Chloroform → 5-Amino-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one

HRID 410715Notes

Reaction equation

HRID 410715 reaction equation
CC(S([NH:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)=O)(C)C.C(Cl)(Cl)Cl.[N-:45]=[N+]=[N-].[Na+].CS(O)(=O)=O>O>[NH2:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][NH:45][C:11](=[O:12])[CH2:10][CH2:9]1

Participants

6

Reactant 4

HCID 6212ChloroformHCID 6395Methanesulfonic AcidHCID 33557Sodium AzideHCID 672609322-methyl-N-{8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]dec-8-yl}propane-2-sulfinamide

Product 1

HCID 584562585-Amino-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-oneYield 66%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
65 °C

Procedure

To the product of Step 2 (100 mg, 0.13 mmol) was added chloroform (630 μL), sodium azide (24.5 mg, 0.38 mmol), and methanesulfonic acid (98 μL, 1.51 mmol). The mixture was heated to 65° C. for 1.5 h., cooled to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (35:65 to 70:30 acetonitrile:water with a 0.1% trifluoroacetic acid modifier). The fractions containing the desired product were diluted with ethyl acetate and free based with saturated aqueous sodium bicarbonate. The separated organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (38 mg, 0.083 mmol, 66% yield) as an orange oil. MS ESI: [M+H]+ m/z 463. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.49 (s, 1H), 7.28 (d, J=4.7, 1H), 7.16 (s, 1H), 2.39-2.08 (m, 9H), 1.30-0.99 (m, 4H). rhSYK activity=+++

Workup

  1. temperaturecooled to room temperature
  2. extractionextracted with ethyl acetate (2×)
  3. dry with materialThe combined organic layers were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by reverse phase HPLC (35:65 to 70:30 acetonitrile
  7. additionThe fractions containing the desired product
  8. additionwere diluted with ethyl acetate
  9. dry with materialThe separated organic layer was dried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-e9b053cd26284622b5043512c7c84b9f
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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