Water → HCID 86600753, compound

HRID 2212499Notes

Reaction equation

HRID 2212499 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH3:28])[C:23]([C:25](O)=O)=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33].[CH2:47]([N:49](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH2:71]>C1COCC1.C1(C)C=CC=CC=1>[CH2:23]([C:22]1[C:28]([NH:49][C:47]([O:46][CH2:45][C@@H:40]2[CH2:41][O:42][CH2:43][CH2:44][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[O:71])=[CH:24][N:20]2[C:21]=1[C:16]([NH:15][C:11]1[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:29]=[CH:30][CH:31]=[C:2]([F:1])[CH:3]=1)[N:7]=[CH:8]3)=[N:17][CH:18]=[N:19]2)[CH3:25]

Participants

8

Reactant 5

HCID 962WaterHCID 8471TriethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 5058359Tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylateHCID 219664944-({1-[(3-Fluorophenyl)methyl]-1H-indazol-5-yl}amino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid

Product 1

HCID 86600753HCID 86600753, compoundYield 82%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
87 °C

Procedure

A flask was charged with 4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (20) (1 equiv.) and toluene (15 volumes). Residual water was removed by azeotropic distillation and the supernatant was analyzed for water content (KF: <200 ppm water). The flask was then charged with 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (1.05 equiv.) at about 77° C. Triethyl amine (1.2 equiv) and diphenylphosphoryl azide (1.2 equiv) were added between 77–85° C. The reaction was heated at ˜87° C. until it was found complete by HPLC. The reaction was cooled to 25° C. diluted with THF (15 volumes) and washed with 10% K2CO3 (10 volumes), saturated NaCl (10 volumes) and water (10 volumes) respectively. The rich organic was polish filtered and distilled at atmospheric pressure until the pot temperature was >100° C. The final volume was adjusted to 15 volumes by adding toluene (if necessary). The mixture was cooled to 80° C., water (1 equiv) was added and the product was crystallized. The slurry was cooled to 25° C. over 1 h and held for 17 h. The solid was collected by filtration and the filter cake was rinsed with toluene (2×2 volumes). The solid was air dried overnight and then dried under vacuum at 50° C. to give the product in 82% yield.

Workup

  1. customResidual water was removed by azeotropic distillation
  2. temperatureThe reaction was cooled to 25° C.
  3. washwashed with 10% K2CO3 (10 volumes), saturated NaCl (10 volumes) and water (10 volumes) respectively
  4. filtrationfiltered
  5. distillationdistilled at atmospheric pressure until the pot temperature
  6. customwas >100° C
  7. additionby adding toluene (if necessary)
  8. temperatureThe mixture was cooled to 80° C.
  9. customthe product was crystallized
  10. temperatureThe slurry was cooled to 25° C. over 1 h
  11. filtrationThe solid was collected by filtration
  12. washthe filter cake was rinsed with toluene (2×2 volumes)
  13. customdried overnight
  14. customdried under vacuum at 50° C.
  15. customto give the product in 82% yield

Sources & evidence

ORD record
ord-b70fc21c630d418bb3a5575f8e045766
Source dataset
uspto-grants-2006_09
Patent number
US07102001B2

Reaction notes

Loading…