O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate → N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester

HRID 2299969Notes

Reaction equation

HRID 2299969 reaction equation
[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25](OC(C)(C)C)=O)[C:12](N[C@H](C(=O)NC)C(C)(C)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@H:34]([C:39]1[NH:40][CH:41]=[CH:42][N:43]=1)[CH2:35][CH:36]([CH3:38])[CH3:37].O=C1[C@@H](NC(=O)[C@H:64]([N:69]2[CH:73]=[CH:72][C:71]([C:74]3[CH:79]=[CH:78][C:77]([C:80]4[CH:85]=CC=CN=4)=[CH:76][CH:75]=3)=[CH:70]2)CC(O)=O)CC2=CN(C3C2=CC=CC=3)CCOCCN1.[CH3:88]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:24]1[CH:25]=[CH:85][C:80]([C:77]2[CH:76]=[CH:75][C:74]([C:71]3[CH:70]=[CH:64][N:69]=[CH:73][CH:72]=3)=[CH:79][CH:78]=2)=[CH:88]1)[C:12]([NH:33][C@H:34]([C:39]1[NH:43][CH:42]=[CH:41][N:40]=1)[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 4

HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 183412702-(1(S)-amino-3-methyl-butyl)-imidazoleHCID 537065323(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl esterHCID 70157731N-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12,14,16-tetraen-9(S)-yl)-3(R)-[3-[4-(pyridinyl)phenyl]-1H-pyrrol-1-yl]succinamic acid

Product 1

HCID 53669781N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl esterYield 41%

Procedure

According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2-(1(S)-amino-3-methyl-butyl)-imidazole (See Chen, J. J.; Zhang, Y.; Hammond, S.; Dewdney, N.: Ho, T.; Browner, M. F.; Castelhano, A. L., submitted for publication; and Abel-Meguid, S. S.; Metcalf B. W.; Caw, T. J.; DeMarsh, P.; Des Jarlais, R. L.; Fisher, S.; Green, D. W.; et al. Biochemistry, 1994, 33, 11671-11677) and 2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinic acid 4-benzyl ester hydrochloride (prepared as described in Example 7(a)) were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant and recrystallization from EtOAc gave in 41% yield N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as white crystals, mp 179-81° C. (d). 1H NMR (DMSO-d6): δ 11.84 (bs, 1H), 8.68 (d, 1H, J=8.5 Hz), 8.59 (d, 2H, J=4.4 Hz), 7.76 (d, 2H, J=8.5 Hz), 7.71 (d, 2H, J=6.3 Hz), 7.60 (d, 2H, J=8.5 Hz), 7.36 (s, 1H), 7.30 (s, 5H), 6.94-6.80 (m, 3H), 6.46 (s, 1H), 5.17 (t, 1H, J=7.5 Hz), 5.11, 5.05 (AB quartet, 2H, J=12.7 Hz), 4.97 (dd, 1H, J=7.7, 15.4 Hz), 3.24 (dd, 1H, J=7.4, 12.9 Hz), 3.11 (dd, 1H, J=7.7, 16.6 Hz), 1.67 (t, 2H, J=7.7 Hz), 1.48-1.40 (m, 1H), 0.85 (d, 3H, J=6.6 Hz), 0.81 (d, 3H, J=6.6 Hz). Anal. Calculated for C34H35N5O3: C, 72.70; H, 6.28; N, 12.47. Found: C, 72.43, H, 6.33; N, 12.34.

Workup

  1. customFlash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant and recrystallization from EtOAc

Sources & evidence

ORD record
ord-0bfe01df877f4342aae0619098b64929
Source dataset
uspto-grants-2002_12
Patent number
US06495699B2

Reaction notes

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