1,2-Dichloroethane → HCID 58456147, compound

HRID 1040201Notes

Reaction equation

HRID 1040201 reaction equation
[CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:4][CH:3]1[C:31](O)=[O:32].C(Cl)CCl.C1C=CC2N(O)N=[N:45]C=2C=1.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O.CS(C)=O>[CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:4][CH:3]1[C:31]([NH2:45])=[O:32]

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 25517Ammonium ChlorideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 67431413HCID 67431413, compound

Product 1

HCID 58456147HCID 58456147, compound

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 6228DimethylformamideSolvent

Procedure

The product from Step 3 was taken up in N,N-dimethylformamide (2.9 ml) and EDC (66.1 mg, 0.35 mmol), HOBT (52.8 mg, 0.35 mmol), ammonium chloride (55.3 mg, 1.04 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (301 μl, 1.724 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was then diluted with 1 mL of DMSO and directly purified by reverse phase HPLC (acetonitrile/water+0.1% TPA modifier). The desired fractions were combined, diluted with ethyl acetate and washed once with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subject to purification by chiral supercritical fluid chromatography (4/6 2-Propanol/CO2 with a flow rate of 60 mL/min and a 19 minute run time) to afford the four stereoisomers of 2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide. Isomer 1 (11 mg, 0.022 mmol, 13% yield). MS ESI: [M+H]+ m/z 490.2. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=5.0 Hz, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.45 (s, 1H), 7.27 (d, J=5.0 Hz, 1H), 7.23 (s, 1H), 7.14 (s, 1H), 6.61 (s, 1H), 3.16 (m, 1H), 2.31 (s, 3H), 2:24 (m, 1H), 2.10 (m, 2H), 1.87 (m, 1H), 1.80 (m, 1H), 1.68 (m, 1H), 1.48 (m, 1H), 1.03 (s, 3H), 0.94 (s, 3H). rhSYK activity=+++

Workup

  1. customdirectly purified by reverse phase HPLC (acetonitrile/water+0.1% TPA modifier)
  2. additiondiluted with ethyl acetate
  3. washwashed once with saturated aqueous sodium bicarbonate
  4. dry with materialThe organic layer was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting residue was subject to purification by chiral supercritical fluid chromatography (4/6 2-Propanol/CO2 with a flow rate of 60 mL/min
  8. customa 19 minute

Sources & evidence

ORD record
ord-f190ea4e3b374c35b62f305c426c5c5f
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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