Hydrochloric Acid → (3S,5S,8S)-3-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-8-tert-butyl-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-yl (dimethylamino)acetate

HRID 1174413Notes

Reaction equation

HRID 1174413 reaction equation
[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:58]([CH3:61])([CH3:60])[CH3:59])[C:14]([NH:16][C@@H:17]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:18]([O:47][CH2:48]SC)[CH2:19][C@@H:20]([NH:34][C:35](=[O:46])[C@H:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[NH:37][C:38]([O:40][CH3:41])=[O:39])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:62])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:64][N:65]([CH3:70])[CH2:66][C:67]([OH:69])=[O:68].IN1C(=O)CCC1=O.Cl>O1CCOCC1>[CH3:64][N:65]([CH2:66][C:67]([O:69][CH2:48][O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:19][C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1)[NH:34][C:35](=[O:46])[C@H:36]([C:42]([CH3:45])([CH3:43])[CH3:44])[NH:37][C:38](=[O:39])[O:40][CH3:41])=[O:68])[CH3:70]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 75605N,N-Dimethylglycine hydrochlorideHCID 120273N-IodosuccinimideHCID 67407202N1-[(1S,3S,4S)-4-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-3-[(methylthio)methoxy]-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]-N2-(methoxycarbonyl)-3-methyl-L-valinamide

Product 1

HCID 86646202(3S,5S,8S)-3-((1S)-1-{[(2S)-2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoyl]amino}-2-phenylethyl)-8-tert-butyl-7,10-dioxo-5-(4-pyridin-2-ylbenzyl)-2,11-dioxa-6,9-diazadodec-1-yl (dimethylamino)acetate

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a solution of the product from Example 195A (0.045 g, 0.052 mmol) in 1,2-dichloromethane (1.5 mL) were added molecular sieves (4 Å, 0.24 g), N,N-dimethylglycine hydrochloride (0.075 g, 0.537 mmol), followed by N-iodosuccinimide (0.013 g, 0.058 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was filtered through celite. The filtrate was diluted with ethyl acetate and was washed with a mixture of dilute NaHCO3 and Na2S2O3, dried over MgSO4, filtered and evaporated. The residue was dissolved in ether and 2 equivalents of 4 N HCl in dioxane were added. The crude product was purified by chromatography on silica gel eluting with a gradient starting with dichloromethane and ending with methanol to give the title compound as the bis hydrochloride salt (0.037 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.87 (s, 9 H), 0.88 (s, 9 H), 1.60-1.73 (m, 2 H), 2.22 (s, 6 H), 2.29 (q, J=9.6 Hz, 1 H), 2.54-2.84 (m, 6 H), 2.93 (q, J=8.8 Hz, 1 H), 3.08-3.24 (m, 4 H), 3.53 (s, 3 H), 3.72-3.76 (m, 1 H), 3.87 (d, J=9.6 Hz, 1 H), 4.11-4.35 (m, 5 H), 5.26 (d, J=6.6 Hz, 1 H), 5.37 (d, J=6.6 Hz, 1 H), 6.78 (d, J=9.6 Hz, 1 H), 6.94-7.15 (m, 5 H), 7.22-7.40 (m, 8 H), 7.82-7.95 (m, 6 H), 8.63 (m, 1 H).

Workup

  1. filtrationThe reaction was filtered through celite
  2. additionThe filtrate was diluted with ethyl acetate
  3. washwas washed with a mixture of dilute NaHCO3 and Na2S2O3
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customevaporated
  7. dissolutionThe residue was dissolved in ether
  8. customThe crude product was purified by chromatography on silica gel eluting with a gradient

Sources & evidence

ORD record
ord-316df44c94e94e2daf0e6cd75c6d0455
Source dataset
uspto-grants-2010_11
Patent number
US07834043B2

Reaction notes

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