Ethyl acetate hexane acetic acid → 1-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline

HRID 903462Notes

Reaction equation

HRID 903462 reaction equation
BrC(C(=O)C1C=CC=CC=1F)C(C)C(N1CCC[C@H]1C(O)=O)=O.Br[CH:25]([C:38](=[O:46])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1)[CH:26]([CH3:37])[C:27]([N:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32])=[O:28].[C:47]([O-:50])(=[S:49])[CH3:48].[K+].C(OCC)(=O)C.CCCCCC.C(O)(=O)C>C(O)C>[C:47]([S:49][CH:25]([C:38](=[O:46])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1)[CH:26]([CH3:37])[C:27]([N:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32])=[O:28])(=[O:50])[CH3:48]

Participants

6

Reactant 4

HCID 21901998Ethyl acetate hexane acetic acidHCID 23670855Potassium ethanethioate2×HCID 53775156HCID 53775156, compoundHCID 54029099HCID 54029099, compound

Product 1

HCID 542170881-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Procedure

As described in Example 55, 4.0 g. of (S)-1-[3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline (isomer A); m.p. 182°-185° C. is brominated to give the bromo derivative of isomer A [mixture of [S-(R*,S*)]-1-[3-bromo-3-(fluorobenzoyl)-2-methylpropionyl]-L-proline and [S-(R*,R*)]-1-[3-bromo-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline]. Separation of the mixture by chromatography on a prep LC/500 column with hexane-ethyl acetate-acetic acid (75:25:2) as solvent gives 1.68 g. of pure diastereomer labelled X and 0.74 g. of pure diastereomer labelled Y. Reaction of diastereomer labelled X with potassium thioacetate in ethanol for 4 days gives the products of the Example (mixture of diastereomers). Reaction of diastereomer labelled Y with potassium thioacetate in ethanol for 4 days gives the products of the Example (mixture of diastereomers). Chromatography of the mixture on a silica gel column with ethyl acetate-hexane-acetic acid (5:5:0.2) separates the diastereomers to give [S-(R*,S*)]-1-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl] -L-proline, m.p. 158°-159° C.; [α]D +252°±3(c, 0.318 ethanol) and [S-(R*,R*)]-1-[3 -acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline as a white glass, [α]D -147°±1(c, 0.834 ethanol).

Workup

  1. customSeparation of the mixture by chromatography on a prep LC/500 column with hexane-ethyl acetate-acetic acid (75:25:2) as solvent
  2. customgives 1.68 g
  3. customReaction of diastereomer
  4. customfor 4 days
  5. customgives
  6. customReaction of diastereomer
  7. customfor 4 days
  8. customgives

Sources & evidence

ORD record
ord-6a35b7c2283e493bb514ac097dcfe5e1
Source dataset
uspto-grants-1980_10
Patent number
US04226775

Reaction notes

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