Hydrochloric Acid → 1-(4-Methylpiperazin-1-yl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)ethanone dihydrochloride

HRID 1426111Notes

Reaction equation

HRID 1426111 reaction equation
FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[O:26][CH2:27][C:28]([OH:30])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[S:12][CH:13]=1.C(N(CC)CC)C.[Cl:41]C(OCC)=O.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.[ClH:54]>O.C1COCC1>[ClH:41].[ClH:54].[CH3:47][N:48]1[CH2:53][CH2:52][N:51]([C:28](=[O:30])[CH2:27][O:26][C:25]2[CH:31]=[CH:32][CH:33]=[C:23]([CH2:22][O:21][C:20]3[C:15]([NH:14][C:11]4[S:12][CH:13]=[C:9]([CH3:8])[N:10]=4)=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:24]=2)[CH2:50][CH2:49]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 10928Ethyl chloroformateHCID 531671-MethylpiperazineHCID 166603332-(3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate salt

Product 1

HCID 866396601-(4-Methylpiperazin-1-yl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)ethanone dihydrochlorideYield 64.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A 1 dram vial was charged with 2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate (prepared according to Example 26; 70 mg, 0.14 mmol), triethylamine (0.10 mL, 0.72 mmol) and THF (2 mL) and cooled to 0° C. Ethyl chloroformate (0.035 mL, 0.36 mmol) was added and the reaction mixture was stirred at 0° C. for 30 minutes. N-methylpiperazine (0.080 mL, 0.72 mmol) was added and the reaction mixture was warmed to room temperature and stirred at room temperature for 1.5 hours. The reaction was poured into water and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified over silica gel (10% methanol in EtOAc to 10% methanol in EtOAc with ammonia) to afford 1-(4-methylpiperazin-1-yl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)ethanone dihydrochloride (51.3 mg, 64.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.64 (bs, 2H), 8.00 (dd, 1H), 7.67 (d, 1H), 7.28 (m, 2H), 7.17 (m, 2H), 6.91 (m, 2H), 5.33 (s, 2H), 4.97 (d, 2H), 4.39 (m, 1H), 4.08 (m, 2H), 3.59 (m, 1H), 3.40 (m, 2H), 3.14 (m, 2H), 2.96 (m, 1H), 2.75 (s, 3H), 2.35 (s, 3H). Mass spectrum (apci) m/z=454.2 (M+H-2HCl).

Workup

  1. temperaturethe reaction mixture was warmed to room temperature
  2. stirringstirred at room temperature for 1.5 hours
  3. extractionextracted with EtOAc
  4. dry with materialThe organic layer was dried with sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified over silica gel (10% methanol in EtOAc to 10% methanol in EtOAc with ammonia)

Sources & evidence

ORD record
ord-2301f93f7e6d423faa9f8b8caca899d3
Source dataset
uspto-grants-2015_01
Patent number
US08933077B2

Reaction notes

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