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【结 构 式】 
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【分子编号】23611 【品名】N-cyanoguanidine 【CA登记号】461-58-5 |
【 分 子 式 】C2H4N4 【 分 子 量 】84.08072 【元素组成】C 28.57% H 4.8% N 66.63% |
合成路线1
该中间体在本合成路线中的序号：(II)This compound can be obtained by two different ways: 1) By cyclization of 2,5-dichlorobenzonitrile (I) with dicyandiamide (II) with KOH in refluxing methyl cellosolve, followed by treatment with maleic acid in dioxane. 2) By treatment of 2,4-dichloro-6-(2,5-dichlorophenyl)-s-triazine (III) with 28% aqueous ammonia at 100 C.
| 【1】 Murai, H.; Ohata, K.; Aoyagi, Y.; Ueda, F.; Kitano, M.; Takata, S.; Toda, S. (Nippon Shinyaku Co., Ltd.); Benzoguanamine derivatives. CH 592638; DE 2506814; FR 2261009; GB 1441904; JP 77111086; JP 7746955; NL 7501575; US 3966728 . |
| 【2】 Murai, H.; Ohata, K.; Aoyagi, Y.; Ueda, F. (Nippon Shinyaku Co., Ltd.); Dihalobenzoguanamines with anti-ulcus activity. CH 596193; JP 51075083; NL 7514062 . |
| 【3】 Serradell, M.N.; Blancafort, P.; Castaner, J.; MN-1695. Drugs Fut 1983, 8, 6, 502. |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of 2-chloro-4-fluorosulfonylbenzyl bromide (I) with triphenylphosphine (II) in refluxing benzene gives the corresponding triphenylphosphonium bromide (III), which is submitted to a Wittig condensation with 2-chloro-4-nitrocinnamaldehyde (IV) [prepared by an aldol condensation of 2-chloro-4-nitrobenzaldehyde (V) and acetaldehyde (VI)] yielding 1-(4-fluorosulfonyl-2-chlorophenyl)-4-(2-chloro-4-nitrophenyl)butadiene (VII). The reduction of (VII) with H2 over PtO2 in methoxyethanol affords 1-(4-fluorosulfonyl-2-chlorophenyl)-4-(2-chloro-4-aminophenyl)butane (VIII), which is finally cyclized with cyanoguanidine (IX) and acetone and treated with ethanesultonic acid.
| 【1】 Vermeulen, N.M.J.; Baker, B.R.; Irreversible enzyme inhibitors. CLXXVII. Active-site-directed irreversible inhibitos of dihydrofolate reductase derived from 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(phenylalkylphenyl)-s-triazines. J Med Chem 1970, 13, 6, 1154-60. |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Hillier, K.; NSC-127,755. Drugs Fut 1983, 8, 7, 596. |
| 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) | 36142 | 4-(bromomethyl)-3-chlorobenzenesulfonyl fluoride | C7H5BrClFO2S | 详情 | 详情 | |
| (III) | 36143 | [2-chloro-4-(fluorosulfonyl)benzyl](triphenyl)phosphonium bromide | C25H20BrClFO2PS | 详情 | 详情 | |
| (IV) | 36144 | (E)-3-(2-chloro-4-nitrophenyl)-2-propenal | C9H6ClNO3 | 详情 | 详情 | |
| (V) | 36145 | 2-chloro-4-nitrobenzaldehyde | C7H4ClNO3 | 详情 | 详情 | |
| (VI) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (VII) | 36146 | 4-[(1E,3E)-4-(4-amino-2-chlorophenyl)-1,3-butadienyl]-3-chlorobenzenesulfonyl fluoride | C16H12Cl2FNO2S | 详情 | 详情 | |
| (VIII) | 36147 | 4-[4-(4-amino-2-chlorophenyl)butyl]-3-chlorobenzenesulfonyl fluoride | C16H16Cl2FNO2S | 详情 | 详情 | |
| (IX) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
| (X) | 29169 | 1-ethanesulfonic acid | 594-45-6 | C2H6O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：The key intermediate alpha-(2-chloro-4-nitrophenoxy)-m-toluic acid (IV) is prepared from methyl m-toluate (I) by bromination with N-bromosuccinimide in the presence of benzoyl peroxide, then condensation with 2-chloro-4-nitrophenol, followed by basic hydrolysis. The carboxylic acid group of compound (IV) is converted to dimethylamide (VI) via acyl chloride (V). The nitro intermediate (VI) is hydrogenated over platinum oxide in 2-methoxyethanol. The resulting amine (VII) is then condensed with cyanoguanidine and acetone in the presence of ethanesulfonic acid to give triazinate.
| 【1】 Baker, B.R.; Ashton, W.T.; Irreversible enzyme inhibitors. CLXXIX. Active-site-directed irreversible enzyme inhibitors of dihydrofolate reductase from 1-(3-chlorophenyl)-4, 6-diamino-1,2-dihydro-2,2-dimethyl-s-triazine with oxyamine bridges to a terminal sulfonyl flouride. J Med Chem 1970, 13, 1165-70. |
| 【2】 Chang, P.; TRIAZINATE. Drugs Fut 1989, 14, 2, 138. |
| 【3】 Baker, B.R.; Ashton, W.T.; Water-soluble reversible inhibitors of dihydrofolate reductase with potent antitumor activity derived from 4,6-diamino-1,2-dihydro-2, 2-dimethyl-1-phenyl-s-triazine. J Med Chem 1973, 16, 209-14. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 | |
| 49872 | 1-Chloro-2-Hydroxy-5-Nitrobenzene; 2-Chloro-4-nitrophenol; 4-Nitro-2-chlorophenol; p-Nitro-o-chlorophenol | 619-08-9 | C6H4ClNO3 | 详情 | 详情 | |
| (I) | 20391 | methyl 3-methylbenzoate | 99-36-5 | C9H10O2 | 详情 | 详情 |
| (II) | 20392 | methyl 3-(bromomethyl)benzoate | 1129-28-8 | C9H9BrO2 | 详情 | 详情 |
| (III) | 20393 | methyl 3-[(2-chloro-4-nitrophenoxy)methyl]benzoate | C15H12ClNO5 | 详情 | 详情 | |
| (IV) | 20394 | 3-[(2-chloro-4-nitrophenoxy)methyl]benzoic acid | C14H10ClNO5 | 详情 | 详情 | |
| (V) | 20395 | 3-[(2-chloro-4-nitrophenoxy)methyl]benzoyl chloride | C14H9Cl2NO4 | 详情 | 详情 | |
| (VI) | 20396 | 3-[(2-chloro-4-nitrophenoxy)methyl]-N,N-dimethylbenzamide | C16H15ClN2O4 | 详情 | 详情 | |
| (VII) | 20397 | 3-[(4-amino-2-chlorophenoxy)methyl]-N,N-dimethylbenzamide | C16H17ClN2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Reduction of 3,4-dimethoxybenzaldehyde (I) with NaBH4 provided benzyl alcohol (II). After conversion of (II) to the benzyl chloride (III) using SOCl2, its reaction with PPh3 (IV) in refluxing xylene afforded phosphonium salt (V). Subsequent Wittig reaction of the corresponding ylide with 4,4-(ethylenedioxy)cyclohexanone (VI) produced the benzylidene derivative (VII), which was reduced to benzyl compound (VIII) by catalytic hydrogenation over Pd/C. The ketal protecting group of (VIII) was then removed by acid hydrolysis to yield cyclohexanone (IX). Finally, the target tetrahydroquinazoline was obtained by condensation of (IX) with cyanoguanidine (X) at 180 C.
| 【1】 Papoulis, A.T.; Queener, S.F.; Rosowsky, A.; Forsch, R.A.; Synthesis and antiparasitic and antitumor activity. J Med Chem 1999, 42, 6, 1007. |
| 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) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (II) | 23603 | (3,4-dimethoxyphenyl)methanol | 93-03-8 | C9H12O3 | 详情 | 详情 |
| (III) | 23604 | 4-(chloromethyl)-2-methoxyphenyl methyl ether; 4-(chloromethyl)-1,2-dimethoxybenzene | 7306-46-9 | C9H11ClO2 | 详情 | 详情 |
| (IV) | 23605 | trimethylphosphine | 594-09-2 | C3H9P | 详情 | 详情 |
| (V) | 23606 | (3,4-dimethoxybenzyl)(trimethyl)phosphonium | C12H20O2P | 详情 | 详情 | |
| (VI) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (VII) | 23608 | 8-(3,4-dimethoxybenzylidene)-1,4-dioxaspiro[4.5]decane; 4-(1,4-dioxaspiro[4.5]dec-8-ylidenemethyl)-2-methoxyphenyl methyl ether | C17H22O4 | 详情 | 详情 | |
| (VIII) | 23609 | 4-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-2-methoxyphenyl methyl ether; 8-(3,4-dimethoxybenzyl)-1,4-dioxaspiro[4.5]decane | C17H24O4 | 详情 | 详情 | |
| (IX) | 23610 | 4-(3,4-dimethoxybenzyl)cyclohexanone | C15H20O3 | 详情 | 详情 | |
| (X) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)Reduction of 3,4,5-trimethoxybenzaldehyde (I) with NaBH4 provided benzyl alcohol (II). After conversion of (II) to the benzyl chloride (III) using SOCl2, its reaction with PPh3 (IV) in refluxing xylene afforded phosphonium salt (V). Subsequent Wittig reaction of the corresponding ylide with 4,4-(ethylenedioxy)cyclohexanone (VI) produced the benzylidene derivative (VII), which was reduced to benzyl compound (VIII) by catalytic hydrogenation over Pd/C. The ketal protecting group of (VIII) was then removed by acid hydrolysis to yield cyclohexanone (IX). Finally, the target tetrahydroquinazoline was obtained by condensation of (IX) with cyanoguanidine (X) at 180 C.
| 【1】 Papoulis, A.T.; Queener, S.F.; Rosowsky, A.; Forsch, R.A.; Synthesis and antiparasitic and antitumor activity. J Med Chem 1999, 42, 6, 1007. |
| 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) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (II) | 23613 | (3,4,5-trimethoxyphenyl)methanol | 3840-31-1 | C10H14O4 | 详情 | 详情 |
| (III) | 14072 | 3,4,5-Trimethoxybenzyl chloride; 5-(Chloromethyl)-1,2,3-trimethoxybenzene; 4-(Chloromethyl)-2,6-dimethoxyphenyl methyl ether | 3840-30-0 | C10H13ClO3 | 详情 | 详情 |
| (IV) | 23605 | trimethylphosphine | 594-09-2 | C3H9P | 详情 | 详情 |
| (V) | 23615 | triphenyl(3,4,5-trimethoxybenzyl)phosphonium | C28H28O3P | 详情 | 详情 | |
| (VI) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (VII) | 23616 | 4-(1,4-dioxaspiro[4.5]dec-8-ylidenemethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzylidene)-1,4-dioxaspiro[4.5]decane | C18H24O5 | 详情 | 详情 | |
| (VIII) | 23617 | 4-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzyl)-1,4-dioxaspiro[4.5]decane | C18H26O5 | 详情 | 详情 | |
| (IX) | 23618 | 4-(3,4,5-trimethoxybenzyl)cyclohexanone | C16H22O4 | 详情 | 详情 | |
| (X) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The reaction of benzohydroxamic acid (I) with benzyl bromide (II) by means of NaOH on ethanol gives the corresponding benzyl ester (III), which is treated with HCl yielding O-benzylhydroxylamine (IV). The reaction of (IV) with dicyaniamide (V) in ethanol affords the biguanide (VI), which is cyclized with cyclopentanone (VII) and HCl giving 1-benzyloxy-2,2-dimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine (VIII). The debenzylation of (VIII) with H2 over PtO2 in ethanol yields 1-hydroxy-2,2-dimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine (IX), which is finally condensed with 1,6-dibromohexane (X) by means of NaOH in methanol.
| 【1】 Zhang, X.P.; Shen, J.; Xin, Z.M.; Qiu, Q.P.; Zhou, W.C.; Synthesis and antiprotozoal activities of some new triazine derivatives including a new antitrypanosomal agent: SIPI-1029. Acta Pharm Sin 1996, 31, 11, 823. |
| 【2】 Zhou, W.; Zhang, X.; Trybizine Hydrochloride. Drugs Fut 1999, 24, 10, 1084. |
| 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) | 24777 | N-hydroxybenzamide | 495-18-1 | C7H7NO2 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 24779 | N-(benzyloxy)benzamide | C14H13NO2 | 详情 | 详情 | |
| (IV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (V) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
| (VI) | 24782 | 1-[([[[[amino(imino)methyl]amino](imino)methyl]amino]oxy)methyl]benzene | C9H13N5O | 详情 | 详情 | |
| (VII) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (VIII) | 24784 | 10-(benzyloxy)-6,8,10-triazaspiro[4.5]deca-6,8-diene-7,9-diamine | C14H19N5O | 详情 | 详情 | |
| (IX) | 24785 | 7,9-diamino-6,8,10-triazaspiro[4.5]deca-7,9-dien-6-ol | C7H13N5O | 详情 | 详情 | |
| (X) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The reaction of benzohydroxamic acid (I) with 1,6-dibromohexane (X) by means of NaOH in methanol gives the bis benzohydroxamic ester (XI), which is treated with HCl to afford the subituted bis hydroxylamine (XII). The reaction of (XII) with dicyandiamide (V) in ethanol yields the bis biguanide (XIII), which is finally cyclized with cyclopentanone (VII) and HCl as before.
| 【1】 Zhang, X.P.; Shen, J.; Xin, Z.M.; Qiu, Q.P.; Zhou, W.C.; Synthesis and antiprotozoal activities of some new triazine derivatives including a new antitrypanosomal agent: SIPI-1029. Acta Pharm Sin 1996, 31, 11, 823. |
| 【2】 Zhou, W.; Zhang, X.; Trybizine Hydrochloride. Drugs Fut 1999, 24, 10, 1084. |
| 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) | 24777 | N-hydroxybenzamide | 495-18-1 | C7H7NO2 | 详情 | 详情 |
| (V) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
| (VII) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (X) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (XI) | 24787 | N-([6-[(benzoylamino)oxy]hexyl]oxy)benzamide | C20H24N2O4 | 详情 | 详情 | |
| (XII) | 24788 | 1,6-bis(aminooxy)hexane | C6H16N2O2 | 详情 | 详情 | |
| (XIII) | 24789 | 1,6-bis([[[[amino(imino)methyl]amino](imino)methyl]amino]oxy)hexane | C10H24N10O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)The reaction of 2,4,5-trichlorophenol (I) with 1,3-dibromopropane (II) by means of refluxing 25% aqueous NaOH gives 3-(2,4,5-trichlorophenoxy)propyl bromide (III), which is condensed with benzhydroxamic acid (IV) by means of NaOH in refluxing methanol yielding 3-(2,4,5-trichlorophenoxy)propyl benzhydroxamate (V). The hydrolysis of (V) with HCl in refluxing methanol affords 3-(2,4,5-trichlorophenoxy)propyloxyamine (VI), which is then condensed with dicyandiamide (VII) in refluxing ethanol to give 3'-(2,4,5-trichlorophenoxy)propyloxydiguanide (VIII). Finally, this compound is cyclized with acetone (IX) by means of HCl.
| 【1】 Castañer, J.; Thorpe, P.J.; Blancafort, P.; Serradell, M.N.; BRL-6231. Drugs Fut 1982, 7, 10, 724. |
| 【2】 Mamalis, P.; Outred, D.I. (SmithKline Beecham plc); Di-hydro triazine derivatives and processes for their manufacture. DE 1957769; ES 373657; FR 2023866; GB 1270831 . |
| 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) | 16126 | 2,4,5-trichlorophenol | 95-95-4 | C6H3Cl3O | 详情 | 详情 |
| (II) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (III) | 37140 | 1-(3-bromopropoxy)-2,4,5-trichlorobenzene; 3-bromopropyl 2,4,5-trichlorophenyl ether | C9H8BrCl3O | 详情 | 详情 | |
| (IV) | 37141 | N-hydroxybenzenecarboximidic acid | C7H7NO2 | 详情 | 详情 | |
| (V) | 37142 | N-[3-(2,4,5-trichlorophenoxy)propoxy]benzenecarboximidic acid | C16H14Cl3NO3 | 详情 | 详情 | |
| (VI) | 37143 | O-[3-(2,4,5-trichlorophenoxy)propyl]hydroxylamine; 1-[3-(aminooxy)propoxy]-2,4,5-trichlorobenzene | C9H10Cl3NO2 | 详情 | 详情 | |
| (VII) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
| (VIII) | 37144 | 1-[3-([[[[amino(imino)methyl]amino](imino)methyl]amino]oxy)propoxy]-2,4,5-trichlorobenzene | C11H14Cl3N5O2 | 详情 | 详情 | |
| (IX) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |