Methanesulfonic Acid → 2-Benzhydryloxycarbonyl-3-(2-methoxycarbonylaminothiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene

HRID 2413425Notes

Reaction equation

HRID 2413425 reaction equation
CS(O)(=O)=O.[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([NH:35][C:36]([O:38][CH3:39])=[O:37])=[N:32][CH:31]=1)[CH:25]([NH:40][C:41](OC(C)(C)C)=[O:42])[C:24]2=[O:48])=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[S:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[CH2:54]C(Cl)=O.C(N(CC)CC)C>C(#N)C.C(Cl)Cl.C(=O)(O)[O-].[Na+].O1CCCC1>[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([NH:35][C:36]([O:38][CH3:39])=[O:37])=[N:32][CH:31]=1)[CH:25]([NH:40][C:41](=[O:42])[CH2:54][C:50]1[S:49][CH:53]=[CH:52][CH:51]=1)[C:24]2=[O:48])=[O:21])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1

Participants

9

Reactant 4

HCID 6395Methanesulfonic AcidHCID 8471TriethylamineHCID 1623622-Thiopheneacetyl chlorideHCID 204304182-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene

Product 1

HCID 204304102-Benzhydryloxycarbonyl-3-(2-methoxycarbonylaminothiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene

Reagents, catalysts & solvents 4

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent3×HCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
4 °C

Procedure

Methanesulphonic acid (6 cc) is added to a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (6.2 g) in acetonitrile (60 cc). After 15 minutes at 20° C., the reaction mixture is diluted with methylene chloride (150 cc) and with a half-saturated sodium bicarbonate solution (200 cc). The aqueous layer is washed with methylene chloride (3×50 cc) and the combined organic phases are washed with distilled water (2×100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. Crude 7-amino-2-benzhydryloxycarbonyl-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.2 g) is obtained and is redissolved in dry tetrahydrofuran (50 cc). The solution obtained is cooled to 4° C. and treated with a solution of (thien-2-yl)-acetyl chloride (1.23 cc) in dry tetrahydrofuran (10 cc) and then with a solution of triethylamine (1.4 cc) in dry tetrahydrofuran (5 cc), in accordance with the working method described in Example 1. The crude product is chromatographed on a column (height: 32 cm, diameter: 6 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with a 45.55 (by volume) mixture of cyclohexane and ethyl acetate, and 100 cc fractions being collected. Fractions 8 to 21, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 2-Benzhydryloxycarbonyl-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (1.91 g) is obtained in the form of a whitish solid.

Workup

  1. washThe aqueous layer is washed with methylene chloride (3×50 cc)
  2. washthe combined organic phases are washed with distilled water (2×100 cc)
  3. dry with materialdried over magnesium sulphate
  4. concentrationconcentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C
  5. customCrude 7-amino-2-benzhydryloxycarbonyl-3-(2-methoxycarbonylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (5.2 g) is obtained
  6. customThe solution obtained
  7. customThe crude product is chromatographed on a column (height: 32 cm, diameter: 6 cm) of silica gel (0.04-0.06 mm), elution
  8. additionbeing carried out under a pressure of 0.4 bar (40 kPa) with a 45.55 (by volume) mixture of cyclohexane and ethyl acetate, and 100 cc fractions
  9. custombeing collected
  10. additionFractions 8 to 21, containing the pure product
  11. concentrationconcentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C

Sources & evidence

ORD record
ord-180a8bff394947b7827262294fbfc484
Source dataset
uspto-grants-1985_01
Patent number
US04496560

Reaction notes

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