2-(2-Boc-amino-5-chlorothiazol-4-YL)-2-oxoacetic acid → (2Z)-2-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-[(2S)-1-[(4-methoxyphenyl)methoxy]-4-[(2-methylpropan-2-yl)oxy]-1,4-dioxobutan-2-yl]oxyiminoacetic acid

HRID 525911Notes

Reaction equation

HRID 525911 reaction equation
[NH2:1][O:2][C@@H:3]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].[C:24]([O:28][C:29]([NH:31][C:32]1[S:33][C:34]([Cl:42])=[C:35]([C:37](=O)[C:38]([OH:40])=[O:39])[N:36]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CO>[C:20]([O:19][C:17](=[O:18])[CH2:16][C@H:3]([O:2]/[N:1]=[C:37](/[C:35]1[N:36]=[C:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[S:33][C:34]=1[Cl:42])\[C:38]([OH:40])=[O:39])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5])([CH3:23])([CH3:22])[CH3:21]

Participants

4

Reactant 2

HCID 597314162-(2-Boc-amino-5-chlorothiazol-4-YL)-2-oxoacetic acidHCID 86732775(S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(aminooxy)succinate

Product 1

HCID 90373537(2Z)-2-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-[(2S)-1-[(4-methoxyphenyl)methoxy]-4-[(2-methylpropan-2-yl)oxy]-1,4-dioxobutan-2-yl]oxyiminoacetic acidYield 67.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(aminooxy)succinate (39.7 g, 122 mmol) in Methanol (300 mL) was added a solution of 2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoacetic acid (Example 21b) (34 g, 111 mmol) at 0° C. Then the mixture was allowed to warm up to rt and stirred for 2 h. LCMS indicated completion of the reaction and the product as a mixture of Z/E isomer (19:1). The reaction mixture was concentrated and the residue was purified by reverse phase automatic C18 column chromatography (Combinflash RF, 150 g column, six runs), eluting with Acetonitrile/Water (0-90%) to afford (S,Z)-2-(((4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (46 g, 74.9 mmol, 67.6% yield) as pale yellow solid. LCMS: (M+H)+: 614.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.44 (s, 9 H) 1.55 (s, 9 H) 2.74-2.96 (m, 2 H) 3.78 (s, 3 H) 5.06-5.13 (m, 1 H) 5.17 (s, 2 H) 6.86 (d, J=8.84 Hz, 2 H) 7.32 (d. J=8.59 Hz, 2 H)

Workup

  1. customcompletion of the reaction
  2. additionthe product as a mixture of Z/E isomer (19:1)
  3. concentrationThe reaction mixture was concentrated
  4. customthe residue was purified by reverse phase automatic C18 column chromatography (Combinflash RF, 150 g column, six runs)
  5. washeluting with Acetonitrile/Water (0-90%)

Sources & evidence

ORD record
ord-25cc22f637cd4288853331cf17ae4527
Source dataset
uspto-grants-2016_05
Patent number
US09340556B2

Reaction notes

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