Diisopropylethylamine → methyl(1S)-1-{[((1s,2s,4s)-1-benzyl-2-hydroxy-4-{[(2s)-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamate

HRID 1174147Notes

Reaction equation

HRID 1174147 reaction equation
[NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:41][C@@H:42]([CH2:65][CH3:66])[C@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[N:54]=[C:55]([C:58]3[CH:63]=[CH:62][CH:61]=CN=3)[S:56][CH:57]=2)[C:48]1=[O:64])[C:44]([OH:46])=O.CCOP(O[N:76]1N=NC2C=CC=CC=2[C:77]1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:44](=[O:46])[C@@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[N:54]=[C:55]([C:58]3[CH:77]=[N:76][CH:61]=[CH:62][CH:63]=3)[S:56][CH:57]=2)[C:48]1=[O:64])[CH:42]([CH3:41])[CH2:65][CH3:66])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 42939953-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneHCID 67406377(2s,3s)-3-Methyl-2-(2-oxo-3-{[2-(2-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoic acid trifluoroacetateHCID 86726171methyl (1S)-1-({[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate

Product 1

HCID 91550283methyl(1S)-1-{[((1s,2s,4s)-1-benzyl-2-hydroxy-4-{[(2s)-3-methyl-2-(2-oxo-3-{[2-(3-pyridinyl)-1,3-thiazol-4-yl]methyl}-1-imidazolidinyl)pentanoyl]amino}-5-phenylpentyl)amino]carbonyl}-2,2-dimethylpropylcarbamateYield 83.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
25 °C

Procedure

A solution containing the product from Example 8B (0.275 g, 0.56 mmol) in THF (6 mL) was treated with the product from Example 3L (0.227 g, 0.61 mmol), DEPBT (0.275 g, 0.92 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.16 mmol), stirred at 25° C. for 64 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 5% methanol in ethyl acetate to give the title compound (0.378 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.67 (d, J=6.62 Hz, 3 H), 0.80 (m, 14 H), 0.94 (m, 1 H), 1.29 (m, 1 H), 1.49 (m, 2 H), 1.78 (m, 1 H), 2.42 (m, 1 H), 2.68 (m, 3 H), 2.86 (m, 1 H), 3.13 (m, 4 H), 3.58 (m, 4 H), 3.89 (m, 2 H), 4.12 (m, 2 H), 4.47 (s, 2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d, J=9.19 Hz, 1 H), 7.07 (m, 7 H), 7.52 (m, 2 H), 7.57 (s, 1 H), 7.82 (d, J=8.82 Hz, 1 H), 8.29 (m, 1 H), 8.66 (dd, J=4.78, 1.84 Hz, 1 H), 9.13 (d, J=1.47 Hz, 1 H).

Workup

  1. custompartitioned between ethyl acetate and 10% Na2CO3 solution
  2. washThe organic phase was washed with additional 10% Na2CO3 solution and brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane
  7. washfollowed by elution with 5% methanol in ethyl acetate

Sources & evidence

ORD record
ord-2953bdfbee1c40a2a270530f977509a4
Source dataset
uspto-grants-2010_11
Patent number
US07834043B2

Reaction notes

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