Formic Acid → HCID 59456071, compound

HRID 1808600Notes

Reaction equation

HRID 1808600 reaction equation
[CH:1]([OH:3])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][N:43]2[C:51]3[C:46](=[C:47]([O:52][CH3:53])[CH:48]=[CH:49][CH:50]=3)[C:45]([NH:54][S:55]([C:58]3[S:59][C:60]([Cl:63])=[CH:61][CH:62]=3)(=[O:57])=[O:56])=[N:44]2)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C>[Cl:63][C:60]1[S:59][C:58]([S:55]([NH:54][C:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][C:47]=3[O:52][CH3:53])[N:43]([CH2:42][C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][CH:1]=[O:3])[CH:37]=3)[N:44]=2)(=[O:56])=[O:57])=[CH:62][CH:61]=1

Participants

6

Reactant 4

HCID 284Formic AcidHCID 8471TriethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate2×HCID 66632476N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride

Product 1

HCID 59456071HCID 59456071, compoundYield 36%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of formic acid (5 μL, 0.13 mmol) in dry DMF (0.3 mL) was added TBTU (34.7 mg, 0.108 mmol) followed with triethylamine (50.2 μl, 0.360 mmol). This mixture was stirred at room temperature for about 10 min before adding N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (45 mg, 0.09 mmol). The resultant pale yellow mixture was stirred at room temperature overnight. LCMS showed very little reaction, so more acid (˜0.25 mL), followed with TBTU (˜30 mg) were added. This addition was repeated 3 more times over 20 h until by LCMS analysis, there was more product than SM. The reaction mixture was partitioned between ethylacetate (2 mL) and saturated sodium bicarbonate solution (2 mL). The aqueous was extracted with ethyl acetate (×2). The combined organic solutions were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to leave a pale oil which crystallised on standing. This was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by Mass Directed AutoPrep on supelcosil ABZ+Plus column eluting with a gradient of MeCN-Water (95:5+0.05% Formic acid)-Water (+0.1% Formic acid). The solvent was evaporated in vacuo to give the title compound (15.9 mg, 36%) as a pale yellow powder: LCMS (System A) RT=1.02 min, ES+ve m/z 491/493 (M+H)+.

Workup

  1. stirringThe resultant pale yellow mixture was stirred at room temperature overnight
  2. customreaction
  3. additionwere added
  4. additionThis addition
  5. customover 20 h
  6. customThe reaction mixture was partitioned between ethylacetate (2 mL) and saturated sodium bicarbonate solution (2 mL)
  7. extractionThe aqueous was extracted with ethyl acetate (×2)
  8. washThe combined organic solutions were washed with water, brine
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated in vacuo
  11. customto leave a pale oil which
  12. customcrystallised
  13. dissolutionThis was dissolved in 1:1 MeOH
  14. customDMSO (1 mL) and purified by Mass Directed AutoPrep on supelcosil ABZ+Plus column
  15. washeluting with a gradient of MeCN-Water (95:5+0.05% Formic acid)-Water (+0.1% Formic acid)
  16. customThe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-e3da5babb059469dbdf92b54c68e0a1e
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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