Benzyl chloroformate → HCID 86609085, compound

HRID 2223815Notes

Reaction equation

HRID 2223815 reaction equation
Cl[C:2](=[O:19])[CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(OC(N1CCC[C@H]1CC(O)=O)=O)C1C=CC=CC=1.[OH-].[Na+].ClC(OCC1C=CC=CC=1)=O.C(Cl)(=O)C(Cl)=O.[CH3:58][C:59]1[N:60]([C:65]2[CH:66]=[C:67]3[C:71](=[CH:72][CH:73]=2)[NH:70][CH:69]=[C:68]3C([C@H]2CCCN2C(OCC2C=CC=CC=2)=O)=O)[C:61]([CH3:64])=[CH:62][CH:63]=1>CN(C=O)C.ClCCl.CCOCC>[CH3:58][C:59]1[N:60]([C:65]2[CH:66]=[C:67]3[C:71](=[CH:72][CH:73]=2)[NH:70][CH:69]=[C:68]3[C:2](=[O:19])[CH2:3][C@@H:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:61]([CH3:64])=[CH:62][CH:63]=1

Participants

10

Reactant 6

HCID 10387Benzyl chloroformateHCID 14798Sodium Hydroxide2×HCID 65578Oxalyl chlorideHCID 10048938HCID 10048938, compoundHCID 10869111(S)-1-Cbz-2-pyrrolidineacetic acid2×HCID 59715779HCID 59715779, compound

Product 1

HCID 86609085HCID 86609085, compound

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Procedure

See Example 26 for experimental details. Preparation of (S)-benzyl 2-(2-chloro-2-oxoethyl)pyrrolidine-1-carboxylate (143): i) Formation of (S)-2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)acetic acid: To a reaction vial fitted with a magnetic stirbar was added L-B-Homoproline hydrochloride (250 mg, 1.51 mmol) as an off-white solid. The vessel was closed with a septum and cap, and placed in an ice-water bath. 2 N Sodium hydroxide solution (1.45 mL) was added, and the salt dissolved to give a brown solution. The septum was pierced with 2 syringes, one containg benzyl chloroformate (280 μL, 1.96 mmol), the second with 1.1 mL of 2 N sodium hydroxide (2.20 mmol). A 3rd needle was added to relieve pressure. The two liquids were added alternatively, a little at a time to attempt to maintain a constant pH. After all reagents were added, the reaction was allowed to stir for 2 hours in the icewater bath. The reaction was transferred to a separatory funnel and ether (5 mL) was added. The ether layer was removed, and the aqueous acidified to a pH of 3 by the addition of 1 M aqueous HCl. The aqueous was extracted with ethyl acetate (3×5 mL). The combined organis were washed with brine, dried over sodium sulfate, decanted and concentrated to afford a yellow oil. Yield: 264 mg (66%) 1H NMR (DMSO-d6) δ 12.22 (bs, 1H), 7.35 (m, 5H), 5.07 (s, 2H), 4.05-4.02 (t, J=7.2 Hz, 2H), 3.32-2.63 (m, 1H), 2.31-2.28 (m, 1H), 1.99 (s, 2H), 1.90-1.68 (m, 4H), 1.20-1.15 (t, J=7.2 Hz, 1H). ii) To an argon purged round bottom flask fitted with a magnetic stirbar was added (S)-2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)acetic acid (235 mg, 0.893 mmol) followed by anhydrous dichloromethane (5 mL). The reaction was treated with anhydrous DMF (2 drops ˜5 μL). The flow of argon was stopped, and the reaction vessel fitted with a balloon. Oxalyl chloride (0.12 mL, 1.38 mmol) was added in two portions, resulting in effervescence. The reaction was stirred at room temperature for 3 hours, before being concentrated to dryness under reduced pressure and dried overnight under high vacuum. Preparation of (S)-benzyl 2-(2-(5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indol-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (144): In a similar fashion to the synthesis of compound 94, Example 26, compound 144 was isolated as a yellow solid (240 mg, 59%).

Workup

  1. customvial fitted with a magnetic stirbar
  2. customThe vessel was closed with a septum
  3. customcap
  4. customplaced in an ice-water bath
  5. dissolutionthe salt dissolved
  6. customto give a brown solution
  7. additionA 3rd needle was added
  8. additionThe two liquids were added alternatively
  9. temperatureto maintain a constant pH
  10. additionAfter all reagents were added
  11. customThe reaction was transferred to a separatory funnel
  12. customThe ether layer was removed
  13. additionthe aqueous acidified to a pH of 3 by the addition of 1 M aqueous HCl
  14. extractionThe aqueous was extracted with ethyl acetate (3×5 mL)
  15. washThe combined organis were washed with brine
  16. dry with materialdried over sodium sulfate
  17. customdecanted
  18. concentrationconcentrated
  19. customto afford a yellow oil
  20. customthe reaction vessel fitted with a balloon
  21. customresulting in effervescence
  22. stirringThe reaction was stirred at room temperature for 3 hours
  23. concentrationbefore being concentrated to dryness under reduced pressure
  24. customdried overnight under high vacuum
  25. customPreparation of (S)-benzyl 2-(2-(5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indol-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (144)

Sources & evidence

ORD record
ord-4e8b71d7bd9c424786992099a538712e
Source dataset
uspto-grants-2008_05
Patent number
US07375219B2

Reaction notes

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