Diethyl Pyrocarbonate → 1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

HRID 1479891Notes

Reaction equation

HRID 1479891 reaction equation
[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[CH:30]1([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[C:42]([C:48]4[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=4)[N:41]=3)[CH2:36][CH2:35]2)[CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:47][CH2:46][C:44]3[CH:43]=[C:42]([C:48]4[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:50][CH:49]=4)[N:41]=[C:40]([N:37]4[CH2:36][CH2:35][N:34]([CH2:33][CH:30]5[CH2:31][CH2:32]5)[CH2:39][CH2:38]4)[CH:45]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 3051Diethyl PyrocarbonateHCID 903841961-[(5-Chloro-2-thienyl)sulfonyl-ethyl-amino]cyclopropanecarboxylic acidHCID 90390267[2-[4-(Cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine

Product 1

HCID 903913431-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideYield 21.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of acid 18 (463 mg, 1.5 mmol) in THF (30 mL) was added with DEPC (0.23 mL, 1.0 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27G (560 mg, 1.04 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (40 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over Na2SO4 and evaporated under reduced pressure and the residue was purified by flash chromatography (9:1 EtOAc:methanol) to afford a white solid (220 mg) after crystallization from diethyl ether. Yield=21.5%, 1HNMR (DMSO, 200 MHz) δ 0.40 (m, 2H), 0.65 (bm, 2H), 0.94 (m, 1H), 1.12 (m, 2H), 1.28 (t, 3H), 1.40 (bm, 2H), 3.04 (bm, 4H), 3.39 (bm, 4H), 3.43 (bm, 2H), 3.44 (m, 4H); 4.40 (bm, 4H), 6.87 (s, 1H), 7.30 (m, 2H), 7.60 (d, 1H, J=3.2), 7.82 (d, 2H, J=8.2), 8.25 (bm, 3H). [M+1] 682.98 (C31H35ClF3N5O3S2 requires 682.22).

Workup

  1. stirringthe reaction mixture was stirred at room temperature overnight
  2. customThe solvent was removed under reduced pressure
  3. washwashed with water (50 mL) and brine
  4. dry with materialThe separated organic phase was dried over Na2SO4
  5. customevaporated under reduced pressure
  6. customthe residue was purified by flash chromatography (9:1 EtOAc:methanol)

Sources & evidence

ORD record
ord-9ec35a21ba3a4008afea5c702b6debfc
Source dataset
uspto-grants-2016_08
Patent number
US09409864B2

Reaction notes

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