3-Chloropropionyl chloride → HCID 86732034, compound

HRID 527425Notes

Reaction equation

HRID 527425 reaction equation
FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.[Cl:51][CH2:52][CH2:53][C:54](Cl)=[O:55]>C(Cl)Cl>[Cl:51][CH2:52][CH2:53][C:54]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:55]

Participants

5

Reactant 3

HCID 693643-Chloropropionyl chloride2×HCID 81531DiisopropylethylamineHCID 86732023HCID 86732023, compound

Product 1

HCID 86732034HCID 86732034, compoundYield 23%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b; 200 mg, 0.44 mmol) in DCM (5 mL) at 0° C. was treated with DIEA (0.19 mL, 1.09 mmol) and cooled in an ice bath at 0° C. The solution was then treated with 3-chloropropionyl chloride (Sigma Aldrich, St. Louis, Mo.; 0.042 mL, 0.44 mmol) dropwise over 10 min and stirred at 0° C. for 30 min then stirred at RT for 2 h. 3 more drops of 3-chloropropionyl chloride was added and the reaction stirred at RT overnight. The reaction mixture was then concentrated, treated with DMSO (8 mL) and purified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated under reduced pressure (rotary evaporator) and the resulting aqueous solution treated with a 10% solution of Na2CO3 and extracted with DCM (4×30 mL), dried over Na2SO4 and concentrated under vacuum overnight affording 3-chloro-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propanamide (57 mg, 0.10 mmol, 23% yield) as a yellow solid. m/z (ESI, +ve ion) 548.0 (M+H)+ in about 65% purity with the mass balance corresponding to the acrylamide. The material was used in the subsequent step without further purification.

Workup

  1. stirringthen stirred at RT for 2 h
  2. stirringthe reaction stirred at RT overnight
  3. concentrationThe reaction mixture was then concentrated
  4. additiontreated with DMSO (8 mL)
  5. custompurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water)
  6. additionThe product containing fractions
  7. concentrationwere concentrated under reduced pressure (rotary evaporator)
  8. additionthe resulting aqueous solution treated with a 10% solution of Na2CO3
  9. extractionextracted with DCM (4×30 mL)
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated under vacuum overnight

Sources & evidence

ORD record
ord-39d193a60cda449a82cbdc4b98f5c838
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

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