Triethylamine → 2-oxo-2-phenylethyl (3R,4S)-3-azido-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylate

HRID 61401Notes

Reaction equation

HRID 61401 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[N:48]([C@:51]1([C:68]([O:70][CH2:71][C:72](=[O:79])[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:69])[C@@H:55]([CH2:56][CH2:57][CH2:58][B:59]2[O:63][C:62]([CH3:65])([CH3:64])[C:61]([CH3:67])([CH3:66])[O:60]2)[CH2:54][NH:53][CH2:52]1)=[N+:49]=[N-:50].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[N:48]([C@:51]1([C:68]([O:70][CH2:71][C:72](=[O:79])[C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:69])[C@@H:55]([CH2:56][CH2:57][CH2:58][B:59]2[O:60][C:61]([CH3:67])([CH3:66])[C:62]([CH3:65])([CH3:64])[O:63]2)[CH2:54][N:53]([C:21](=[O:22])[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:52]1)=[N+:49]=[N-:50]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 7021025N-((1,1-Dimethylethoxy)carbonyl)-4-(trifluoromethyl)-L-phenylalanineHCID 131734493HCID 131734493, compound

Product 1

HCID 866657932-oxo-2-phenylethyl (3R,4S)-3-azido-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylateYield 60%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent3×

Procedure

A mixture of N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanine (268 mg, 0.804 mmol), 1-hydroxybenzotriazole hydrate (123 mg, 0.804 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (154 mg, 0.804 mmol) in dry methylene chloride (10 mL) and DMF (3 mL) was stirred at room temperature. After 1 h, a second solution of racemic 2-oxo-2-phenylethyl (3R,4S)-3-azido-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylate hydrochloride (350 mg, 0.73 mmol) in methylene chloride (3.5 mL) was added, followed immediately by Et3N (204 uL, 1.46 mmol), and the resulting homogeneous mixture was stirred at room temperature for 3.5 h. Once complete, the mixture was diluted with dichloromethane (8 mL), washed successively with water (2×20 mL), saturated aqueous NaHCO3 (2×20 mL) and saturated aqueous sodium chloride, dried over Na2SO4 and concentrated. Purification by silica gel chromatography (90 g column, 15-35% ethyl acetate in hexanes) gave 2-oxo-2-phenylethyl (3R,4S)-3-azido-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylate (233 mg, ˜60% purity) as a white foam which was used without further purification. LC-MS ESI+MS found for C37H47BF3N5O8 m/z 758.3 (M+H), 780.3 (M+Na); ESI−MS m/z 756.5 (M−H).

Workup

  1. stirringthe resulting homogeneous mixture was stirred at room temperature for 3.5 h
  2. washwashed successively with water (2×20 mL), saturated aqueous NaHCO3 (2×20 mL) and saturated aqueous sodium chloride
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customPurification by silica gel chromatography (90 g column, 15-35% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-d7769027eaee4b8bba14277128aded74
Source dataset
uspto-grants-2016_09
Patent number
US09440995B2

Reaction notes

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