Trifluoroacetic acid → HCID 140652229, compound

HRID 525906Notes

Reaction equation

HRID 525906 reaction equation
C([O:5][C:6](=[O:91])[C:7]([O:10]/[N:11]=[C:12](/[C:78]1[N:79]=[C:80]([NH:83]C(OC(C)(C)C)=O)[S:81][CH:82]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18][CH2:19][C:20]([CH2:37][N+:38]1([CH2:43][C:44]3[C:53](=[O:54])[C:52]4[C:47](=[CH:48][C:49]([O:66]CC5C=CC(OC)=CC=5)=[C:50]([O:56]CC5C=CC(OC)=CC=5)[C:51]=4[Cl:55])[N:46]([CH2:76][CH3:77])[CH:45]=3)[CH2:42][CH2:41][CH2:40][CH2:39]1)=[C:21]2[C:25]([O:27]CC1C=CC(OC)=CC=1)=[O:26])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.C(OC(C)C)(C)C>ClCCl>[NH2:83][C:80]1[S:81][CH:82]=[C:78](/[C:12](=[N:11]/[O:10][C:7]([C:6]([OH:91])=[O:5])([CH3:8])[CH3:9])/[C:13]([NH:15][C@@H:16]2[C:23](=[O:24])[N:22]3[C@@H:17]2[S:18][CH2:19][C:20]([CH2:37][N+:38]2([CH2:43][C:44]4[C:53](=[O:54])[C:52]5[C:47](=[CH:48][C:49]([OH:66])=[C:50]([OH:56])[C:51]=5[Cl:55])[N:46]([CH2:76][CH3:77])[CH:45]=4)[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:21]3[C:25]([O-:27])=[O:26])=[O:14])[N:79]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 7914Diisopropyl EtherHCID 90373385HCID 90373385, compound

Product 1

HCID 140652229HCID 140652229, compoundYield 48.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 1-(((6R,7R)-7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((4-methoxybenzyl)oxy)carbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-1-((5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium (2.668 g, 80% purity, 1.632 mmol) in Dichloromethane (DCM) (15 mL) under N2 at 0° C. was added anisole (1.783 mL, 16.32 mmol), followed by TFA (5.0 mL, 64.9 mmol). The mixture was warmed up to rt and stirred at rt over night. LCMS indicated completion of the deprotection. The mixture was cooled to 0° C. Diisopropyl ether (50 mL) was then added. The mixture was stirred for 10 min and the solid was collected by filtration, and washed twice with diisopropyl ether (2×10 mL). The solid (˜2.0 g) was dissolved in a mixture of CH3CN (10 mL)/water (10 mL)/2M HCl (2.5 mL), HP20SS resin (12 g) was then added. The mixture was concentrated to dryness, and the resin was loaded in a pre-column containing HP20SS resin (15 g), and was then purified by reverse phase Combiflash using C18 column and eluting with 0-30% CH3CN/water to afford (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-((5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (0.66 g, 0.793 mmol, 48.6% yield) as a slightly brown solid. LCMS: (M+H)+: 790.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.50 (s, 3 H) 1.62 (d, J=6.57 Hz, 6 H) 2.12-2.28 (m, 4 H) 3.42-3.63 (m, 6 H) 3.95-4.05 (m, 1 H) 4.07-4.16 (m, 1 H) 4.26-4.40 (m, 3 H) 4.47-4.55 (m, 1 H) 5.30-5.37 (m, 1 H) 5.89-5.97 (m, 1 H) 6.91 (s, 1 H) 7.04-7.10 (m, 1 H) 8.17-8.24 (m, 1 H).

Workup

  1. temperatureThe mixture was cooled to 0° C
  2. stirringThe mixture was stirred for 10 min
  3. filtrationthe solid was collected by filtration
  4. washwashed twice with diisopropyl ether (2×10 mL)
  5. dissolutionThe solid (˜2.0 g) was dissolved in a mixture of CH3CN (10 mL)/water (10 mL)/2M HCl (2.5 mL), HP20SS resin (12 g)
  6. additionwas then added
  7. concentrationThe mixture was concentrated to dryness
  8. additioncontaining HP20SS resin (15 g)
  9. customwas then purified by reverse phase Combiflash
  10. washeluting with 0-30% CH3CN/water

Sources & evidence

ORD record
ord-0e994e27de8c4298a7d63ba824f24608
Source dataset
uspto-grants-2016_05
Patent number
US09340556B2

Reaction notes

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