Pyridine → tert-butyl (6R,7R)-7-[[(2Z)-2-methoxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino]-8-oxo-3-(oxolan-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

HRID 1421785Notes

Reaction equation

HRID 1421785 reaction equation
S(Cl)(C)(=O)=O.Cl.[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)\[C:11](O)=[O:12].C(N(CC)C(C)C)(C)C.[NH2:48][C@@H:49]1[C:68](=[O:69])[N:51]2[C:52]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[C:53]([CH:56]3[CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[S:17][CH:18]=1)\[C:11]([NH:48][C@@H:49]1[C:68](=[O:69])[N:51]2[C:52]([C:61]([O:63][C:64]([CH3:65])([CH3:67])[CH3:66])=[O:62])=[C:53]([CH:56]3[CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12)=[O:12]

Participants

8

Reactant 5

HCID 1049PyridineHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 95660662-(Tritylamino)-alpha-(methoxyimino)-4-thiazoleacetic acid, predominantly syn hydrochlorideHCID 54097811t-Butyl (6R,7R)-7-Amino-3-(tetrahydrofuran-2-yl)ceph-3-em-4-carboxylate

Product 1

HCID 141582269tert-butyl (6R,7R)-7-[[(2Z)-2-methoxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino]-8-oxo-3-(oxolan-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateYield 84%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-30 °C

Procedure

Mesyl chloride (14 μl, 1.8 mmol) was added to 2-(Z)-methoxyimino-2-(2-tritylaminothiazol-4-yl) acetic acid hydrochloride (0.744 g, 1.65 mmol) and N,N-diisopropylethylamine (576 μl, 3.3 mmol) in DMF (5 ml) at -40° C. The reaction mixture was stirred 0.5 h at -30±10° C. then t-butyl (6R,7R)-7-amino-3-(tetrahydrofuran-2-yl)ceph-3-em-4-carboxylate, more mobile diastereoisomer (0.431 g, 1.3 mmol) in DMF (5 ml) followed by pyridine (147 μl, 1.8 mmol) were added. Stirred 1 h without further cooling then diluted with ethyl acetate, washed twice with water and with brine, dried, concentrated and flash chromatographed on silica gel eluting with 30,35 and 40% ethyl acetate in hexane to give the title compound as a foam (0.83 g, 84%); νmax (CH2Cl2) 3396, 3277, 1782, 1732, 1683, 1526, 1248, 1156 and 1051 cm-1 ; δH [(CD3)2SO, 250 MHz] 1.47 (9H, s), 1.55-1.75 (1H, m), 1.8-2.0 (2H, m), 2.05-2.2 (1H, m), 3.44 and 3.50 (2H, ABq, J18.3 Hz), 3.65-3.95 (2H, m), 3.81 (3H, s), 4.6-4.7 (1H, m), 5.14 (1H, d, J4.8 Hz), 5.66 (1H, dd, J4.8, 7.9 Hz), 6.70 (1H, s), 7.2-7.4 (15H, m), 8.88 (1H, s) and 9.54 (1H, d, J7.9 Hz). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (774)].

Workup

  1. additionwere added
  2. stirringStirred 1 h
  3. temperaturewithout further cooling
  4. washwashed twice with water and with brine
  5. customdried
  6. concentrationconcentrated
  7. customflash chromatographed on silica gel eluting with 30,35 and 40% ethyl acetate in hexane

Sources & evidence

ORD record
ord-b60569638fb94da597aa47d49550fe03
Source dataset
uspto-grants-2000_06
Patent number
US06077952

Reaction notes

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