Toluene → (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile

HRID 642924Notes

Reaction equation

HRID 642924 reaction equation
[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:4]1[CH2:8][CH2:7][N:6]([C:9](=O)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH2:17][CH2:16][C:15]=3[CH:19]=2)[CH2:5]1)#[N:2].C1(C)C=CC=CC=1.[BH4-].[Na+].[B-](F)(F)(F)[O+]1CCCC1.N1CCNCC1>O1CCCC1>[O:18]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:6]3[CH2:7][CH2:8][C@@H:4]([C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:1]#[N:2])[CH2:5]3)=[CH:19][C:15]=2[CH2:16][CH2:17]1

Participants

7

Reactant 5

HCID 1140TolueneHCID 4837PiperazineHCID 4311764Sodium borohydrideHCID 60024333(S)-3-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)acetyl]pyrrolidineHCID 60146129Trifluoro(oxolan-1-ium-1-yl)boranuide

Product 1

HCID 24860221(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a cooled (0° C.) mixture of (S)-3-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)acetyl]pyrrolidine (IV) as a toluene solution (7.43 Kg active, 17.59 moles) and sodium borohydride (0.87 Kg, 23 moles) in tetrahydrofuran (29.7 L) is added boron trifluoride tetrahydrofuran complex (4.31 Kg, 30.81 moles) at such a rate as to maintain the temperature of the reaction below 10° C. The reaction is warmed to ambient temperature and stirred for a further 4 hours. Aqueous piperazine solution is added and the mixture is heated at reflux for 8 hours. The aqueous layer is separated and washed with 1% aqueous sodium chloride solution (22.3 L) at 40° C. The organic layer is concentrated and essentially replaced by isopropyl alcohol at atmospheric pressure to a total volume of about 30 L. The product crystallises on cooling and is collected at 0-5° C. by filtration. (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol and dried under vacuum at 50° C. Yield 6.34 Kg (88%).

Workup

  1. temperatureTo a cooled
  2. temperatureto maintain
  3. customthe temperature of the reaction below 10° C
  4. temperaturethe mixture is heated
  5. temperatureat reflux for 8 hours
  6. customThe aqueous layer is separated
  7. washwashed with 1% aqueous sodium chloride solution (22.3 L) at 40° C
  8. concentrationThe organic layer is concentrated
  9. customThe product crystallises
  10. temperatureon cooling
  11. filtrationis collected at 0-5° C. by filtration
  12. wash(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetonitrile (V) is washed with chilled isopropyl alcohol
  13. customdried under vacuum at 50° C

Sources & evidence

ORD record
ord-f6f13d8d0dfe436a9c556a01f3029c5e
Source dataset
uspto-grants-2010_04
Patent number
US07696357B2

Reaction notes

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