Diisopropylethylamine → HCID 136346361, compound

HRID 1808649Notes

Reaction equation

HRID 1808649 reaction equation
N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[C:25]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[C:38]([OH:40])=O)([O:27]C(C)(C)C)=[O:26].C(N(CC)C(C)C)(C)C.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH2:58][N:59]2[C:67]3[C:62](=[C:63]([OH:68])[CH:64]=[CH:65][CH:66]=3)[C:61]([NH:69][S:70]([C:73]3[S:74][C:75]([Cl:78])=[CH:76][CH:77]=3)(=[O:72])=[O:71])=[N:60]2)[CH:55]=[CH:56][CH:57]=1>CN(C)C=O>[CH:25]([OH:27])=[O:26].[Cl:78][C:75]1[S:74][C:73]([S:70]([NH:69][C:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][C:63]=3[OH:68])[N:59]([CH2:58][C:54]3[CH:53]=[C:52]([CH2:51][NH:50][C:38]([C@@H:33]4[CH2:34][O:35][CH2:36][CH2:37][NH:32]4)=[O:40])[CH:57]=[CH:56][CH:55]=3)[N:60]=2)(=[O:71])=[O:72])=[CH:77][CH:76]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 1512537(3S)-4-(tert-Butoxycarbonyl)morpholine-3-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 136116030HCID 136116030, compound

Product 1

HCID 136346361HCID 136346361, compoundYield 19%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (77 mg, 0.124 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added at room temperature (S)-4-Boc-morpholine-3-carboxylic acid (26.2 mg, 0.113 mmol), followed by N,N-diisopropylethylamine 0.059 mL, 0.339 mmol) and finally a solution of N-(1-{[3-(aminomethyl)phenyl]methyl}-4-hydroxy-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide (formate salt) (for a preparation see intermediate 15) ((56 mg, 0.113 mmol) in anhydrous N,N-dimethylformamide (2 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine:water (1:1), passed through a hydrophobic frit and evaporated in-vacuo. The was treated with hydrogen chloride (4M solution in 1,4-dioxane) (1 mL) and then added methanol (˜4 mL) until the reaction was in solution. Reaction stirred at room temperature for 2 hours. The reaction mixture was evaporated in-vacuo and the residue was dissolved in MeOH/DMSO (1 mL) and purified by Mass Directed AutoPreparative HPLC (MDAP) on (Sunfire C18 column Method A) eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) using a method B over 25 min. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a colourless oil (13 mg, 19%). LCMS (System B) RT=1.63 min, ES+ve m/z 562/564 (M+H)+.

Workup

  1. customThe reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate
  2. customThe organic layer was separated
  3. washwashed with brine:water (1:1)
  4. customevaporated in-vacuo
  5. additionThe was treated with hydrogen chloride (4M solution in 1,4-dioxane) (1 mL)
  6. customReaction
  7. stirringstirred at room temperature for 2 hours
  8. customThe reaction mixture was evaporated in-vacuo
  9. dissolutionthe residue was dissolved in MeOH/DMSO (1 mL)
  10. custompurified by Mass Directed AutoPreparative HPLC (MDAP) on (Sunfire C18 column Method A)
  11. washeluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B
  12. customover 25 min
  13. customevaporated in-vacuo

Sources & evidence

ORD record
ord-d9d2bd9087384665a321e52feee472c3
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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