1-Methylpiperazine → (S)-2-(3-(2-Chloro-4-(4-methylpiperazin-1-yl)phenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile

HRID 38048Notes

Reaction equation

HRID 38048 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13]1)(=[O:11])=[O:10].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13]1)(=[O:11])=[O:10]

Participants

5

Reactant 3

HCID 531671-Methylpiperazine3×HCID 81531Diisopropylethylamine3×HCID 57334444HCID 57334444, compound

Product 1

HCID 57334446(S)-2-(3-(2-Chloro-4-(4-methylpiperazin-1-yl)phenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrileYield 69.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

In a 10 mL round-bottomed flask, (S)-2-(3-(2-chloro-4-fluorophenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile (example 73) (50 mg, 136 μmol, 1 eq) was combined with acetonitrile (4 mL) to give a light yellow solution. 1-Methylpiperazine (20.7 mg, 22.9 μl, 204 μmol, 1.5 eq) and DIEA (35.2 mg, 47.6 μl, 273 μmol, 2 eq) were added. The reaction mixture was heated to 60° C. and stirred for 20 h. After that, 1-methylpiperazine (0.7 eq) and of DIEA (1 eq) were added. The reaction mixture was stirred at 60° C. for 5 h. After that, additional 1-methylpiperazine (1 eq) and DIEA (1.2 eq) were added. The reaction mixture was stirred at 60° C. for 16 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into aqueous 5% Na2CO3 solution and extracted with EtOAc (3×10 mL). The organic layers were combined and washed with saturated aqueous NaCl solution (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, CH2Cl2/MeOH 98/2) to yield a light yellow foam (42 mg, 69%). MS: m/z=447.1409 [M+H]+.

Workup

  1. customto give a light yellow solution
  2. stirringThe reaction mixture was stirred at 60° C. for 5 h
  3. stirringThe reaction mixture was stirred at 60° C. for 16 h
  4. customThe crude reaction mixture
  5. concentrationwas concentrated in vacuo
  6. additionThe reaction mixture was poured into aqueous 5% Na2CO3 solution
  7. extractionextracted with EtOAc (3×10 mL)
  8. washwashed with saturated aqueous NaCl solution (1×)
  9. dry with materialThe organic layers were dried over Na2SO4
  10. concentrationconcentrated in vacuo
  11. customThe crude material was purified by flash chromatography (silica gel, 10 g, CH2Cl2/MeOH 98/2)

Sources & evidence

ORD record
ord-7432178087cb45758020ae5a3e0b3c09
Source dataset
uspto-grants-2013_09
Patent number
US08524710B2

Reaction notes

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