Trifluoroacetic acid → 3-Chloro-9-cyclopentyl-9H-pyrimido[5',4':4,5]pyrrolo[2,3-c]pyridazin-7-amine

HRID 876021Notes

Reaction equation

HRID 876021 reaction equation
[CH:1]1([NH:6][C:7]2[C:12]([C:13]3[CH:18]=[C:17]([Cl:19])[N:16]=[N:15][C:14]=3Cl)=[CH:11][N:10]=[C:9]([NH2:21])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[NH4+].[Cl-].C(O)(C(F)(F)F)=O>CS(C)=O.C(#N)C.O>[Cl:19][C:17]1[N:16]=[N:15][C:14]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:7]3[N:8]=[C:9]([NH2:21])[N:10]=[CH:11][C:12]=3[C:13]=2[CH:18]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 25517Ammonium ChlorideHCID 516892Sodium BicarbonateHCID 58299981N4-Cyclopentyl-5-(3,6-dichloro-4-pyridazinyl)-2,4-pyrimidinediamine

Product 1

HCID 582998383-Chloro-9-cyclopentyl-9H-pyrimido[5',4':4,5]pyrrolo[2,3-c]pyridazin-7-amineYield 6.3%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
110 °C

Procedure

A mixture of crude N4-cyclopentyl-5-(3,6-dichloropyridazin-4-yl)pyrimidine-2,4-diamine (323) (0.27 g, 0.83 mmol) and sodium bicarbonate (0.065 mL, 1.7 mmol) in DMSO (10 mL) was heated in an oil bath at 110° C. for 11 h. Then the temperature was raised to 125° C. and stirred at this temperature for 200 min at which time LC-MS showed completion. Upon workup, the mixture was poured into ice and saturated NH4Cl aqueous solution and extracted with ethyl acetate (3×). The combined organics were washed with saturated NH4Cl aqueous solution (1×), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM). The impure product thus obtained was subjected to subjected to preparative reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each). After lyophilization, 15 mg of compound 322 was obtained as a TFA salt as an off-white solid. 1H NMR (400 MHz, CD3OD) δ ppm 9.06 (1 H, s), 8.21 (1 H, s), 5.50 (1 H, quin, J=8.6 Hz), 2.43-2.60 (2 H, m), 1.99-2.25 (4 H, m), 1.71-1.89 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 289.1.

Workup

  1. temperatureThen the temperature was raised to 125° C.
  2. extractionextracted with ethyl acetate (3×)
  3. washThe combined organics were washed with saturated NH4Cl aqueous solution (1×)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe impure product thus obtained

Sources & evidence

ORD record
ord-1cb0ac000b1f4c6e93b97ea174259acf
Source dataset
uspto-grants-2015_03
Patent number
US08980903B2

Reaction notes

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