1,2-Dichloroethane → HCID 69655581, compound

HRID 857765Notes

Reaction equation

HRID 857765 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH:16]([CH3:18])[CH3:17])[C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)=[C:24]([CH:34]=1)[CH2:25][NH:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CC#N.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH:16]([CH3:18])[CH3:17])[C@H:9]1[C:10]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27]([NH:26][CH2:25][C:24]1[CH:34]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=1[N:35]1[CH:39]=[N:38][N:37]=[N:36]1)=[O:33])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 181649HOAtHCID 69655818N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamideHCID 69656055HCID 69656055, compound

Product 1

HCID 69655581HCID 69655581, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent2×

Procedure

1-(tert-Butoxycarbonyl)-3-isopropylprolyl-N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide was prepared from 1-(tert-butoxycarbonyl)-3-isopropylproline (from the previous step, 252 mg, 0.98 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 300 mg, 0.98 mmol, 1.0 equiv), EDC (282 mg, 1.47 mmol, 1.5 equiv) and HOAt (67 mg, 0.49 mmol, 0.5 equiv) in DMF (1 mL) essentially according to the procedure described in Example 39, Step D. Reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the four separate diastereomers as clear oils. Each diastereomer was then dissolved in 2:1 CH2Cl2/TFA (3 mL) and stirred for 1 h. All reactions were concentrated to oils. Purification of each by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the diastereomers as clear oils. Diastereomer A (most polar): 1H NMR (400 MHz, CD3OD): δ 9.54 (s, 1 H), 7.76 (d, J=2.0 Hz, 1 H), 7.55 (dd, J=2.0, 8.4 Hz, 1 H), 7.49 (d, J=8.4 Hz, 1 H), 4.49 (d, J=4.0 Hz, 1 H), 4.44–4.40 (m, 1 H), 4.33 (d, J=16.0 Hz, 1 H), 4.15 (d, J=15.6 Hz, 1 H), 3.80–3.75 (m, 1 H), 3.61–3.49 (m, 2 H), 3.41–3.35 (m, 1 H), 2.44–2.38 (m, 1 H), 2.30–2.22 (m, 1 H), 2.13–2.09 (m, 1 H), 2.04–1.93 (m, 3 H), 1.91–1.82 (m, 1 H), 1.81–1.73 (m, 1 H), 1.06 (d, J=6.8 Hz, 3 H), 1.01 (d, J=6.4 Hz, 3 H). HRMS (APCI) M+H: calculated for (C21H28N7O2Cl)+ 446.2066, found 446.2055. Diastereomer B: 1H NMR (400 MHz, CD3OD): δ 9.57 (s, 1 H), 8.61 (t, J=5.6 Hz, 1 H), 7.78 (d, J=2.4 Hz, 1 H), 7.54 (dd, J=2.4, 8.4 Hz, 1 H), 7.49 (d, J=8.4 Hz, 1 H), 4.60 (d, J=8.4 Hz, 1 H), 4.45–4.41 (m, 1 H), 4.32 (dd, J=6.0, 16.0 Hz, 1 H), 4.11 (dd, J=5.2, 16.0 Hz, 1 H), 3.81–3.77 (m, 1 H), 3.62–3.50 (m, 2 H), 3.36–3.30 (m, 1 H), 2.48–2.45 (m, 1 H), 2.26–2.11 (m, 4 H), 2.01–1.87 (m, 3 H), 0.97 (d, J=6.4 Hz, 3 H), 0.81 (d, J=6.4 Hz, 3 H). HRMS (APCI) M+H: calculated for (C21H28N7O2Cl)+ 446.2066, found 446.2057. Diastereomer C: 1H NMR (400 MHz, CD3OD): δ 9.53 (s, 1 H), 7.73 (d, J=2.4 Hz, 1 H), 7.57 (dd, J=2.4, 8.4 Hz, 1 H), 7.50 (d, J=8.4 Hz, 1 H), 4.37–4.34 (m, 2 H), 4.31 (d, J=15.6 Hz, 1 H), 4.19 (d, 16.0 Hz, 1 H), 3.80–3.76 (m, 1 H), 3.62–3.56 (m, 1 H), 3.48–3.43 (m, 1 H), 3.41–3.34 (m, 2 H), 2.37–2.34 (m, 1 H), 2.24–2.19 (m, 1 H), 2.12–1.88 (m, 4 H), 1.79–1.73 (m, 1 H), 1.02 (dd, J=6.8, 8.4 Hz, 6 H). HRMS (APCI) M+H: calculated for (C21H28N7O2Cl)+ 446.2066, found 446.2053. Diastereomer D (least polar): 1H NMR (400 MHz, CD3OD): δ 9.53 (s, 1 H), 7.76 (d, J=2.0 Hz, 1 H), 7.56 (dd, J=2.4, 8.4 Hz, 1 H), 7.50 (d, J=8.4 Hz, 1 H), 4.56 (d, J=7.6 Hz, 1 H), 4.36–4.31 (m, 2 H), 4.18 (d, J=15.6 Hz, 1 H), 3.80–3.76 (m, 1 H), 3.64–3.58 (m, 1 H), 3.53–3.48 (m, 1 H), 3.33–3.28 (m, 2 H), 2.53–2.49 (m, 1 H), 2.52–2.17 (m, 2 H), 2.13–2.06 (m, 1 H), 2.02–1.89 (m, 2 H), 1.74–1.69 (m, 1 H), 0.96 (d, J=6.8 Hz, 3 H), 0.95 (d, J=6.8 Hz, 3 H). HRMS (APCI) M+H: calculated for (C21H28N7O2Cl)+ 446.2066, found 446.2054.

Workup

  1. customseparate diastereomers as clear oils
  2. dissolutionEach diastereomer was then dissolved in 2:1 CH2Cl2/TFA (3 mL)
  3. concentrationAll reactions were concentrated to oils
  4. customPurification of each by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1% TFA)]
  5. customafforded the diastereomers as clear oils

Sources & evidence

ORD record
ord-3eafa79c1a06499e9361037a63cd96ea
Source dataset
uspto-grants-2006_12
Patent number
US07144899B2

Reaction notes

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