Diisopropylethylamine → HCID 46918066, compound

HRID 516356Notes

Reaction equation

HRID 516356 reaction equation
[F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.FC(F)(F)C(O)=O.[NH:45]1[CH2:50][CH2:49][S:48](=[O:51])[CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:45]4[CH2:50][CH2:49][S:48](=[O:51])[CH2:47][CH2:46]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1

Participants

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 469174972-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazoleHCID 66698075HCID 66698075, compound2×

Product 1

HCID 46918066HCID 46918066, compoundYield 56%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (200 mg, 0.373 mmol), thiomorpholine 1-oxide trifluoroacetate (U.S. Pat. No. 6,372,773) (242 mg, 1.12 mmol), and DIPEA (0.45 mL, 2.61 mmol) was refluxed in THF (60 mL) for 4 days. The THF was removed under vacuum and the residue was dissolved in dioxane (60 mL). Additional thiomorpholine 1-oxide trifluoroacetate (161 mg, 0.745 mmol) and DIPEA (0.45 mL, 2.61 mmol) were added and the mixture was refluxed for 2 days. The solvent was removed under vacuum and the residue was diluted with water. The resulting precipitate was filtered, washed with water, and dissolved in CH2Cl2. The solution was dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (95:5), followed by recrystallization from CH2Cl2/hexane gave 138 mg (56% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-oxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (CH2Cl2/hexane) 229-231° C.; 1H NMR (CDCl3) δ7.85 (d, J=8.0 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.89 (br s, 4H), 3.79 (m, 4H), 3.38 (t, J=5.0 Hz, 4H), 3.15 (m, 4H), 2.99 (dd, J=8.8, 5.4, 2H), 2.79 (m, 6H); Anal. Calcd. for C26H35F2N9O5S2.0.2H2O: C, 47.4; H, 5.4; N, 19.1. Found: C, 47.3; H, 5.5; N, 18.7.

Workup

  1. customThe THF was removed under vacuum
  2. dissolutionthe residue was dissolved in dioxane (60 mL)
  3. temperaturethe mixture was refluxed for 2 days
  4. customThe solvent was removed under vacuum
  5. additionthe residue was diluted with water
  6. filtrationThe resulting precipitate was filtered
  7. washwashed with water
  8. dissolutiondissolved in CH2Cl2
  9. dry with materialThe solution was dried (Na2SO4)
  10. customthe solvent was removed under vacuum
  11. washChromatography on silica, eluting with CH2Cl2/MeOH (95:5)
  12. customfollowed by recrystallization from CH2Cl2/hexane

Sources & evidence

ORD record
ord-cf5fd0e225a94bb9a0df51ce2b3b66c1
Source dataset
uspto-grants-2015_08
Patent number
US09108980B2

Reaction notes

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