Hydrochloric Acid → Saracatinib

HRID 1873654Notes

Reaction equation

HRID 1873654 reaction equation
[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15](F)=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:27][CH2:28][O:29][C:5]2=[CH:4][CH:3]=1.[OH-].[K+].[OH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1.Cl>COCCOCCOC>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:27][CH2:28][O:29][C:5]2=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 2311841-(2-Hydroxyethyl)-4-methylpiperazineHCID 11654626N-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

Product 1

HCID 10302451Saracatinib

Reagents, catalysts & solvents 1

HCID 8150DiglymeSolvent

Conditions

Temperature
120 °C

Procedure

4-(6-Chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (0.5 g) was added to a stirred mixture of potassium hydroxide (0.168 g), 1-(2-hydroxyethyl)-4-methylpiperazine (0.69 g) and di-(2-methoxyethyl)ether (10 ml) that had been warmed to 120° C. and the resultant reaction mixture was heated to 120° C. for 12 hours. The reaction mixture was cooled to ambient temperature, acidified to pH 1 to 3 by the addition of 1M aqueous hydrochloric acid (9 ml) and washed with isopropyl acetate (20 ml). The aqueous solution was stirred and basified to pH 13 to 14 by the addition of 2M aqueous sodium hydroxide (5 ml). After 10 minutes, water (22 ml) was added and the mixture was stirred for 2 hours to allow precipitation of a solid to finish. The mixture was cooled to 10° C. and filtered. The resultant solid was washed with water (20 ml) and dried in vacuo at 40° C. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.47 g, 92.5% purity by HPLC using Method B, retention time 7.3 minutes); NMR Spectrum: (CDCl3) 1.65 (br s, 3H), 1.9-2.05 (m, 2H), 2.2-2.3 (m, 2H), 2.31 (s, 3H), 2.4-2.8 (m, 8H), 2.9 (m, 2H), 3.6-3.7 (m, 2H), 3.95-4.05 (m, 2H), 4.2-4.25 (m, 2H), 4.8 (m, 1H), 6.05 (s, 2H), 6.55 (s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.25 (s, 1H).

Workup

  1. customthe resultant reaction mixture
  2. temperaturewas heated to 120° C. for 12 hours
  3. temperatureThe reaction mixture was cooled to ambient temperature
  4. washwashed with isopropyl acetate (20 ml)
  5. additionbasified to pH 13 to 14 by the addition of 2M aqueous sodium hydroxide (5 ml)
  6. additionwater (22 ml) was added
  7. stirringthe mixture was stirred for 2 hours
  8. customprecipitation of a solid
  9. temperatureThe mixture was cooled to 10° C.
  10. filtrationfiltered
  11. washThe resultant solid was washed with water (20 ml)
  12. customdried in vacuo at 40° C

Sources & evidence

ORD record
ord-7cacc918b43041f0be9148889d5d56b0
Source dataset
uspto-grants-2012_11
Patent number
US08304417B2

Reaction notes

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