N-芳基（烷基）-N'-芳基（烷基）-N"-（糖基硫代亚脲基）磷酰三胺的合成
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摘要
磷酰三胺类化合物具有优良的杀菌、抗病毒作用，其中部分还有抗肿瘤活性。硫脲类化合物有很好的杀菌和抗甲状腺活性等生理作用；硫脲的糖基衍生物也有很强的生理活性，同时它又是一种重要的有机合成中间体。国内曾有报道，利用磷酰二氨基异硫氰酸酯与胺反应合成磷酰三胺，但有关磷酰二氨基肼与糖基异硫氰酸酯反应的研究还未见报道。我们利用磷酰二氨基肼与糖基异硫氰酸酯反应，设计并合成了一系列同时含有磷酰三胺、糖基和硫脲基片段的新化合物共42个：N-芳基(烷基)-N′-芳基(烷基)-N″-(乙酰化糖基硫代亚脲基)磷酰三胺(21个)和N-芳基(烷基)-N′-芳基(烷基)-N″-(糖基硫代亚脲基)磷酰三胺(21个)。
本论文的主要工作是：
1．通过POCl_3的胺解、肼解等反应，制备磷酰二氨基肼；
2．利用亲核加成反应，制备N-芳基(烷基)-N′-芳基(烷基)-N″-(乙酰化糖基硫代亚脲基)磷酰三胺；
3．用糖的脱乙酰化反应制备N-芳基(烷基)-N′-芳基(烷基)-N″-(糖基硫代亚脲基)磷酰三胺。
所有新化合物的结构均经IR、~1H NMR、~(31)P NMR、MS、元素分析进行确证。文中并对代表性化合物的质谱裂解做了诠释。
Phosphorotriamides have strong antibacterial activity and antiviral action, but parts of them have antitumorial activity. Ureas and thioureas not only have strong antibacterial activity, but also have other bioactivities such as antithyroid activity etc. Glycosyl derivatives of thiourea have many strong biological activities. It also is versatile reagent in organic synthesis. There were some reports about preparation the phosphorotriamides through the reaction of phosphorodiamidic isocycanates with amine. There are no reports on the study about the reaction of phosphorodiamidohydrazides with glycosylisothiocycanates. We designed and synthesized a series new compound, which contain the fragments of phosphorotiamide, glycosyl and thioureylene. We have synthesized 42 compounds, they are the derivatives of N-Aryl (Alkyl)-N' -Aryl (Alkyl)-N" -(Acetylglycosyl thioureylene) Phosphoric triamides and N-Aryl (Alkyl)-N' -Aryl (Alkyl)-N" -(Glycosyl thioureylene) Phosphoric triamides.
The major work of the thesis:
1. The preparation of phosphorodiamidohydrazides through animation and hydrazinolysis reaction.
2. Preparation the N-Aryl (Alkyl)-N' -Aryl (Alkyl)-N" -(acetylGlycosyl thioureylene) phosphoric Triamides using the nuclephilic addition reaction.
3. Preparation the N-Aryl (Alkyl)-N ' -Aryl (Alkyl)-N " -(Glycosyl thioureylene) Phosphoric triamides by the action of deacetylation of suger.
Their structures were confirmed by IR, 'H NMR, 31P NMR , MS spectral data and elemental analysis. The mass spectrums of some representative compounds were explained in detail.
本论文的主要工作是：
1．通过POCl_3的胺解、肼解等反应，制备磷酰二氨基肼；
2．利用亲核加成反应，制备N-芳基(烷基)-N′-芳基(烷基)-N″-(乙酰化糖基硫代亚脲基)磷酰三胺；
3．用糖的脱乙酰化反应制备N-芳基(烷基)-N′-芳基(烷基)-N″-(糖基硫代亚脲基)磷酰三胺。
所有新化合物的结构均经IR、~1H NMR、~(31)P NMR、MS、元素分析进行确证。文中并对代表性化合物的质谱裂解做了诠释。
Phosphorotriamides have strong antibacterial activity and antiviral action, but parts of them have antitumorial activity. Ureas and thioureas not only have strong antibacterial activity, but also have other bioactivities such as antithyroid activity etc. Glycosyl derivatives of thiourea have many strong biological activities. It also is versatile reagent in organic synthesis. There were some reports about preparation the phosphorotriamides through the reaction of phosphorodiamidic isocycanates with amine. There are no reports on the study about the reaction of phosphorodiamidohydrazides with glycosylisothiocycanates. We designed and synthesized a series new compound, which contain the fragments of phosphorotiamide, glycosyl and thioureylene. We have synthesized 42 compounds, they are the derivatives of N-Aryl (Alkyl)-N' -Aryl (Alkyl)-N" -(Acetylglycosyl thioureylene) Phosphoric triamides and N-Aryl (Alkyl)-N' -Aryl (Alkyl)-N" -(Glycosyl thioureylene) Phosphoric triamides.
The major work of the thesis:
1. The preparation of phosphorodiamidohydrazides through animation and hydrazinolysis reaction.
2. Preparation the N-Aryl (Alkyl)-N' -Aryl (Alkyl)-N" -(acetylGlycosyl thioureylene) phosphoric Triamides using the nuclephilic addition reaction.
3. Preparation the N-Aryl (Alkyl)-N ' -Aryl (Alkyl)-N " -(Glycosyl thioureylene) Phosphoric triamides by the action of deacetylation of suger.
Their structures were confirmed by IR, 'H NMR, 31P NMR , MS spectral data and elemental analysis. The mass spectrums of some representative compounds were explained in detail.
引文
[1] C.费斯特 K，J.施密特编．有机磷农药的化学[M]．石油化学工业出版社．P147
[2] Schroeder D C. Thioureas[J]. Chem Rev, 1955,181～228
[3] Goodman I. Glycosyl Ureides[J]. Advanced in Carbohydrate Chenistry, 1958, 13:215～236
[4] 林长学，李艳梅，成昌梅，韩波，万荣，冯亚兵，赵玉芬．五配位磷化合物与生物化学[J]，中国科学(B辑)，2002，32(3)：193～203
[5] C.费斯特 K，J.施密特编．有机磷农药的化学[M]．石油化学工业出版社．P212
[6] U.S.P. 2.906.770(1959)
[7] U.s.P. 3.909.556(1959)
[8] U.S.P. 3.146.228(1960)
[9] 陈茹玉，刘纶祖著．有机磷化学研究[M]．高等教育出版社．2001年，70，121
[10] Cremlyn R J W, Dewhurst B B, Wakeford D H. Studies of Organophosphorochloridates. Part Ⅳ. Synthesis of N-Substituted Phosphoramidic Hydrazides, Hydrazones, and Azides[J]. J Chem Soc (C), 1971, 3011～3017
[11] Richard F H, Joseph J K. Carbohydrate-urea-phenol-based adhesives: Transient Formation of mono-and di-D-Glucosylurea[J]. Carbohydr Res, 1989, 189: 103～112
[12] Fischer E. Synthesis of new glucosides[J]. Ber, 1914, 47:1377～1393
[13] Johson T B, Bergmann W. Researches on nitrogenous glycosides. I. The
utilization of glycose isocyanates for glycoside syntheses[J]. J Am Chem Soc, 1932, 54:3360～3363
[14] Johson T B, Bergmann W. Researches on nitrogenous glucosides.Ⅳ. Some new attempts to synthesize pyrimidine glucosides[J]. J Am Chem Soc, 1938, 60: 1916～1918
[15] Haring K M, Johson T B. Researches on nitrogenous glycosides. Ⅱ. The synthesis of glycosido ureides[J]. J Am Chem Soc, 1933, 55:395～402
[16] Jochims J C, Seeliger A. Isocyanato-und Isothiocyanato-derivate des D-Glucosamins[J]. Tetrahedron, 1965, 21: 2611～2616
[17] Valentiny M, Martvon A, Kovac P. Synthesis of nucleoside analogs by additioncyclization reaction of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate[J]. Collect Czech Chem Comm, 1981, 46:2197～2202
[18] Wojtowicz M. Synthesis of the N-D-and N-L-xylopyranosides of 2-amino-5- carbamoyl-1,3,4-oxadiazole[J]. Acta Pol Pharm, 1993, 50(2-3): 275～282(Pol)
[19] Wojtowicz M. Synthesis of N-glucosides of 2-amino-5-(N, N-dimethylaminopropylcarbamoyl)-1,3,4-oxadiazole[J]. Acta Pol Pharm, 1994, 51(1): 81～87
[20] Ogura H, Takahashi H. Studies on nucleoside analogs. ⅩⅩⅣ. Mono-and disaccharide isothiocyanates[J]. Heterocycles, 1982, 17:87～90
[21] Lindhorst T K, Kieburg C. Solvent-Free Preparation of Glycosyl Isothiocyanates[J]. Synthesis, 1995:1228～1230
[22] Jose F, Wenceslao M, Carmen O, Inmaculada R, Colin W. Partially Protected D-Glucopyranosyl Isothiocyanates. Synthesis and Transformations into Thiourea and Heterocyclic Derivatives[J]. Tetrahedron, 1992, 48(31): 6413～6424
[23] Jose Camarasa M, Fernandez-Resa P, Carcia-Lopez M T, De Las Heras,
Federico G, Mendez-Castrillon P P, San Felix A[J]. Synthesis, 1984, (6): 509～510
[24] Klimov E M, Demchenko A V, et al. Reaction of 2-deoxy-α-D-arabino-hexopyranosyl bromides with KSCN [J]. Dokl Akad Nauk, 1993, 331(1): 53～55(Russ)
[25] Peshushkova S G, Povlov A E, et al. Structure and reactivity of glycosides Ⅱ. Synthesis and Structure of O-aryl-N-(2,3,4,6-tetra-O-acetyl-β-D- glucopyranosyl) thiocarbanates[J]. Zh Obshch Khim, 1993, 63(5): 1134～1139(Russ)
[26] Gonzalez M A, Mota J F, et al. Synthesis of 1,3,4,6-Tetra-O-Acetyl-2-[3- alkyl(aryl)-thioureido]-2-deoxy-a-D-Glucopyranoses and their transformation into 2-alkyl(aryl)amino-(1,2-dideoxy-a-D-Glucopyrano) [2,1-d]-2- Thiazolines[J]. Carbohydr Res, 1986, 154:49～62
[27] Fernandez J M G, Mellet C O, Blanco J L J, Jose F. Chiral 2-Thioxotetrahydro-1,3-O, N-heterocycles from Carbohydrates. 2. Stereocontrolled Synthesis of Oxazolidine Pseudo-C-nucleosides and Bicyclic Oxazine-2-thiones[J]. J Org Chem, 1993, 58:5192～5199
[28] Fernandez J M G, Mellet C O, Blanco J L J, Jose F. Enantiopure 2-Thioxotetrahydro-1,3-O, N-heterocycles from Carbohydrates. 3. Enantiopure C-4 Chiral Oxazine-and Oxazolidine-2-thiones from 3-Deoxy-3-isothiocyanato Sugars[J]. J Org Chem, 1994, 59:5565～5572
[29] Mota J F, Blanco J L J, Mellet C O, Fernandez J M G. 1-Deoxy-1- isothiocyanato-D-fructose as intermediate in syntheses of 1,3-O (S), N-heterocycles[J]. Carbohydr Res, 1994, 257:127～135
[30] 陈茹玉，杨华铮，胡式贤．O-烷基，O-芳基硫代磷酰取代硫脲和O-烷基硫代磷酰-双-取代硫脲的研究[J]，中国科学B辑．1983，(2)：109～118
[31] Grabiak R C, Miles J A, Schwenzer G M. Synthesis of Phosphonic dichlorides and Correlation of Their P-31 Chemical Shifts[J]. Phosphorus and Sulfur. 1980,
(9): 197～202
[32] Wardakhan W W, Fleita D H, Mohareb R M. Reaction of 4-Aryl-3-thiosemicarbazides with phenylisotiocyanate:A Facile Synthesis of Thiazole, Pyrazole and Pyrimidine Derivatives[J]. J Chin Chem Soc, 1999, 46, 97～104
[33] 杨华铮，黄战鏖．硫代磷(膦)酰基脲类衍生物的合成及其生物活性[J]．高等学校化学学报．1993，14(6)：787～790
[34] 金桂玉，沙跃武，蔡建平，陈茹玉，缪方明，刘小兰．O-芳基苯基硫代膦酰肼与异(硫)氰酸酯的加成反应[J]．高等学校化学学报．1989，10(2)：158～163
[35] 丛蒲珠编著．质谱学在天然有机化学中的应用[M]．科学出版社，1987，914
[36] Whistler R L, Welfrom M L. Methods in Carbohydrate Chemistry[M]. Vol. Ⅱ, Academic Press Inc. New York and London, 1963, 221
[37] Cao L H, Zhou C J, Gao H Y, Liu Y T. The Synthesis of N-(glycosylthioureylene)aminothiophosPhonic and diaminothiophosphinic O-aryl Esters[J]. J Chin Chem Soc, 2001, 48:207～210
[38] Caven R M C. ⅩⅩⅩⅦ. The Molecular Configuration of Phosphoryl Chloride and its Derivatives[J]. J Chem Soc, 1902, 8): 1362～1376
[39] Cremlyn R J W, Dewhurst B B, Wakeford D H. Studies of Organophosphorochloridates. Part Ⅰ. Synthesis of N-Substituted Phosphoramidic Chlorides and Acids[J]. J Chem Soc (C), 1971:300～303
[40] Cook H G, Ilett J D, Saunders B C, Stacey G J, Watson H G, Wildins I G E, Woodcock S J. Esters containing Phosphorus. Part Ⅸ[J]. J Chem Soc, 1949, 2921～2927
[41] Whistler R L, Welfrom M L. Methods in Carbohydrate Chemistry[M]. Vol. Ⅱ, Academic Press Inc. New York and London, 1963, 309
[2] Schroeder D C. Thioureas[J]. Chem Rev, 1955,181～228
[3] Goodman I. Glycosyl Ureides[J]. Advanced in Carbohydrate Chenistry, 1958, 13:215～236
[4] 林长学，李艳梅，成昌梅，韩波，万荣，冯亚兵，赵玉芬．五配位磷化合物与生物化学[J]，中国科学(B辑)，2002，32(3)：193～203
[5] C.费斯特 K，J.施密特编．有机磷农药的化学[M]．石油化学工业出版社．P212
[6] U.S.P. 2.906.770(1959)
[7] U.s.P. 3.909.556(1959)
[8] U.S.P. 3.146.228(1960)
[9] 陈茹玉，刘纶祖著．有机磷化学研究[M]．高等教育出版社．2001年，70，121
[10] Cremlyn R J W, Dewhurst B B, Wakeford D H. Studies of Organophosphorochloridates. Part Ⅳ. Synthesis of N-Substituted Phosphoramidic Hydrazides, Hydrazones, and Azides[J]. J Chem Soc (C), 1971, 3011～3017
[11] Richard F H, Joseph J K. Carbohydrate-urea-phenol-based adhesives: Transient Formation of mono-and di-D-Glucosylurea[J]. Carbohydr Res, 1989, 189: 103～112
[12] Fischer E. Synthesis of new glucosides[J]. Ber, 1914, 47:1377～1393
[13] Johson T B, Bergmann W. Researches on nitrogenous glycosides. I. The
utilization of glycose isocyanates for glycoside syntheses[J]. J Am Chem Soc, 1932, 54:3360～3363
[14] Johson T B, Bergmann W. Researches on nitrogenous glucosides.Ⅳ. Some new attempts to synthesize pyrimidine glucosides[J]. J Am Chem Soc, 1938, 60: 1916～1918
[15] Haring K M, Johson T B. Researches on nitrogenous glycosides. Ⅱ. The synthesis of glycosido ureides[J]. J Am Chem Soc, 1933, 55:395～402
[16] Jochims J C, Seeliger A. Isocyanato-und Isothiocyanato-derivate des D-Glucosamins[J]. Tetrahedron, 1965, 21: 2611～2616
[17] Valentiny M, Martvon A, Kovac P. Synthesis of nucleoside analogs by additioncyclization reaction of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate[J]. Collect Czech Chem Comm, 1981, 46:2197～2202
[18] Wojtowicz M. Synthesis of the N-D-and N-L-xylopyranosides of 2-amino-5- carbamoyl-1,3,4-oxadiazole[J]. Acta Pol Pharm, 1993, 50(2-3): 275～282(Pol)
[19] Wojtowicz M. Synthesis of N-glucosides of 2-amino-5-(N, N-dimethylaminopropylcarbamoyl)-1,3,4-oxadiazole[J]. Acta Pol Pharm, 1994, 51(1): 81～87
[20] Ogura H, Takahashi H. Studies on nucleoside analogs. ⅩⅩⅣ. Mono-and disaccharide isothiocyanates[J]. Heterocycles, 1982, 17:87～90
[21] Lindhorst T K, Kieburg C. Solvent-Free Preparation of Glycosyl Isothiocyanates[J]. Synthesis, 1995:1228～1230
[22] Jose F, Wenceslao M, Carmen O, Inmaculada R, Colin W. Partially Protected D-Glucopyranosyl Isothiocyanates. Synthesis and Transformations into Thiourea and Heterocyclic Derivatives[J]. Tetrahedron, 1992, 48(31): 6413～6424
[23] Jose Camarasa M, Fernandez-Resa P, Carcia-Lopez M T, De Las Heras,
Federico G, Mendez-Castrillon P P, San Felix A[J]. Synthesis, 1984, (6): 509～510
[24] Klimov E M, Demchenko A V, et al. Reaction of 2-deoxy-α-D-arabino-hexopyranosyl bromides with KSCN [J]. Dokl Akad Nauk, 1993, 331(1): 53～55(Russ)
[25] Peshushkova S G, Povlov A E, et al. Structure and reactivity of glycosides Ⅱ. Synthesis and Structure of O-aryl-N-(2,3,4,6-tetra-O-acetyl-β-D- glucopyranosyl) thiocarbanates[J]. Zh Obshch Khim, 1993, 63(5): 1134～1139(Russ)
[26] Gonzalez M A, Mota J F, et al. Synthesis of 1,3,4,6-Tetra-O-Acetyl-2-[3- alkyl(aryl)-thioureido]-2-deoxy-a-D-Glucopyranoses and their transformation into 2-alkyl(aryl)amino-(1,2-dideoxy-a-D-Glucopyrano) [2,1-d]-2- Thiazolines[J]. Carbohydr Res, 1986, 154:49～62
[27] Fernandez J M G, Mellet C O, Blanco J L J, Jose F. Chiral 2-Thioxotetrahydro-1,3-O, N-heterocycles from Carbohydrates. 2. Stereocontrolled Synthesis of Oxazolidine Pseudo-C-nucleosides and Bicyclic Oxazine-2-thiones[J]. J Org Chem, 1993, 58:5192～5199
[28] Fernandez J M G, Mellet C O, Blanco J L J, Jose F. Enantiopure 2-Thioxotetrahydro-1,3-O, N-heterocycles from Carbohydrates. 3. Enantiopure C-4 Chiral Oxazine-and Oxazolidine-2-thiones from 3-Deoxy-3-isothiocyanato Sugars[J]. J Org Chem, 1994, 59:5565～5572
[29] Mota J F, Blanco J L J, Mellet C O, Fernandez J M G. 1-Deoxy-1- isothiocyanato-D-fructose as intermediate in syntheses of 1,3-O (S), N-heterocycles[J]. Carbohydr Res, 1994, 257:127～135
[30] 陈茹玉，杨华铮，胡式贤．O-烷基，O-芳基硫代磷酰取代硫脲和O-烷基硫代磷酰-双-取代硫脲的研究[J]，中国科学B辑．1983，(2)：109～118
[31] Grabiak R C, Miles J A, Schwenzer G M. Synthesis of Phosphonic dichlorides and Correlation of Their P-31 Chemical Shifts[J]. Phosphorus and Sulfur. 1980,
(9): 197～202
[32] Wardakhan W W, Fleita D H, Mohareb R M. Reaction of 4-Aryl-3-thiosemicarbazides with phenylisotiocyanate:A Facile Synthesis of Thiazole, Pyrazole and Pyrimidine Derivatives[J]. J Chin Chem Soc, 1999, 46, 97～104
[33] 杨华铮，黄战鏖．硫代磷(膦)酰基脲类衍生物的合成及其生物活性[J]．高等学校化学学报．1993，14(6)：787～790
[34] 金桂玉，沙跃武，蔡建平，陈茹玉，缪方明，刘小兰．O-芳基苯基硫代膦酰肼与异(硫)氰酸酯的加成反应[J]．高等学校化学学报．1989，10(2)：158～163
[35] 丛蒲珠编著．质谱学在天然有机化学中的应用[M]．科学出版社，1987，914
[36] Whistler R L, Welfrom M L. Methods in Carbohydrate Chemistry[M]. Vol. Ⅱ, Academic Press Inc. New York and London, 1963, 221
[37] Cao L H, Zhou C J, Gao H Y, Liu Y T. The Synthesis of N-(glycosylthioureylene)aminothiophosPhonic and diaminothiophosphinic O-aryl Esters[J]. J Chin Chem Soc, 2001, 48:207～210
[38] Caven R M C. ⅩⅩⅩⅦ. The Molecular Configuration of Phosphoryl Chloride and its Derivatives[J]. J Chem Soc, 1902, 8): 1362～1376
[39] Cremlyn R J W, Dewhurst B B, Wakeford D H. Studies of Organophosphorochloridates. Part Ⅰ. Synthesis of N-Substituted Phosphoramidic Chlorides and Acids[J]. J Chem Soc (C), 1971:300～303
[40] Cook H G, Ilett J D, Saunders B C, Stacey G J, Watson H G, Wildins I G E, Woodcock S J. Esters containing Phosphorus. Part Ⅸ[J]. J Chem Soc, 1949, 2921～2927
[41] Whistler R L, Welfrom M L. Methods in Carbohydrate Chemistry[M]. Vol. Ⅱ, Academic Press Inc. New York and London, 1963, 309