4'-(2,5-Dimethoxytetrahydrofuran-3-yl)-biphenyl-4-carbonitrile → N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4'-cyano-biphenyl4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester

HRID 566768Notes

Reaction equation

HRID 566768 reaction equation
FC(F)(F)C(O)=O.C(OC(=O)C[C@@H](N)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH2:40]([O:47][C:48](=[O:65])[CH2:49][C@@H:50]([NH2:64])[C:51]([NH:53][C@@H:54]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:55][OH:56])=[O:52])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CO[CH:68]1[CH:72]([C:73]2[CH:78]=[CH:77][C:76]([C:79]3[CH:84]=[CH:83][C:82]([C:85]#[N:86])=[CH:81][CH:80]=3)=[CH:75][CH:74]=2)[CH2:71][CH:70](OC)O1>ClCCCl>[CH2:40]([O:47][C:48](=[O:65])[CH2:49][C@@H:50]([N:64]1[CH:70]=[CH:71][C:72]([C:73]2[CH:78]=[CH:77][C:76]([C:79]3[CH:80]=[CH:81][C:82]([C:85]#[N:86])=[CH:83][CH:84]=3)=[CH:75][CH:74]=2)=[CH:68]1)[C:51]([NH:53][C@@H:54]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:55][OH:56])=[O:52])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1

Participants

5

Reactant 3

HCID 183804024'-(2,5-Dimethoxytetrahydrofuran-3-yl)-biphenyl-4-carbonitrileHCID 700814343(r)-Amino-n-(2,2-dimethyl-1(s)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluoroacetate saltHCID 701436173(R)-amino-N-(l(S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt

Product 1

HCID 15459675N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4'-cyano-biphenyl4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl esterYield 39.1%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
87.5 °C

Procedure

As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluroacetate salt, crude 3(R)-amino-N-(1(S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 1(a); 0.876 mmol) was condensed with 4′-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitrile (326 mg, 1.05 mmol) in 1,2-dichloroethane (5 mL). The solution was heated at 85-90° C. for 5 hours, allowed to cool, and evaporated to give a brown oil which was purified via flash column chromatography with 1% HOAc/30% EtOAc/hex as eluant. HOAc was removed via azeotrope with n-heptane layers to provide 200 mg (39%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a pale yellow powder, mp 149-50° C. 1H NMR (CDCl3): ∂ 7.74 (s, 4H), 7.59 (d, 4H, J=4.1 Hz), 7.32-7.18 (m, 10H), 7.05 (bm, 2H), 6.94 (t, 1H, J=2.2 Hz), 6.64 (t, 1H, 2.5 Hz), 6.58 (bm, 1H), 5.48 (d, 1H, J=7.8 Hz), 5.10 (d, 2H, J=3.1 Hz), 5.00 (dd, 1H, J=5.0, 9.3 Hz), 4.46-4.32 (m, 2H), 4.22-4.12 (m, 1H), 3.41 (dd, 1H, J=5.3, 17.1 Hz), 3.04 (dd, 1H, J=9.1, 17.1 Hz), 2.70-2.63 (m, 2H). IR: 3389, 3030, 2948, 2225, 1735, 1665, 1603, 1528, 1495 cm−1. HRFABMS: Calculated for C37H33N3O4Cs (MH+Cs+): 716.1525. Found: 716.1503. Anal. Calculated for C37H33N3O4•0.4 CH2Cl2: C, 72.73; H, 5.52; N, 6.80. Found: C, 72.67, H, 5.53; N, 6.81.

Workup

  1. temperatureto cool
  2. customevaporated
  3. customto give a brown oil which
  4. customwas purified via flash column chromatography with 1% HOAc/30% EtOAc/hex as eluant
  5. customHOAc was removed via azeotrope with n-heptane layers

Sources & evidence

ORD record
ord-007cdd8f84a044a7827561abd3d25f06
Source dataset
uspto-grants-2001_01
Patent number
US06174915B1

Reaction notes

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