【结 构 式】 |
【药物名称】Temozolomide, Sch-52365, CCRG-81045, NSC-362856, M&B-39831, Temodar, Temodal 【化学名称】8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one 【CA登记号】85622-93-1 【 分 子 式 】C6H6N6O2 【 分 子 量 】194.15372 |
【开发单位】Cancer Research UK (Originator), Antigenics (Not Determined), M.D. Anderson Cancer Center (Not Determined), Schering-Plough (Licensee), National Cancer Institute (Codevelopment) 【药理作用】Astrocytoma Therapy, Brain Cancer Therapy, Glioblastoma MultiformeTherapy, Lymphoma Therapy, Melanoma Therapy, Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, DNA Alkylating Drugs |
合成路线1
【1】 Kuo SC. Mas JL, Houn 2002. Synthesis of temozolomide and analogs. US 2002095036 |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 66804 | N-(tert-butyl)-2-cyanoacetamide | C7H12N2O | 详情 | 详情 | |
(II) | 66810 | 2-(tert-butylamino)-N-hydroxy-2-oxoacetimidoyl cyanide | C7H11N3O2 | 详情 | 详情 | |
(III) | 66812 | 2-aminoacetonitrile hydrochloride | C2H4N2.HCl | 详情 | 详情 | |
(IV) | 46416 | 2-[(dibenzylene)amino]acetonitrile | 70591-20-7 | C15H12N2 | 详情 | 详情 |
(V) | 66813 | N-(tert-butyl)-2-cyano-2-((diphenylmethylene)amino)acetamide | C20H21N3O | 详情 | 详情 | |
(VI) | 66811 | 2-amino-N-(tert-butyl)-2-cyanoacetamide | C7H13N3O | 详情 | 详情 | |
(VII) | 66815 | (E)-N,N'-bis(methylcarbamoyl)formimidamide | C5H10N4O2 | 详情 | 详情 | |
(VIII) | 66816 | 5-amino-N4-(tert-butyl)-N1-methyl-1H-imidazole-1,4-dicarboxamide | C10H17N5O2 | 详情 | 详情 | |
(IX) | 66817 | N-(tert-butyl)-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide | C10H14N6O2 | 详情 | 详情 | |
(X) | 66814 | 2-amino-N-(tert-butyl)-2-cyanoacetamide hydrochloride | C7H13N3O.HCl | 详情 | 详情 |
合成路线2
【1】 Ku SC. 2002. A process tor the prepn. of temoiolomide and its analogs via the oxiadative cyclization of 5-amino-4-aminocarbonylirmdazolylbyrkuides. W0 2002057268 |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 66818 | 2-amino-2-cyanoacetamide;Aminocyanacetamide | 6719-21-7 | C3H5N3O | 详情 | 详情 |
(II) | 66815 | (E)-N,N'-bis(methylcarbamoyl)formimidamide | C5H10N4O2 | 详情 | 详情 | |
(III) | 66819 | 5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide | C6H9N5O2 | 详情 | 详情 | |
(IV) | 66820 | 5-amino-1H-imidazole-4-carboxamide hydrochloride | 21299-72-9 | C4H6N4O.HCl | 详情 | 详情 |
(V) | 66811 | 2-amino-N-(tert-butyl)-2-cyanoacetamide | C7H13N3O | 详情 | 详情 | |
(VI) | 66816 | 5-amino-N4-(tert-butyl)-N1-methyl-1H-imidazole-1,4-dicarboxamide | C10H17N5O2 | 详情 | 详情 | |
(VII) | 66821 | 4-nitrophenyl 5-amino-4-carbamoyl-1H-imidazole-1-carboxylate | C11H9N5O5 | 详情 | 详情 | |
(VIII) | 66822 | 5-amino-1-(1-methylhydrazinecarbonyl)-1H-imidazole-4-carboxamide | C6H10N6O2 | 详情 | 详情 |
合成路线3
【1】 Stevens MF, Hickman JA, StoneR,et al.1984. Antitumour imidazotetnzines. 1. Synthesis an chemistry of 8-carbamoyl-3-(2-chloroethyl) imidazo[5,1-d] -1,2,3,5-tetrazirr4(3H) -one.a novel broad-spectrum antitumor agent. J Med Chem, 27(2):196~201 |
合成路线4
【1】 Wang YF, Stevens MF. 1996. Synthetic studies of 8-arbamoylimidazo-[5,l-D] -1,2,3,5-tetnzin-4(3H)-one: a key derivative of antitumor drug ternozolomide. Bioorg Med Chem lett, 6(2):185~188 |
合成路线5
【1】 Wang YF, Stevens MF, Thomson W. 1994. Altemative syntheses of the antitumor drug temozolomide avoiding the use of methyl isocyanate. Journal of the Chemical Society, Chenucal Communications, (14): 1687~1688. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 66820 | 5-amino-1H-imidazole-4-carboxamide hydrochloride | 21299-72-9 | C4H6N4O.HCl | 详情 | 详情 |
(II) | 66824 | ethyl 2-(5-amino-4-carbamoyl-1H-imidazole-1-carboxamido)acetate hydrochloride | C9H13N5O4.HCl | 详情 | 详情 | |
(III) | 66825 | ethyl 2-(8-carbamoyl-4-methyleneimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)acetate | C10H12N6O3 | 详情 | 详情 | |
(IV) | 66826 | 2-(8-carbamoyl-4-methyleneimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)acetic acid | C8H8N6O3 | 详情 | 详情 | |
(V) | 66827 | 2-thioxopyridin-1(2H)-yl 2-(8-carbamoyl-4-methyleneimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)acetate | C13H11N7O3S | 详情 | 详情 |
合成路线6
By reaction of 5-diazoimidazole-4-carboxamide (II), prepared by diazotization of 5-aminoimidazole-4-carboxamide (I) with nitrous acid, with methylisocyanate (III) either alone or in dichloromethane.
【1】 Stevens, M.F.G.; Baig, G.U.; Triazines and related products, part 22. Synthesis and reactions of imidazo[5,1-c][1,2,4]triazines. J Chem Soc Perkin Trans I. J Chem Soc - Perkins Trans I 1981, 1424. |
【2】 Lunt, E.; Stevens, M.F.G.; Stone, R.; Woolbridge, K.R.H. (Cancer Research Campaign Technology Ltd.); Tetrazine derivs., process for their preparation and pharmaceutical compsns. containing them. BE 894175; DE 3231255; FR 2511679; GB 2104522; JP 1983043975; US 5260291 . |
【3】 Prous, J.; Castaner, J.; Graul, A.; Temozolomide. Drugs Fut 1994, 19, 8, 746. |
【4】 Stevens, M.F.G.; Hickman, J.A.; Stone, R.; Gibson, N.W.; Baig, G.U.; Lunt, E.; Newton, C.G.; Antitumor imidazotetrazinones. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one, a novel broad-spectrum antitumor agent. J Med Chem 1984, 27, 196-201, 196. |
合成路线7
The synthesis of several forms of [13C]- and [15N]-labeled temozolomide has been reported: 1) The diazotation of 3-aminopyrazole-4-carboxamide (I) with [15N]-labeled sodium nitrite and HCl gives the corresponding labeled diazonium salt (II), which is cyclized with methyl isocyanate (II) at room temperature, yielding temozolomide labeled at the N in the 2-position.
【1】 Wilman, D.E.V.; Thomson, W.; Wheelhouse, R.T.; Stevens, M.F.G.; Antitumour imidazotetrazines. 31. The synthesis of isotopically labelled temozolomide and a multinuclear (H-1, C-13, N-15) magnetic resonance investigation of temozolomide and mitozolomide. J Chem Soc - Perkins Trans I 1995, 3, 3, 249. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 11015 | 5-Amino-1H-imidazole-4-carboxamide | 360-97-4 | C4H6N4O | 详情 | 详情 |
(II) | 11018 | 5-Carbamoylimidazolidin-4-yldiazonium salt | C4H3N5O | 详情 | 详情 | |
(II) | 45040 | 5-(aminocarbonyl)-4-imidazolidinediazonium | C4H8N5O | 详情 | 详情 | |
(III) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 |
合成路线8
2) The condensation of N,N-diphenylcarbamoyl chloride (IV) with [13C]-labeled methylamine (V) gives the corresponding urea (VI), which by heating at 240 C is converted to the [13C]-labeled methyl isocyanate (VII). Finally, this compound is cyclized with the diazonium salt (VIII) (obtained by diazotation of 3-aminopyrazole-4-carbonitrile with NaNO2-HCl in the usual way) to afford temozolomide labeled at the methyl in the 3-position. 3) The preceding sequence performed with [15N]-labeled methylamine (X) gives urea (XI), isocyanate (XII) and finally temozolomide labeled at the N in the 3-position.
【1】 Wilman, D.E.V.; Thomson, W.; Wheelhouse, R.T.; Stevens, M.F.G.; Antitumour imidazotetrazines. 31. The synthesis of isotopically labelled temozolomide and a multinuclear (H-1, C-13, N-15) magnetic resonance investigation of temozolomide and mitozolomide. J Chem Soc - Perkins Trans I 1995, 3, 3, 249. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII),(XII) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
(V),(X) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
(VI),(XI) | 11022 | 1-Methyl-3,3-diphenylurea; N'-Methyl-N,N-diphenylurea | 13114-72-2 | C14H14N2O | 详情 | 详情 |
(IV) | 11020 | N,N-Diphenylcarbamic chloride; Diphenylcarbamyl chloride | 83-01-2 | C13H10ClNO | 详情 | 详情 |
(V) | 45041 | methylamine; methanamine | CH5N | 详情 | 详情 | |
(VI) | 45042 | N'-methyl-N,N-diphenylurea | C14H14N2O | 详情 | 详情 | |
(VII) | 45043 | (methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
(VIII) | 11016 | 1-[5-(Aminocarbonyl)-4-imidazolidinyl]diazonium | C4H3N5O | 详情 | 详情 | |
(IX) | 11015 | 5-Amino-1H-imidazole-4-carboxamide | 360-97-4 | C4H6N4O | 详情 | 详情 |
(X) | 45044 | methylamine; methanamine | CH5N | 详情 | 详情 | |
(XI) | 45045 | N'-methyl-N,N-diphenylurea | C14H14N2O | 详情 | 详情 | |
(XII) | 45046 | methyl isocyanate; (methylimino)(oxo)methane | C2H3NO | 详情 | 详情 |
合成路线9
This compound has been obtained by two related ways: 1. The reaction of 5-diazoimidazole (I) with methylamine gives the triazene (II), which is then cyclized with 11C-phosgene (III) to yield the target 11C-carbonyl labeled compound. 2. The cyclization of 5-diazoimidazole-4-carboxamide (I) with 11C-carbonyl labeled methyl isocyanate (IV) gives the target 11C carbonyl labeled compound.
【1】 Brock, C.S.; Brady, F.; Stevens, M.F.G.; Brown, G.D.; Price, P.M.; Luthra, S.K.; Antitumor imidazotetrazines. 40.(1) Radiosyntheses of [4-11C-carbonyl]- and 3-N-11C-methyl]-8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) for positron emission tomography (PET) studies. J Med Chem 2002, 45, 25, 5448. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 56930 | 4-diazo-4H-imidazole-5-carboxamide | C4H3N5O | 详情 | 详情 | |
(II) | 56931 | 4-[(E)-3-methyl-2-triazenyl]-4H-imidazole-5-carboxamide | C5H8N6O | 详情 | 详情 | |
(III) | 56932 | Carbonyl chloride | CCl2O | 详情 | 详情 | |
(III) | 56933 | carbonic dichloride | CCl2O | 详情 | 详情 | |
(IV) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
(IV) | 56934 | (methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 |
合成路线10
The cyclization of 5-diazoimidazole-4-carboxamide (I) with 11C-methyl isocyanate (II) gives the target 11C methyl labelled compound.
【1】 Brock, C.S.; Brady, F.; Stevens, M.F.G.; Brown, G.D.; Price, P.M.; Luthra, S.K.; Antitumor imidazotetrazines. 40.(1) Radiosyntheses of [4-11C-carbonyl]- and 3-N-11C-methyl]-8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) for positron emission tomography (PET) studies. J Med Chem 2002, 45, 25, 5448. |
合成路线11
Further nitration of the nitroimidazole (I) with HNO3, Ac2O gives the 1,4-dinitroimidazole (II), which is treated with KCN and NaHCO3 in methanol/water to yield 5-nitro-1H-imidazole-4-carbonitrile (III). The reaction of (III) with dihydropyran and Ts-OH in ethyl acetate affords the N-protected imidazole (IV). The reduction of (IV) with H2 over Pt/C in ethyl acetate provides the hydroxylamine (V), which is oxidized with NaIO4 in ethyl acetate/water to give the nitroso derivative (VI). The condensation of (VI) with phenyl 2-methylcarbazate (VII) by means of HOAc and TFA yields the triazene (VIII), which is treated with conc. HCL in ethyl acetate to afford the carboxamide (IX). Finally, this compound is cyclized to the target imidazo-tetrazinone by irradiation with daylight in acetone/MeOH, most probably through the non isolated cis intermediate (X).
【1】 Wanner, M.J.; Koomen, G.J.; A new synthesis of temozolomide. J Chem Soc - Perkins Trans I 2002, 16, 1877. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 57883 | 5-Nitroimidazole | C3H3N3O2 | 详情 | 详情 | |
(II) | 57884 | 1,4-dinitro-1H-imidazole | 19182-81-1 | C3H2N4O4 | 详情 | 详情 |
(III) | 57885 | 5-nitro-1H-imidazole-4-carbonitrile | C4H2N4O2 | 详情 | 详情 | |
(IV) | 57886 | 5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-imidazole-4-carbonitrile | C9H10N4O3 | 详情 | 详情 | |
(V) | 57887 | 5-(hydroxyamino)-1-tetrahydro-2H-pyran-2-yl-1H-imidazole-4-carbonitrile | C9H12N4O2 | 详情 | 详情 | |
(VI) | 57888 | 5-nitroso-1-tetrahydro-2H-pyran-2-yl-1H-imidazole-4-carbonitrile | C9H10N4O2 | 详情 | 详情 | |
(VII) | 57889 | phenyl 1-methyl-1-hydrazinecarboxylate | C8H10N2O2 | 详情 | 详情 | |
(VIII) | 57890 | phenyl (E)-3-(4-cyano-1H-imidazol-5-yl)-1-methyl-2-triazene-1-carboxylate | C12H10N6O2 | 详情 | 详情 | |
(IX) | 57891 | phenyl (E)-3-[4-(aminocarbonyl)-1H-imidazol-5-yl]-1-methyl-2-triazene-1-carboxylate | C12H12N6O3 | 详情 | 详情 | |
(X) | 57892 | phenyl (Z)-3-[4-(aminocarbonyl)-1H-imidazol-5-yl]-1-methyl-2-triazene-1-carboxylate | C12H12N6O3 | 详情 | 详情 |