Water → 2-fluoro-beta(R)-[(triphenylmethyl)oxy]benzenepropionitrile

HRID 1638166Notes

Reaction equation

HRID 1638166 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8](CO)[CH2:9][C:10]#[N:11].C1(C)C=CC=CC=1.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH2:41]>CO.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:41][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][C:10]#[N:11]

Participants

7

Reactant 4

HCID 962Water4×HCID 1140TolueneHCID 6456Trityl chloride2×HCID 109976222-fluoro-beta(R)-(hydroxymethyl)benzenepropionitrile

Product 1

HCID 219677352-fluoro-beta(R)-[(triphenylmethyl)oxy]benzenepropionitrile

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
21 °C

Procedure

A mixture of 64.5 g of 2-fluoro-β(R)-(hydroxymethyl)benzenepropionitrile, 450 mL of toluene, and 106.2 g of triphenylmethyl chloride is stirred at 20-22° C. for 10 minutes to afford a brown solution; 54 g of triethylanine is added rapidly over a period of 10 minutes while maintaining an internal temperature of <30° C. The reaction mixture is stirred at an internal temperature of 35° C., (external temperature: 41° C.) for 24 hours to obtain a light, brown suspension. The tritylation reaction is catalyzed by water. The reaction progress is monitored by HPLC to determine if water addition is required. If after 4 hours, more than about 30% of starting material is left, 1 g of water is added. If after 20 hours, the amount of starting material is still more than 15%, an additional 1 g of water is added. After 24 hours, an additional 17 g of triphenylmethyl chloride and 7 g of triethylamine are added, the resulting suspension is stirred for an additional 24 hours at 35° C. and cooled to room temperature; 58 mL of methanol is added dropwise over 10 minutes, while maintaining an internal temperature of 30-35° C. The reaction mixture is stirred for 40 minutes at an internal temperature of 20-25° C. The mixture is concentrated under reduced pressure (20-50 mbar; bath temperature 45-50° C.) to obtain crude 2-fluoro-β(R)-[(triphenylmethyl)oxy]benzenepropionitrile as a red semi-solid. The semi-solid is suspended in 800 mL of methanol. The slurry is stirred at an internal temperature of 50° C. for 40 minutes, then at 20-22° C. for 30 minutes, and filtered to obtain, after washing the product with methanol and drying it under vacuum (30 mbar) at 45-50° C. for 4 hours or to constant weight, 2-fluoro-β(R)-[(triphenylmethyl)oxy]benzenepropionitrile; chiral purity: >99% ee.

Workup

  1. customto afford a brown solution
  2. addition54 g of triethylanine is added rapidly over a period of 10 minutes
  3. temperaturewhile maintaining an internal temperature of <30° C
  4. stirringThe reaction mixture is stirred at an internal temperature of 35° C., (external temperature: 41° C.) for 24 hours
  5. customto obtain a light, brown suspension
  6. customThe tritylation reaction
  7. waitIf after 4 hours
  8. waitIf after 20 hours
  9. waitAfter 24 hours
  10. stirringthe resulting suspension is stirred for an additional 24 hours at 35° C.
  11. temperaturecooled to room temperature
  12. temperaturewhile maintaining an internal temperature of 30-35° C
  13. stirringThe reaction mixture is stirred for 40 minutes at an internal temperature of 20-25° C
  14. concentrationThe mixture is concentrated under reduced pressure (20-50 mbar; bath temperature 45-50° C.)

Sources & evidence

ORD record
ord-0a9f3b28cf064b888a8f8ca398a5e9e2
Source dataset
uspto-grants-2000_03
Patent number
US06043365

Reaction notes

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