Trifluoroacetic acid → HCID 178476863, compound

HRID 1948077Notes

Reaction equation

HRID 1948077 reaction equation
Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl.[CH2:14]([O:16][P:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1)(=[O:21])[O:18][CH2:19][CH3:20])[CH3:15].CCN(C(C)C)C(C)C.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([C@H:51]2[CH2:56][CH2:55][C@H:54]([OH:57])[CH2:53][CH2:52]2)=[C:44]2[C:48]=1[C:47](=[O:49])[N:46]([CH3:50])[CH2:45]2.C(O)(C(F)(F)F)=O>C1COCC1>[CH2:14]([O:16][P:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[N:7]=[C:6]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([C@H:51]4[CH2:52][CH2:53][C@H:54]([OH:57])[CH2:55][CH2:56]4)=[C:44]4[C:48]=3[C:47](=[O:49])[N:46]([CH3:50])[CH2:45]4)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[CH:25][N:24]=1)(=[O:21])[O:18][CH2:19][CH3:20])[CH3:15].[CH2:14]([O:16][P:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:6]2[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([C@H:51]4[CH2:52][CH2:53][C@H:54]([OH:57])[CH2:55][CH2:56]4)=[C:44]4[C:48]=3[C:47](=[O:49])[N:46]([CH3:50])[CH2:45]4)[N:7]=2)=[CH:25][N:24]=1)(=[O:21])[O:18][CH2:19][CH3:20])[CH3:15]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 86654049Diethyl [(5-aminopyridin-2-yl)methyl]phosphonate hydrochloride2×HCID 178479967HCID 178479967, compound

Product 2

HCID 178476863HCID 178476863, compoundHCID 178476878HCID 178476878, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 2,4-dichloro-5-trifluoromethylpyrimidine (59 mg, 0.27 mmol), diethyl[(5-aminopyridin-2-yl)methyl]phosphonate hydrochloride (Compound 260A, 76.6 mg, 0.27 mmol), and DIPEA (0.14 mL, 0.82 mmol) in THF (0.5 mL) was stirred at 60° C. for 2 h, after which, the solvents were removed in vacuo. The residue was treated with 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (71.1 mg, 0.27 mmol), TFA (0.063 mL, 0.82 mmol, TFE (0.8 mL). The resulting mixture was irradiated in a microwave reactor at 100° C. for 45 min. Solvents were removed in vacuo and the residue was dissolved in DCM (5 mL) and neutralized with sat. NaHCO3 (aq.) (5 mL). The organic phase was separated, aqueous phase extracted with DCM (2×5 mL). The organic phases were combined, dried over MgSO4, filtered, concentrated, and residue was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 1.3 mg of diethyl[(5-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-pyridin-2-yl)methyl]phosphonate (Example 260) as the more polar spot on TLC (yield: 0.73%) and 3.8 mg of diethyl[(5-{[2-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}pyridin-2-yl)methyl]phosphonate (Compound 261) as the less polar spot on TLC (yield: 2.1%).

Workup

  1. customafter which, the solvents were removed in vacuo
  2. customThe resulting mixture was irradiated in a microwave reactor at 100° C. for 45 min
  3. customSolvents were removed in vacuo
  4. dissolutionthe residue was dissolved in DCM (5 mL)
  5. customThe organic phase was separated
  6. extractionaqueous phase extracted with DCM (2×5 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customresidue was purified by prep TLC (5% 7 N ammonia in MeOH in DCM)

Sources & evidence

ORD record
ord-acad6aa5ed744b4ba5d97c9a4c76edd0
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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