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【结 构 式】 
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【分子编号】23813 【品名】2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine 【CA登记号】108-77-0 |
【 分 子 式 】C3Cl3N3 【 分 子 量 】184.41132 【元素组成】C 19.54% Cl 57.67% N 22.79% |
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 in two different ways: 1) By reaction of cyanuric chloride (I) with dimethylamine (A) in acetone. 2) By reduction of hexamethylolmelamine hexamethyl ether (II) with H2 over Raney-Ni in methanol - water at 100 C and under pressure.
| 【1】 Gunduz, T.; Hexamethylmelamine [2,4,6-tris(dimethylamino)-1,3,5-triazine]. Commun Fac Sci Univ Ankara 1968, 15, 6, 69-73. |
| 【2】 US 3424752 . |
| 【3】 Rutty, C.J.; Castaner, J.; Blancafort, P.; Serradell, M.N.; Hexamethylmelamine. Drugs Fut 1980, 5, 10, 492. |
| 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) | 19443 | N-methylmethanamine; N,N-dimethylamine | 124-40-3 | C2H7N | 详情 | 详情 |
| (I) | 23813 | 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine | 108-77-0 | C3Cl3N3 | 详情 | 详情 |
| (II) | 39213 | N(2),N(2),N(4),N(4),N(6),N(6)-hexakis(methoxymethyl)-1,3,5-triazine-2,4,6-triamine; N-[4,6-bis[bis(methoxymethyl)amino]-1,3,5-triazin-2-yl]-N,N-bis(methoxymethyl)amine | 3089-11-0 | C15H30N6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Treatment of cyanuric chloride (I) with methylmagnesium chloride afforded 2,4-dichloro-6-methyltriazine (II), which was condensed with aniline (III) to produce the anilinotriazine (IV). Subsequent displacement of the remaining chlorine atom of (IV) with morpholine (V) provided (VI). The target compound was then obtained by N-alkylation with iodoethane in the presence of NaH, followed by conversion to the methanesulfonate salt).
| 【1】 Arvanitis, A.G.; Chorvat, R.J.; Gilligan, P.J.; et al.; Non-peptide corticotropin-releasing hormone antago. J Med Chem 1999, 42, 5, 805. |
| 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) | 23813 | 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine | 108-77-0 | C3Cl3N3 | 详情 | 详情 |
| (II) | 23814 | 2,4-dichloro-6-methyl-1,3,5-triazine | C4H3Cl2N3 | 详情 | 详情 | |
| (III) | 23815 | 2-bromo-4,6-dimethoxyphenylamine; 2-bromo-4,6-dimethoxyaniline | C8H10BrNO2 | 详情 | 详情 | |
| (IV) | 23816 | N-(2-bromo-4,6-dimethoxyphenyl)-N-(4-chloro-6-methyl-1,3,5-triazin-2-yl)amine; N-(2-bromo-4,6-dimethoxyphenyl)-4-chloro-6-methyl-1,3,5-triazin-2-amine | C12H12BrClN4O2 | 详情 | 详情 | |
| (VI) | 23818 | N-(2-bromo-4,6-dimethoxyphenyl)-N-[4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amine; N-(2-bromo-4,6-dimethoxyphenyl)-4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine | C16H20BrN5O3 | 详情 | 详情 | |
| (X) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(B)Treatment of N-(benzyloxycarbonyl)-L-glutamine (XXVIII) with (trimethylsilyl)-diazomethane provided methyl ester (XXIX). Nitrile (XXX) was then obtained from (XXIX) by dehydration with cyanuryl chloride. Hydrolysis of the methyl ester of (XXX) with LiOH gave (XXXI), and hydrogenolysis of the carbobenzoxy group provided amino acid (XXXII). Alternatively, amino acid (XXXII) could be obtained by direct amide dehydration of (XXVIII) with Ac2O and pyridine, followed by transfer hydrogenolysis of the Cbz protecting group. Diazotization of amino acid (XXXII) with NaNO2 in the presence of H2SO4 then furnished (S)-2-hydroxy-4-cyanobutyric acid (XXXIII).
| 【1】 Boger, D.L.; et al.; Total synthesis of HUN-7293. J Am Chem Soc 1999, 121, 26, 6197. |
| 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) | 23813 | 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine | 108-77-0 | C3Cl3N3 | 详情 | 详情 |
| (XXVIII) | 26289 | (2S)-5-amino-2-[[(benzyloxy)carbonyl]amino]-5-oxopentanoic acid | C13H16N2O5 | 详情 | 详情 | |
| (XXIX) | 26290 | methyl (2S)-5-amino-2-[[(benzyloxy)carbonyl]amino]-5-oxopentanoate | C14H18N2O5 | 详情 | 详情 | |
| (XXX) | 26291 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-4-cyanobutanoate | C14H16N2O4 | 详情 | 详情 | |
| (XXXI) | 26292 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-cyanobutyric acid | C13H14N2O4 | 详情 | 详情 | |
| (XXXII) | 26293 | (2S)-2-amino-4-cyanobutyric acid | C5H8N2O2 | 详情 | 详情 | |
| (XXXIII) | 26294 | (2S)-4-cyano-2-hydroxybutyric acid | C5H7NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The reaction of stilbenediamine (I) with cyanuryl chloride (II) in dioxane gives the bis triazine derivative (III), which is further condensed with the substituted 3-aminobenzenesulfonamide (IV) in DMSO. The preceding synthesis can also be performed using cyanuryl fluoride instead of cyanuryl chloride as before.
| 【1】 Mitsner, B.; Ding, W.-D.; Krishnamurthy, G.; et al.; Novel and specific respiratory syncytial virus inhibitors that target virus fusion. J Med Chem 1998, 41, 15, 2671. |
| 【2】 Ding, W.-D.; Gluzman, Y.; Morin, J.E.; Mitsner, B.; Ellestad, G.A.; Nikitenko, A.A.; O'Hara, B.M.; Larocque, J.P.; Raifeld, Y.E. (American Cyanamid Co.); Bis-aryloxy(amino)-triazinyl-oxy(amino)aryl derivs., their preparation and their use as antiviral agents. CA 2197393; EP 0795549; JP 1997309882; US 5852015 . |
| 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) | 25917 | 5-amino-2-[(E)-2-(4-amino-2-sulfonatophenyl)ethenyl]benzenesulfonate | C14H12N2O6S2 | 详情 | 详情 | |
| (II) | 23813 | 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine | 108-77-0 | C3Cl3N3 | 详情 | 详情 |
| (III) | 25918 | 5-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-2-((E)-2-[4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-2-sulfonatophenyl]ethenyl)benzenesulfonate | C20H10Cl4N8O6S2 | 详情 | 详情 | |
| (IV) | 25919 | 3-[(3-amino-3-oxopropyl)[(3-aminophenyl)sulfonyl]amino]propanamide | C12H18N4O4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of cyanuryl chloride (II) with the substituted 3-aminobenzenesulfonamide (IV) in dioxane gives the bissulfonamide (V), which is finally condensed with stilbenediamine in sulfolane (I).
| 【1】 Ding, W.-D.; Gluzman, Y.; Morin, J.E.; Mitsner, B.; Ellestad, G.A.; Nikitenko, A.A.; O'Hara, B.M.; Larocque, J.P.; Raifeld, Y.E. (American Cyanamid Co.); Bis-aryloxy(amino)-triazinyl-oxy(amino)aryl derivs., their preparation and their use as antiviral agents. CA 2197393; EP 0795549; JP 1997309882; US 5852015 . |
| 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) | 25917 | 5-amino-2-[(E)-2-(4-amino-2-sulfonatophenyl)ethenyl]benzenesulfonate | C14H12N2O6S2 | 详情 | 详情 | |
| (II) | 23813 | 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine | 108-77-0 | C3Cl3N3 | 详情 | 详情 |
| (IV) | 25919 | 3-[(3-amino-3-oxopropyl)[(3-aminophenyl)sulfonyl]amino]propanamide | C12H18N4O4S | 详情 | 详情 | |
| (V) | 25920 | 3-[(3-amino-3-oxopropyl)[(3-[[4-(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-6-chloro-1,3,5-triazin-2-yl]amino]phenyl)sulfonyl]amino]propanamide | C27H34ClN11O8S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)As shown in Scheme 26628603a, both pathways are based on the stepwise replacement of the chlorine atoms in cyanuric chloride (I) with amines under increasingly harsher conditions. For example, the first chlorine atom was exchanged quite easily with the appropriate amine at 0 C for a few minutes. Exchange of the second chlorine required a reaction temperature of about 50 C for 3 h. Displacement of the third chlorine required still more drastic conditions with temperatures between 100-120 C and for 20-40 h. The stepwise condensation of the diaminobiphenyldisulfonate (II) corresponding to the central core of the inhibitor, with 2 moles of cyanuric chloride yielded the tetrachloro intermediate (III). The latter was transformed to the dichloro derivatives (IV) with the appropriate amine and then to the target compound by adding addition al amine to fill out the periphery of the molecule. These stepwise procedures were carried out in organic-aqueous media at neutral pH. For the alternative pathway, reaction of cyanuric chloride with an amine (VI) at 0 C and then the same amine (VI) at 50 C gave the uncharged synthon (VII). Condensation of the substituted monochlorotriazine (VII) with the aminobiphonyldisulfonate (II) at 100-120 C in dry organic media and in the presence of an amine provided the target compound. The reaction of substituted chlorotriazinea with amines at intermediate stages could be stopped to isolate compounds (VIII) or (IX). These were then used for the synthesis of RSV fusion inhibitors with specific functional groups such as those suitable for photoaffinity and radio labeling experiments. Biotinylated derivatives with spacers or linkers were also prepared from these intermediates for use in surface plasmon resonance studies.
| 【1】 Aulabaugh, A.; et al.; Inhibition of respiratory syncytial virus by a new class of chemotherapeutic agents. Drugs Fut 2000, 25, 3, 287. |
| 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) | 23813 | 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine | 108-77-0 | C3Cl3N3 | 详情 | 详情 |
| (II) | 33840 | disodium 5-amino-2-[(E)-2-(4-amino-2-sulfonatophenyl)ethenyl]benzenesulfonate | C14H12N2Na2O6S2 | 详情 | 详情 | |
| (III) | 33847 | disodium 5-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-2-((E)-2-[4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-2-sulfonatophenyl]ethenyl)benzenesulfonate | C20H10Cl4N8Na2O6S2 | 详情 | 详情 | |
| (IV) | 33836 | disodium 5-[[4-(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-6-chloro-1,3,5-triazin-2-yl]amino]-2-[(E)-2-(4-[[4-(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-6-chloro-1,3,5-triazin-2-yl]amino]-2-sulfonatophenyl)ethenyl]benzenesulfonate | C44H44Cl2N16Na2O14S4 | 详情 | 详情 | |
| (V) | 25919 | 3-[(3-amino-3-oxopropyl)[(3-aminophenyl)sulfonyl]amino]propanamide | C12H18N4O4S | 详情 | 详情 | |
| (VI) | 33838 | 3-[(3-amino-3-oxopropyl)([3-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]phenyl]sulfonyl)amino]propanamide | C15H17Cl2N7O4S | 详情 | 详情 | |
| (VII) | 25920 | 3-[(3-amino-3-oxopropyl)[(3-[[4-(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-6-chloro-1,3,5-triazin-2-yl]amino]phenyl)sulfonyl]amino]propanamide | C27H34ClN11O8S2 | 详情 | 详情 | |
| (VIII) | 33837 | disodium 5-[[4-(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-6-chloro-1,3,5-triazin-2-yl]amino]-2-[(E)-2-(4-[[4,6-bis(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-1,3,5-triazin-2-yl]amino]-2-sulfonatophenyl)ethenyl]benzenesulfonate | C56H61ClN20Na2O18S5 | 详情 | 详情 | |
| (IX) | 33841 | disodium 5-amino-2-[(E)-2-(4-[[4,6-bis(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-1,3,5-triazin-2-yl]amino]-2-sulfonatophenyl)ethenyl]benzenesulfonate | C41H45N13Na2O14S4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)As shown in Scheme 26628701a, both pathways are based on the stepwise replacement of the chlorine atoms in cyanuric chloride (I) with amines under increasingly harsher conditions. For example, the first chlorine atom was exchanged quite easily with the appropriate amine at 0 C for a few minutes. Exchange of the second chlorine required a reaction temperature of about 50 C for 3 h. Displacement of the third chlorine required still more drastic conditions with temperatures between 100-120 C and for 20-40 h. The stepwise condensation of the diaminobiphenyldisulfonate (II) corresponding to the central core of the inhibitor, with 2 moles of cyanuric chloride yielded the tetrachloro intermediate (III). The latter was transformed to the dichloro derivatives (IV) with the appropriate amine and then to the target compound by adding addition al amine to fill out the periphery of the molecule. These stepwise procedures were carried out in organic-aqueous media at neutral pH. For the alternative pathway, reaction of cyanuric chloride with an amine (VI) at 0 C and then the same amine (VI) at 50 C gave the uncharged synthon (VII). Condensation of the substituted monochlorotriazine (VII) with the aminobiphonyldisulfonate (II) at 100-120 C in dry organic media and in the presence of an amine provided the target compound. The reaction of substituted chlorotriazinea with amines at intermediate stages could be stopped to isolate compounds (VIII) or (IX). These were then used for the synthesis of RSV fusion inhibitors with specific functional groups such as those suitable for photoaffinity and radio labeling experiments. Biotinylated derivatives with spacers or linkers were also prepared from these intermediates for use in surface plasmon resonance studies.
| 【1】 Aulabaugh, A.; et al.; Inhibition of respiratory syncytial virus by a new class of chemotherapeutic agents. Drugs Fut 2000, 25, 3, 287. |
| 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) | 23813 | 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine | 108-77-0 | C3Cl3N3 | 详情 | 详情 |
| (II) | 33843 | disodium 4,4'-diamino[1,1'-biphenyl]-2,2'-disulfonate | C12H10N2Na2O6S2 | 详情 | 详情 | |
| (III) | 33846 | disodium 4,4'-bis[(4,6-dichloro-1,3,5-triazin-2-yl)amino][1,1'-biphenyl]-2,2'-disulfonate | C18H8Cl4N8Na2O6S2 | 详情 | 详情 | |
| (IV) | 33844 | disodium 4,4'-bis[[4-(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-6-chloro-1,3,5-triazin-2-yl]amino][1,1'-biphenyl]-2,2'-disulfonate | C42H42Cl2N16Na2O14S4 | 详情 | 详情 | |
| (V) | 25919 | 3-[(3-amino-3-oxopropyl)[(3-aminophenyl)sulfonyl]amino]propanamide | C12H18N4O4S | 详情 | 详情 | |
| (VI) | 33838 | 3-[(3-amino-3-oxopropyl)([3-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]phenyl]sulfonyl)amino]propanamide | C15H17Cl2N7O4S | 详情 | 详情 | |
| (VII) | 25920 | 3-[(3-amino-3-oxopropyl)[(3-[[4-(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-6-chloro-1,3,5-triazin-2-yl]amino]phenyl)sulfonyl]amino]propanamide | C27H34ClN11O8S2 | 详情 | 详情 | |
| (VIII) | 33845 | disodium 4-[[4-(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-6-chloro-1,3,5-triazin-2-yl]amino]-4'-[[4,6-bis(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-1,3,5-triazin-2-yl]amino][1,1'-biphenyl]-2,2'-disulfonate | C54H59ClN20Na2O18S5 | 详情 | 详情 | |
| (IX) | 33842 | disodium 4-amino-4'-[[4,6-bis(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-1,3,5-triazin-2-yl]amino][1,1'-biphenyl]-2,2'-disulfonate | C39H43N13Na2O14S4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)Addition of phenylmagnesium bromide (VII) to cyanuric chloride (VI) provided 2,4-dichloro-6-phenyltriazine (VIII). This was subsequently condensed with aniline (V) to afford the aminotriazine (IX). Finally, displacement of the remaining chlorine of (IX) with 2-(3-pyridyl)ethylamine (X) furnished the target diaminotriazine derivative.
| 【1】 Murali Dhar, T.G.; Pitts, W.J.; Guo, J.; et al.; Rapid synthesis of novel inosine monophosphate dehydrogenase (IMPDH) inhibitors. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 214. |
| 【2】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 39658 | C10H10N2O2 | 详情 | 详情 | ||
| (VI) | 23813 | 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine | 108-77-0 | C3Cl3N3 | 详情 | 详情 |
| (VII) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (VIII) | 53552 | 4,6-Dichloro-2-phenyltriazine | 1700-02-3 | C9H5Cl2N3 | 详情 | 详情 |
| (IX) | 53553 | N-(4-chloro-6-phenyl-1,3,5-triazin-2-yl)-N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]amine; 4-chloro-N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]-6-phenyl-1,3,5-triazin-2-amine | n/a | C19H14ClN5O2 | 详情 | 详情 |
| (X) | 53554 | 2-(3-Pyridyl)ethylamine; 3-(2-Aminoethyl)pyridine | 20173-24-4 | C7H10N2 | 详情 | 详情 |