8.08 Hz, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.08 (t, J=2.02 Hz, 1H), 6.94 (dt, 1H), 4.52 (s, 2H), 4.26 (q, J=7.07 Hz, 2H), 4.11 (quin, J=7.26 Hz, 4H), 3.92 (s, 3H), 3.36 (br. s., 1H), 3.30 (br. s., 1H), 3.20 (s, 3H), 2.79 (br. s., 1H), 2.68 (br. s., 1H), 2.28-2.33 (m, 2H), 2.30 (d, J=6.82 Hz, 2H), 1.77 (d, J=5.81 Hz, 6H), 1.27-1.37 (m, 9H). MS (ES+): m/z=734.23 [MH+]. HPLC: tR=1.77 min (UPLC TOF, polar—3 min).

Workup

  1. customirradiated on the microwave at 105° C. for 30 minutes
  2. concentrationThe reaction mixture was concentrated under reduced pressure to a solid
  3. customThe material was purified on a CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dry loaded, elution gradient: 0→5% MeOH in 1:1 DCM/EtOAc]

Sources & evidence

ORD record
ord-c59119466289454e86c09e260c40e295
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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