Diisopropylethylamine → ((3E)-4-(N-((1R)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester

HRID 366124Notes

Reaction equation

HRID 366124 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][N:41]1[C:50](=[O:65])[C@H:51]([NH:63][CH3:64])[CH2:52][C:53]1[CH:62]=[CH:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:63]([C@H:51]([CH2:52][C:53]1[CH:62]=[CH:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1)[C:50]([N:41]1[CH2:42][CH2:43][C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:65])[CH3:64])([CH3:2])([CH3:3])[CH3:4]

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 10783666(2R)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)-1-propanoneHCID 10847814(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid

Product 1

HCID 59965072((3E)-4-(N-((1R)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl esterYield 97.9%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (283 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (5.5 ml) and dichloromethane (6.5 ml). 1-Hydroxy-7-azabenzotriazole (158 mg, 1.16 mmol) was added. The mixture was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (223 mg, 1.16 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)-1-propanone (400 mg, 1.16 mmol) in dichloromethane (4 ml) and ethyldiisopropylamine (0.2 ml, 1.16 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. I was diluted with ethyl acetate (60 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (60 ml). The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane 1:1 as eluent to give 647 mg of ((3E)-4-(N-((1R)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.

Workup

  1. stirringThe reaction mixture was stirred for 16 h, while it
  2. temperaturewas warming up to room temperature
  3. washwashed with 10% aqueous sodium hydrogen sulfate solution (60 ml)
  4. extractionThe aqueous phase was extracted with ethyl acetate (3×50 ml)
  5. washThe combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml)
  6. dry with materialdried over magnesium sulfate
  7. customThe solvent was removed in vacuo
  8. customThe crude product was purified by flash chromatography on silica (80 g)

Sources & evidence

ORD record
ord-f678b00cccd94873aece9ccbc3fd6775
Source dataset
uspto-grants-2000_10
Patent number
US06127354

Reaction notes

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