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【结 构 式】 
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【分子编号】20004 【品名】p-aminobenzoic acid; 4-aminobenzoic acid 【CA登记号】150-13-0 |
【 分 子 式 】C7H7NO2 【 分 子 量 】137.13812 【元素组成】C 61.31% H 5.14% N 10.21% O 23.33% |
合成路线1
该中间体在本合成路线中的序号：(III)The reaction of ethyl mycophenolate (I) with phosgene in benzene gives ethyl 5-(4'-chloroformyloxy-6'-methoxy-7'-methyl-3'-oxo-5'-phthalanyl)-3-methyl-3-penten-1-carboxylate (II), which is then condensed with p-aminobenzoic acid (III) in THF.
| 【1】 Mori, T.; et al.; DE 2237549 . |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Hillier, K.; CAM. Drugs Fut 1981, 6, 5, 272. |
| 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) | 37445 | ethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methyl-4-hexenoate | C19H24O6 | 详情 | 详情 | |
| (II) | 37446 | ethyl (E)-6-[4-[(chlorocarbonyl)oxy]-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl]-4-methyl-4-hexenoate | C20H23ClO7 | 详情 | 详情 | |
| (III) | 20004 | p-aminobenzoic acid; 4-aminobenzoic acid | 150-13-0 | C7H7NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)1-p-(3,3-Dimethyl-1-triazeno)benzoic acid (I) Ia prepared by coupling the aryldiazonium chloride (II) with aqueous dimethylamine in an excess of sodium carbonate, and by precipitation with HCl (m.p. 170.5-1.5 C; lit. 171 C). The potassium salt is prepared by adding two equivalents of 3M KOH in MeOH to a dioxan solution of the acid. After filtration, the crude compound is dissolved in MeOH and boiled with activated charcoal; the clarified MeOH solution is diluted with ether to precipitate the purified product.
| 【1】 Kolar, G.F.; Synthesis of biologically active triazenes from isolable diazonium salts. Z Naturforsch 1972, 276, 1183-1185. |
| 【2】 Vadlamudi, S.; Loo, T.L.; Lin, Y.T.; Goldin, A.; Preparation and antitumor activity of derivatives of 1-phenyl-3,3-dimethytltriazenes. J Med Chem 1972, 15, 2, 201-203. |
| 【3】 Giraldi, T.; DM-COOK. Drugs Fut 1984, 9, 7, 503. |
合成路线3
该中间体在本合成路线中的序号：(II)The earlier synthesis starts with the reaction of 4-chloro-7-(trifluoromethyl)quinoline (I) with 4-aminobenzoic acid (II) in ethanol-HCl giving 4-(4-carboxyphenylamino)-7-(trifluoromethyl)quinoline (III), which is converted to its acyl chloride (IV) by treatment with SOCl2. The reaction of (IV) with piperazine (V) yields 1-[4-[7-(trifluoromethyl)quinolin-4-ylamino]benzoyl]piperazine (VI), which is finally acylated with 4-fluorobenzenesulfonyl chloride (VII) to give U-54669 F. However, this method is not economically efficient, since the most expensive compound [quinoline (I)] is already used in the first step of the synthesis.
| 【1】 McCall, J.M. (Pharmacia Corp.); Aminoquinolines. GB 2021567 . |
| 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) | 20003 | 4-chloro-7-(trifluoromethyl)quinoline | 346-55-4 | C10H5ClF3N | 详情 | 详情 |
| (II) | 20004 | p-aminobenzoic acid; 4-aminobenzoic acid | 150-13-0 | C7H7NO2 | 详情 | 详情 |
| (III) | 20005 | 4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoic acid | C17H11F3N2O2 | 详情 | 详情 | |
| (IV) | 20006 | 4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl chloride | C17H10ClF3N2O | 详情 | 详情 | |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VI) | 20008 | 1-piperazinyl(4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl)methanone | C21H19F3N4O | 详情 | 详情 | |
| (VII) | 12292 | 4-Fluorobenzenesulfonyl chloride | 349-88-2 | C6H4ClFO2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)By reaction of 4-aminobenzoic acid (I) with rhamnose (II) in ethanol in the presence of NaOH and NH4Cl.
| 【1】 Omura, Y.; Hirose, F.; Ikusawa, M.; Fujii, T.; Matsunaga, K.; Ohara, M.; Ando, T.; Yoshikumi, C. (Kureha Chemical Industry Co. Ltd.); Hypotensive agent containing aminobenzoic acidderivative. JP 1982114522 . |
| 【2】 Hoshi, A.; K-AM. Drugs Fut 1987, 12, 10, 942. |
合成路线5
该中间体在本合成路线中的序号：(V)1) The condensation of 2,4,5,6-tetraaminopyrimidine sulfate (I) with dihydroxyacetone dimer (II) in the presence of cysteine and O2 furnished 2,4-diamino-6-(hydroxymethyl)pteridine (III). Subsequent reaction of (III) with dibromotriphenylphosphorane in dimethylacetamide afforded bromide (IV) which, without isolation, was condensed with 4-aminobenzoic acid (V) in the presence of BaO to give 4-amino-4-deoxypteroic acid (VI). Formylation of (VI) with acetic-formic anhydride yielded formamide (VII), and subsequent activation as the 4-nitrophenyl ester (IX) was carried out upon reaction with bis(4-nitrophenyl)carbonate (VIII). Then Nd-Boc-L-ornithine, after conversion to the corresponding Na,O-bis(trimethylsilyl) derivative (X) by treatment with ClSiMe3 and triethylamine, was condensed with active ester (IX) to furnish amide (XI). Subsequent deprotection of the Boc group of (XI) with cold trifluoroacetic acid provided (XII), which was then condensed with phthalic anhydride (XIII) in the presence of triethylamine in N-methylpyrrolidinone, yielding the hemiphthaloyl amide (XIV). Finally, the formamide function was hydrolyzed with aqueous NaOH at r.t. to provide the target compound, after chromatographic separation of some phthaloyl-hydrolyzed byproduct.
| 【1】 Rosowsky, A.; et al.; Methotrexate analogues. 26. Inhibition of dihydrofolate reductase and folypolyglutamate synthetase activity and in vitro tumor cell growth by methotrexate and aminopterin analogues containing a basic amino acid side chain. J Med Chem 1986, 29, 655. |
| 【2】 Rosowsky, A.; et al.; Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin. J Med Chem 1985, 28, 5, 660. |
| 【3】 Rosowsky, A.; et al.; Methotrexate analogues. 33. Ndelta-Acyl-Nalpha-(4-amino-4-deoxypteroyl)-L-ornithine derivatives: Synthesis and in vitro antitumor activity. J Med Chem 1988, 31, 1332-7. |
| 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) | 19522 | 2,4,6-triamino-5-pyrimidinylamine; 2,4,5,6-pyrimidinetetramine | 1004-74-6 | C4H8N6 | 详情 | 详情 |
| (II) | 20067 | 2,5-bis(hydroxymethyl)-1,4-dioxane-2,5-diol | 89727-88-8 | C6H12O6 | 详情 | 详情 |
| (III) | 20068 | (2,4-diamino-6-pteridinyl)methanol | 945-24-4 | C7H8N6O | 详情 | 详情 |
| (IV) | 20069 | 6-(bromomethyl)pyrido[3,2-d]pyrimidine-2,4-diamine; 2-amino-6-(bromomethyl)pyrido[3,2-d]pyrimidin-4-ylamine | C8H8BrN5 | 详情 | 详情 | |
| (V) | 20004 | p-aminobenzoic acid; 4-aminobenzoic acid | 150-13-0 | C7H7NO2 | 详情 | 详情 |
| (VI) | 20071 | 4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoic acid | C14H13N7O2 | 详情 | 详情 | |
| (VII) | 20072 | 4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoic acid | C15H13N7O3 | 详情 | 详情 | |
| (VIII) | 20073 | bis(4-nitrophenyl) carbonate;bis(4-nitrophenyl) carbonate;4,4'-Dinitrodiphenyl carbonate;Carbonic acid,bis(4-nitrophenyl) ester;Di-4-nitrophenylcarbonate;Di-p-nitrophenyl carbonate;p,p'-Dinitrodiphenylcarbonate | 5070-13-3 | C13H8N2O7 | 详情 | 详情 |
| (IX) | 20074 | 4-nitrophenyl 4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoate | C21H16N8O5 | 详情 | 详情 | |
| (X) | 20075 | trimethylsilyl (2S)-5-[(tert-butoxycarbonyl)amino]-2-[(trimethylsilyl)amino]pentanoate | C16H36N2O4Si2 | 详情 | 详情 | |
| (XI) | 20076 | (2S)-5-[(tert-butoxycarbonyl)amino]-2-([4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoyl]amino)pentanoic acid | C25H31N9O6 | 详情 | 详情 | |
| (XII) | 20077 | (2S)-5-amino-2-([4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoyl]amino)pentanoic acid | C20H23N9O4 | 详情 | 详情 | |
| (XIII) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (XIV) | 20079 | 2-([[(4S)-4-carboxy-4-([4-[[(2,4-diamino-6-pteridinyl)methyl](formyl)amino]benzoyl]amino)butyl]amino]carbonyl)benzoic acid | C28H27N9O7 | 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 22540502a, initially, starting material (I) is converted to benzothiazol (II) by treatment of sodium thiocyanate in the presence of bromine. Alkali hydrolysis of compound (II) gives thiol (III), which is immediatly submitted to S-alkylation with 1-bromo-2-chloroethane, followed by acid esterification, which gives thioether (IV). After protection of the amino group of compound (IV) with tosyl chloride, treatment of NaOH affords benzothiazine ester (V), and next hydrolysis produces the key intermediate (VI). Subsequently, compound (VI) is converted to the corresponding acid chloride and amidated with dimethyl homoglutamate to give the amide (VII). The tosyl group of the amide (VII) is removed with HBr-AcOH to give the amine (VIII), which is effectively alkilated with 6-(bromomethyl)-,4-diaminopteridine (IX) to produce (X). Finally, compound (X) is hydrolyzed with 1N NaOH to yield MX-68.
| 【1】 Matsuoka, H.; et al.; Antirheumatic agents: Novel methotrexate derivatives bearing a benzoxazine or benzothiazine moiety. J Med Chem 1997, 40, 1, 105. |
| 【2】 Mihara, M.; Matsuoka, H.; The synthesis and biological evaluation of new methotrexate derivatives in rheumatoid arthritis. Drugs Fut 1998, 23, 9, 1015. |
| 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) | 20004 | p-aminobenzoic acid; 4-aminobenzoic acid | 150-13-0 | C7H7NO2 | 详情 | 详情 |
| (II) | 25039 | 2-amino-1,3-benzothiazole-6-carboxylic acid | C8H6N2O2S | 详情 | 详情 | |
| (III) | 25040 | 4-amino-3-sulfanylbenzoic acid hydrochloride | C7H8ClNO2S | 详情 | 详情 | |
| (IV) | 25041 | methyl 4-amino-3-[(2-chloroethyl)sulfanyl]benzoate hydrochloride | C10H13Cl2NO2S | 详情 | 详情 | |
| (V) | 25042 | methyl 4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylate | C17H17NO4S2 | 详情 | 详情 | |
| (VI) | 25043 | 4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid | C16H15NO4S2 | 详情 | 详情 | |
| (VII) | 25044 | dimethyl 2-[([4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate | C24H28N2O7S2 | 详情 | 详情 | |
| (VIII) | 19823 | dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate | C17H22N2O5S | 详情 | 详情 | |
| (IX) | 11006 | 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine | 52853-40-4 | C7H7BrN6 | 详情 | 详情 |
| (X) | 19825 | dimethyl (2S)-2-[([4-[(2,4-diamino-6-pteridinyl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate | C24H28N8O5S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XVII)Alternatively, treatment of biphenyl-2-carboxylic acid (V) with SOCl2 and DMF in CH2Cl2 provides the acyl chloride (XVI), which is condensed with 4-aminobenzoic acid (XVII) by means of N,N-dimethylaniline in acetone to give the corresponding 4-(2-phenylbenzamido)benzoic acid (XVIII). Treatment of (XVIII) with SOCl2 and DMF in dry THF affords the acyl chloride (XIX), which is finally condensed with the inmidazobenzazepine (XII) by means of pyridine in MeCN and treated with 4N HCl.
| 【1】 Castañer, R.M.; Norman, P.; Rabasseda, X.; Leeson, P.A.; Castañer, J.; Conivaptan Hydrochloride. Drugs Fut 2000, 25, 11, 1121. |
| 【2】 Yamazaki, A.; Tanaka, A.; Tsunoda, T. (Yamanouchi Pharmaceutical Co., Ltd.); Novel preparation method of condensed benzazepine derivs.. JP 1996198879 . |
| 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) | 18505 | [1,1'-biphenyl]-2-carboxylic acid | 947-84-2 | C13H10O2 | 详情 | 详情 |
| (XII) | 41817 | 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine | 318237-73-9 | C12H13N3 | 详情 | 详情 |
| (XVI) | 18506 | [1,1'-biphenyl]-2-carbonyl chloride | C13H9ClO | 详情 | 详情 | |
| (XVII) | 20004 | p-aminobenzoic acid; 4-aminobenzoic acid | 150-13-0 | C7H7NO2 | 详情 | 详情 |
| (XVIII) | 41820 | 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]benzoic acid | C20H15NO3 | 详情 | 详情 | |
| (XIX) | 36810 | 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]benzoyl chloride | C20H14ClNO2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)Coupling between 4-nitrobenzoyl chloride (VI) and 4-aminobenzoic acid (VII) afforded nitrobenzamide (VIII), which was further reduced to amine (IX) by catalytic hydrogenation over Pd/C. Acylation of (IX) with phthalimidoacetyl chloride (X) yielded diamide (XI). The carboxyl group of (XI) was then activated as the corresponding acid chloride (XII) by treatment with SOCl2. Then, condensation of the glycylamide derivative (XIII) with acid chloride (XII) furnished amide (XIV).
| 【1】 Rousseaux, O.; Simonot, C. (Guerbet SA); Gadolinium complex tetramides and use in medical imaging. EP 1178975; FR 2793795; WO 0071526 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (VII) | 20004 | p-aminobenzoic acid; 4-aminobenzoic acid | 150-13-0 | C7H7NO2 | 详情 | 详情 |
| (VIII) | 56045 | 4-[(4-nitrobenzoyl)amino]benzoic acid | C14H10N2O5 | 详情 | 详情 | |
| (IX) | 56046 | 4-[(4-aminobenzoyl)amino]benzoic acid | C14H12N2O3 | 详情 | 详情 | |
| (X) | 10278 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | 6780-38-7 | C10H6ClNO3 | 详情 | 详情 |
| (XI) | 56047 | 4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoic acid | C24H17N3O6 | 详情 | 详情 | |
| (XII) | 56048 | 4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoyl chloride | C24H16ClN3O5 | 详情 | 详情 | |
| (XIII) | 56049 | 5-[(2-aminoacetyl)amino]-2,4,6-tribromo-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide | C34H57Br3N4O23 | 详情 | 详情 | |
| (XIV) | 56050 | 2,4,6-tribromo-5-{[2-({4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoyl}amino)acetyl]amino}-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide | C58H72Br3N7O28 | 详情 | 详情 |