2-Hydroxyisobutyric acid → N-[[3-[[3-[[(5-Chloro-2-thienyl)sulfonyl]amino]-4-methoxy-1H-indazol-1-yl]methyl]phenyl]methyl]-2-hydroxy-2-methylpropanamide

HRID 1808603Notes

Reaction equation

HRID 1808603 reaction equation
[OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].ClC(N(C)C)=C(C)C.Cl.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]([CH2:25][N:26]2[C:34]3[C:29](=[C:30]([O:35][CH3:36])[CH:31]=[CH:32][CH:33]=3)[C:28]([NH:37][S:38]([C:41]3[S:42][C:43]([Cl:46])=[CH:44][CH:45]=3)(=[O:40])=[O:39])=[N:27]2)[CH:22]=[CH:23][CH:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:46][C:43]1[S:42][C:41]([S:38]([NH:37][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:26]([CH2:25][C:21]3[CH:20]=[C:19]([CH2:18][NH:17][C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[CH:24]=[CH:23][CH:22]=3)[N:27]=2)(=[O:39])=[O:40])=[CH:45][CH:44]=1

Participants

6

Reactant 4

HCID 116712-Hydroxyisobutyric acidHCID 81531DiisopropylethylamineHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 66632476N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride

Product 1

HCID 46861584N-[[3-[[3-[[(5-Chloro-2-thienyl)sulfonyl]amino]-4-methoxy-1H-indazol-1-yl]methyl]phenyl]methyl]-2-hydroxy-2-methylpropanamideYield 88%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-hydroxy-2-methylpropanoic acid (Aldrich) (20.84 mg, 0.200 mmol) in THF (2 mL) was added dropwise at room temperature 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.026 mL, 0.200 mmol). The resulting mixture was stirred at room temperature for 30 min. To this were successively added N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (50 mg, 0.100 mmol) and DIPEA (0.052 mL, 0.300 mmol). After 1 hour of stirring at room temperature LCMS showed product as the major peak. The reaction mixture was concentrated under a stream of nitrogen in the Radleys blowdown apparatus, the residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (48.5 mg, 88%). LCMS (System A) RT=1.05 min, ES+ve m/z 549/551 (M+H)+.

Workup

  1. stirringAfter 1 hour of stirring at room temperature LCMS
  2. concentrationThe reaction mixture was concentrated under a stream of nitrogen in the Radleys blowdown apparatus
  3. dissolutionthe residue was dissolved in 1:1 MeOH
  4. customDMSO (1 mL) and purified by MDAP on Sunfire C18 column
  5. customThe solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus

Sources & evidence

ORD record
ord-e3e98b6fb301471493c88f3eea01e99b
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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