Diisopropylethylamine → N-[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]-4-methyl-3-morpholinecarboxamide

HRID 1874734Notes

Reaction equation

HRID 1874734 reaction equation
Cl.[CH3:2][N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:46][CH2:47][C:48]1[CH:49]=[C:50]([CH2:54][N:55]2[C:63]3[C:58](=[C:59]([O:64][CH3:65])[CH:60]=[CH:61][CH:62]=3)[C:57]([NH:66][S:67]([C:70]3[S:71][C:72]([Cl:75])=[CH:73][CH:74]=3)(=[O:69])=[O:68])=[N:56]2)[CH:51]=[CH:52][CH:53]=1>C(#N)C.C(Cl)Cl.O>[Cl:75][C:72]1[S:71][C:70]([S:67]([NH:66][C:57]2[C:58]3[C:63](=[CH:62][CH:61]=[CH:60][C:59]=3[O:64][CH3:65])[N:55]([CH2:54][C:50]3[CH:49]=[C:48]([CH2:47][NH:46][C:9]([CH:4]4[CH2:5][O:6][CH2:7][CH2:8][N:3]4[CH3:2])=[O:11])[CH:53]=[CH:52][CH:51]=3)[N:56]=2)(=[O:68])=[O:69])=[CH:74][CH:73]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 534080194-Methylmorpholine-3-carboxylic acid hydrochlorideHCID 66632476N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride

Product 1

HCID 59456050N-[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]-4-methyl-3-morpholinecarboxamideYield 30%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 4-methyl-3-morpholinecarboxylic acid hydrochloride (Chem-Impex International) (60.0 mg, 0.33 mmol) in acetonitrile (2 mL) was treated with HATU (126 mg, 0.33 mmol) and DIPEA (0.157 ml, 0.901 mmol). The resulting mixture was stirred for 15 min at ambient temperature and then N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (150 mg, 0.300 mmol) was added, and the resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM (3 mL) and water (3 mL). Organic phase was separated and the aqueous layer was further extracted with 3 mL of DCM. The combined organic solutions were washed with water (3 mL), dried through an hydrophobic frit and concentrated in a nitrogen blow-down apparatus. The residue was dissolved in 1:1 MeOH-DMSO 2 mL and purified by Mass Directed AutoPrep (Method C) on Xbridge column using acetonitrile water with an ammonium carbonate modifier. The solvent was evaporated under reduced pressure to give the required product (53.1 mg, 30%). LCMS (System F) RT=0.85 min, ES+ve m/z 590/592 (M+H)+.

Workup

  1. additionwas added
  2. stirringthe resulting mixture was stirred at ambient temperature for 1 h
  3. customOrganic phase was separated
  4. extractionthe aqueous layer was further extracted with 3 mL of DCM
  5. washThe combined organic solutions were washed with water (3 mL)
  6. customdried through an hydrophobic frit
  7. concentrationconcentrated in a nitrogen blow-down apparatus
  8. dissolutionThe residue was dissolved in 1:1 MeOH-DMSO 2 mL
  9. custompurified by Mass Directed AutoPrep (Method C) on Xbridge column
  10. customThe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-3a97c0b3d4d24ce0b5f7d22cae7095df
Source dataset
uspto-grants-2012_11
Patent number
US08304446B2

Reaction notes

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