4-Methylmorpholine → Diethyl (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylate

HRID 2037300Notes

Reaction equation

HRID 2037300 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[NH2:33][C@@:34]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][C:38]2([CH2:40][CH2:39]2)[C@@H:37]2[C@H:35]1[C@H:36]2[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([NH:33][C@@:34]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][C:38]2([CH2:40][CH2:39]2)[C@@H:37]2[C@H:35]1[C@H:36]2[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 79724-Methylmorpholine2×HCID 184502-Chloro-4,6-dimethoxy-1,3,5-triazineHCID 85082Tert-butoxycarbonylalanineHCID 86691274Diethyl (1S,2S,5R,6S)-2-aminospiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylate hydrochloride

Product 1

HCID 86691276Diethyl (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylateYield 100%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
22.5 °C

Procedure

Charge tetrahydrofuran (45 mL, 10 volumes) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (3.4 g, 1.2 equivalents) to a reactor followed by N-methylmorpholine (1.96 mL, 1.2 equivalents) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (3.12 g, 1.2 equivalents). Stir the resulting thin slurry between 20-25° C. for at least 3 hours until the reaction is complete by HPLC. Charge diethyl (1S,2S,5R,6S)-2-aminospiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate hydrochloride (4.55 g, 14.81 mmol) in one portion between 20-25° C. followed by N-methylmorpholine (1.63 mL, 1.0 equivalents) over at least 10 minutes keeping the temperature between 20-25° C. Stir the resulting slurry between 20-25° C. for at least 2 hours until the reaction is complete by HPLC. Filter the resulting solids and wash the wet cake with tetrahydrofuran (2×10 mL, 2.2 volumes) to provide the title compound assuming 100% yield. Use the pale amber tetrahydrofuran solution of the title compound without further purification assuming a 100% yield. 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (s, 1H), 6.72 (d, J=7.9, 1H), 4.08-3.92 (m, 5H), 2.42-2.37 (m, 1H), 1.81-1.64 (m, 3H), 1.47 (dd, J=6.6, 3.1, 1H), 1.34 (s, 9H), 1.18-1.08 (m, 9H), 0.66-0.59 (m, 1H), 0.57-0.52 (m, 1H), 0.46-0.36 (m, 2H).

Workup

  1. custombetween 20-25° C
  2. stirringStir the resulting slurry between 20-25° C. for at least 2 hours until the reaction
  3. filtrationFilter the resulting solids
  4. washwash the wet cake with tetrahydrofuran (2×10 mL, 2.2 volumes)

Sources & evidence

ORD record
ord-02ca2bfddc9b4f5985ef1d71df41000f
Source dataset
uspto-grants-2013_11
Patent number
US08575214B2

Reaction notes

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