1,2-Dichloroethane → HCID 22956504, compound

HRID 2231076Notes

Reaction equation

HRID 2231076 reaction equation
[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:10](=[O:29])[N:9]1[CH2:30]C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(O[C:52](=[O:68])[NH:53][CH:54]1[CH2:58][C:57](=[O:59])[O:56][CH:55]1[O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.ClCCl.CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:10](=[O:29])[N:9]1[CH2:30][C:52](=[O:68])[NH:53][CH:54]1[CH2:58][C:57](=[O:59])[O:56][CH:55]1[O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

10

Reactant 5

HCID 111,2-DichloroethaneHCID 69860Dimethylbarbituric acidHCID 757711-HydroxybenzotriazoleHCID 18463938HCID 18463938, compoundHCID 22321532(2-Benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester

Product 1

HCID 22956504HCID 22956504, compoundYield 67%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

{2-Benzyl-6-[(isoquinoline-1-carbonyl)-amino]-3,7-dioxo-[1,2]diazepan-1-yl}-acetic acid tert-butyl ester (7a) (115 mg, 0.23 mmol) was stirred in 20% of trifluoroacetic acid (TFA) in dichloromethane (2 mL) overnight. The solution was evaporated to afford {2-benzyl-6-[(isoquinoline-1-carbonyl)-amino]-3,7-dioxo-[1,2]diazepan-1-yl}-acetic acid (8a). 1H-NMR (500 MHz, CDCl3) δ 2.05-2.11 (m, 1H), 2,45-2.50 (m, 1H), 2.72-2.83 (m, 1H), 3.45-3.54 (m, 1H), 4.01-4.06 (d, 1H), 4.59-4.63 (d, 1H), 4.70-4.82 (m, 2H), 4.93-4.98 (d, 1H), 7.28-7.42 (m, 5H), 7.80-8.10 (m, 4H), 8.40-8.52 (m, 2H), 8.85 (d, 1H). The acid (8a) was dissolved in dichloromethane (2 mL) followed by addition of HOBT (77 mg, 0.57 mmol) and EDC (110 mg, 0.57 mmol) and stirred for 30 min. A solution of (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (9, anti diastereomer) (166 mg, 0.57 mmol) in dichloromethane/DMF (3/1 mL), charged with 1,3-dimethylbarbituric acid (DMBA) (90 mg, 0.57 mmol) and Pd(PPh3)4 (66 mg, 0.057 mmol) for 30 min, was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×3), dried over Na2SO4, filtered and evaporated to give a pale yellow solid, that was purified by flash chromatography using dichloromethane/methanol (99.5/0.5 to 98.5/1.5) to afford 97.5 mg (67% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 2.03-2.13 (m, 1H), 2.40-2.43 (d, 1H), 2.55-2.60 (m, 1H), 2.83-2.92 (m, 1H), 3.04-3.10 (q, 1H), 3.28-3.38 (m, 1H), 4.08-4.11 (d, 1H), 4.20-4.24 (d, 1H), 4.38-4.41 (m, 1H), 4.67-4.70 (d, 1H), 4.78-4.87 (m, 2H), 4.91-5.02 (m, 2H), 5.36 (s, 1H), 6.05 (d, 1H), 7.20-7.38 (m, 10H), 7.68-7.78 (m, 2H), 7.80-7.88 (m, 2H), 8.48 (d, 1H), 8.70 (d, 1H), 9.49 (d, 1H). Analytical HPLC: 12.53 min. LC-MS (ES+): m/e=636 (M+H+).

Workup

  1. additionwas added
  2. stirringthe resulting mixture was stirred at room temperature for 16 hours
  3. washwashed with water (50 mL×3)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customto give a pale yellow solid, that
  8. customwas purified by flash chromatography

Sources & evidence

ORD record
ord-513d9e4e4e584f57955dd5eb913bed5a
Source dataset
uspto-grants-2002_07
Patent number
US06426413B1

Reaction notes

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