Hydrochloric Acid → (3r)-n-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-(1-hydroxy-1-methylethyl)-1h-indazol-1-yl]methyl}phenyl)methyl]-3-morpholinecarboxamide formate salt

HRID 1874751Notes

Reaction equation

HRID 1874751 reaction equation
CCN(C(C)C)C(C)C.CC([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[C:23]([OH:25])=O)=[O:16])(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH2:58][N:59]2[C:67]3[C:62](=[C:63]([C:68]([OH:71])([CH3:70])[CH3:69])[CH:64]=[CH:65][CH:66]=3)[C:61]([NH:72][S:73]([C:76]3[S:77][C:78]([Cl:81])=[CH:79][CH:80]=3)(=[O:75])=[O:74])=[N:60]2)[CH:55]=[CH:56][CH:57]=1.Cl.O1CCOCC1>C(Cl)Cl.CO>[CH:15]([OH:16])=[O:14].[Cl:81][C:78]1[S:77][C:76]([S:73]([NH:72][C:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][C:63]=3[C:68]([OH:71])([CH3:69])[CH3:70])[N:59]([CH2:58][C:54]3[CH:53]=[C:52]([CH2:51][NH:50][C:23]([C@H:18]4[CH2:19][O:20][CH2:21][CH2:22][NH:17]4)=[O:25])[CH:57]=[CH:56][CH:55]=3)[N:60]=2)(=[O:74])=[O:75])=[CH:80][CH:79]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 1512538(3R)-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 59456043N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(1-hydroxy-1-methylethyl)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide

Product 1

HCID 66664136(3r)-n-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-(1-hydroxy-1-methylethyl)-1h-indazol-1-yl]methyl}phenyl)methyl]-3-morpholinecarboxamide formate saltYield 5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

DIPEA (0.057 mL, 0.326 mmol) was added to a stirring solution of (3R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-morpholinecarboxylic acid (18.84 mg, 0.081 mmol) in DCM (1 mL). HATU (31.0 mg, 0.081 mmol) was then added, followed by N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(1-hydroxy-1-methylethyl)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 78) (40 mg, 0.081 mmol) and the reaction was stirred for an hour at room temp. The reaction mixture was concentrated and 4N Hydrogen chloride in dioxane (0.020 mL, 0.081 mmol) was then added and the reaction stirred at room temperature for 0.5 h. The reaction mixture was passed through a pre-conditioned (MeOH) SCX-2 cartridge, washed with methanol and then eluted using 2M ammonia in methanol. The appropriate ammoniacal fractions were concentrated, and the residue was dissolved in DMSO (0.5 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (2.7 mg, 5%). LCMS (System F) RT=0.84 min, ES+ve m/z 604/606 (M+H)+.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. stirringthe reaction stirred at room temperature for 0.5 h
  3. washwashed with methanol
  4. washeluted
  5. concentrationThe appropriate ammoniacal fractions were concentrated
  6. dissolutionthe residue was dissolved in DMSO (0.5 mL)
  7. custompurified by Mass Directed AutoPrep on Sunfire C18 column
  8. customThe solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus

Sources & evidence

ORD record
ord-6466f6655f814a0a849526c2c7c9f765
Source dataset
uspto-grants-2012_11
Patent number
US08304446B2

Reaction notes

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