Dimethylformamide → HCID 24991567, compound

HRID 1878673Notes

Reaction equation

HRID 1878673 reaction equation
[CH3:1][C:2](C)([O-:4])[CH3:3].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.C(O)(=O)/[CH:16]=[CH:17]/[C:18](O)=O.[CH3:23][N:24]([CH:26]=O)[CH3:25]>CS(C)=O>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:4][C@@H:2]2[CH:3]3[CH2:26][N:24]4[CH2:25][CH:17]([CH2:16][CH:1]2[CH2:23]4)[CH2:18]3)[CH:13]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 709434,6-DichloropyrimidineHCID 444972Fumaric AcidHCID 23665647Potassium tert-butoxide

Product 1

HCID 24991567HCID 24991567, compound

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
25 °C

Procedure

The product of Example 10B (73 mg, 0.437 mmol) and potassium tert-butoxide (51 mg, 0.454 mmol) were dissolved in dimethyl sulfoxide (2.5 mL) and stirred at 25° C. for 1 hour. 4,6-Dichloropyrimidine (111 mg, 0.743 mmol) was added. The reaction mixture was stirred at 25° C. for 18 hours. The mixture was dissolved in DMF (2 mL), filtered and purified by preparative HPLC [Waters® XTerra RP18 5 μm column, 30×100 mm, flow rate 40 mL/min, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 min, with UV detection at 254 nm]. Fractions containing the desired product were pooled, concentrated under vacuum and then processed as described in Method C to provide the free base. It was then reacted with fumaric acid according to Method H to provide the titled compound: 1H NMR (400 MHz, methanol-D4) δ ppm 1.89-2.01 (m, 2H), 2.18 (br s, 1H), 2.27-2.39 (m, 2H), 2.53 (br s, 2H), 3.55 (br s, 2H), 3.59-3.72 (m, 4H), 5.58 (t, J=3.1 Hz, 1H), 6.68 (s, 2H, C4H4O4), 7.10 (d, J=0.9 Hz, 1H), 8.58 (s, 1H). MS (ESI) m/z=266 (M+H)+.

Workup

  1. stirringThe reaction mixture was stirred at 25° C. for 18 hours
  2. filtrationfiltered
  3. custompurified by preparative HPLC [Waters® XTerra RP18 5 μm column, 30×100 mm, flow rate 40 mL/min, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 min, with UV detection at 254 nm]
  4. additionFractions containing the desired product
  5. concentrationconcentrated under vacuum
  6. customto provide the free base

Sources & evidence

ORD record
ord-cc9c6b3e2ac3463aaf22a5f21b0fd180
Source dataset
uspto-grants-2012_11
Patent number
US08314119B2

Reaction notes

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