1,3-Dibromo-5,5-dimethylhydantoin → Tert-butyl 4-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate

HRID 1972930Notes

Reaction equation

HRID 1972930 reaction equation
[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:30]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:30])[CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 64791,3-Dibromo-5,5-dimethylhydantoinHCID 24437Sodium SulfiteHCID 58529456Tert-butyl 4-[4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate

Product 1

HCID 58529297Tert-butyl 4-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylateYield 59.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

To a cooled (−20° C.) solution of tert-butyl 4-[4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate (1.20 g, 3.04 mmol) in tetrahydrofuran (15 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (435 mg, 1.21 mmol) in four portions over 15 min. The mixture stirred at −20° C. for 3 h. Saturated, aqueous Na2SO3 (20 mL) was added and the mixture was allowed to warm to rt. The mixture was extracted with ethyl acetate (2×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes. 1H-NMR indicated the presence of residual hydantoin side product, thus the material was partitioned between ethyl acetate (50 mL) and 5% aqueous K2CO3 (50 mL). The layers were separated and the organic layer was further washed with 5% aqueous K2CO3 (2×25 mL). The combined aqueous layer was extracted with ethyl acetate (2×25 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford 340 mg (23%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.91-7.83 (m, 3 H), 7.09 (s, 1 H), 7.00 (d, 2 H), 3.50-3.42 (m, 4 H), 3.20-3.14 (m, 4 H), 1.42 (s, 9 H); ES-MS m/z 473.0 [M+H]+, HPLC RT (min) 3.25.

Workup

  1. temperatureto warm to rt
  2. extractionThe mixture was extracted with ethyl acetate (2×25 mL)
  3. dry with materialThe combined organic layers were dried (Na2SO4)
  4. concentrationconcentrated
  5. customThe crude material was purified by ISCO® chromatography
  6. customthus the material was partitioned between ethyl acetate (50 mL) and 5% aqueous K2CO3 (50 mL)
  7. customThe layers were separated
  8. washthe organic layer was further washed with 5% aqueous K2CO3 (2×25 mL)
  9. extractionThe combined aqueous layer was extracted with ethyl acetate (2×25 mL)
  10. washthe combined organic layers were washed with brine
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-9470e612bb1c4f4caa21dc9a493ad9b3
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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