Formaldehyde → 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl-2,6-diaza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

HRID 449600Notes

Reaction equation

HRID 449600 reaction equation
[CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][N:2]1[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:20](=[O:21])[N:19]([CH3:22])[N:18]=[C:17]([C:23]3[C:24]([CH2:45][OH:46])=[C:25]([N:29]4[N:38]=[CH:37][C:36]5[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=5)[C:30]4=[O:44])[CH:26]=[CH:27][CH:28]=3)[CH:16]=2)=[N:12][CH:13]=1.C=O.[C:49]([BH3-])#N.[Na+]>CO>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:17]3[CH:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([N:2]5[CH2:3][C:4]6([CH2:7][N:6]([CH3:49])[CH2:5]6)[CH2:1]5)=[CH:13][N:12]=4)[C:20](=[O:21])[N:19]([CH3:22])[N:18]=3)[C:24]=1[CH2:45][OH:46])[N:38]=[CH:37]2)([CH3:40])([CH3:41])[CH3:42]

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 667419712-(3-(5-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one

Product 1

HCID 566556676-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(6-methyl-2,6-diaza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-oneYield 221.5%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
25 °C

Procedure

In a 25 mL round-bottomed flask, 2-(3-(5-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one (146 mg, 234 μmol), 30% formaldehyde (42.2 mg, 38.8 μl, 1.41 mmol) and sodium cyanoborohydride (177 mg, 2.81 mmol) were combined with methanol (9 ml) to give an orange solution. The reaction mixture was stirred at 25° C. for 4 h. The crude reaction mixture was concentrated in vacuo, diluted with 10 mL 0.1 M NaOH and extracted with DCM (3×15 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM). The light yellow powder was dried under vacuum at 25° C. for 3 hrs to give 0.33 g (22%) of the title compound. (M+H)+=637 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.37 (s, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.38-7.71 (m, 6H), 6.75-6.93 (m, 2H), 4.40 (s, 2H), 3.96 (s, 4H), 3.88 (s, 3H), 3.47 (s, 4H), 2.37 (s, 3H), 1.42 (s, 9H).

Workup

  1. customto give an orange solution
  2. customThe crude reaction mixture
  3. concentrationwas concentrated in vacuo
  4. additiondiluted with 10 mL 0.1 M NaOH
  5. extractionextracted with DCM (3×15 mL)
  6. dry with materialThe organic layers were dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM)
  9. customThe light yellow powder was dried under vacuum at 25° C. for 3 hrs

Sources & evidence

ORD record
ord-7e448edbadc64b518cb77b16e5d33ae6
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Reaction notes

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