Hydrochloric Acid → HCID 67505791, compound

HRID 881839Notes

Reaction equation

HRID 881839 reaction equation
[C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[S:24][C:23]([C:25]([OH:27])=O)=[CH:22][CH:21]=2)=[O:19])[CH2:9][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:11])=[CH:3][CH:2]=1.C([N:37](C(C)C)CC)(C)C.ClC(OCC(C)C)=O.[OH-].[NH4+].Cl>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])[C@H:10]([CH3:11])[CH2:9][C@H:8]([NH:17][C:18]([C:20]1[S:24][C:23]([C:25](=[O:27])[NH2:37])=[CH:22][CH:21]=1)=[O:19])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)[CH3:16]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 14923Ammonium HydroxideHCID 62365Isobutyl chloroformateHCID 81531DiisopropylethylamineHCID 59608128HCID 59608128, compound

Product 1

HCID 67505791HCID 67505791, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 5-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-thiophene-2-carboxylic acid (Example 26: 115 mg, 0.247 mmol) in THF (1 mL) at 0° C. is added diisopropylethylamine (63.8 mg, 0.494 mmol) followed by dropwise addition of a solution of isobutyl chloroformate (33.7 mg, 0.247 mmol) in THF (0.1 mL). The mixture is stirred at 0° C. for 30 minutes then ammonium hydroxide (0.3 mL of 14.8 M solution) is added. The mixture is allowed to warm to room temperature then aqueous 1M HCl (3 mL) is added. Most of the THF is removed under reduced pressure and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester. MS 465.3 (M+1). Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (115 mg, 0.248 mmol) in ethanol (8 mL) is added aqueous 1M NaOH (0.866 mL, 0.866 mmol) and the mixture is stirred at 50° C. for 3.5 hours. The ethanol is removed under reduced pressure and water is added to the residue. The resulting solution is acidified with aqueous 1M HCl and the resulting precipitate is filtered and washed with water. The solid is purified by preparative HPLC using 50% MeCN/water to elute the product. The appropriate fractions are lyophilized to give (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid. MS 437.2 (M+1); 1H-NMR (400 MHz, DMSO-d6); δ ppm 1.09 (d, J=7.20 Hz, 3H), 1.57 (m, 1H), 1.88 (m, 1H), 2.46 (m, 1H), 2.84 (m, 2H), 4.18 (m, 1H), 7.28 (d, J=8.21 Hz, 1H), 7.33 (t, 1H), 7.44 (t, 1H), 7.57 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.33, 2H), 7.69 (m, 2H), 8.06 (s, 1H), 8.38 (d, J=8.59 Hz, 1H), 12.07 (s, broad, 1H).

Workup

  1. temperatureto warm to room temperature
  2. customMost of the THF is removed under reduced pressure
  3. extractionthe mixture is extracted with ethyl acetate
  4. dry with materialThe organic phase is dried over sodium sulfate
  5. customthe solvent is removed under reduced pressure

Sources & evidence

ORD record
ord-823ded98c64f44528db5f009b4dc1a6a
Source dataset
uspto-grants-2015_03
Patent number
US08993631B2

Reaction notes

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