Triethylamine → (R)-1-(1-(2-Cyclopropylacetyl)pyrrolidin-3-yl)-3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)urea

HRID 1807763Notes

Reaction equation

HRID 1807763 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:33][C:34]([NH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=[O:35].[CH:42]1([CH2:45][C:46](O)=[O:47])[CH2:44][CH2:43]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:42]1([CH2:45][C:46]([N:39]2[CH2:40][CH2:41][C@@H:37]([NH:36][C:34]([NH:33][C:3]3[CH:4]=[CH:5][C:6]([C:8]([N:10]4[CH2:11][CH2:12][N:13]([CH2:16][C:17]5[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:21][CH:22]=5)[CH2:14][CH2:15]4)=[O:9])=[CH:7][C:2]=3[F:1])=[O:35])[CH2:38]2)=[O:47])[CH2:44][CH2:43]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 111923Propylphosphonic anhydrideHCID 138440Cyclopropaneacetic acidHCID 59175832(R)-1-(2-Fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyrrolidin-3-yl)urea

Product 1

HCID 59175843(R)-1-(1-(2-Cyclopropylacetyl)pyrrolidin-3-yl)-3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)ureaYield 33.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a stirring solution of (R)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyrrolidin-3-yl)urea (0.123 mmol, 73 mg), 2-cyclopropylacetic acid (0.123 mmol, 12.4 mg) and triethylamine (0.370 mmol, 35.5 mg) in dichloromethane (2 mL) was added 1-propanephosphonic acid cyclic anhydride (0.370 mmol, 118 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (2 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (3 mL). The organic phase was concentrated and the resulting residue was purified by HPLC and then treated with strong cation exchange column chromatography to afford the title compound (28 mg). MS (ESI) m/z 674.3 [M+H]+

Workup

  1. washwashed with saturated aqueous sodium hydrogen carbonate solution (3 mL)
  2. concentrationThe organic phase was concentrated
  3. customthe resulting residue was purified by HPLC
  4. additiontreated with strong cation exchange column chromatography

Sources & evidence

ORD record
ord-3b066e8b217c4ef0b4ca96197d66280c
Source dataset
uspto-grants-2013_01
Patent number
US08357679B2

Reaction notes

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