79-17-4,CH6N4,74.0858,1-Hydrazinecarboximidamide; Hydrazinec

更新日期：2018-11-23 浏览次数：376

摘要：79-17-4,CH6N4,74.0858,1-Hydrazinecarboximidamide; Hydrazinecarboximidamide

【化学名】1-Hydrazinecarboximidamide; Hydrazinecarboximidamide
【CAS登记号】79-17-4
【结构式】
【分子式】CH6N4
【分子量】74.0858
【来源】Acros Organics; Moravek Biochemicals Inc.

【合成情况】　
〖目标产物〗Mitoguazone, Win-10708-2, NSC-30609(acetate), NSC-32946(diHCl), MGBG, Methyl-GAG, Zyrkamine
〖合成路线〗
〖合成方法〗The synthesis of [14C]-mitoguazone has been reported: The methylation of [14C]-labeled potassium acetate (I) with dimethyl sulfate in HMPT gives the corresponding ester (II), which by reaction with the sodium salt of dimethylsulfoxide (III) in DMSO affords the hemithioketal (IV). Finally, this compound is condensed with aminoguanidine (V) in DMSO/water.
〖参考〗Burgos, A.; Ellames, G.J.; Convenient synthesis of [2-C-14]-methylglyoxal bis(guanylhydrazone), [C-14]-mitoguazone. J Label Compd Radiopharm 1995, 36, 1, 93

〖目标产物〗Mitoguazone, Win-10708-2, NSC-30609(acetate), NSC-32946(diHCl), MGBG, Methyl-GAG, Zyrkamine
〖合成路线〗
〖合成方法〗The oxidation of acetone (I) with butyl nitrite (II) with a catalytic amount of HCl gives methylglyoxal 1-oxime (III), which is then condensed with aminoguanidine (IV) in hot water acidified with HCl.
〖参考〗Serradell, M.N.; Eastland, G.W.; Castaer, J.; Mitoguazone. Drugs Fut 1984, 9, 3, 199

〖目标产物〗Mitoguazone, Win-10708-2, NSC-30609(acetate), NSC-32946(diHCl), MGBG, Methyl-GAG, Zyrkamine
〖合成路线〗
〖合成方法〗The oxidation of acetone (I) with butyl nitrite (II) with a catalytic amount of HCl gives methylglyoxal 1-oxime (III), which is then condensed with aminoguanidine (IV) in hot water acidified with HCl.
〖参考〗Nagaki, D.; Nishimura, T.; Hasegawa, K.; Toku, H.; Sakaguchi, H.; Yamazaki, C.; Antiviral compounds. IX. Synthesis and anti-influenza virus activity of bis-amidinohydrazones of glyoxal and methylglyoxal. Kitasato Arch Exp Med 1975, 48, 4, 171-181

〖目标产物〗Guanabenz acetate, WY-8678 acetate, Wytensin
〖合成路线〗
〖合成方法〗By condensation of 2,6-dichlorobenzaldehyde (I) and aminoguanidine carbonate (II).
〖参考〗Bundgaard, H.; Castaer, J.; Guanabenz. Drugs Fut 1976, 1, 11, 523

〖目标产物〗Guanabenz acetate, WY-8678 acetate, Wytensin
〖合成路线〗
〖合成方法〗By condensation of 2,6-dichlorobenzaldehyde (I) and aminoguanidine carbonate (II).
〖参考〗Wuesthoff, F.; et al.; Novel hydrazine compounds and compositions containing them. BE 0661193; CH 453793; DE 1567104; FR 1455835; GB 1019120

〖目标产物〗Lamotrigine, BW-430C, Labileno, Lamictal
〖合成路线〗
〖合成方法〗The Grignard condensation of 2,3-dichloroiodobenzene (I) with CO2 by means of Mg / ether gives 2,3-dichlorobenzoic acid (II), which is converted to the corresponding acyl chloride (III) by refluxing with SOCl2.The reaction of (III) with cuprous cyanide and KI in refluxing xylene yields 2,3-dichlorobenzoyl cyanide (IV). Finally, this compound is cyclized with aminoguanidine (V) in DMSO.
〖参考〗Castaer, J.; Prous, J.; Lamotrigine. Drugs Fut 1986, 11, 6, 456

〖目标产物〗Lamotrigine, BW-430C, Labileno, Lamictal
〖合成路线〗
〖合成方法〗The Grignard condensation of 2,3-dichloroiodobenzene (I) with CO2 by means of Mg / ether gives 2,3-dichlorobenzoic acid (II), which is converted to the corresponding acyl chloride (III) by refluxing with SOCl2.The reaction of (III) with cuprous cyanide and KI in refluxing xylene yields 2,3-dichlorobenzoyl cyanide (IV). Finally, this compound is cyclized with aminoguanidine (V) in DMSO.
〖参考〗Baxter, M.G.; Elphick, A.R.; Miller, A.A.; Sawyer, D.A. (Glaxo Wellcome plc); 1,2,4-Triazine derivs., process for preparing such cpds., pharmaceutical compsns. and intermediates utilized for this process. CA 1133938; EP 0021121

〖目标产物〗Lamotrigine, BW-430C, Labileno, Lamictal
〖合成路线〗
〖合成方法〗Condensation of 2,3-dichlorobenzoyl cyanide (I) with aminoguanidine (II) by means of PPA in hot acetonitrile yields 2,3-dichlorobenzoyl cyanide amidinohydrazone (III), which is cyclized to the target 1,2,4-triazine by heating in refluxing propanol with or without DMSO.
〖参考〗Nadaka, V.; Lexner, J.; Kaspi, J. (Chemagis Ltd.); Process for preparing substd. benzoyl cyanide amidinohydrazones. EP 1127873

〖目标产物〗Lamotrigine, BW-430C, Labileno, Lamictal
〖合成路线〗
〖合成方法〗Hydrogenation of 2,3-dichloronitrobenzene (I) with H2 over Ra-Ni in methanol gives 2,3-dichloroaniline (II), which is diazotized with NaNO2 and HCl and treated with CuCN to yield 2,3-dichlorobenzonitrile (III). Hydrolysis of the nitrile (III) with NaOH in refluxing methanol/water affords 2,3-dichlorobenzoic acid (IV), which is treated with hot SOCl2 to provide the corresponding acyl chloride (V). Reaction of (V) with CuCN and KI in refluxing chlorobenzene gives 2,3-dichlorobenzoyl cyanide (VI), which is condensed with aminoguanidine (VII) by means of H2SO4/TsOH in hot toluene to yield 2,3-dichlorobenzoyl cyanide amidinohydrazone (VIII). Finally, this compound is cyclized by treatment with NaOMe in refluxing methanol.
〖参考〗Srivastava, A.R.; Sasikumar, T.M.; Radhakrishnan, T.V. (RPG Life Sciences Ltd); A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine. WO 0149669

〖目标产物〗Sanazole, AK-2123
〖合成路线〗
〖合成方法〗Condensation of aminoguanidine carbonate (I) with formic acid gives 3-aminotriazole (II), which by treatment with concentrated nitric acid in a sodium nitrite solution gives 3-nitrotriazole (III). N-Alkylation of (III) with bromoacetic acid ethyl ester affords 2-(3-nitro-1,2,4-triazol-1-yl)acetic acid ethyl ester (IV). Reaction of (IV) with 2-methoxyethylamine in dioxane yields AK-2123.
〖参考〗Huan, L.C.; Rong, S.; AK-2123. Drugs Fut 1995, 20, 7, 659

〖目标产物〗Sanazole, AK-2123
〖合成路线〗
〖合成方法〗Condensation of aminoguanidine carbonate (I) with formic acid gives 3-aminotriazole (II), which by treatment with concentrated nitric acid in a sodium nitrite solution gives 3-nitrotriazole (III). N-Alkylation of (III) with bromoacetic acid ethyl ester affords 2-(3-nitro-1,2,4-triazol-1-yl)acetic acid ethyl ester (IV). Reaction of (IV) with 2-methoxyethylamine in dioxane yields AK-2123.
〖参考〗Sugita, T.; Masuoka, M.; Nishikawa, Y.; Nishimoto, S.; Zhuo, L.; Sasai, K.; Kagiya, T.; Nitrotriazoles bearing sulfur-substituted side chains: Preparation and characterization as hypoxic cell radiosensitizers. Anti-Cancer Drug Des 1992, 7, 277-84

〖目标产物〗Sanazole, AK-2123
〖合成路线〗
〖合成方法〗Condensation of aminoguanidine carbonate (I) with formic acid gives 3-aminotriazole (II), which by treatment with concentrated nitric acid in a sodium nitrite solution gives 3-nitrotriazole (III). N-Alkylation of (III) with bromoacetic acid ethyl ester affords 2-(3-nitro-1,2,4-triazol-1-yl)acetic acid ethyl ester (IV). Reaction of (IV) with 2-methoxyethylamine in dioxane yields AK-2123.
〖参考〗Horning, E.C.; . Organic Syntheses, Vol. 3, 1st Ed. University of Missouri 1995, 95

〖目标产物〗Ocinaplon, DOV-273547, CL-273547
〖合成路线〗
〖合成方法〗Reaction of 4-acetylpyridine (I) with hot dimethylformamide dimethyl acetal (II) gives the enamino ketone (III), which is then condensed with (3-amino-1H-pyrazol-4-yl)(2-pyridyl)methanone (IV) in boiling acetic acid. Intermediate (IV), (3-amino-1H-pyrazol-4-yl)(2-pyrid-yl)methanone, is obtained by condensation of 3-oxo-3-(2-pyridyl)propionitrile (V) with dimethylformamide dimethyl acetal (II) to provide 2-(dimethylaminomethylene)-3-oxo-3-(2-pyridyl)propionitrile (VI), which is finally coupled with aminoguanidine nitrate (VII) by means of 10N NaOH in refluxing EtOH
〖参考〗Castaer, J.; Silvestre, J.S.; Chilman-Blair, K.; Ocinaplon. Drugs Fut 2003, 28, 2, 115-120

〖目标产物〗Ocinaplon, DOV-273547, CL-273547
〖合成路线〗
〖合成方法〗Reaction of 4-acetylpyridine (I) with hot dimethylformamide dimethyl acetal (II) gives the enamino ketone (III), which is then condensed with (3-amino-1H-pyrazol-4-yl)(2-pyridyl)methanone (IV) in boiling acetic acid. Intermediate (IV), (3-amino-1H-pyrazol-4-yl)(2-pyrid-yl)methanone, is obtained by condensation of 3-oxo-3-(2-pyridyl)propionitrile (V) with dimethylformamide dimethyl acetal (II) to provide 2-(dimethylaminomethylene)-3-oxo-3-(2-pyridyl)propionitrile (VI), which is finally coupled with aminoguanidine nitrate (VII) by means of 10N NaOH in refluxing EtOH
〖参考〗Tomcufcik, A.S.; Dusza, J.P. (Wyeth); (3-Amino-1H-pyrazol-4-yl)(aryl)methanones. EP 0129846; JP 1985013764; US 4900836

〖目标产物〗Ocinaplon, DOV-273547, CL-273547
〖合成路线〗
〖合成方法〗Reaction of 4-acetylpyridine (I) with hot dimethylformamide dimethyl acetal (II) gives the enamino ketone (III), which is then condensed with (3-amino-1H-pyrazol-4-yl)(2-pyridyl)methanone (IV) in boiling acetic acid. Intermediate (IV), (3-amino-1H-pyrazol-4-yl)(2-pyrid-yl)methanone, is obtained by condensation of 3-oxo-3-(2-pyridyl)propionitrile (V) with dimethylformamide dimethyl acetal (II) to provide 2-(dimethylaminomethylene)-3-oxo-3-(2-pyridyl)propionitrile (VI), which is finally coupled with aminoguanidine nitrate (VII) by means of 10N NaOH in refluxing EtOH
〖参考〗Dusza, J.P.; Tomcufcik, A.S.; Albright, J.D. (Wyeth); Aryl and heteroaryl 7-(aryl and heteroaryl)-pyrazolo[1,5-a]pyrimidin-3-ylmethanones. DE 3422844; EP 0129847; JP 1985019788

〖目标产物〗Semapimod hydrochloride, AXD-455, CNI-1493
〖合成路线〗
〖合成方法〗The reaction of decanedioyl dichloride (I) with 3,5-diacetylaniline (II) by means of pyridine in dichloromethane gives the corresponding diamide (III), which is condensed with aminoguanidine (IV) in refluxing aqueous ethanol to afford the target tetrakis amidinohydrazone.
〖参考〗Cerami, A.; Ulrich, P.; Tracey, K.J.; Bianchi, M. (Picower Institute for Medical Research); Guanylhydrazones for treating inflammatory conditions. EP 0746312; EP 1160240; US 5599984; WO 9519767

〖目标产物〗
〖合成路线〗
〖合成方法〗Orcinol (I) is first derivatized to (III) by reaction with sulfonyl chloride (II) in a mixture of aqueous NaHCO3 (sat) and Et2O. Monosulfonate (III) undergoes Mitsunobu reaction with monobenzylated diol (IV) in the presence of PPh3 and DEAD in dichloromethane to yield derivative (V), which is then debenzylated by hydrogenolysis over Pd/C in MeOH, or in THF/HCl/dioxane, to afford (VI). Alcohol (VI) is oxidized with SO3pyr complex in DMSO/dichloromethane in the presence of DIEA to provide aldehyde (VIII), which finally reacts with aminoguanidine nitrate in EtOH in the presence of HCl/dioxane.
〖参考〗Soll, R.M.; Lu, T.; Tomczuk, B.; et al.; Amidinohydrazones as guanidine bioisosteres: Application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors. Bioorg Med Chem Lett 2000, 10, 1, 1

〖目标产物〗
〖合成路线〗
〖合成方法〗Orcinol (I) is first derivatized to (III) by reaction with sulfonyl chloride (II) in a mixture of aqueous NaHCO3 (sat) and Et2O. Monosulfonate (III) undergoes Mitsunobu reaction with monobenzylated diol (IV) in the presence of PPh3 and DEAD in dichloromethane to yield derivative (V), which is then debenzylated by hydrogenolysis over Pd/C in MeOH, or in THF/HCl/dioxane, to afford (VI). Alcohol (VI) is oxidized with SO3pyr complex in DMSO/dichloromethane in the presence of DIEA to provide aldehyde (VIII), which finally reacts with aminoguanidine nitrate in EtOH in the presence of HCl/dioxane.
〖参考〗Soll, R.M.; Lu, T.; Fedde, C.L.; Tomczuk, B.E.; Illig, C. (3-Dimensional Pharmaceuticals, Inc.); Amidinohydrazones as protease inhibitors. EP 0906091; JP 2000507588; US 5891909; WO 9736580

〖目标产物〗Indiplon, NBI-34060
〖合成路线〗
〖合成方法〗Condensation of 2-acetylthiophene (I) with dimethylformamide dimethylacetal produced enaminone (II), which was subsequently cyclized to the isoxazole (III) upon treatment with hydroxylamine. Further condensation of (III) with dimethylformamide dimethylacetal, with concomitant isoxazole ring opening, gave rise to the enamino nitrile (IV). This was then cyclized with aminoguanidine nitrate (V) under basic conditions to furnish the intermediate aminopyrazole (VI).
〖参考〗Sorbera, L.A.; Castaer, J.; Martn, L.; Indiplon. Drugs Fut 2003, 28, 8, 739

〖目标产物〗Indiplon, NBI-34060
〖合成路线〗
〖合成方法〗Condensation of 2-acetylthiophene (I) with dimethylformamide dimethylacetal produced enaminone (II), which was subsequently cyclized to the isoxazole (III) upon treatment with hydroxylamine. Further condensation of (III) with dimethylformamide dimethylacetal, with concomitant isoxazole ring opening, gave rise to the enamino nitrile (IV). This was then cyclized with aminoguanidine nitrate (V) under basic conditions to furnish the intermediate aminopyrazole (VI).
〖参考〗Tomcufcik, A.S.; Dusza, J.P.; Albright, J.D.; Beer, B. (Wyeth); N-Methyl-N-(-[3-[-2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl]phenyl)acetamide and compsns. and methods related thereto. US 6399621

〖目标产物〗Indiplon, NBI-34060
〖合成路线〗
〖合成方法〗Reaction of 3-(acetamido)acetophenone (VIII) with iodomethane and NaH gives 3-(N-methylacetamido)acetophenone (XXVIII), which is mixed with 3-oxo-3-(2-thienyl)propionitrile (VII) and treated with dimethylformamide dimethylacetal to yield a mixture of the dimethylaminomethylene derivatives (IV) and (X). This mixture, without isolation, is cyclized with aminoguanidine (V) by treatment first with NaOH in ethanol and then with refluxing AcOH.
〖参考〗Sorbera, L.A.; Castaer, J.; Martn, L.; Indiplon. Drugs Fut 2003, 28, 8, 739

〖目标产物〗Indiplon, NBI-34060
〖合成路线〗
〖合成方法〗Reaction of 3-(acetamido)acetophenone (VIII) with iodomethane and NaH gives 3-(N-methylacetamido)acetophenone (XXVIII), which is mixed with 3-oxo-3-(2-thienyl)propionitrile (VII) and treated with dimethylformamide dimethylacetal to yield a mixture of the dimethylaminomethylene derivatives (IV) and (X). This mixture, without isolation, is cyclized with aminoguanidine (V) by treatment first with NaOH in ethanol and then with refluxing AcOH.
〖参考〗Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868

〖目标产物〗
〖合成路线〗
〖合成方法〗2-Chlorobenzenesulfonyl chloride (I) was coupled to orcinol (II) to give sulfonate (III). Subsequent condensation of (III) with 3-benzyloxypropanol (IV) under Mitsunobu conditions afforded ether (V). After hydrogenolytic deprotection of the benzyl group, Swern oxidation of the resulting alcohol (VI) with DMSO and SO3-pyridine complex provided aldehyde (VII). The title amidinohydrazone was then obtained by treatment of (VII) with aminoguanidine nitrate (VIII).
〖参考〗Soll, R.M.; Lu, T.; Fedde, C.L.; Tomczuk, B.E.; Illig, C. (3-Dimensional Pharmaceuticals, Inc.); Amidinohydrazones as protease inhibitors. EP 0906091; JP 2000507588; US 5891909; WO 9736580

〖目标产物〗
〖合成路线〗
〖合成方法〗2-Chlorobenzenesulfonyl chloride (I) was coupled to orcinol (II) to give sulfonate (III). Subsequent condensation of (III) with 3-benzyloxypropanol (IV) under Mitsunobu conditions afforded ether (V). After hydrogenolytic deprotection of the benzyl group, Swern oxidation of the resulting alcohol (VI) with DMSO and SO3-pyridine complex provided aldehyde (VII). The title amidinohydrazone was then obtained by treatment of (VII) with aminoguanidine nitrate (VIII).
〖参考〗Tomczuk, B.E.; Stagnaro, T.P.; Fedde, C.L.; Lu, T.; Markotan, T.P.; Illig, C.R.; Soll, R.M. (3-Dimensional Pharmaceuticals, Inc.); Aminoguanidines and alkoxyguanidines as protease inhibitors. EP 0944590; WO 9823565

〖目标产物〗
〖合成路线〗
〖合成方法〗The condensation of nitroenamine (I) with aminoguanidine (II) afforded compound (III), which was subsequently cyclized to the title pyrazole by treatment with NaOH.
〖参考〗Makarov, V.; et al.; 4-Nitropyrazole derivatives as new exogenic donors of nitric oxide. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-120

〖目标产物〗T-162559, T-559
〖合成路线〗
〖合成方法〗Amination of cyclohexanedione derivative (I) with ammonium acetate in refluxing ethanol affords compound (II), which is converted into tetrahydroquinolinone derivative (IV) by condensation with 3-oxobutylaldehyde dimethylacetal (III) and cyclization by means of KOH in refluxing EtOH. The desired compound is finally obtained by first reaction of ketone (IV) with aminoguanidine hydrochloride (V) in refluxing EtOH/HCl, followed by formation of the corresponding dimethanesulfonate salt by treatment with methanesulfonic acid.
〖参考〗Imamiya, E.; Fujiwara, S.; Watanabe, T.; Shiraishi, M.; Fukumoto, S.; Kusumoto, K.; Novel, non-acylguanidine type Na+/H+ exchanger inhibitors: Synthesis and biological evaluation of tetrahydroquinolinylidene aminoguanidine derivatives. 20th Symp Med Chem blank'" title="点击查看详细合成路线">img s??缙

〖目标产物〗T-162559, T-559
〖合成路线〗
〖合成方法〗Amination of cyclohexanedione derivative (I) with ammonium acetate in refluxing ethanol affords compound (II), which is converted into tetrahydroquinolinone derivative (IV) by condensation with 3-oxobutylaldehyde dimethylacetal (III) and cyclization by means of KOH in refluxing EtOH. The desired compound is finally obtained by first reaction of ketone (IV) with aminoguanidine hydrochloride (V) in refluxing EtOH/HCl, followed by formation of the corresponding dimethanesulfonate salt by treatment with methanesulfonic acid.
〖参考〗Fukumoto, S.; et al.; Novel, non-acylguanidine-type Na+/H+ exchanger inhibitors: Synthesis and pharmacology of 5-tetrahydroquinolinylidene aminoguanidine derivatives. J Med Chem 2002, 45, 14, 3009

〖目标产物〗T-162559, T-559
〖合成路线〗
〖合成方法〗Amination of cyclohexanedione derivative (I) with ammonium acetate in refluxing ethanol affords compound (II), which is converted into tetrahydroquinolinone derivative (IV) by condensation with 3-oxobutylaldehyde dimethylacetal (III) and cyclization by means of KOH in refluxing EtOH. The desired compound is finally obtained by first reaction of ketone (IV) with aminoguanidine hydrochloride (V) in refluxing EtOH/HCl, followed by formation of the corresponding dimethanesulfonate salt by treatment with methanesulfonic acid.
〖参考〗Shiraishi, M.; Fukumoto, S.; Kusumoto, K. (Takeda Chemical Industries, Ltd.); Aminoguanidine hydrazone derivs., process for producing the same and drugs thereof. EP 1057812; JP 2000191641; WO 9942442

〖目标产物〗PR-9, ME-10092
〖合成路线〗
〖合成方法〗The title compound is prepared by condensation of 2-chloro-3,4-dimethoxybenzaldehyde (I) with aminoguanidine bicarbonate (II) in the presence of HOAc in refluxing MeOH.
〖参考〗Skottner, A.; Lundstedt, T.; Seifert, E.; Veveris, M.; Piskunova, I.; Rozhkov, E.; Wikberg, J.; Pett, C.P.; Kalvins, I.; Andrianov, V.; Semenikhina, V.; Dambrova, M. (Melacure Therapeutics); Guanidine derivs. and their use in the production of a medicamenblank'" title="点击查看详细合成路线">img s??缙i?jdth:500px;border: