Diisopropylethylamine → 4-((1R,3 S)-3-amino-2,2,3-trimethylcyclopentylamino)-6-bromopyrrolo[1,2-b]-pyridazine-3-carboxamide

HRID 1408949Notes

Reaction equation

HRID 1408949 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][C@:16]1([NH2:24])[CH2:20][CH2:19][C@@H:18]([NH2:21])[C:17]1([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CO.C(Cl)Cl>CN(C=O)C>[NH2:24][C@@:16]1([CH3:15])[CH2:20][CH2:19][C@@H:18]([NH:21][C:9]2[C:4]3[N:5]([CH:14]=[C:2]([Br:1])[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:11]([NH2:13])=[O:12])[C:17]1([CH3:23])[CH3:22]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 21226129Dichloromethane methanolHCID 24271783(1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine2×HCID 682911926-Bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 682922884-((1R,3 S)-3-amino-2,2,3-trimethylcyclopentylamino)-6-bromopyrrolo[1,2-b]-pyridazine-3-carboxamideYield 239%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 638 mg, 2.325 mmol) and (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (prepared as described in Intermediate 10, 430 mg, 3.02 mmol) in DMF (3.5 mL) was added DIPEA (1.218 mL, 6.98 mmol). The reaction vessel was purged with N2, sealed and heated to at 95° C. for 90 min. The reaction was cooled and partitioned between ethyl acetate (35 mL) and water (20 mL). The layers were separated and the aqueous layer further extracted with ethyl acetate (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude extracts were combined with two previous reactions and concentrated onto SiO2 and eluted onto a silica gel column with 100% ethyl acetate. After the non-polar impurities had eluted, the solvent was changed to 5% MeOH/CH2Cl2 then 10% then 15% MeOH/CH2Cl2 to afford the title compound (2.113 grams, 67% yield). HPLC (condition 0): retention time=2.61 min; LCMS: 382.08 (M+2); 1H NMR (methanol-d4, 400 MHz) δ 8.14 (s, 1H), 7.63 (d, J=1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 4.41 (t, J=8.4 Hz, 1H), 2.34 (m, 1H), 1.85 (m, 2H), 1.70 (m, 1H), 1.22 (s, 3H), 1.08 (s, 3H), 0.96 (s, 3H).

Workup

  1. customThe reaction vessel was purged with N2
  2. customsealed
  3. temperatureThe reaction was cooled
  4. custompartitioned between ethyl acetate (35 mL) and water (20 mL)
  5. customThe layers were separated
  6. extractionthe aqueous layer further extracted with ethyl acetate (2×)
  7. dry with materialThe combined organic extracts were dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. concentrationconcentrated onto SiO2
  11. washeluted onto a silica gel column with 100% ethyl acetate
  12. washAfter the non-polar impurities had eluted

Sources & evidence

ORD record
ord-8e3115fbf4c344b4b1cc7ebf0b32d7c3
Source dataset
uspto-grants-2014_12
Patent number
US08921368B2

Reaction notes

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