Ammonia → Vatalanib

HRID 1384120Notes

Reaction equation

HRID 1384120 reaction equation
O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](=O)[NH:40][N:39]=2)=[CH:33][CH:32]=1.CN(C)C(=O)N(C)C.N>CCOCC.O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[N:39][N:40]=2)=[CH:26][CH:25]=1

Participants

9

Reactant 6

HCID 222AmmoniaHCID 78124-ChloroanilineHCID 11130Triethylamine hydrochlorideHCID 12437TetramethylureaHCID 14812Phosphorus oxide (P4O10)HCID 7899544-(4-Pyridylmethyl)-1(2H)-phtalazinone

Product 1

HCID 151194Vatalanib

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 3283Diethyl EtherSolvent

Conditions

Temperature
200 °C

Procedure

A mixture of 17.03 g (0.12 mol) phosphorus pentoxide, 11.56 g (0.084 mol) triethylamine hydrochloride and 15.31 g (0.12 mol) 4-chloroaniline is heated and stirred under argon atmosphere at 200° C. (oil bath temperature) until a homogeneous melt has formed (about 45 min). To the melt (internal temperature about 160° C.) 7.12 g (0.03 mol) of 4-(4-pyridylmethyl)-1 (2H)-phthalazinone (for preparation see German Auslegeschriftno. 1 061 788 [published Jul. 23, 1959]) is added and the reaction mixture stirred for 4 h at an internal temperature of 160-170° C. After cooling to about 120° C. (internal temperature) 28 ml tetramethylurea is added dropwise, the temperature rising temporarily to 150° C. For about 10 min at 120° C., 100 ml water is then added to the reaction mixture, which is stirred for 0.5 h at 100-103° C. (internal temperature), then cooled to 60° C., before a mixture of 40 ml water and 37 ml concentrated ammonia solution is added dropwise to the brown solution, whereupon a suspension forms. While cooling to an ultimate temperature of 15° C., the suspension is stirred for 0.5 h, then mixed with 80 ml ether and stirred for a further 10 min. The mixture is filtered, the filter residue is washed with water, then ether, and dried in air. After recrystallization from methanol/ether (under treatment with activated carbon) and drying under HV for 8 h at 120° C., the title compound is obtained with a water content of 0.31%; m.p. 207-209° C.; 1H NMR (DMSO-d6) 9.29 (s, 1H), 8.58-8.63 (m, 1H), 8.44-8.47 (m, 2H), 8.10-8.15 (m, 1H), 7.89-8.05 (m, 4H), 7.37-7.45 (m, 2H), 7.31-7.34 (m, 2H), 4.59 (s, 2H). A further portion of title compound can be obtained from the mother liquor.

Workup

  1. temperatureis heated
  2. customhas formed (about 45 min)
  3. stirringthe reaction mixture stirred for 4 h at an internal temperature of 160-170° C
  4. additionis added dropwise
  5. customrising temporarily to 150° C
  6. stirringis stirred for 0.5 h at 100-103° C. (internal temperature)
  7. additionis added dropwise to the brown solution, whereupon a suspension forms
  8. temperatureWhile cooling to an ultimate temperature of 15° C.
  9. stirringthe suspension is stirred for 0.5 h
  10. stirringstirred for a further 10 min
  11. filtrationThe mixture is filtered
  12. washthe filter residue is washed with water
  13. dry with materialether, and dried in air
  14. customAfter recrystallization from methanol/ether (under treatment with activated carbon)
  15. customdrying under HV for 8 h at 120° C.

Sources & evidence

ORD record
ord-ff0292fb764f4b289a5bc3559f8a10f3
Source dataset
uspto-grants-2001_07
Patent number
US06258812B1

Reaction notes

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