1,8-Diazabicyclo(5.4.0)undec-7-ene → HCID 178461716, compound

HRID 1469611Notes

Reaction equation

HRID 1469611 reaction equation
C([O:3][C:4](=[O:36])[C@H:5]([CH3:35])[CH2:6][C@H:7]([NH:21][C:22](=[O:34])[CH2:23][CH2:24][C:25]1[N:29](CCC#N)[N:28]=[N:27][N:26]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.C1CCN2C(=NCCC2)CC1>ClCCl>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:34])[CH2:23][CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH2:6][C@@H:5]([CH3:35])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=1

Participants

4

Reactant 2

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-ene2×HCID 59608222(2R,4S)-5-Biphenyl-4-yl-4-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-2-methyl-pentanoic acid ethyl ester

Product 1

HCID 178461716HCID 178461716, compoundYield 52.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (2R,4S)-5-Biphenyl-4-yl-4-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-2-methyl-pentanoic acid ethyl ester (32 mg, 0.065 mmol) in dichloromethane (1 mL) is added DBU (24 mg, 0.164 mmol). After stirring for 3 hours, additional DBU (24 mg, 0.146 mmol) is added. After stirring for 2 hours, the reaction mixture is diluted with dichloromethane and washed with saturated aqueous NH4Cl. The organic layer is dried over Na2SO4 and concentrated. The residue is dissolved in MeOH and treated with aqueous 2M NaOH. After stirring for 1 hours, the reaction mixture is diluted with ethyl acetate and acidified with aqueous 1M HCl. The mixture is extracted with ethyl acetate and washed with brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by reverse phase HPLC (0.1% TFA-H2O/MeCN) to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(3-1H-tetrazol-5-yl-propionylamino)-pentanoic acid (14 mg). HPLC Retention time 1.17 minutes (condition C); MS 408.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J=7.07Hz, 3H), 1.34 (ddd, J=4.80, 10.11, 14.91Hz, 1H), 1.78 (ddd, J=4.04, 9.60, 13.64Hz, 1H), 2.31-2.42 (m, 1H), 2.52-2.59 (m, 2H), 2.68 (d, J=7.07Hz, 2H), 3.03 (dd, J=7.58, 7.58Hz, 2H), 3.90-4.01 (m, 1H), 7.20 (d, J=8.08Hz, 2H), 7.34 (t, J=9.09Hz, 1H), 7.45 (d, J=7.83Hz, 2H), 7.55 (d, J=8.34Hz, 2H), 7.64 (d, J=7.33Hz, 2H), 7.84 (d, J=8.34Hz, 1H), 11.99 (bs, 1H).

Workup

  1. stirringAfter stirring for 2 hours
  2. washwashed with saturated aqueous NH4Cl
  3. dry with materialThe organic layer is dried over Na2SO4
  4. concentrationconcentrated
  5. dissolutionThe residue is dissolved in MeOH
  6. additiontreated with aqueous 2M NaOH
  7. stirringAfter stirring for 1 hours
  8. additionthe reaction mixture is diluted with ethyl acetate
  9. extractionThe mixture is extracted with ethyl acetate
  10. washwashed with brine
  11. dry with materialThe organic layer is dried over Na2SO4
  12. concentrationconcentrated
  13. customThe residue is purified by reverse phase HPLC (0.1% TFA-H2O/MeCN)

Sources & evidence

ORD record
ord-21ff8e5112a24af485100d40707ff425
Source dataset
uspto-grants-2015_04
Patent number
US09006249B2

Reaction notes

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