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【结 构 式】 
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【分子编号】11292 【品名】3,6-Dichloropyridazine 【CA登记号】141-30-0 |
【 分 子 式 】C4H2Cl2N2 【 分 子 量 】148.97876 【元素组成】C 32.25% H 1.35% Cl 47.59% N 18.8% |
合成路线1
该中间体在本合成路线中的序号：(I)This compound can be prepared by two related ways: 1) The reaction of ethyl (2-hydroxypropyl)amine (A) with 3,6-dichloropyridazine (I) in refluxing toluene gives 3-chloro-6-[ethyl(2-hydroxypropyl)amino]pyridazine (II). This intermediate is then reacted with ethyl hydrazinecarboxylate (B) to afford (III). 2) Alternatively, compound (II) may be treated with hydrazine hydrate to afford the hydrazinopyridazine (IV); acylation of (IV) with ethoxycarbonyl chloride provides the final compound (III).
| 【1】 Pifferi, G.; Parravicini, F.; Scarpitta, G.; Dorigotti, L.; Derivati della 3-idrazinopiridazina. Nota III. Sintesi ed attivita antiipertensiva di nuove 3-(2-acilidrazino)piridazine-6-alchilamino sostituite. Farm Sci Ed 1979, 34, 299-310. |
| 【2】 Citero, L.; Visconti, M.; Borsa, M.; Pifferi, G.; Analytical profile of cadralazine, a new antihypttensive agent. Boll Chim Farm 1981, 120, 222-233. |
| 【3】 Carpi, C.; Dorigotti, L.; Pifferi, G. (ISF SpA); 6-Substituted 3-carbethoxyhydrazinopyridazines. US 4002753 . |
| 【4】 Meran, C.; Cadralazine. Drugs Fut 1982, 7, 6, 382. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 27366 | Ethyl hydrazinecarboxylate; Ethyl 1-hydrazinecarboxylate | 4114-31-2 | C3H8N2O2 | 详情 | 详情 |
| (A) | 31956 | Ethyl (2-hydroxypropyl)amine; 1-(Ethylamino)-2-propanol | 40171-86-6 | C5H13NO | 详情 | 详情 |
| (I) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (II) | 31957 | 3-Chloro-6-[ethyl(2-hydroxypropyl)amino]pyridazine; 1-[(6-Chloro-3-pyridazinyl)(ethyl)amino]-2-propanol | 64241-33-4 | C9H14ClN3O | 详情 | 详情 |
| (III) | 31958 | ethyl 2-[6-[ethyl(2-hydroxypropyl)amino]-3-pyridazinyl]-1-hydrazinecarboxylate | C12H21N5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The starting compound is 3,6-dichloropyridazine (I), which is reacted with morpholine (II) in a suitable solvent to give 3-morpholino-6-chloropyridazine (III). This, upon reaction with hydrazine hydrate as solvent, gives the hydrazine derivative (IV), which by reaction with acetonylacetone (V) in acetic acid yields directly the title compound. [14C]-Labeled compound is synthesized by a microscale procedure with 45% chemical yield and 98% radiochemical purity.
| 【1】 Assandri, A.; et al.; Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog. Arzneim-Forsch Drug Res 1985, 35, 2, 508. |
| 【2】 Koch, H.; Mopidralazine. Drugs Fut 1985, 10, 8, 634. |
| 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) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (II) | 10308 | 2-Chloronicotinonitrile; 2-Chloro-3-cyanopyridine | 6602-54-6 | C6H3ClN2 | 详情 | 详情 |
| (III) | 24846 | 4-(6-chloro-3-pyridazinyl)morpholine | C8H10ClN3O | 详情 | 详情 | |
| (IV) | 24847 | 4-(6-hydrazino-3-pyridazinyl)morpholine | C8H13N5O | 详情 | 详情 | |
| (V) | 24848 | acetonyl acetone;1,2-Diacetylethane;a,b-Diacetylethane;2,5-Diketohexane;Diacetonyl;Acetonylacetone;2,5-Dioxohexane;2,5-hexanedione | 110-13-4 | C6H10O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Heating of 3,6-dichloropyridazine (I) with hydrazine hydrate at 100 C gives 6-chloro-3-pyridazinylhydrazine (II). The hydrazino group is protected by transforming it with camphor (III) to the camphorhydrazone (IV), which is aminated by heating with morpholine to give the morpholinylhydrazone (V). After liberating the hydrazine function by acidic hydrolysis in a biphasic system, the resulting 6-morpholino-3-pyridazinylhydrazine (VI) is reacted either with tert-butylacetoacetate (VII) or with tert-butylpropiolate (VIII) to yield RGH-5526.
| 【1】 Inoue, H.; Yoshida, M.; Aizawa, H.; et al.; Eur J Med Chem 1984, 19, 6, 111-117. |
| 【2】 Szilagyi, G.; et al. (Gedeon Richter Ltd.); Morpholino pyridazinylhydrazones. DE 2825861; FR 2394535; GB 2000125; HU 176972; JP 54016486; US 4259328; US 4308386 . |
| 【3】 Nogradi, M.; RGH-5526. Drugs Fut 1985, 10, 1, 32. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (I) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (II) | 28922 | 3-chloro-6-hydrazinopyridazine | 17284-97-8 | C4H5ClN4 | 详情 | 详情 |
| (III) | 28926 | 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one | 464-48-2 | C10H16O | 详情 | 详情 |
| (IV) | 28923 | 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one N-(6-chloro-3-pyridazinyl)hydrazone | C14H19ClN4 | 详情 | 详情 | |
| (V) | 28924 | 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one N-[6-(4-morpholinyl)-3-pyridazinyl]hydrazone | C18H27N5O | 详情 | 详情 | |
| (VI) | 24847 | 4-(6-hydrazino-3-pyridazinyl)morpholine | C8H13N5O | 详情 | 详情 | |
| (VII) | 27907 | Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate | 1694-31-1 | C8H14O3 | 详情 | 详情 |
| (VIII) | 28925 | tert-butyl propiolate | 13831-03-3 | C7H10O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)N-Alkylation of 1-(3-methylphenyl)piperazine with 3,6-dichloropyridazine in dimethylformamide as a solvent and in the presence of sodium carbonate afforded 3-chloro-6-[4-(3-methylphenyl-1-piperazinyl]pyridazine. The reactive chlorine atom in this intermediate was replaced by a methoxy group, by refluxing the compound in methanol containing an excess of sodium methoxide. After addition of water to the cooled reaction mixture the product crystallized. Recrystallization from 2-propanol produced pure 3-methoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine.
| 【1】 Andries, K.; Stokbroekx, R.; R 61837. Drugs Fut 1990, 15, 3, 237. |
合成路线5
该中间体在本合成路线中的序号：(I)Title compound can be prepared as shown in Scheme: 1) 3,6-Dichloropyridazine (I) is converted to 3(2H)-pyridazinone (III) in two steps. 2) 3-N-(2-Benzo[1,4]dioxanylmethyl)amino-1-propanol (V), obtained by the reaction of (2-benzo[1,4]dioxanylmethyl)-4-toluenesulfonate (IV) with 3-amino-1-propanol, is N-benzylated to form the N-protected amino alcohol (VI), which on treatment with thionyl chloride affords the chloroalkyl derivative (VII). 3) Alkylation of 3(2H)-pyridazinone (III) with (VII) under phase-transfer catalysis conditions to the N-benzylated GYKI-12743 (VIII) and then removal of the N-benzyl group by hydrogenation gives GYKI-12743.
| 【1】 Kasztreiner, E.; Rabloczky, G.; Makk, N.; Jaszlits, L.; Matyus, P.; Cseh, G.; Pribusz, geb. Rapp, I.; Czakó, K.; Diesler, E.; Elekes, I.; Kaufer, L.; Kuhár, geb. Kürthy, M.; Kincsessy, J.; Kosáry, J.; Nagy, Gyöngyi geb. C. (Richter Gedeon Vegyeszeti); 3(2H)-Pyridazinone derivs., a process and intermediates for preparing them and medicaments containing them and/or other 3(2H)-pyridazinone derivatives. AU 8664496; EP 0220735; JP 87161768 . |
| 【2】 Kasztreiner, E.; Matyus, P.; Rabloczky, G.; Jaszlits, L.; GYKI-12743. Drugs Fut 1989, 14, 7, 622. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 | |
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (II) | 20957 | 6-chloro-3(2H)-pyridazinone | C4H3ClN2O | 详情 | 详情 | |
| (III) | 20958 | 3(2H)-pyridazinone | C4H4N2O | 详情 | 详情 | |
| (IV) | 20959 | 2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylbenzenesulfonate | C16H16O5S | 详情 | 详情 | |
| (V) | 20960 | 3-[(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]-1-propanol | C12H17NO3 | 详情 | 详情 | |
| (VI) | 20961 | 3-[benzyl(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]-1-propanol | C19H23NO3 | 详情 | 详情 | |
| (VII) | 20962 | N-benzyl-3-chloro-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-propanamine; N-benzyl-N-(3-chloropropyl)-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amine | C19H22ClNO2 | 详情 | 详情 | |
| (VIII) | 20963 | 2-[3-[benzyl(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]propyl]-3(2H)-pyridazinone | C23H25N3O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(X)The pyridazinone intermediate (XII) was prepared from dihydroxypyridazine (IX) in three synthetic steps.
| 【1】 Matyus, P.; GYKI-16084. Drugs Fut 1999, 24, 10, 1072. |
| 【2】 3(2H)-Pyridazinone derivs. and pharmaceutical compsns. containing these cpds.. WO 9638441 . |
合成路线7
该中间体在本合成路线中的序号：(IV)3-Benzyl-3,8-diazabicyclo[3.2.1]octane (I) was protected at the N8 position with di tert-butyl dicarbonate in CH2Cl2, and carbamate (II) was then debenzylated by catalytic hydrogenolysis over Pd/C. The resulting bicyclic amine (III) was condensed with 3,6-dichloropyridazine (IV) in the presence of Et3N to give the Boc-protected intermediate (V), which was finally deprotected with HCl in Et2O.
| 【1】 Barlocco, D.; Tondi, D.; Cignarella, G.; et al.; Mono- and disubstituted-3,8-diazabicyclo[3.2.1]octane derivatives as analgesics structurally related to epibatidine: Synthesis, activity, and modeling. J Med Chem 1998, 41, 5, 674. |
| 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) | 25765 | 3-benzyl-3,8-diazabicyclo[3.2.1]octane | C13H18N2 | 详情 | 详情 | |
| (II) | 25766 | tert-butyl 3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate | C18H26N2O2 | 详情 | 详情 | |
| (III) | 25767 | tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate | C11H20N2O2 | 详情 | 详情 | |
| (IV) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (V) | 25768 | tert-butyl 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate | C15H21ClN4O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The condensation of 2-(2,6-dichlorophenyl)acetonitrile (I) with 3,6-dichloropyridazin-3-yl)acetonitrile (III), wich is condensed with 2,4-difluorothiophenol (IV) by means of NaH in THF to yield the thioether (V). The partial hydrolysis of the cyano group of (V) with conc. H2SO4 at 100 CC affords the acetamide (VI), wich is finally cyclized with N,N-dimethylformamidedimethylacetal (VII) in refluxing toluene te provide the target pyrimido-pyridazine derivative.
| 【1】 Salituro, F.G.; Duffy, J.P.; Murcko, M.A.; Bemis, G.W.; Su, M.; Wilson, K.P.; Cochran, J.E.; Harrington, E.M.; Galullo, V.P. (Vertex Pharmaceuticals Inc.); Substd. nitrogen containing heterocycles as inhibitors of p38 protein kinase. EP 0951467; JP 2001506266; WO 9827098 . |
| 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) | 18202 | 2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile | 3215-64-3 | C8H5Cl2N | 详情 | 详情 |
| (II) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (III) | 60561 | 2-(2,6-dichlorophenyl)-2-(6-methyl-3-pyridazinyl)acetonitrile | C13H9Cl2N3 | 详情 | 详情 | |
| (IV) | 60562 | 2,4-difluorobenzenethiol; 2,4-difluorophenylhydrosulfide | C6H4F2S | 详情 | 详情 | |
| (V) | 60563 | 2-(2,6-dichlorophenyl)-2-{6-[(2,4-difluorophenyl)sulfanyl]-3-pyridazinyl}acetonitrile | C18H9Cl2F2N3S | 详情 | 详情 | |
| (VI) | 60564 | 2-(2,6-dichlorophenyl)-2-{6-[(2,4-difluorophenyl)sulfanyl]-3-pyridazinyl}acetamide | C18H11Cl2F2N3OS | 详情 | 详情 | |
| (VII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Decarboxylative radical alkylation of 3,6-dichloropyridazine (I) using pivalic acid (II) and ammonium persulfate in the presence of silver nitrate catalyst furnished 3,6-dichloro-4-tert-butylpyridiazine (III). This was then condensed with 2,5-difluorobenzoyl hydrazide (IV) to produce the triazolopyridazine derivative (V). The remaining chlorine atom was finally displaced with (2-methyl-2H-1,2,4-triazol-3-yl)methanol (VI) using NaH in DMF to afford the title compound.
| 【1】 Madin, A.; Castro Pineiro, J.L.; Carling, W.R.; Street, L.J.; Russell, M.G.; Moore, K.W.; Guiblin, A.R.; Broughton, H.B. (Merck Sharp & Dohme Ltd.); Substd. triazolo-pyridazine derivs. as ligands for GABA receptors. EP 0915875; WO 9804559 . |
| 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) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (II) | 44281 | pivalic acid | 75-98-9 | C5H10O2 | 详情 | 详情 |
| (III) | 44282 | 4-(tert-butyl)-3,6-dichloropyridazine | C8H10Cl2N2 | 详情 | 详情 | |
| (IV) | 44283 | 2,5-difluorobenzohydrazide | C7H6F2N2O | 详情 | 详情 | |
| (V) | 44284 | 7-(tert-butyl)-6-chloro-3-(2,5-difluorophenyl)[1,2,4]triazolo[4,3-b]pyridazine | C15H13ClF2N4 | 详情 | 详情 | |
| (VI) | 44285 | (1-methyl-1H-1,2,4-triazol-5-yl)methanol | C4H7N3O | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)Pyridazinylpiperazine (III) was prepared from 3,6-dichloropyridazine (I) and N-methylpiperazine (II) according to a literature method. Subsequent quaternization of piperazine (III) with methyl iodide gave the title ammonium salt.
| 【1】 Romanelli, M.N.; et al.; Structure-affinity relationships of a unique nicotinic ligand: N1-dimethyl-N4-phenylpiperazinium iodide (DMPP). J Med Chem 2001, 44, 23, 3946. |
合成路线11
该中间体在本合成路线中的序号：(I)The condensation of 3,6-dichloropyridazine (I) with piperazine (II) by means of TEA in refluxing toluene gives 3-chloro-6-(1-piperazinyl)pyridazine (III), which is methylated with HCHO/ HCOOH at 110 C, yielding 3-chloro-6-(4-methylpiperazin-1-yl)pyridazine (IV). Finally, this compound is quaternized with methyl iodide in ethyl ether to provide the target dimethylpiperidinium salt.
| 【1】 Toma, L.; et al.; 6-Chloropyridazin-3-yl derivatives active as nicotinic agents: Synthesis, binding, and modeling studies. J Med Chem 2002, 45, 18, 4011. |
| 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) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 57015 | 3-chloro-6-(1-piperazinyl)pyridazine | C8H11ClN4 | 详情 | 详情 | |
| (IV) | 53381 | 3-chloro-6-(4-methyl-1-piperazinyl)pyridazine | 27464-17-1 | C9H13ClN4 | 详情 | 详情 |