2,4,6-Trichlorobenzoyl chloride → N-(3-cyclopropyl-1-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

HRID 79460Notes

Reaction equation

HRID 79460 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:36]1([C:39]2[C:47]3[C:46]([NH2:48])=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]([CH2:49][C:50]3[S:51][C:52]([CH3:55])=[N:53][N:54]=3)[N:40]=2)[CH2:38][CH2:37]1>CN1CCCC1=O.O>[CH:36]1([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][C:46]=3[NH:48][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:21])[N:41]([CH2:49][C:50]3[S:51][C:52]([CH3:55])=[N:53][N:54]=3)[N:40]=2)[CH2:37][CH2:38]1

Participants

6

Reactant 3

HCID 27337032,4,6-Trichlorobenzoyl chlorideHCID 67252742Lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylateHCID 672599493-cyclopropyl-1-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-indazol-4-amine

Product 1

HCID 67261049N-(3-cyclopropyl-1-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamideYield 53.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent2×

Conditions

Temperature
88 °C

Procedure

To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Example 56, Step A; 70.5 mg, 0.23 mmol) was added N-Methylpyrrolidinone (1 mL). The suspension was heated in order to affect dissolution. The reaction mixture was cooled in an ice-water bath under nitrogen, and 2,4,6-trichlorobenzoyl chloride (35.5 μL, 0.23 mmol) was added dropwise. The cold bath was removed once the addition was complete and the reaction mixture was stirred for a further 1 hour. The reaction mixture became cloudy. A solution of 3-cyclopropyl-1-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-indazol-4-amine (48 mg, 0.168 mmol) in anhydrous N-Methylpyrrolidinone (1 mL) was then added to the reaction mixture, and the mixture was heated to 88° C. for 13.5 hours. The reaction mixture was cooled, diluted with water, and extracted multiple times with dichloromethane. The combined dichloromethane extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, eluting with 7N ammonia/MeOH:MeOH:DCM in a 3:7:90 ratio) to afford the product (51.6 mg) as a dark yellow solid. MS (ES+APCI) m/z=572 (M+H).

Workup

  1. temperatureThe suspension was heated in order
  2. dissolutiondissolution
  3. temperatureThe reaction mixture was cooled in an ice-water bath under nitrogen
  4. customThe cold bath was removed once the addition
  5. temperatureThe reaction mixture was cooled
  6. extractionextracted multiple times with dichloromethane
  7. dry with materialThe combined dichloromethane extracts were dried over anhydrous sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customThe crude residue was purified by preparative thin-layer chromatography (silica
  10. washeluting with 7N ammonia/MeOH

Sources & evidence

ORD record
ord-ab85acb3e5464acb876263c72a330144
Source dataset
uspto-grants-2014_09
Patent number
US08841455B2

Reaction notes

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