Ethyl difluoroacetate → 4-(5-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-2-((3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine

HRID 1922948Notes

Reaction equation

HRID 1922948 reaction equation
[N:1]1([C:7]2[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:35][CH:36]([F:42])[C:37](OCC)=O>O1CCOCC1>[F:35][CH:36]([F:42])[C:37]1[N:13]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1

Participants

4

Reactant 2

HCID 9961Ethyl difluoroacetateHCID 59605399N1-(7-morpholino-2-((3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-5-yl)benzene-1,2-diamine

Product 1

HCID 674919604-(5-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-2-((3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholineYield 35%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-[7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidin-5-yl]benzene-1,2-diamine (65 mg, 0.14 mmol) and ethyl difluoroacetate (0.3 mL, 2.8 mmol) in 1,4-dioxane (0.5 mL) was heated at 100° C. for 3 days. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 30:70 to 2:98) to afford 184 as a white solid (26 mg, 35%). LCMS (Method G): RT=8.03 min, M+H+=543. 1 H NMR (CDCl3, 400 MHz) δ 8.29 (d, J=8.1 Hz, 1 H); 7.91 (d, J=7.8 Hz, 1 H); 7.60 (t, J=53.8 Hz, 1 H); 7.45-7.37 (m, 2 H); 4.43 (m, 4 H); 4.02 (s, 2 H); 3.89 (t, J=4.7 Hz, 4 H); 3.74 (t, J=4.5 Hz, 4 H); 3.69 (t, J=6.2 Hz, 2 H); 3.21-3.07 (m, 3 H) and 2.37 (m, 4 H)

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. washThe cartridge was then washed with MeOH
  3. washthe desired product was subsequently eluted
  4. customThe product was collected
  5. concentrationconcentrated in vacuo
  6. customThe resultant residue was purified by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 30:70 to 2:98)

Sources & evidence

ORD record
ord-8a113698409940a7a62ae9e2c6f91005
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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