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

HRID 1479893Notes

Reaction equation

HRID 1479893 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([N:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:47]=[C:46]([CH2:48][NH2:49])[CH:45]=[C:44]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=4)[N:43]=3)[CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][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:49][CH2:48][C:46]3[CH:45]=[C:44]([C:50]4[CH:51]=[CH:52][C:53]([C:56]([F:59])([F:57])[F:58])=[CH:54][CH:55]=4)[N:43]=[C:42]([N:39]4[CH2:38][CH2:37][N:36]([CH:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:41][CH2:40]4)[CH:47]=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 90390288[2-[4-(Cyclohexyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine

Product 1

HCID 903904281-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideYield 10.3%

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 27E (628 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 (110 mg) after crystallization from diethyl ether. Yield=10%, 1HNMR (DMSO, 200 MHz) δ 1.15 (bm, 9H), 1.80 (bm, 4H), 2.35 (bm, 1H), 2.59 (bm, 4H), 3.37 (bm, 2H), 3.65 (bm, 4H), 4.45 (bd, 2H), 6.89 (s, 1H), 7.35 (m, 2H), 7.60 (d, 1H, J=3.4), 7.82 (d, 2H, J=8), 8.25 (bm, 3H). [M+1] 711.65 (C33H39ClF3N5O3S2 requires 710.27).

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-792f389a015c47e2a58ebf8dfd18a1cb
Source dataset
uspto-grants-2016_08
Patent number
US09409864B2

Reaction notes

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