Citric Acid → ethyl (4R)-4-[(8-bromo-9-methoxy-1,2,3,4-tetrahydrophenanthridin-6-yl)oxy]-1-[(2S)-2-cyclohexyl-2-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetyl]-L-prolinate

HRID 1423373Notes

Reaction equation

HRID 1423373 reaction equation
Cl.[Br:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:5](=[C:6]([O:19][C@H:20]3[CH2:24][NH:23][C@H:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21]3)[N:7]=[C:8]3[C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:4]=1.[CH:30]1([C@H:36]([NH:40][C:41]([O:43][CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][CH:47]=[CH2:48])=[O:42])[C:37](O)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:5](=[C:6]([O:19][C@H:20]3[CH2:24][N:23]([C:37](=[O:38])[C@H:36]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[NH:40][C:41]([O:43][CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][CH:47]=[CH2:48])=[O:42])[C@H:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21]3)[N:7]=[C:8]3[C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:4]=1

Participants

8

Reactant 5

HCID 311Citric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57617041(2S)-cyclohexyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acidHCID 86643485ethyl (4R)-4-[(8-bromo-9-methoxy-1,2,3,4-tetrahydrophenanthridin-6-yl)oxy]-L-prolinate hydrochloride2×

Product 1

HCID 86643487ethyl (4R)-4-[(8-bromo-9-methoxy-1,2,3,4-tetrahydrophenanthridin-6-yl)oxy]-1-[(2S)-2-cyclohexyl-2-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetyl]-L-prolinate

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To a solution of the product from Step 2, ethyl (4R)-4-[(8-bromo-9-methoxy-1,2,3,4-tetrahydrophenanthridin-6-yl)oxy]-L-prolinate hydrochloride (466 mg, 0.96 mmol) in DMF (8 mL) was added linker intermediate B20, (2S)-cyclohexyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acid (300 mg, 1.0 mmol)), DIPEA (0.50 mL, 2.88 mmol), HATU (547 mg, 1.44 mmol), and DMAP (59 mg, 0.48 mmol) were added. The mixture was stirred at r.t. for 18 h and then the mixture was poured into 120 mL of aqueous citric acid. The resulting solid was removed by filtration and washed with water. The solid was then dissolved in EtOAc, dried over Na2SO4, and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 20-50% EtOAc/hexanes) to yield the title compound. LRMS (M+H)+=728.0.

Workup

  1. additionwere added
  2. customThe resulting solid was removed by filtration
  3. washwashed with water
  4. dissolutionThe solid was then dissolved in EtOAc
  5. dry with materialdried over Na2SO4
  6. customthe solvent was removed in vacuo
  7. customThe crude material was then purified on silica (gradient elution, 20-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-c78797790b734c3eae3ffd1be2343bdb
Source dataset
uspto-grants-2015_01
Patent number
US08927569B2

Reaction notes

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