Triethylamine → 1-(2-{[6-({6-[{3-[({[(2S)-1'-{2-[(5R)-3-[3,5-Bis(trifluoromethyl)benzoyl]-5-(4-fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl]oxy}acetyl)(methyl)amino]propyl}(methyl)carbamoyl]pyridazin-3-yl}amino)hexanoyl](methyl)amino}ethyl)piperidin-4-yl biphenyl-2-ylcarbamate

HRID 446512Notes

Reaction equation

HRID 446512 reaction equation
[F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:64]1([C:107]2[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=2)[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[NH:70][C:71](=[O:106])[O:72][CH:73]1[CH2:78][CH2:77][N:76]([CH2:79][CH2:80][N:81]([CH3:105])[C:82](=[O:104])[CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][NH:88][C:89]2[N:90]=[N:91][C:92]([C:95](=[O:103])[N:96]([CH3:102])[CH2:97][CH2:98][CH2:99][NH:100][CH3:101])=[CH:93][CH:94]=2)[CH2:75][CH2:74]1>C(Cl)Cl>[CH:38]([O-:40])=[O:39].[NH4+:8].[C:64]1([C:107]2[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=2)[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[NH:70][C:71](=[O:106])[O:72][CH:73]1[CH2:78][CH2:77][N:76]([CH2:79][CH2:80][N:81]([C:82](=[O:104])[CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][NH:88][C:89]2[N:90]=[N:91][C:92]([C:95](=[O:103])[N:96]([CH2:97][CH2:98][CH2:99][N:100]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]3[C:25]4([CH2:26][CH2:27][N:22]([CH2:21][CH2:20][C@:11]5([C:13]6[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=6)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]6[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:3]([C:2]([F:49])([F:1])[F:48])[CH:4]=6)[CH2:12]5)[CH2:23][CH2:24]4)[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29]3)[CH3:101])[CH3:102])=[CH:93][CH:94]=2)[CH3:105])[CH2:75][CH2:74]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 62493Pivaloyl chlorideHCID 666714761-[2-(Methyl{6-[(6-{methyl[3-(methylamino)propyl]carbamoyl}pyridazin-3-yl)amino]hexanoyl}amino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamateHCID 86663420HCID 86663420, compound

Product 2

HCID 2723923Ammonium formateYield 0.1%HCID 870995521-(2-{[6-({6-[{3-[({[(2S)-1'-{2-[(5R)-3-[3,5-Bis(trifluoromethyl)benzoyl]-5-(4-fluorophenyl)-1,3-oxazolidin-5-yl]ethyl}-2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl]oxy}acetyl)(methyl)amino]propyl}(methyl)carbamoyl]pyridazin-3-yl}amino)hexanoyl](methyl)amino}ethyl)piperidin-4-yl biphenyl-2-ylcarbamateYield 81%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

The compound (67 mg, 0.097 mmol) obtained in Example 1j was dissolved in methylene chloride (2 mL), triethylamine (18 μL, 0.13 mmol) and pivaloyl chloride (12 μL, 0.097 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A solution of the compound (59 mg, 0.088 mmol) obtained in Example 11d in methylene chloride (2 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=40:1→20:1, v/v) and further purified by reverse phase preparative column chromatography (Waters; XTerra Prep MS C18 OBD, 5 μm, 30×100 mm) (acetonitrile:0.1% aqueous ammonium formate solution=50:50→60:40, v/v) to give the title compound (53 mg; yield, 41%) as a light yellow solid.

Workup

  1. stirringthe mixture was stirred at room temperature for 2 hours
  2. customThe solvent was evaporated under reduced pressure
  3. customthe resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=40:1→20:1, v/v)
  4. customfurther purified by reverse phase preparative column chromatography (Waters; XTerra Prep MS C18 OBD, 5 μm, 30×100 mm) (acetonitrile

Sources & evidence

ORD record
ord-a6a2e3791e064392b3c2345e35f84575
Source dataset
uspto-grants-2013_07
Patent number
US08476253B2

Reaction notes

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