Triethylamine → ethyl 3-amino-5({[(1S)-2-(dimethylamino)-1-phenylethyl]hydroxy}carbonyl)-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate

HRID 41363Notes

Reaction equation

HRID 41363 reaction equation
[CH3:1][N:2]([CH3:12])[CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].C(N(CC)CC)C.Cl[C:21](OC1C=CC([N+]([O-])=O)=CC=1)=[O:22].CCN(C(C)C)C(C)C.Cl.Cl.[NH2:44][C:45]1[C:46]2[CH2:57][NH:56][C:55]([CH3:59])([CH3:58])[C:47]=2[N:48]([C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:49]=1>ClCCCl.ClCCl>[NH2:44][C:45]1[C:46]2[CH2:57][N:56]([C:21]([O:5][C@@H:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3][N:2]([CH3:12])[CH3:1])=[O:22])[C:55]([CH3:58])([CH3:59])[C:47]=2[N:48]([C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:49]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 10921572(S)-2-Dimethylamino-1-phenylethanolHCID 67008245ethyl 3-amino-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate dihydrochloride

Product 1

HCID 67008599ethyl 3-amino-5({[(1S)-2-(dimethylamino)-1-phenylethyl]hydroxy}carbonyl)-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylateYield 20%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
50 °C

Procedure

To a stirred solution of (S)-2-dimethylamino-1-phenyl-ethanol (68b, 21.50 g, 130.0 mmol) in 1,2-dichloroethane (500 mL) was added triethylamine (26.30 g, 260.0 mmol) and 4-nitrophenyl chloroformate (68c, 27.00 g, 130.0 mmol) at room temperature under nitrogen. The solution was stirred at 50° C. overnight. A total of 16.8 g (130.0 mmol) of Hünig's base was then added, followed by ethyl 3-amino-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate dihydrochloride salt (54a, 17.90 g, 60.25 mmol). The reaction mixture was stirred at 50° C. for another 12 h. It was diluted with dichloromethane (1.5 L) and washed with water (2×1.0 L) and brine (1.0 L), dried over Na2SO4. Another batch with the exact scale was also carried out. These two batches were combined together during workup. Filtration and evaporation followed by flash chromatography (4.75% MeOH/0.25% NEt3/95% DCM) afforded compound 68e ethyl 3-amino-5({[(1S)-2-(dimethylamino)-1-phenylethyl]hydroxy}carbonyl)-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate as a light-yellow gummy oil (5.00 g, 10%). 1H NMR (CDCl3, a mixture of rotamers, only the chemical shifts of the major form is reported) δ: 1.45 (t, J=7.1 Hz, 3H), 1.63 (s, 3H), 1.72 (s, 3H), 2.29 (s, 3H), 2.36 (s, 3H), 2.55-2.63 (m, 1H), 2.88 (dd, J=13, 8.3 Hz, 1H), 4.29 (q, J=13 Hz, 1H), 4.51 (q, J=7.1 Hz, 2H), 5.44 (d, J=10.7 Hz, 1H), 5.8-5.95 (m, 1H), 7.25-7.42 (m, 5H). LCMS (APCI, M+H+) 416.

Workup

  1. stirringThe reaction mixture was stirred at 50° C. for another 12 h
  2. washwashed with water (2×1.0 L) and brine (1.0 L)
  3. dry with materialdried over Na2SO4
  4. filtrationFiltration and evaporation

Sources & evidence

ORD record
ord-b552941dc0e44361ae1ad57b32657290
Source dataset
uspto-grants-2013_09
Patent number
US08530652B2

Reaction notes

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