1-Hydroxybenzotriazole → Tert-butyl[(1r)-1-(2,5-difluorobenzyl)-3-(2-isoquinolin-1-ylhydrazino)-3-oxopropyl]carbamate

HRID 1863956Notes

Reaction equation

HRID 1863956 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:45]([C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1)[NH2:46].C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([NH:46][NH:45][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1)=[O:13])([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 11347588(R)-b-(Boc-amino)-2,5-difluorobenzenebutanoic acid2×HCID 115573331-Hydrazinoisoquinoline2×

Product 1

HCID 131727791Tert-butyl[(1r)-1-(2,5-difluorobenzyl)-3-(2-isoquinolin-1-ylhydrazino)-3-oxopropyl]carbamate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution of 158 mg (0.5 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1), 96 mg (0.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 89 mg (0.63 mmol based on 95% purity) of 1-hydroxybenzotriazole (HOBT) in 4 mL of anhydrous dichloromethane was stirred at room temperature in a stoppered flask. After 15-20 min, this solution was added dropwise by syringe through a septum to a second solution of 95.5 mg (0.6 mmol) of 1-hydrazinoisoquinoline (Intermediate 8) and 0.261 mL (194 mg, 1.5 mmol) of N,N-diisopropylethylamine in 2 mL of anhydrous dichloromethane and 2 mL of anhydrous DMF. Stirring under nitrogen was continued for 4 h. The solution was then concentrated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with more 5% citric acid, then with water, and finally with saturated sodium carbonate aqueous solution. The organic solution was dried over magnesium sulfate, filtered and concentrated. The residue contained the title compound along with some material that had already undergone ring closure. LC-MS 457 (M+1 for title compound), 439 (M+1 for ring-closed product).

Workup

  1. waitwas continued for 4 h
  2. concentrationThe solution was then concentrated under vacuum
  3. customThe residue was partitioned between ethyl acetate and 5% aqueous citric acid solution
  4. washThe organic phase was washed with more 5% citric acid
  5. dry with materialThe organic solution was dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customLC-MS 457 (M+1 for title compound), 439 (M+1 for ring-closed product)

Sources & evidence

ORD record
ord-e3fd1e0d0eb64e428e37be21ef46a633
Source dataset
uspto-grants-2009_12
Patent number
US07625888B2

Reaction notes

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