Acetic Acid → Di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]imidodicarbonate

HRID 20152Notes

Reaction equation

HRID 20152 reaction equation
[C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:9]([C:23]([OH:25])=O)[CH2:10][CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]([C:35]1[S:36][CH:37]=[CH:38][N:39]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCCl.C(=O)(O)[O-].[Na+].ClCCl>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:13][N:14]([CH2:33][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[C:23](=[O:25])[C@H:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:10][CH2:11]1

Participants

10

Reactant 6

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 27349031,3-Thiazole-2-carbaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 67526479(5S)-N2,N2-Bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine

Product 1

HCID 21114342Di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]imidodicarbonateYield 56.3%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolvent2×HCID 6344DichloromethaneSolventHCID 516892Sodium BicarbonateSolvent2×

Procedure

A solution of (5S)—N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.871 g, 1.90 mmol), 2-formylthiazole (0.183 g, 1.62 mmol) and acetic acid (0.137 g, 2.28 mmol) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.604 g, 2.85 mmol) was added and the reaction stirred overnight. The reaction was diluted with saturated aqueous sodium bicarbonate, the layers separated, and the aqueous phase extracted with DCM (2×). The organic washes were combined, dried over magnesium sulfate, and concentrated. This residue was diluted with dichloromethane (20 mL) and EDC (0.569 g, 2.97 mmol), HOAT (0.401 g, 2.97 mmol) were added followed by diisopropylethylamine (1.04 mL, 5.94 mmol). After stirring overnight, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (0%→40% EtOAc/hexanes) to give the title compound (0.49 g). MS 538.0 (M+1).) 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=3.5 Hz, 1H), 7.37 (d, J=3.4 Hz, 1H), 7.0 (m, 2H), 6.8 (m, 1H), 5.20 (d, J=10.3 Hz, 1H), 5.03 (d, J=15.5 Hz, 1H), 4.96 (d, J=15.5 Hz, 1H), 3.84 (dd, J=10.3, 15.2 Hz, 1H), 3.48 (d, J=15.5 Hz, 1H), 2.94 (dd, J=11.0, 11.0 Hz, 1H), 2.50 (dd, 1H), 2.0 (m, 4H), 1.5 (s, 18H).

Workup

  1. customthe layers separated
  2. extractionthe aqueous phase extracted with DCM (2×)
  3. dry with materialdried over magnesium sulfate
  4. concentrationconcentrated
  5. additionwere added
  6. stirringAfter stirring overnight
  7. customthe layers separated
  8. dry with materialThe combined organics were dried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customthe residue purified by silica gel chromatography (0%→40% EtOAc/hexanes)

Sources & evidence

ORD record
ord-07222f0e0e0145758487fd8832cc98bd
Source dataset
uspto-grants-2010_06
Patent number
US07745427B2

Reaction notes

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