Dichloromethane → Diphenylmethyl 7beta-Amino-3-(6-nitrobenzothiazol-2-ylthiomethyl)-ceph-3-em-4-carboxylate, hydrochloride

HRID 839193Notes

Reaction equation

HRID 839193 reaction equation
Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27]C=O)[C:25](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[SH:31][C:32]1[S:33][C:34]2[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:35]=2[N:36]=1.P(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)[Cl:54]>CN(C)C=O.C(N(CC)CC)C>[ClH:54].[NH2:27][C@@H:26]1[C:25](=[O:30])[N:7]2[C:8]([C:9]([O:11][CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])=[C:3]([CH2:2][S:31][C:32]3[S:33][C:34]4[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:35]=4[N:36]=3)[CH2:4][S:5][C@H:6]12

Participants

8

Reactant 5

HCID 6344DichloromethaneHCID 24614Phosphorus tribromideHCID 516892Sodium BicarbonateHCID 56977568HCID 56977568, compoundHCID 178418579HCID 178418579, compound

Product 1

HCID 131711115Diphenylmethyl 7beta-Amino-3-(6-nitrobenzothiazol-2-ylthiomethyl)-ceph-3-em-4-carboxylate, hydrochloride

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8471TriethylamineSolvent

Procedure

A solution of diphenylmethyl 3-bromomethyl-7β-formamidoceph-3-em-4-carboxylate, 1β-oxide (10.068g) and 2-mercapto-6-nitrobenzothiazole (4.244g) in dry N,N-dimethylformamide (125ml.) was stirred at 0°; a solution of triethylamine (3.2ml) in N,N-dimethylformamide (25ml) was added, dropwise, over 5 minutes, and stirring continued for a further 2 hours, during which time the temperature was allowed to rise to ca. 23°. The solvent was removed at 40°(2mm.); the residue was partitioned between methylene dichloride (300ml) and water (300ml), and the organic phase washed with 2N-hydrochloric acid, water, and brine and dried and evaporated to a foam (14.35g). A solution of this foam in dry methylene dichloride (200ml) was stirred at -20°, a solution of phosphorus tribromide (2.5ml, ca 1.5 equiv.) in methylene dichloride (25 ml) was added, dropwise, over 5 minutes, and stirring continued for a further 30 minutes at -10 to -15°. The resulting solution was stirred for 30 minutes with saturated sodium bicarbonate (250ml); the organic phase was separated, and washed with saturated sodium bicarbonate and brine and treated with some charcoal. The suspension was filtered through a kieselguhr pad, and the filtrate dried and evaporated to a foam (10.71g). A suspension of this foam in methanol (200ml) was stirred at 0°; phosphorus oxychloride (3.66 ml - 2 equivs.) was added, over 2 minutes, and stirring continued for a further 2 hours at ca. 23°, during which time the solid all dissolved. The solvent was evaporated off; ethyl acetate (100ml) was added, and the resulting suspension evaporated to dryness in vacuo. The residual gum was dissolved in methylene dichloride (100ml); the solution was stirred at 0° and ether (300 ml) was added, over 5 minutes. The precipitate was filtered off, and washed with ether (100 ml), and dried in vacuo to give the hydrochloride as pale-yellow flakes (9.744g, 78%); [α]D23 - 94° (c, 1.0, DMSO); λmax. (EtOH) 328nm. (ε 13,400); τ (DMS0-d6) values include 4.72 (6H and 7-H), 5.10 and 5.57 (3-CH2, q, J 14 Hz.), and 6.10 (2 CH2).

Workup

  1. waitcontinued for a further 2 hours, during which time
  2. customto rise to ca. 23°
  3. customThe solvent was removed at 40°(2mm.)
  4. customthe residue was partitioned between methylene dichloride (300ml) and water (300ml)
  5. washthe organic phase washed with 2N-hydrochloric acid, water, and brine
  6. customdried
  7. customevaporated to a foam (14.35g)
  8. stirringA solution of this foam in dry methylene dichloride (200ml) was stirred at -20°
  9. waitdropwise, over 5 minutes
  10. stirringstirring
  11. waitcontinued for a further 30 minutes at -10 to -15°
  12. customthe organic phase was separated
  13. washwashed with saturated sodium bicarbonate and brine
  14. additiontreated with some charcoal
  15. filtrationThe suspension was filtered through a kieselguhr pad
  16. customthe filtrate dried
  17. customevaporated to a foam (10.71g)
  18. additionA suspension of this foam in methanol (200ml)
  19. stirringwas stirred at 0°
  20. additionphosphorus oxychloride (3.66 ml - 2 equivs.) was added, over 2 minutes
  21. stirringstirring
  22. waitcontinued for a further 2 hours at ca. 23°, during which time
  23. customThe solvent was evaporated off
  24. additionethyl acetate (100ml) was added
  25. customthe resulting suspension evaporated to dryness in vacuo
  26. dissolutionThe residual gum was dissolved in methylene dichloride (100ml)
  27. stirringthe solution was stirred at 0°
  28. additionether (300 ml) was added, over 5 minutes
  29. filtrationThe precipitate was filtered off
  30. washwashed with ether (100 ml)
  31. customdried in vacuo

Sources & evidence

ORD record
ord-83c6ac87d9ad43d991afcb676fa30588
Source dataset
uspto-grants-1978_06
Patent number
US04093803

Reaction notes

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