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【结 构 式】 
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【分子编号】28804 【品名】2,4,6-trimethylaniline 【CA登记号】88-05-1 |
【 分 子 式 】C9H13N 【 分 子 量 】135.20896 【元素组成】C 79.95% H 9.69% N 10.36% |
合成路线1
该中间体在本合成路线中的序号：(C)HL-725 has been synthesized in a variety of ways: 1) 1-Carbamoylmethylene-6,7-methoxy-1,2,3,4-tetrahydroisoquinoline (I) was cyclized on treatment with diethylcarbonate (A) to give 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-2,4-dione (II). Methylation of (II) with methyliodide in dimethylformamide in the presence of sodium hydride afforded (III). The N-methyl compound (III) was treated with phosphorous pentasulfide to give the thio compound (IV). Reaction of (IV) with mesidine (C) afforded HL-725. 2) Alternately, the compound (II) was reacted with phosphorous oxychloride to yield the chloro compound (V), which was then reacted with mesidine to give the mesitylino derivative (VI). Methylation of (VI) with methyliodide afforded HL-725 and the exo-N-methyl isomer (VII), which were separated chromatographcally. 3) 3,4-Dimethoxy-beta-phenethyl bromide (VIII) was reacted with barbituric acid (B) to give the alkylated product (IX). Bischler-Napieralski-type cyclization afforded (II), which was then converted to HL-725 by the appropriate route.
| 【1】 DE 2720085 . |
| 【2】 Lal, B.; D'Sa, A.; 33rd Ind Pharm Cong (Dec 21, Jaipur) 1981, 16, Suppl. 1. |
| 【3】 de Souza, N.J.; Dadkar, N.K.; Lal, B.; D'Sa, A.; Dohadwalla, A.N.; Trequinsin, a potent antihypertensive vasodilator in the series of 2-(arylimino)-3-alkyl-9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido-[6,1-a]isoquinolin-4-ones. J Med Chem 1984, 27, 1470-80. |
| 【4】 Sas, G.; Blasko, G.; Trequinsin and its analogs. Drugs Fut 1989, 14, 11, 1083-91. |
| 【5】 Arya, V.P.; HL-725. Drugs Fut 1982, 7, 6, 390. |
| 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) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (B) | 36445 | 2,4,6(1H,3H,5H)-pyrimidinetrione | 67-52-7 | C4H4N2O3 | 详情 | 详情 |
| (I) | 36436 | 2-[6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene]acetamide | C13H16N2O3 | 详情 | 详情 | |
| (II) | 36437 | 9,10-dimethoxy-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-2,4(3H)-dione | C14H14N2O4 | 详情 | 详情 | |
| (III) | 36438 | 9,10-dimethoxy-3-methyl-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-2,4(3H)-dione | C15H16N2O4 | 详情 | 详情 | |
| (IV) | 36439 | 9,10-dimethoxy-3-methyl-2-thioxo-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one | C15H16N2O3S | 详情 | 详情 | |
| (V) | 36440 | 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one | C14H13ClN2O3 | 详情 | 详情 | |
| (VI) | 36441 | 2-(mesitylamino)-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one | C23H25N3O3 | 详情 | 详情 | |
| (VII) | 36442 | 2-[mesityl(methyl)amino]-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one | C24H27N3O3 | 详情 | 详情 | |
| (VIII) | 36443 | 1-(3,4-dimethoxyphenyl)-2-bromoenthane | C10H13BrO2 | 详情 | 详情 | |
| (IX) | 36444 | 1-(3,4-dimethoxyphenethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione | C14H16N2O5 | 详情 | 详情 | |
| (C) | 28804 | 2,4,6-trimethylaniline | 88-05-1 | C9H13N | 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 bromination of 2,4,6-trimethylaniline (I) with Br2 in aqueous HCl gives 3-bromo-2,4,6-trimethyl-aniline (II), which is then condensed with nitrilotriacetic acid (III) by means of pyridine and acetic anhydride.
| 【1】 Nunn, A.; Loberg, M. (Bristol-Myers Squibb Co.); N-substituted iminodiacetic acids. BE 0891534; DE 3151686; FR 2497197; GB 2090252; JP 2160727; JP 58000948 . |
| 【2】 Ashkinazi, R.I. (Natural Drug Sciences LLC); 5H-Pyrano[2,3-d:6,5-d']dipyrimidine derivs. having an antibacterial, antiviral and immuno-modulating activity. EP 1033369; US 6340755; WO 9925718 . |
合成路线3
该中间体在本合成路线中的序号：(XI)A further route to benzyl ester (X) is shown in the next scheme: Protection of 2,4,6-trimethylaniline (XI) with Boc2O gave carbamate (XII). Condensation of (XII) with diethyl oxalate in the presence of sec-butyllithium produced the intermediate ketoester (XIII), which was deprotected and cyclized under acidic conditions to yield indole (V). Hydrolysis, followed by alkylation with benzyl bromide as above provided the corresponding benzyl ester (X). An alternative and more direct procedure consisted in the condensation of protected aniline (XII) with dibenzyl oxalate, and then cyclization upon treatment with trifluoroacetic acid. The intermediate indole (X) was N-alkylated with tert-butyl bromoacetate and NaH to give the indole diester (XIV). Subsequent deprotection of the benzyl ester group by hydrogenation over Pd/C gave rise to diacid mono tert-butyl ester (XV). Optionally, the analogous methyl ester (XVII) was prepared by alkylation of indole (X) with methyl bromoacetate, followed by benzyl group hydrogenolysis.
| 【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 | |
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| 40591 | benzyl 2-(benzyloxy)-2-oxoacetate | C16H14O4 | 详情 | 详情 | ||
| (V) | 32914 | ethyl 5,7-dimethyl-1H-indole-2-carboxylate | C13H15NO2 | 详情 | 详情 | |
| (X) | 32919 | benzyl 5,7-dimethyl-1H-indole-2-carboxylate | C18H17NO2 | 详情 | 详情 | |
| (XI) | 28804 | 2,4,6-trimethylaniline | 88-05-1 | C9H13N | 详情 | 详情 |
| (XII) | 32920 | tert-butyl mesitylcarbamate | C14H21NO2 | 详情 | 详情 | |
| (XIII) | 32921 | ethyl 3-[2-[(tert-butoxycarbonyl)amino]-3,5-dimethylphenyl]-2-oxopropanoate | C18H25NO5 | 详情 | 详情 | |
| (XIV) | 32922 | benzyl 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylate | C24H27NO4 | 详情 | 详情 | |
| (XV) | 32923 | 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid | C17H21NO4 | 详情 | 详情 | |
| (XVI) | 32924 | benzyl 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylate | C21H21NO4 | 详情 | 详情 | |
| (XVII) | 32925 | 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid | C14H15NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The synthesis can be performed by two related ways: 1) The condensation of 2-(methylsulfanyl)pyrimidin-4-ol (I) with 4-aminobenzonitrile (II) in hot diglyme gives 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile (III), which is treated with POCl3 to yield the corresponding chloro derivative (IV). Finally, this compound is condensed with 2,4,6-trimethylaniline (V) in dioxane to afford the target 4-aminobenzonitrile derivative. 2) Condensation of 2,4,6-trimethylaniline (VI) with 2,4-dichloropyrimidine (VII) by means of DIEA in refluxing 1,4-dioxane, followed by chromatographic purification furnishes intermediate (VIII), which is finally converted into the desired compound by condensation with 4-aminobenzonitrile (II) in refluxing water by means of HCl in 2-propanol.
| 【2】 Heeres, J.; Kukla, M.J.; Andries, K.J.L.M.; Janssen, P.A.J.; Ho, C.Y.; Janssen, M.A.C.; Ludovici, D.W.; de Corte, B.; de Jonge, M.R.; Koymans, L.M.H.; van Aken, K.J.A. (Janssen Pharmaceutica NV); HIV inhibiting pyrimidine derivs.. EP 0945442; EP 0945443; US 6197779; US 6440986; WO 9950250 . |
| 【1】 Ludovici, D.W.; De Corte, B.L.; Kukla, M.J.; et al.; Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. Bioorg Med Chem Lett 2001, 11, 17, 2235. |
| 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) | 54374 | 2-Methylsulfanylpyrimidin-4-ol; 2-Methylthio-4-hydroxy pyrimidine | 124700-70-5 | C5H6N2OS | 详情 | 详情 |
| (II) | 15361 | 4-Aminobenzonitrile | 873-74-5 | C7H6N2 | 详情 | 详情 |
| (III) | 54375 | 4-[(4-hydroxy-2-pyrimidinyl)amino]benzonitrile; 4-[(1,4-Dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile | 189956-45-4 | C11H8N4O | 详情 | 详情 |
| (IV) | 54376 | 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile | 244768-32-9 | C11H7ClN4 | 详情 | 详情 |
| (V) | 28804 | 2,4,6-trimethylaniline | 88-05-1 | C9H13N | 详情 | 详情 |
| (VII) | 54377 | 2,4-Dichloropyrimidine | 3934-20-1 | C4H2Cl2N2 | 详情 | 详情 |
| (VIII) | 54378 | 2-chloro-N-mesityl-4-pyrimidinamine; N-(2-chloro-4-pyrimidinyl)-N-mesitylamine | C13H14ClN3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of 2,4,6-trimethylaniline (I) with adipoin (II) in hot toluene, followed by reaction of the resulting intermediate (III) with malononitrile (IV), gave rise to the tetrahydroindole (V). Subsequent condensation of amino nitrile (V) with 2-methoxypropene (VI) produced the tetrahydropyrido[2,3-b]indole system (VII), which was dehydrogenated to (VIII) by means of Pd/C in boiling decalin. Acylation of (VIII) with isobutyryl chloride (IX) afforded amide (X), which was reduced to amine (XI) employing borane-dimethyl sulfide complex. Further acylation with chloroacetyl chloride (XII), and then reduction of the resulting chloroacetamide (XIII) with borane-dimethyl sulfide, provided the chloroethyl amine (XIV). This was finally treated with dimethylamine in hot N-methylpyrrolidinone in a steel bomb to furnish the desired dimethylamino compound.
| 【1】 Darrow, J.W.; Maynard, G.D.; Horvath, R.F. (Neurogen Corp.); Aminoalkyl substd. 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivs.. EP 1068207; US 6147085; WO 9951600 . |
| 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) | 28804 | 2,4,6-trimethylaniline | 88-05-1 | C9H13N | 详情 | 详情 |
| (II) | 44979 | 2-hydroxycyclohexanone | 533-60-8 | C6H10O2 | 详情 | 详情 |
| (III) | 44980 | 2-(mesitylamino)-1-cyclohexen-1-ol | C15H21NO | 详情 | 详情 | |
| (IV) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (V) | 44981 | 2-amino-1-mesityl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile | C18H21N3 | 详情 | 详情 | |
| (VI) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VII) | 44982 | 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-amine | C21H25N3 | 详情 | 详情 | |
| (VIII) | 44983 | 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine | C21H21N3 | 详情 | 详情 | |
| (IX) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (X) | 44984 | N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)-2-methylpropanamide | C25H27N3O | 详情 | 详情 | |
| (XI) | 44985 | N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine | C25H29N3 | 详情 | 详情 | |
| (XII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XIII) | 44986 | 2-chloro-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)acetamide | C27H30ClN3O | 详情 | 详情 | |
| (XIV) | 44987 | N-(2-chloroethyl)-N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-(2-chloroethyl)-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine | C27H32ClN3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Condensation of 2,4,6-trimethylaniline (I) with malononitrile derivative (II) in isopropanol yields carbonitrile (III), which is then acetylated by means of Ac2O in HOAc to provide acetamide (IV). Cyclization of (IV) is induced by treatment with phosphoric acid to furnish pyrimidinone (V), which is then converted into chloro derivative (VI) in refluxing POCl3 (1). Coupling of (VI) with secondary amine (VII) in DMSO affords compound (VIII), which is finally fluorinated by treatment with tetrabutylammonium fluoride (TBAF) and toluenesulfonyl fluoride (TsF) in refluxing THF.
| 【1】 Chen, Y.L. (Pfizer Inc.); Pyrrolopyrimidines as CRF antagonists. EP 0674641; JP 1995509726; WO 9413676 . |
| 【2】 Chrousos, G.P.; Rice, K.C.; Hsin, L.-W.; Gold, P.W.; Webster, E.L.; Contoreggi, C.; Eckelman, W.C.; Synthesis and biological activity of fluoro-substituted pyrrolo[2,3-d]pyrimidines: The development of potential positron emission tomography imaging agents for the corticotropin-releasing hormone type 1 receptor. Bioorg Med Chem Lett 2000, 10, 8, 707. |
| 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) | 28804 | 2,4,6-trimethylaniline | 88-05-1 | C9H13N | 详情 | 详情 |
| (II) | 45876 | 2-(2-bromo-1-methylpropylidene)malononitrile | C7H7BrN2 | 详情 | 详情 | |
| (III) | 45877 | 2-amino-1-mesityl-4,5-dimethyl-1H-pyrrole-3-carbonitrile | C16H19N3 | 详情 | 详情 | |
| (IV) | 45878 | N-(3-cyano-1-mesityl-4,5-dimethyl-1H-pyrrol-2-yl)acetamide | C18H21N3O | 详情 | 详情 | |
| (V) | 45879 | 7-mesityl-2,5,6-trimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | C18H21N3O | 详情 | 详情 | |
| (VI) | 45880 | 4-chloro-7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine | C18H20ClN3 | 详情 | 详情 | |
| (VII) | 45881 | 4-(propylamino)-1-butanol | C7H17NO | 详情 | 详情 | |
| (VIII) | 45882 | 4-[(7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(propyl)amino]-1-butanol | C25H36N4O | 详情 | 详情 |