Hydrochloric Acid → Methyl {4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-iodophenyl)-4-oxoazetidin-2-yl]phenoxy}acetate

HRID 1176078Notes

Reaction equation

HRID 1176078 reaction equation
[I:1][C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[CH:9]/[C:10]2[CH:21]=[CH:20][C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[I-].ClC1C=CC=C[N+]=1C.[Si:38]([O:45][C@H:46]([C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[CH2:47][S:48][CH2:49][C:50](O)=[O:51])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:38]([O:45][C@H:46]([C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[CH2:47][S:48][C@H:49]1[C:50](=[O:51])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[C@@H:9]1[C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 1670692-Chloro-1-methylpyridinium iodideHCID 516892Sodium BicarbonateHCID 59326673(R)-2-((2-((Tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)ethyl)thio)acetic acidHCID 178501771HCID 178501771, compound

Product 1

HCID 86628621Methyl {4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-iodophenyl)-4-oxoazetidin-2-yl]phenoxy}acetateYield 62.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

Methyl (4-{(E)-[(4-iodophenyl)imino]methyl}phenoxy)acetate (7.0 g, 17.7 mmol), was placed in a dry 250 ml 3-necked flask under inert atmosphere and dissolved in 100 ml dry DCM. Et3N (5.5 ml, 39.5 mmol) and 2-chloro-1-methylpyridinium iodide (4.2 g, 16.4 mmol) were added. {[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}acetic acid (5.4 g, 15.7 mmol) was dissolved in 50 ml dry DCM and slowly added to the above solution over 7-8 h. The mixture was stirred over night and diluted with 50 ml DCM. HCl (1 M, 100 ml) was added followed by NaHCO3 (5%) until pH was 8-9 of the aqueous. The organic phase was washed with 0.3 M KHSO4, brine until neutral pH, dried with MgSO4 and concentrated. The solid was dissolved in EtOAc:heptane (4:1) and filtered on a short SiO2 column using a gradient from ¼ to 1/1 of EtOAc/heptane as eluent. Concentration yielded 10.65 g. The mixture was purified by preparative HPLC on a C8 column (500×50 mm) using a gradient from 20-100% MeCN in 0.1 M ammonium acetate as eluent. The product fraction was concentrated to yield 7.13 g of the trans diastereomeric mixture. M/z: 720.2 (M−1). The diastereomeric mixture was separated by HPLC on a Chiralpak IA column (4.6×250 mm) using heptane/THF (80/20) as mobile phase. The second eluting diastereomer was collected and the solution concentrated to yield the title compound. 1H-NMR (400 MHz, MeOD) δ: −0.13 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 3.00 (ddd, 2H), 3.81 (s, 3H), 4.02 (d, 1H), 4.76 (s, 2H), 4.84-4.90 (m, 1H), 4.94 (dd, 1H), 6.97-7.06 (m, 4H), 7.09 (d, 2H), 7.30-7.40 (m, 4H), 7.61 (d, 2H).

Workup

  1. additionslowly added to the above solution over 7-8 h
  2. washThe organic phase was washed with 0.3 M KHSO4, brine until neutral pH
  3. dry with materialdried with MgSO4
  4. concentrationconcentrated
  5. dissolutionThe solid was dissolved in EtOAc:heptane (4:1)
  6. filtrationfiltered on a short SiO2 column
  7. concentrationConcentration
  8. customyielded 10.65 g
  9. customThe mixture was purified by preparative HPLC on a C8 column (500×50 mm)
  10. concentrationThe product fraction was concentrated

Sources & evidence

ORD record
ord-f28efad4a60a4e89b93c7223206efcca
Source dataset
uspto-grants-2010_11
Patent number
US07842684B2

Reaction notes

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