D-Lactic Acid → (R)-2-hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-one

HRID 2385841Notes

Reaction equation

HRID 2385841 reaction equation
OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:67](O)(=[O:71])[C@@H:68]([CH3:70])[OH:69]>C1COCC1>[OH:69][C@H:68]([CH3:70])[C:67]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:71]

Participants

6

Reactant 4

HCID 61503D-Lactic AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 866523168-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt

Product 1

HCID 58204116(R)-2-hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-oneYield 32%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in THF (3 mL) was added diisopropylethylamine (0.22 mL, 1.26 mmol), HATU (175 mg, 0.46 mmol) and D-(−)-lactic acid (41 mg, 0.46 mmol). The reaction mixture was stirred at RT for 18 hours and then concentrated in vacuo. The resultant residue was partitioned between DCM and an aqueous saturated sodium bicarbonate solution and the organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in DCM) to give a cream solid that was freeze-dried from methanol and water to give 318 as a white solid (59 mg, 32%). LCMS: RT=4.44 min, [M+H]+=440. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1 H, d, J=8.19 Hz), 8.05 (1 H, s), 7.18 (1 H, ddd, J=8.24, 4.14, 1.84 Hz), 7.01 (1 H, s), 5.82-5.72 (1 H, m), 5.04 (1 H, s), 4.65-4.55 (1 H, m), 4.35-4.29 (2 H, m), 4.28-4.17 (2 H, m), 4.11 (1 H, dd, J=13.38, 6.69 Hz), 3.86-3.75 (2 H, m), 3.42-3.36 (2 H, m), 1.50 (6 H, d, J=6.59 Hz), 1.16 (3H, d, J=6.70 Hz)

Workup

  1. concentrationconcentrated in vacuo
  2. customThe resultant residue was partitioned between DCM
  3. washan aqueous saturated sodium bicarbonate solution and the organic layer was washed with water
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customThe resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in DCM)
  7. customto give a cream solid that
  8. dry with materialwas freeze-dried from methanol and water

Sources & evidence

ORD record
ord-8c0a41587d754ee6aea815dffdfb1474
Source dataset
uspto-grants-2012_09
Patent number
US08263633B2

Reaction notes

Loading…