Hydrochloric Acid → tert-Butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

HRID 1779045Notes

Reaction equation

HRID 1779045 reaction equation
C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]3[N:47]=[C:46]([CH2:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=4[CH2:56][C:57]([OH:59])=O)[C:45]([C:60]([F:63])([F:62])[F:61])=[CH:44][N:43]=3)=[CH:37][CH:36]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(CC)CC.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C>[NH2:7][C:57](=[O:59])[CH2:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][CH2:48][C:46]1[C:45]([C:60]([F:62])([F:61])[F:63])=[CH:44][N:43]=[C:42]([NH:41][C:38]2[CH:39]=[CH:40][C:35]([CH:33]3[CH2:32][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])[CH2:34]3)=[CH:36][CH:37]=2)[N:47]=1

Participants

8

Reactant 6

HCID 313Hydrochloric Acid2×HCID 8471TriethylamineHCID 757711-Hydroxybenzotriazole2×HCID 517111Ammonium Carbonate2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 867126882-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)azetidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid

Product 1

HCID 86712689tert-Butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

HOBt (146 mg, 1.07 mmol) and EDCl.HCl (207 mg, 1.07 mmol) were added to a solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A81) (0.500 g, 0.898 mmol) and Et3N (455 μL, 4.49 mmol) in DMF (13 mL). After 10 minutes ammonium carbonate (1.65 g, 18.0 mmol) was added and the resulting mixture was stirred at 40° C. for 22 hours. Additional HOBt (0.072 g, 0.539 mmol), EDCl.HCl (0.103 g, 0.539 mmol) and ammonium carbonate (0.413 g, 4.49 mmol) were added and the mixture stirred at 45° C. for 24 hours. The volatiles were removed in vacuo and water (25 mL) added to the residue resulting in the formation of a precipitate. The resulting suspension was sonicated for several minutes, filtered and the filter cake dried to give a solid which was adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 25-70% EtOAc in cyclohexane) to give the title compound A82 as a white solid (346 mg, 69%); 1H NMR (300 MHz, d6-DMSO) δ 10.21 (s, 1H), 8.68 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.24-7.16 (m, 4H), 6.91 (s, 1H), 4.23 (t, J=8.0 Hz, 2H), 3.85-3.71 (m, 3H), 3.50 (s, 2H), 3.12-3.04 (m, 4H), 1.40 (s, 9H). LCMS-B: rt 8.187 min; m/z 556 [M+H]+.

Workup

  1. stirringthe mixture stirred at 45° C. for 24 hours
  2. customThe volatiles were removed in vacuo and water (25 mL)
  3. additionadded to the residue
  4. customresulting in the formation of a precipitate
  5. customThe resulting suspension was sonicated for several minutes
  6. filtrationfiltered
  7. customthe filter cake dried
  8. customto give a solid which
  9. custompurified by column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 25-70% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-b1107e9f614c4ec2aac7990141479f8d
Source dataset
uspto-grants-2016_02
Patent number
US09266864B2

Reaction notes

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