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 1421789Notes

Reaction equation

HRID 1421789 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 (121 mg, 82 μl) was added to 2-(Z)-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid hydrochloride (466 mg) and N,N-diisopropylethylamine (252 mg, 340 μl) in dry DMF (10 ml) at -50° C. under argon and stirred at -50° C. for 1 h. Then t-butyl (6R,7R)-7amino-3-(tetrahydropyran-2-yl)ceph-3-em-4-carboxylate (Isomer A, 300 mg) in dry DMF (5 ml) followed by pyridine (70 mg, 72 μl) were added and reaction mixture left for a further 1 h whilst warming to ambient temperature. The reaction mixture was partitioned between ethyl acetate and water, reextracted with ethyl acetate, organic extracts washed with water (×3) 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 (420 mg, 62%); νmax (CH2Cl2) 3420, 1784, 1732 (shoulder), 1717, 1685 cm-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, J4.8 Hz), 5.90 (1H, dd, J4.5, 9.1 Hz) 6.74 (1H, s), 6.86 (1H, d, J8.8 Hz), 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. waitleft for a further 1 h
  4. temperaturewhilst warming to ambient temperature
  5. customThe reaction mixture was partitioned between ethyl acetate and water
  6. washwashed with water (×3) and brine
  7. customdried
  8. concentrationconcentrated
  9. washflash chromatography (eluting with 30,40,50,60% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-c8dab9bd28814ee283d77140f2865f93
Source dataset
uspto-grants-2000_06
Patent number
US06077952

Reaction notes

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