Morpholine → Diphenylmethyl alpha-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-alpha-(2-bromo-1-morpholinoethylidene)acetate

HRID 1679231Notes

Reaction equation

HRID 1679231 reaction equation
C(C1SC2C(C(=O)N2C(=C(O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.CS(Cl)(=O)=O.C(C1SC2C(C(=O)N2C(=C(OS(C)(=O)=O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1.[CH2:86]([C:93]1[S:99][CH:98]2[CH:95]([C:96](=[O:125])[N:97]2[C:100](=[C:117]([N:119]2[CH2:124][CH2:123][O:122][CH2:121][CH2:120]2)[CH3:118])[C:101]([O:103][CH:104]([C:111]2[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=2)[C:105]2[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=2)=[O:102])[N:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1.[Br:126]Br>O1CCCC1.N1C=CC=CC=1.C(N(CC)CC)C>[CH2:86]([C:93]1[S:99][CH:98]2[CH:95]([C:96](=[O:125])[N:97]2[C:100](=[C:117]([N:119]2[CH2:120][CH2:121][O:122][CH2:123][CH2:124]2)[CH2:118][Br:126])[C:101]([O:103][CH:104]([C:111]2[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=2)[C:105]2[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=2)=[O:102])[N:94]=1)[C:87]1[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=1

Participants

10

Reactant 6

HCID 8083MorpholineHCID 24408BromineHCID 31297Methanesulfonyl chlorideHCID 70504342Diphenylmethyl α-[1-(4-morpholinyl)ethylidene]-7-oxo-3-(phenylmethyl)-4-thia-2,6-diazabicyclo[3.2.0]hept-2-ene-6-acetateHCID 70547058Diphenylmethyl alpha-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-alpha-(1-hydroxyethylidene)-acetateHCID 88716344Diphenylmethyl alpha-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-alpha-(1-methanesulfonyloxyethylidene)acetate

Product 1

HCID 54517846Diphenylmethyl alpha-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-alpha-(2-bromo-1-morpholinoethylidene)acetateYield 70%

Reagents, catalysts & solvents 3

HCID 1049PyridineSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

One dissolves diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)-acetate (4.84 g) in tetrahydrofuran (60 ml), cools to -20° C, adds triethylamine (2.84 ml) with stirring, adds dropwise methanesulfonyl chloride (0.82 ml) to the yellow solution, and lets react for 30 minutes. To the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.96 ml) at -40° C, stirrs for 3.5 hours, adds pyridine (0.77 ml) to the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -40° C, adds bromine (0.49 ml), and stirs for 30 minutes to give diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl] -α-(2-bromo-1-morpholinoethylidene)acetate. To this solution, one adds dropwise for 3 hours at room temperature 5% hydrochloric acids (72 ml) and methanol (60 ml), stirs, and keeps in a refrigerator overnight. The reaction mixture is evaporated to give residue which is dissolved in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. Purification of the obtained residue (5.83 g) by chromatography over silica gel containing 10% water (150 g) gives from the fraction eluted with a mixture of benzene and ethyl acetate (4:1) diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (3.51 g) by recrystallization from n-hexane. m.p. 93° - 96° C. Yield: 70% IR: νmaxCHCl3 3410, 1782, 1674, cm-1. NMR: δCDCl3 3.20s2H, 3.64s2H, 4.97d(4Hz)1H, 5.66dd(9:4Hz)1H, 6.77d(9Hz)1H, 6.90s1H, 7.35m15H.

Workup

  1. customcools to -20° C
  2. customlets react for 30 minutes
  3. customcools to -40° C

Sources & evidence

ORD record
ord-78b8b02549c74ec0b4eb44fcf6551b36
Source dataset
uspto-grants-1978_03
Patent number
US04079181

Reaction notes

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