1-Hydroxybenzotriazole → 2-{(1R,3R)-1-[(2S,3S)-2-tert-Butoxycarbonylamino-3-methyl-pentanoyloxy]-4-methyl-3-methylamino-pentyl}-thiazole-4-carboxylic acid ethyl ester

HRID 446186Notes

Reaction equation

HRID 446186 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([OH:19])[CH2:12][C@@H:13]([NH:17][CH3:18])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:31]([C:36](O)=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([O:19][C:36](=[O:37])[C@@H:31]([NH:30][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[C@@H:32]([CH3:33])[CH2:34][CH3:35])[CH2:12][C@@H:13]([NH:17][CH3:18])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2]

Participants

5

Reactant 3

HCID 757711-HydroxybenzotriazoleHCID 2724762tert-Butoxycarbonyl-L-isoleucineHCID 24906126Ethyl 2-((1R,3R)-1-hydroxy-4-methyl-3-(methylamino)pentyl)thiazole-4-carboxylate

Product 1

HCID 249061272-{(1R,3R)-1-[(2S,3S)-2-tert-Butoxycarbonylamino-3-methyl-pentanoyloxy]-4-methyl-3-methylamino-pentyl}-thiazole-4-carboxylic acid ethyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A 0.1 M solution of N-methyl tubuvaline ethyl ester 35 (0.305 g, 1.06 mmol), 1-hydroxybenzotriazole (HOBt) (0.146 g, 1.08 mmol), and Boc-Ile-OH (0.267 g, 1.11 mmol) in CH2Cl2 (10.6 mL) was cooled in a salted ice-water bath. PS-CCD (1.38 mmol/g, 0.920 g, 1.27 mmol) was added with stirring, and the bath was warmed to rt. Stirring was continued for 14 h, the solution was filtered, and the resin was washed with CH2Cl2. The filtrate was then concentrated, diluted with EtOAc, and washed once with sat. NaHCO3 (aq). The aqueous fraction was back-extracted twice with EtOAc, and the combined organic fractions were dried with Na2SO4, filtered, and concentrated to afford intermediate 36, which was taken on without further purification.

Workup

  1. additionPS-CCD (1.38 mmol/g, 0.920 g, 1.27 mmol) was added
  2. stirringStirring
  3. filtrationthe solution was filtered
  4. washthe resin was washed with CH2Cl2
  5. concentrationThe filtrate was then concentrated
  6. additiondiluted with EtOAc
  7. washwashed once with sat. NaHCO3 (aq)
  8. extractionThe aqueous fraction was back-extracted twice with EtOAc
  9. dry with materialthe combined organic fractions were dried with Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-a17e76c38193417a80a97c58ec57a7fe
Source dataset
uspto-grants-2013_07
Patent number
US08476451B2

Reaction notes

Loading…