Dimethylformamide → HCID 178476852, compound

HRID 1948090Notes

Reaction equation

HRID 1948090 reaction equation
CS(O[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][P:40]([O:45][CH2:46][CH3:47])([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:51])[C:16]3=[O:50])[CH2:8][CH2:7]1)(=O)=O.[CH3:52][N:53](C=O)C>>[C:52]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][P:40](=[O:41])([O:42][CH2:43][CH3:44])[O:45][CH2:46][CH3:47])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:51])[C:16]3=[O:50])[CH2:8][CH2:7]1)#[N:53]

Participants

3

Reactant 2

HCID 6228DimethylformamideHCID 178476877HCID 178476877, compound2×

Product 1

HCID 178476852HCID 178476852, compoundYield 32%

Conditions

Temperature
100 °C

Procedure

In 25 mL Schlenk tube, trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexyl methanesulfonate (Compound 283A, 130.0 mg, 0.17 mmol) was dissolved in DMF (13.0 mL, 168 mmol) and was added degassed (3×) with argon. The reaction was heated at 100° C. under an atmosphere of argon for 7 hrs. The reaction was dissolved in EtOAc and washed with water (2×) and brine (1×) respectfully. The organic layer was collected and concentrated in vacuo to a solid and was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded on 12 g silica load cartridge, 40 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0→4% MeOH in DCM] to afford 37.4 mg (31.7%) of the desired product. 1H NMR (400 MHz, MeOD) δ 8.49 (br. s., 1H), 8.33 (s, 1H), 7.85 (d, J=7.58 Hz, 1H), 7.33 (d, J=8.59 Hz, 1H), 7.03-7.09 (m, 1H), 6.93 (td, J=2.27, 8.08 Hz, 1H), 4.51 (s, 2H), 4.08 (quin, J=7.26 Hz, 4H), 3.90 (s, 3H), 3.33 (s, 1H), 3.27 (s, 1H), 3.17 (s, 4H), 2.68 (d, J=5.56 Hz, 1H), 2.10 (d, J=10.36 Hz, 2H), 1.75-1.93 (m, 6H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 687.17/688.20 (100/70) [MH+]. HPLC: tR=1.54 min (Micromass TOF: polar—3 min).

Workup

  1. additionwas added
  2. customdegassed (3×) with argon
  3. dissolutionThe reaction was dissolved in EtOAc
  4. washwashed with water (2×) and brine (1×) respectfully
  5. customThe organic layer was collected
  6. concentrationconcentrated in vacuo to a solid
  7. customwas purified by CombiFlash®Rf 4X Organic Purification System [dried loaded on 12 g silica load cartridge, 40 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0→4% MeOH in DCM]

Sources & evidence

ORD record
ord-10df6ac1f66c4862890856351d7c77e5
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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