Isopropyl chloroformate → Isopropyl 4-(3-cyano-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate

HRID 386586Notes

Reaction equation

HRID 386586 reaction equation
Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]#[N:25])=[N:11]2)=[CH:6][C:5]=1[F:26])#[N:3].[C:27](Cl)(=[O:32])[O:28][CH:29]([CH3:31])[CH3:30]>C(Cl)Cl>[C:24]([C:12]1[C:13]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:27]([O:28][CH:29]([CH3:31])[CH3:30])=[O:32])[CH2:22][CH2:23]2)=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[C:5]([F:26])[CH:6]=2)[N:11]=1)#[N:25]

Participants

4

Reactant 2

HCID 7917Isopropyl chloroformateHCID 674470261-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt

Product 1

HCID 67072632Isopropyl 4-(3-cyano-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylateYield 70.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirring solution of 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt (Example 36, step A) (19 mg, 0.05 mmol) in DCM (3 mL) at room temperature under argon was added TEA (0.014 mL, 0.10 mmol) and isopropyl carbonochloridate (12 mg, 0.10 mmol). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes. 15 mg (43%) of isopropyl 4-(3-cyano-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.72-7.81 (1H, m), 7.56-7.72 (2H, m), 6.30 (1H, s), 4.82-5.04 (1H, m, J=6.6, 6.3, 6.2, 6.2 Hz), 4.65 (1H, ddd, J=7.0, 3.4, 3.3 Hz), 3.65-3.84 (2H, m), 3.37-3.61 (2H, m), 1.96-2.12 (2H, m), 1.81-1.96 (2H, m), 1.13-1.33 (6H, m). MS (ESI) 426 (M+H).

Workup

  1. customSolvent was removed in vacuo
  2. dissolutionthe crude product was dissolved in a small amount of DCM (˜2 ml)
  3. washwas eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes

Sources & evidence

ORD record
ord-a55e754a76af4900a8a02699ae405f74
Source dataset
uspto-grants-2013_02
Patent number
US08372837B2

Reaction notes

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