4-Methylmorpholine → 3(S)-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid benzyl ester

HRID 566813Notes

Reaction equation

HRID 566813 reaction equation
[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11](NC(OC(C)(C)C)=O)[C:12]([NH:14][C@H:15]([C:20](=[O:23])NC)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[CH:48]=1)C(O)=O)C1C=CC=CC=1.N[C@@H]1C(C)(C)C[O:70]C1=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([C:51]1[CH:47]=[CH:48][N:49]([C:52]2[CH:53]=[CH:54][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:56][CH:57]=2)[CH:50]=1)[C:12]([NH:14][C@H:15]1[C:16]([CH3:17])([CH3:18])[CH2:19][O:70][C:20]1=[O:23])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 5

HCID 79724-MethylmorpholineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 9920392(3R)-3-Amino-4,4-dimethyloxolan-2-oneHCID 537065323(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl esterHCID 540329802(S)-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]succinic acid 4-benzyl ester

Product 1

HCID 599326853(S)-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid benzyl esterYield 29%

Procedure

According to the procedure described in Example 1(b) for the preparation 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]succinic acid 4-benzyl ester (prepared as described in Example 14(b)) and 3(R)-amino-4,4-dimethyl-2-oxo-tetrahydrofuran (see Freskos, J. N. Syn Commun. 1994, 24, 557-563) were coupled using TBTU with N-methylmorpholine as the base to provide a mixture of diastereomers which were separated using chromatography on silica gel column with 0 to 5% MeOH gradient in CH2Cl2. Mixed fraction was repurified on a chromatotron using 0-2.5% MeOH/CH2Cl2 then 0-1.25% MeOH/CH2Cl2 as eluent to obtain 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid benzyl ester in 29% yield as an amorphous solid: 1H NMR (CDCl3): δ 7.75 (d, 2H, 8.1 Hz), 7.69 (d, 2H, J=8.5 Hz), 7.64 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 7.32 (s, 5H), 7.13 (s, 1H), 7.09 (t, 1H, J=2.2 Hz), 6.32 (s, 1H), 6.06 (d, 1H, J=7.7 Hz), 5.13 (s, 2H), 4.67 (d, 1H, J=7.7 Hz), 4.08 -4.01 (m, 3H), 3.31 (dd, 1H, J=16.9, 8.5 Hz), 2.82 (dd, 1H, J=16.7, 6.1 Hz), 1.23 (s, 3H), 0.98 (s, 3H); Anal. Calculated for C34H31N3O5•0.2 H2O: C, 72.25; H, 5.60; N, 7.43. Found: 72.32, 72.26; H, 5.88, 5.91; N, 7.07, 7.02.

Workup

  1. customto provide
  2. additiona mixture of diastereomers which
  3. customwere separated
  4. additionMixed fraction
  5. customwas repurified on a chromatotron

Sources & evidence

ORD record
ord-b627193d077f4ee387099e965cc36392
Source dataset
uspto-grants-2001_01
Patent number
US06174915B1

Reaction notes

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