Preparation of 1-(Benzyloxycarbonyl) Hexahydro-3-Pyridazine Carboxylic Acid, A Protected Piperazic Acid

References

• Johnston , G. A.R. , Stephanson , A. L. and Twitchin , B. 1977 . J. Pharm. Pharmacol. , 29 : 240
   PubMed Web of Science ®Google Scholar
• Attwood , M. R. , Hassal , C. H. , Krohn , A. , Lawron , G. and Redshaw , S. 1986 . J. Chem. Soc. Parkin Trans. I , : 1011
   Google Scholar
• Davies , C. R. and Davies , J. S. 1976 . Trans. 1 , : 2390
   Google Scholar
• Woodward , R. B. , Bader , F. E. , Bickel , H. , Frey , A. J. and Kierstead , R. W. 1958 . Tetrahedron , 2 : 1 This material was not stable at room temperature but could be stored in a freezer for several weeks
   Web of Science ®Google Scholar
• Mintz , M. J. and Walling , C. 1973 . Organic Syntheses , Collective Volume V : 184 – 187 .
   Google Scholar
• Cookson , R. C. , Guple , S. S. , Stevens , I. O.R. and Watts , C. T. 1971 . Organic Syntheses , 51 : 121 – 127 .
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• Oxidation of 4-phenylurazole with, t-butylhypochlorite was carried out in ethyl acetate. It was desirable to carry out the oxidation in methylene chloride to avoid the solvent change (see experimental section). Oxidation of 4-phenylurazole in methylene chloride with NaOCl or Ca(OCl)2, with or without a phase transfer catalyst afforded a complex mixture of products including the desired PTAD. In no case was the oxidation as clean as when t-butylhypochlorite in ethyl acetate was used.
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• Adam , W. , Arias , L. A. and DeLucchi , O. 1981 . Synthesis , : 543 Attempts to remove the urazole moiety using hydrazine, gave little to no conversion of 5
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• Gilani , S. S. and Triggle , D. J. 1966 . J. Org. Chem. , 31 : 2397
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• The hydrochloride salt was isolated as an oil by vacuum concentrating the reaction mixture to a residue then dissolving the residue in water, extracting with methylene chloride and then acidifying the aqueous layer with 6N HCl. The aqueous layer was vacuum concentrated and the resulting solid treated with methanol, the KCl was filtered off and the filtrate concentrated in vacuo to afford the oily hydrochloride salt
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• Reaction times greater than two hours and/or use of excess benzyl chloroformate led to lower yields. This was attributed to the formation of bis-CBz adducts of the piperazic acid.
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• TLC conditions: 5:10:10:0.3 methanol, acetone, hexanes, acetic acid on silica gel 60. 5, Rf 0.36; 6, Rf 0.69; 1a, Rf 0.02; 1b, Rf 0.54.
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• 1b, 200 MHz1HNMR (DMSO-d6) 7.35 (5H, s), 5.08 (2H, s), 3.81 (1H, br d, J = 12.5), 3.33 (1H, m), 3.10 (1H, m), 2.8–3.6 (2H, br[NH2 +]), 1–87 (1H, m), 1.67 (1H.m) 1.58–1.45 (2H, m).
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• 50 MHz13C NMR (DMSO-d6) 172.56, 154.98, 136.85, 128.24 (2), 127.67, 127.44 (2), 66.15, 57.77, 43.92, 27.00, 22.82. IR (KBr) 2946, 1750, 1695, 1414, 1261, 1192
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• Anal. Caled. for C13H16N2O4:C, 59.08; H, 6.10; N, 10.60. Found: C, 58.96; H, 6.13; N, 10.37.
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