Morpholine → HCID 178433101, compound

HRID 1371194Notes

Reaction equation

[F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13]C2)=C)[CH:5]=[CH:6][C:7]=1[F:8].CC(C1C=CC(F)=C(F)C=1)=O.N1CCCC1.[CH3:32][C:33]1[N:38]=C(Cl)C([N+]([O-])=O)=[C:35](Cl)[N:34]=1.C(N(CC)C(C)C)(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.Cl[Sn]Cl>CN(C=O)C.Cl[Ti](Cl)(Cl)Cl.CCN(CC)CC>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:14]3[NH:38][C:33]([CH3:32])=[N:34][C:35]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)=[C:15]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

Conditions

Temperature: 140 °C

Procedure

Using the method described in Example 30 by employing (1-(3,4-difluorophenyl)vinyl)pyrrolidine (freshly prepared before use from 3,4-difluoro acetophenone (Aldrich Chemical Company), pyrrolidine and TiCl4 (2.04 g, 9.76 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.02 g, 9.76 mmol), N,N-diisopropylethylamine (1.7 mL, 9.76 mmol), morpholine (1.4 mL, 15.6 mmol), NEt3 (1.5 mL) and SnCl2 (29 mL of a 2 M soln in DMF). In this example the SnCl2 solution was added to the reaction mixture at 140° C. The mixture was stirred at 140° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant to give 0.78 g (24%) of 4-[6-(3,4-difluorophenyl)-2-methylpyrrolo[2,3-e]pyrimidin-4-yl]morpholine as a beige colored solid. This compound (780 mg, 3.00 mmol) was dissolved in 5:1 EtOAc/MeOH (40 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (3.00 mL, 3.00 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 670 mg (15%) of the title compound as pale yellow colored crystals. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 2.37 (s, 3), 3.59 (br s, 4), 3.89 (br s, 4), 6.78 (s, 1), 7.40 (q, 1, J=8.8), 7.68 (br s, 1), 8.00 (t, 1, J=9.8), 11.94 (s, 1), 14.48 (s, 1). MS m/z: 331 (M+1 for free base). Anal. Calcd for C17H16F2N4O.HCl: C, 55.66; H, 4.67; N, 15.28; Cl, 9.66. Found: C, 55.57; H, 4.77; N, 15.15; Cl, 9.61.

Workup

customwas added to the reaction mixture at 140° C
temperatureto cool to room temperature
customThe residue was purified by flash chromatography on silica gel with 95:5 CHCl3/MeOH as eluant

Sources & evidence

ORD record: ord-1cf533f0b79345e790cf1b21e8e2a26a
Source dataset: uspto-grants-2003_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06583154B1

Reaction notes

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