Methanol → 4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine

HRID 1805798Notes

Reaction equation

HRID 1805798 reaction equation
[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:41][C:15]3[N:16]=[C:17]([C:26]4[C:27]5[C:31]([CH:32]=[CH:33][CH:34]=4)=[N:30][N:29](C4CCCCO4)[CH:28]=5)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].CO.S(=O)(=O)(O)O>O>[NH:30]1[C:31]2[C:27](=[C:26]([C:17]3[N:18]=[C:19]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[C:14]4[CH:13]=[C:12]([CH2:11][N:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH2:7]5)[S:41][C:15]=4[N:16]=3)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[N:29]1

Participants

5

Reactant 3

HCID 887MethanolHCID 1118Sulfuric AcidHCID 252691944-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine

Product 1

HCID 252532304-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholineYield 112.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
0 °C

Procedure

4-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 21 (500 g, 0.836 mole) was charged to a sizable reactor, followed by methanol (9.5 L) and water (250 ml). The resulting slurry was cooled to 0° C. and stirred for 0.5 h. A cold solution of concentrated sulfuric acid (H2SO4, 5.54 ml, assay 95-98%, 1.004 mole, 1.20 equiv.) and water (250 ml) was slowly added while maintaining the temperature below 10° C. The mixture was allowed to warm up to the ambient temperature and stirred for 20 hours. The slurry was cooled to 5° C., filtered and rinsed with cold methanol (2 L). The cake was charged to a reactor and stirred in a mixture of methanol (9.5 L) and water (25 ml) at 50° C. for 3 hours. The slurry was cooled 0-5° C., filtered and rinsed with cold methanol (2 L). The cake was dried in a vacuum oven at 50° C. for 24 hours to afford 4-(2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine II sulfate salt as a light yellow solid (482 g, 94%). 1H NMR (300 MHz, DMSO-d6) 3.00-4.00 (br, 8H), 3.01 (s, 3H), 3.85-3.87 (m, 4H), 4.00-4.02 (m, 4H), 4.69 (s, 2H), 7.46-7.52 (t, 7.8 Hz, 1H), 7.70-7.73 (d, 8.3 Hz, 1H), 7.91 (br, 1H), 8.22-8.25 (d, 7.2 Hz, 1H), 8.82 (s, 1H). LCMS (ESI pos) m/e 514 (M+1).

Workup

  1. temperaturewhile maintaining the temperature below 10° C
  2. temperatureto warm up to the ambient temperature
  3. stirringstirred for 20 hours
  4. temperatureThe slurry was cooled to 5° C.
  5. filtrationfiltered
  6. washrinsed with cold methanol (2 L)
  7. additionThe cake was charged to a reactor
  8. stirringstirred in a mixture of methanol (9.5 L) and water (25 ml) at 50° C. for 3 hours
  9. temperatureThe slurry was cooled 0-5° C.
  10. filtrationfiltered
  11. washrinsed with cold methanol (2 L)
  12. customThe cake was dried in a vacuum oven at 50° C. for 24 hours

Sources & evidence

ORD record
ord-c3bd89466e9343a2b1baaa189e64d4a1
Source dataset
uspto-grants-2013_01
Patent number
US08354528B2

Reaction notes

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