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Trifluoroacetic acid → (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-1,2-dicarboxyethoxy]iminoacetyl]amino]-3-[[1-[2-(7-hydroxy-1,8-dioxo-3,4-dihydropyrido[1,2-a]pyrazin-2-yl)ethyl]pyrrolidin-1-ium-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

HRID 525857
Notes
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Reaction equation

HRID 525857 reaction equation
C([O:5][C:6](=[O:91])[CH2:7][C@H:8]([O:21]/[N:22]=[C:23](/[C:78]1[N:79]=[C:80]([NH:83]C(OC(C)(C)C)=O)[S:81][CH:82]=1)\[C:24]([NH:26][C@@H:27]1[C:34](=[O:35])[N:33]2[C@@H:28]1[S:29][CH2:30][C:31]([CH2:48][N+:49]1([CH2:54][CH2:55][N:56]3[CH2:61][CH2:60][N:59]4[CH:62]=[C:63]([O:67]CC5C=CC(OC)=CC=5)[C:64](=[O:66])[CH:65]=[C:58]4[C:57]3=[O:77])[CH2:53][CH2:52][CH2:51][CH2:50]1)=[C:32]2[C:36]([O:38]CC1C=CC(OC)=CC=1)=[O:37])=[O:25])[C:9]([O:11]CC1C=CC(OC)=CC=1)=[O:10])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl.O>[NH2:83][C:80]1[S:81][CH:82]=[C:78](/[C:23](=[N:22]/[O:21][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][C:6]([OH:91])=[O:5])/[C:24]([NH:26][C@@H:27]2[C:34](=[O:35])[N:33]3[C@@H:28]2[S:29][CH2:30][C:31]([CH2:48][N+:49]2([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][N:59]5[CH:62]=[C:63]([OH:67])[C:64](=[O:66])[CH:65]=[C:58]5[C:57]4=[O:77])[CH2:53][CH2:52][CH2:51][CH2:50]2)=[C:32]3[C:36]([O-:38])=[O:37])=[O:25])[N:79]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acid2×HCID 7519AnisoleHCID 7914Diisopropyl EtherHCID 894959264-O-tert-butyl 1-O-[(4-methoxyphenyl)methyl] (2S)-2-[(Z)-[2-[[(6R,7R)-2-[(4-methoxyphenyl)methoxycarbonyl]-3-[[1-[2-[7-[(4-methoxyphenyl)methoxy]-1,8-dioxo-3,4-dihydropyrido[1,2-a]pyrazin-2-yl]ethyl]pyrrolidin-1-ium-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl]amino]-1-[2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-oxoethylidene]amino]oxybutanedioate

Product 1

HCID 89488636(6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1S)-1,2-dicarboxyethoxy]iminoacetyl]amino]-3-[[1-[2-(7-hydroxy-1,8-dioxo-3,4-dihydropyrido[1,2-a]pyrazin-2-yl)ethyl]pyrrolidin-1-ium-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateYield 21.92%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 1-(((6R,7R)-7-((Z)-2-((((S)-4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-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-(2-(7-((4-methoxybenzyl)oxy)-1,8-dioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2(8H)-yl)ethyl)pyrrolidin-1-ium (1.05 g, 0.812 mmol) in dichloromethane (15 mL) stirred under nitrogen at room temperature was added neat anisole (0.887 mL, 8.12 mmol) in one charge. The reaction mixture was stirred for one minute and trifluoroacetic acid (0.626 mL, 8.12 mmol) was then added. The reaction was allowed to stir at room temperature overnight and another 10 eq trifluoroacetic acid (0.626 mL, 8.12 mmol) was added and the reaction was allowed to stir for another 24 h. Diisopropyl ether (20 mL) and water (4 mL) were added and the suspension was allowed to stir for 5 min. then decanted off the supernate from the solid mass. The solid was dissolved in acetonitrile (10 mL), water (10 mL) and 2N hydrochloric acid (2.5 mL), absorbed onto HP20SS resin, and purified by dual HP20SS plug column and 26 g C18 column eluting with 0-20% acetonitrile in water. The fractions containing pure desired compound were collected and lyophilized to give (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((S)-1,2-dicarboxyethoxy)imino)acetamido)-3-((1-(2-(7-hydroxy-1,8-dioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2(8H)-yl)ethyl)pyrrolidin-1-ium-1-yl)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (138 mg, 0.178 mmol, 21.92% yield) as an off white solid. LCMS: (M+H)+: 775.4. 1H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 2.13 (br. s., 4 H) 2.54-2.71 (m, 2 H) 3.54 (br. s., 8 H) 3.74-3.87 (m, 8 H) 4.04 (br. s., 2 H) 4.27 (br. s., 2 H) 4.85 (br. s., 1 H) 5.23 (d, J=4.80 Hz, 1 H) 5.70 (d, J=4.80 Hz, 1 H) 6.90 (s, 1 H) 7.11 (s, 1 H) 7.57 (s, 1 H).

Workup

  1. additioncharge
  2. stirringto stir at room temperature overnight
  3. stirringto stir for another 24 h
  4. stirringto stir for 5 min.
  5. customthen decanted off the supernate from the solid mass
  6. dissolutionThe solid was dissolved in acetonitrile (10 mL)
  7. customwater (10 mL) and 2N hydrochloric acid (2.5 mL), absorbed onto HP20SS resin
  8. custompurified by dual HP20SS plug column and 26 g C18 column
  9. washeluting with 0-20% acetonitrile in water
  10. additionThe fractions containing pure desired compound
  11. customwere collected

Sources & evidence

ORD record
ord-65783fcefe4c48f7ae5e4491c8e57776
Source dataset
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09340556B2

Reaction notes

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