Lithium Chloride → N-(6-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrazin-2-yl)acetamide

HRID 2170197Notes

Reaction equation

HRID 2170197 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1.C[Sn](C)C.C[Sn](C)C.Cl[C:21]1[N:26]=[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:24]2=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:36]=[CH:37][N:23]2[N:22]=1.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]1([C:35]2[CH:36]=[CH:37][N:23]3[C:24]=2[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:26][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=2)=[N:22]3)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1

Participants

7

Reactant 4

HCID 433294Lithium ChlorideHCID 6327618HexamethylditinHCID 14787673N-(6-chloropyrazin-2-yl)acetamideHCID 903861572-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Product 1

HCID 90386197N-(6-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrazin-2-yl)acetamideYield 15.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of N-(6-chloropyrazin-2-yl)acetamide (77.0 mg, 0.447 mmol) and hexamethylditin (0.124 mL, 0.596 mmol) in 1,4-dioxane (15 mL) was purged with argon gas for 30 min. Pd(Ph3P)4 (34.0 mg, 0.0300 mmol) was added and the reaction mixture was heated at 100° C. for 1 h. Then the reaction mixture was allowed to cool to RT and then 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.100 g, 0.298 mmol) was added followed by LiCl (13.0 mg, 0.298 mmol). The reaction mixture was heated at 100° C. for 12 h. The cooled reaction mixture was filtered through the CELITE® and washed with ethyl acetate (10 mL). The filtrate was evaporated under reduced pressure to give a residue which was purified by preparative TLC plate (40% ethylacetate/petroleum ether) then further purified by preparative HPLC (Condition B-100 as described in general methods) to give N-(6-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrazin-2-yl)acetamide (20.0 mg, 15.4%). LCMS Condition B-34: retention time 2.27 min, [M+1]=437.0. HPLC Condition B-5: retention time 6.86 min, purity 97.45%. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3H), 4.93 (d, J=4.5 Hz, 2H), 6.85-6.88 (m, 1H), 7.29 (ddd, J=7.5 Hz, J=5.0 Hz, J=1.0 Hz, 1H), 7.38 (t, J=4.5 Hz, 1H), 7.46-7.50 (m, 2H), 7.52-7.57 (m, 2H), 7.58-7.63 (m, 2H), 7.79 (td, J=7.7 Hz, J=1.8 Hz, 1H), 7.89 (d, J=2.5 Hz, 1H), 8.39 (td, J=2.5 Hz, J=1.0 Hz, 1H), 9.17 (s, 1H), 9.43 (s, 1H), 11.15 (s, 1H).

Workup

  1. temperatureto cool to RT
  2. temperatureThe reaction mixture was heated at 100° C. for 12 h
  3. customThe cooled reaction mixture
  4. filtrationwas filtered through the CELITE®
  5. washwashed with ethyl acetate (10 mL)
  6. customThe filtrate was evaporated under reduced pressure
  7. customto give a residue which
  8. customwas purified by preparative TLC plate (40% ethylacetate/petroleum ether)
  9. customthen further purified by preparative HPLC (Condition B-100 as described in general methods)

Sources & evidence

ORD record
ord-6f063bf16f8148a2b73b0da3548657f3
Source dataset
uspto-grants-2015_06
Patent number
US09050345B2

Reaction notes

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