Water → HCID 178448979, compound

HRID 2200797Notes

Reaction equation

HRID 2200797 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([O:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:34][C:33]([CH2:57][C:58]#[N:59])([N:35]4[CH:39]=[C:38]([C:40]5[C:41]6[CH:48]=[CH:47][N:46](COCC[Si](C)(C)C)[C:42]=6[N:43]=[CH:44][N:45]=5)[CH:37]=[N:36]4)[CH2:32]3)[CH2:27][CH2:26]2)[CH:15]=1)([CH3:11])([CH3:10])[CH3:9].C(N)C(N)C.[OH-].[NH4+].O>CC#N.O.C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[N:17]=[C:16]([O:24][C@@H:25]2[CH2:26][CH2:27][C@H:28]([N:31]3[CH2:32][C:33]([CH2:57][C:58]#[N:59])([N:35]4[CH:39]=[C:38]([C:40]5[C:41]6[CH:48]=[CH:47][NH:46][C:42]=6[N:43]=[CH:44][N:45]=5)[CH:37]=[N:36]4)[CH2:34]3)[CH2:29][CH2:30]2)[CH:15]=1)([CH3:11])([CH3:10])[CH3:9]

Participants

8

Reactant 5

HCID 962WaterHCID 6422Trifluoroacetic acidHCID 6567PropylenediamineHCID 14923Ammonium HydroxideHCID 178448978HCID 178448978, compound

Product 1

HCID 178448979HCID 178448979, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

Methylene chloride (4.0 mL) and trifluoroacetic acid (4.0 mL, 52 mmol) were added to the {1-(cis-4-{[6-[(tert-butylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, stirred for 1 hour, and then concentrated to remove TFA. LCMS showed clean conversion to the hydroxymethyl intermediate (M+2H 320) and no loss of tert-butyl group. To the residue was added methanol (7.0 mL), followed by 1,2-propanediamine (30 μL, 0.35 mmol), followed by 15.0 M ammonium hydroxide in water (1.8 mL, 27 mmol). The solution was stirred 2.5 hours. LCMS showed complete reaction with no loss of tert-butyl group and no primary amine detected. The product was isolated by preparative LCMS using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 5% CH3CN—H2O (0.1% TFA), 4.0 minutes; 8.0 minute gradient to 30%; 60 mL/min; 8 runs; retention time 11.0 min. The eluent was concentrated by 50%, then freeze-dried to give white solid. Yield 238 mg. NMR showed it to be the tetra-TFA salt. 1H NMR (300 MHz, DMSO-D6): δ 12.5 (s, 1H, NH); 11.0 (s, 1H, NH); 9.13 (t, 2H, NH2); 9.08 (s, 1H); 8.77 (s, 1H); 8.56 (s, 1H); 7.71 (m, 1H); 7.29 (s, 1H); 7.13 (m, 1H); 5.34 (s, 1H, OCH); 4.98 & 4.7 (m, 4H, azetidine); 4.33 (t, 2H, CH2); 3.75 (s, 2H, CH2CN); 3.48 (s, 1H, NCH); 2.08 (m, 2H); 1.90 (m, 21-1); 1.71 (m, 2H); 1.50 (m, 2H); 1.33 (s, 9H). LCMS calculated for C30H36F3N10O (M+H)+: m/z=609.67.

Workup

  1. concentrationconcentrated
  2. customto remove TFA
  3. additionTo the residue was added methanol (7.0 mL)
  4. stirringThe solution was stirred 2.5 hours
  5. customreaction with no loss of tert-butyl group
  6. customThe product was isolated by preparative LCMS
  7. custom8.0 minute
  8. concentrationThe eluent was concentrated by 50%
  9. customfreeze-dried
  10. customto give white solid

Sources & evidence

ORD record
ord-ed02b39153224e4da94ba75ad2dba117
Source dataset
uspto-grants-2016_06
Patent number
US09359358B2

Reaction notes

Loading…