Hydrochloric Acid → n-[(4-{[(3s,4r)-1-Benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1h-indol-5-yloxy)benzamide

HRID 629598Notes

Reaction equation

HRID 629598 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:35][CH2:34]4)[CH:30]=[CH:29][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:55][C@@H:56]1[CH2:61][CH2:60][N:59]([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:58][C@@H:57]1[OH:69].Cl.C(N(CC)CC)C>O1CCOCC1>[CH2:62]([N:59]1[CH2:60][CH2:61][C@@H:56]([NH:55][C:22]2[CH:23]=[CH:24][C:19]([S:16]([NH:15][C:13](=[O:14])[C:12]3[CH:29]=[CH:30][C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:39][C:40]5[CH2:45][CH2:44][C:43]([CH3:46])([CH3:47])[CH2:42][C:41]=5[C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:37][CH2:38]4)=[CH:32][C:11]=3[O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)(=[O:17])=[O:18])=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])[C@@H:57]([OH:69])[CH2:58]1)[C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 13677861cis-4-Amino-1-benzylpiperidin-3-olHCID 672283542-(1h-Indol-5-yloxy)-n-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

Product 1

HCID 53261812n-[(4-{[(3s,4r)-1-Benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1h-indol-5-yloxy)benzamide

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A mixture of EXAMPLE 187A (0.158 g), (3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid (0.049 g), and triethylamine (0.1 mL) in dioxane (2 mL) was heated at 100° C. overnight. The solvent was removed, and the residue was re-dissolved in 1:1 methanol:dimethylsulfoxide (3 mL). It was then purified by reverse phase Prep HPLC. The residue was purified by reverse phase HPLC on a C18 column using a gradient of 20-80% acetonitrile/0.1% TFA in water. The desired fractions were collected, and the organic solvent was partially removed under reduced pressure. The resulting mixture was treated with saturated aqueous NaHCO3 mixture. It was then extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give the desired product. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.14 (s, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 7.77 (dd, 1H), 7.51 (d, 1H), 7.29-7.41 (m, 9H), 7.10-7.13 (m, 1H), 7.13 (d, 2H), 6.84 (dd, 1H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.13 (d, 1H), 5.21-5.22 (br s, 1H), 3.82 (m, 2H), 3.62 (br s, 2H), 3.01 (br s, 4H), 2.71-2.82 (m, 4H), 2.12-2.15 (m, 7H), 1.94 (br s, 2H), 1.81 (br s, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Workup

  1. customThe solvent was removed
  2. dissolutionthe residue was re-dissolved in 1:1 methanol
  3. customIt was then purified by reverse phase Prep HPLC
  4. customThe residue was purified by reverse phase HPLC on a C18 column
  5. customThe desired fractions were collected
  6. customthe organic solvent was partially removed under reduced pressure
  7. additionThe resulting mixture was treated with saturated aqueous NaHCO3 mixture
  8. extractionIt was then extracted with ethyl acetate three times
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-5e8d4797775f4defaf6ed6d39e8e763b
Source dataset
uspto-grants-2016_04
Patent number
US09315488B2

Reaction notes

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