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

HRID 376564Notes

Reaction equation

HRID 376564 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:69](=[O:70])[N:51]2[C:52]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[C:53]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12>CN(C=O)C.N1C=CC=CC=1>[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:17][CH:18]=1)\[C:11]([NH:48][C@@H:49]1[C:69](=[O:70])[N:51]2[C:52]([C:62]([O:64][C:65]([CH3:66])([CH3:68])[CH3:67])=[O:63])=[C:53]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12)=[O:12]

Participants

7

Reactant 4

HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 95660662-(Tritylamino)-alpha-(methoxyimino)-4-thiazoleacetic acid, predominantly syn hydrochlorideHCID 53828043t-butyl (6R,7R)-7amino-3-(tetrahydropyran-2-yl)-ceph-3-em-4-carboxylate

Product 1

HCID 141582271tert-butyl (6R,7R)-7-[[(2Z)-2-methoxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino]-3-(oxan-2-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateYield 62.2%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
-50 °C

Procedure

Mesyl chloride (121mg, 82μl) was added to 2-(Z)-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid hydrochloride (466mg) and N,N-diisopropylethylamine (252mg, 340μl) in dry DMF (10ml) at -50° C. under argon and stirred at -50° C. for 1h. Then t-butyl (6R,7R)-7amino-3-(tetrahydropyran-2-yl)-ceph-3-em-4-carboxylate (Isomer A, 300mg) in dry DMF (5ml) followed by pyridine (70mg, 72μl) were added and reaction mixture left for a further 1h whilst warming to ambient temperature. The reaction mixture was partitioned between ethyl acetate and water, reextracted with ethyl acetate, organic extracts washed with water (x3) and brine, dried, concentrated and flash chromatography (eluting with 30,40,50,60% ethyl acetate in hexane) to afford the title compound as a pale yellow foam (420mg, 62%); vmax (CH2Cl2) 3420, 1784, 1732 (shoulder), 1717, 1685cm-1 ; δH (CDCl3), 1.53 (9H, s) overlapping 1.4-1.7 (4H, m), 1.73-1.94 (2H, m), 3.38-3.58 (3H, m), 3.95-4.00 (1H, m), 4.07 (3H, s), 4.54-4.59 (1H, m), 5.02 (1H, d, J4.8Hz), 5.90 (1H, dd, J4.5, 9.1Hz) 6.74 (1H, s), 6.86 (1H, d, J8.8Hz), 7.04 (1H, s) and 7.30 (15H, s). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (788)].

Workup

  1. additionwere added
  2. customreaction mixture
  3. temperaturewarming to ambient temperature
  4. customThe reaction mixture was partitioned between ethyl acetate and water
  5. washwashed with water (x3) and brine
  6. customdried
  7. concentrationconcentrated
  8. washflash chromatography (eluting with 30,40,50,60% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-04acf7c493b4489980959eb39f5df749
Source dataset
uspto-grants-2000_02
Patent number
US06020329

Reaction notes

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