Pivaloyl chloride → HCID 59318452, compound

HRID 882546Notes

Reaction equation

HRID 882546 reaction equation
[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[C@@H:10]([CH3:14])[CH2:9]2)=[CH:3][CH:2]=1.C(OC(=O)[C@H](C)C[C@H:27]([N:41]1[C:45](=O)[CH2:44][CH2:43][C:42]1=O)CC1C=CC(C2C=CC=CC=2)=CC=1)C.C([Li])CCC.[C:55](Cl)(=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57]>C1COCC1>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C:11](=[O:13])[C@@H:10]([CH3:14])[CH2:9]2)=[CH:5][CH:6]=1.[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([CH2:27][N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9]2)=[CH:5][CH:6]=1

Participants

7

Reactant 4

HCID 62493Pivaloyl chlorideHCID 59318451Sacubitril Impurity 3HCID 66739220Ethyl (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4-(2,5-dioxopyrrolidin-1-yl)butanoateHCID 178418339Butyllithium

Product 2

HCID 59318452HCID 59318452, compoundHCID 68714094HCID 68714094, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

146 mg (3S,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-b, R1=H) [9:1 diastereoisomer mixture [(2S,4S):(2R,4S)]] is added to 10 ml THF. The mixture is cooled to −78° C. and 381 μl butyllithium (1.59 M in hexane) are added. 81 μl Pivaloyl chloride is then added. After 4 h, the mixture is warmed to room temperature. The mixture is then quenched by the addition of saturated ammonium chloride solution and isopropyl acetate. The phases are separated and the organic phase dried (MgSO4) and then concentrated in vacuo. The residue is purified by column chromatography, by eluting with isopropyl acetate/hexane 3:1 to 1:0 to afford (3S,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (2-b, R1=pivaloyl) and (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one (2-a, R1=pivaloyl). Ratio of diastereoisomers determined by 1H NMR to be 4:1 [(3S,5S):(3R,5S)]. 1H NMR (CDCl3) for (2-b, R1=Piv): 1.09, 1.14 (3H), 1.30 (9H), 1.34 (1H), 2.01-2.66 (3H), 3.03, 3.27 (1H), 4.31, 4.50 (1H), 7.21-7.53 (9H). Diastereomeric ratio is determined by integration of the pairs of signals at [3.03 ppm (2-a, R1=Piv) and 3.27 ppm (2-b, R1=Piv)] or those at [4.31 ppm (2-b, R1=Piv) and 4.50 ppm (2-a, R1=Piv)] from the 1H NMR spectrum. Spectroscopic data for (2-a, R1=Piv) as in Example 5.

Workup

  1. temperaturethe mixture is warmed to room temperature
  2. customThe mixture is then quenched by the addition of saturated ammonium chloride solution and isopropyl acetate
  3. customThe phases are separated
  4. dry with materialthe organic phase dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified by column chromatography
  7. washby eluting with isopropyl acetate/hexane 3:1 to 1:0

Sources & evidence

ORD record
ord-d3a0e8ffe33b4c9b9b81d9885175e6c9
Source dataset
uspto-grants-2015_03
Patent number
US08993785B2

Reaction notes

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