4-Chloropyrimidine hydrochloride → 4-(4-fluoro-3-(4-(pyrimidin-4-yloxy)piperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

HRID 1091714Notes

Reaction equation

HRID 1091714 reaction equation
CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)=[CH:10][C:9]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1)=[O:27].Cl.Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1>O1CCCC1>[F:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)=[CH:10][C:9]=1[C:26]([N:28]1[CH2:29][CH2:30][CH:31]([O:34][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[CH2:32][CH2:33]1)=[O:27]

Participants

5

Reactant 3

HCID 219225564-Chloropyrimidine hydrochloride2×HCID 23676156Sodium t-butoxide2×HCID 441993164-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

Product 1

HCID 577917784-(4-fluoro-3-(4-(pyrimidin-4-yloxy)piperidine-1-carbonyl)benzyl)phthalazin-1(2H)-oneYield 50.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

Sodium tert-butoxide (125 mg, 1.30 mmol) was added in one portion to 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2a) (150 mg, 0.39 mmol) in tetrahydrofuran (2 ml) at 20° C. The resulting suspension was stirred at 20° C. for 10 minutes. 4-chloropyrimidine hydrochloride (49.5 mg, 0.43 mmol) was added in one portion and the resulting mixture was stirred at 50° C. for 2 hours. Sodium tert-butoxide (41 mg, 0.43 mmol) was added in one portion followed by 4-chloropyrimidine hydrochloride (65 mg, 0.43 mmol) and the mixture heated at 50° C. for 2 hours and then stirred at ambient temperature overnight. The crude product was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. This was purified by preparative HPLC (Sunfire column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a solid (91 mg, 50.4%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.61 (1H, m), 1.66-1.73 (1H, m), 1.88-1.94 (1H, m), 2.02-2.09 (1H, m), 3.14-3.25 (1H, m), 3.32-3.48 (2H, m), 3.98-4.07 (1H, m), 4.34 (2H, s), 5.33-5.39 (1H, m), 6.95 (1H, d), 7.21-7.25 (1H, m), 7.37-7.44 (2H, m), 7.80-7.84 (1H, m), 7.87-7.90 (1H, m), 7.97 (1H, d), 8.26 (1H, d), 8.54 (1H, d), 8.79 (1H, s), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.69 (M+H 460.6).

Workup

  1. stirringthe resulting mixture was stirred at 50° C. for 2 hours
  2. temperaturethe mixture heated at 50° C. for 2 hours
  3. stirringstirred at ambient temperature overnight
  4. customThe crude product was purified by ion exchange chromatography
  5. washThe desired product was eluted from the column
  6. customwere evaporated to dryness
  7. customto afford crude product
  8. customThis was purified by preparative HPLC (Sunfire column, 5μ silica, 19 mm diameter, 100 mm length)
  9. additionFractions containing the desired compound
  10. customwere evaporated to dryness

Sources & evidence

ORD record
ord-db107d6589d7403eadfce05f6161b984
Source dataset
uspto-grants-2012_03
Patent number
US08129380B2

Reaction notes

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