4-Chloroaniline → Vatalanib dihydrochloride

HRID 49857

Reaction equation

HRID 49857 reaction equation
[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(O)CCC>[ClH:1].[ClH:19].[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:22][CH:21]=1

Participants

4

Reactant 2

HCID 78124-ChloroanilineHCID 19446091-Chloro-4-(4-pyridinylmethyl)phthalazine

Product 1

HCID 22386467Vatalanib dihydrochloride

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Procedure

A mixture of 15.22 g (59.52 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see German Auslegeschrift no. 1061 788 [published Jul. 23, 1959]), 7.73 g (60.59 mmol) 4-chloroaniline and 200 ml 1-butanol is heated for 2 h under reflux. The crystallizate which is obtained when the mixture slowly cools to 5° C. is then filtered off and washed with 1-butanol and ether. The filter residue is dissolved in about 200 ml hot methanol, the solution is treated with 0.75 g activated carbon and filtered via a Hyflo Super Cel, and the pH of the filtrate is adjusted to about 2.5 with 7 ml 3N methanolic HCl. The filtrate is evaporated to about half the original volume and ether added until slight turbidity occurs; cooling then leads to the precipitation of crystals. The crystallizate is filtered off, washed with a mixture of methanol/ether (1:2) as well as ether, dried for 8 h at 110° C. under HV, and equilibrated for 72 h at 20° C. and in room atmosphere. In this way, the title compound is obtained with a water content of 8.6%; m.p. >270° C.; 1H NMR (DMSO-d6) 11.05-12.20 (br), 9.18-9.23 (m, 1H), 8.88 (d, 2H), 8.35-8.40 (m, 1H), 8.18-8.29 (m, 2H), 8.02 (d, 2H), 7.73 (d, 2H), 7.61 (d, 2H), 5.02 (s, 2H); ESI-MS: (M+H)+=347.

Workup

  1. temperatureis heated for 2 h
  2. temperatureunder reflux
  3. customThe crystallizate which is obtained when the mixture
  4. customslowly cools to 5° C.
  5. filtrationis then filtered off
  6. washwashed with 1-butanol and ether
  7. dissolutionThe filter residue is dissolved in about 200 ml hot methanol
  8. additionthe solution is treated with 0.75 g
  9. filtrationfiltered via a Hyflo Super Cel
  10. customThe filtrate is evaporated to about half the original volume and ether
  11. additionadded until slight turbidity
  12. temperaturecooling
  13. customthen leads to the precipitation of crystals
  14. filtrationThe crystallizate is filtered off
  15. washwashed with a mixture of methanol/ether (1:2) as well as ether
  16. customdried for 8 h at 110° C. under HV

Sources & evidence

ORD record
ord-5fd01d19f1294661be3376b9e196bc9e
Source dataset
uspto-grants-2004_03
Patent number
US06710047B2

Linked notes

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