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【结 构 式】 
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【分子编号】10203 【品名】o-Chlorobenzoic acid; 2-Chlorobenzoic acid 【CA登记号】118-91-2 |
【 分 子 式 】C7H5ClO2 【 分 子 量 】156.5682 【元素组成】C 53.7% H 3.22% Cl 22.64% O 20.44% |
合成路线1
该中间体在本合成路线中的序号：(III)A new synthesis of 13C- or 14C-labeled SKF-86466 has been described: The Friedel Craft's condensation of labeled benzene (I) with oxalyl chloride by means of AlCl3 in CS2 yields benzoic acid (II), which is chlorinated by means of cupric chloride and thallium (III) trifluoroacetate in trifluoroacetic acid to give 2-chlorobenzoic acid (III). The reduction of (III) by means of borane/THF complex in THF affords 2-chlorobenzyl alcohol (IV), which is treated with hot concentrated HCl to afford 2-chlorobenzyl chloride (V). The Grignard condensation of (V) with N-methyloxazolidine (VI) by means of Mg in ether gives N-[2-(2-chlorophenyl)ethyl]-N-methyl-2-hydroxyethylamine (VII), which is finally cyclized by treatment with PCl5 in hot trichlorobenzene followed by addition of AlCl3 and heating at 215-25 C.
| 【1】 Etzkorn, F.; Villani, A.J.; Rotert, G.A.; Heys, J.R.; Synthesis of 13C, 14C and 2H13C labeled adrenoceptor antagonists: 6-c hloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine hydrochloride and its N-desmethyl analog. J Label Compd Radiopharm 1988, 25, 12, 1339. |
| 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) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (I) | 44622 | C6H6 | 详情 | 详情 | ||
| (II) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (II) | 44623 | C7H6O2 | 详情 | 详情 | ||
| (III) | 10203 | o-Chlorobenzoic acid; 2-Chlorobenzoic acid | 118-91-2 | C7H5ClO2 | 详情 | 详情 |
| (III) | 44624 | C7H5ClO2 | 详情 | 详情 | ||
| (IV) | 10204 | 2-Chlorobenzyl alcohol; (2-Chlorophenyl)methanol | 17849-38-6 | C7H7ClO | 详情 | 详情 |
| (IV) | 44625 | C7H7ClO | 详情 | 详情 | ||
| (V) | 10205 | 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride | 611-19-8 | C7H6Cl2 | 详情 | 详情 |
| (V) | 44626 | C7H6Cl2 | 详情 | 详情 | ||
| (VI) | 10206 | 3-Methyl-1,3-oxazolane | C4H9NO | 详情 | 详情 | |
| (VII) | 10207 | 2-[(2-Chlorophenethyl)(methyl)amino]-1-ethanol | C11H16ClNO | 详情 | 详情 | |
| (VII) | 44627 | C11H16ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Camprofen has been synthesized previously by Picciola as a chemical intermediate in the preparation of an indazolylpropionic acid, but was apparently not itself evaluated for antiinflammatory activity during that study. The synthetic approach (scheme 16191901a), begins with 1-chloro-4-nitrobenzene (I), which is readily available commercially. Treatment of (I) with the carbanion derived from diethyl methylmalonate (using sodium hydride as base, in N,N-dimethylformamide) provides the intermediate diethyl ester (II), which is saponified in situ and then acidified to the acid (IIIa). Crude (IIIa) is then esterified to the methyl ester (IIIb), purified by column chromatography, the sequence being analogous to that of Hino et al. The nitrophenyl ester (IIIb) is dissolved in 95% ethanol and hydrogenated in the presence of palladium catalyst to provide the 4-aminophenyl compound (IV). Finally, an Ullmann-Jourdan condensation of (IV) with 2-chlorobenzoic acid in the presence of anhydrous potassium carbonate, activated copper powder and N,N-methylformamide provides camprofen. This synthetic scheme uses cheap and readily available reagents and provides racemic camprofen in an overall yield of 52% based on 1-chloro-4-nitrobenzene (I).
| 【1】 Appleton, R.A.; Brown, K.; Conformational requirements at the prostaglandin cyclooxygenase receptor site: A template for designing non-steroidal anti-inflammatory drugs. Prostaglandins 1979, 18, 29. |
| 【2】 Hino, K.; Nakamura, H.; Nagai, Y.; Uno, H.; Nishimura, H.; Non-steroidal anti-inflammatory agents. 2.[(heteroarylamino)phenyl]alkanoic acids. J Med Chem 1983, 26, 222. |
| 【3】 Taraporewala, I.B.; Kauffman, J.M.; Synthesis and structure activity relationships of anti-inflammatory 9,10-dihydro-9-oxo-2-acridine-alkanoic acids and 4-(2-carboxyphenyl)aminobenzenealkanoic acids. J Pharm Sci 1990, 79, 2, 173. |
| 【4】 Kauffman, J.M.; Taraporewala, I.B.; Synthesis of the p-nitrophenyl ester of acridine-2-acetic acid. J Heterocycl Chem 1982, 19, 1557. |
| 【5】 Picciola, G.; Heterocyclic compounds containing 4-aminophenyl-alkanoic acid residues with potential antiinflammatory activity. III. Derivatives of 3-hydroxyindazole. Boll Chim Farm 1981, 120, 8, 458. |
| 【6】 Taraporewala, I.B.; Kauffman, J.M.; CAMPROFEN. Drugs Fut 1990, 15, 6, 563. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10203 | o-Chlorobenzoic acid; 2-Chlorobenzoic acid | 118-91-2 | C7H5ClO2 | 详情 | 详情 | |
| 33989 | C8H13NaO4 | 详情 | 详情 | |||
| (III-b) | 13911 | methyl 2-(4-nitrophenyl)propanoate | C10H11NO4 | 详情 | 详情 | |
| (III-a) | 52520 | 2-(4-nitrophenyl)propanoic acid | C9H9NO4 | 详情 | 详情 | |
| (I) | 13909 | 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene | 100-00-5 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 13910 | diethyl 2-methyl-2-(4-nitrophenyl)malonate | C14H17NO6 | 详情 | 详情 | |
| (IV) | 13912 | methyl 2-(4-aminophenyl)propanoate | 39718-97-3 | C10H13NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Copper-catalyzed condensation of 2-methyl-5-nitrophenol (I) with 2-chlorobenzoic acid (II) in hot nitrobenzene afforded the diphenyl ether (III). Subsequent cyclization of (III) by means of polyphosphoric acid gave 4-methyl-1-nitro-9H-9-xanthenone (IV). Benzylic bromination of (IV) with N-bromosuccinimide furnished bromide (V). This was finally condensed with imidazole in refluxing acetonitrile to yield the title compound.
| 【1】 Cavalli, A.; Bisi, A.; Recanatini, M.; et al.; A new class of nonsteroidal aromatase inhibitors: Design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase. J Med Chem 2001, 44, 5, 672. |
| 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) | 47763 | 2-methyl-5-nitrophenol; 2-Hydroxy-4-nitrotoluene; 4-Nitro-2-hydroxytoluene; 5-Nitro-2-methylphenol; 5-Nitro-o-cresol | 5428-54-6 | C7H7NO3 | 详情 | 详情 |
| (II) | 10203 | o-Chlorobenzoic acid; 2-Chlorobenzoic acid | 118-91-2 | C7H5ClO2 | 详情 | 详情 |
| (III) | 47764 | 2-(2-methyl-5-nitrophenoxy)benzoic acid | C14H11NO5 | 详情 | 详情 | |
| (IV) | 47765 | 4-methyl-1-nitro-9H-xanthen-9-one | C14H9NO4 | 详情 | 详情 | |
| (V) | 47766 | 4-(bromomethyl)-1-nitro-9H-xanthen-9-one | C14H8BrNO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The intermediate 6-methyldiphenylamine-2,2'-dicarboxylic acid (V) has been synthesized in two similar ways. 1. By Jourdan-Ullman copper-catalyzed condensation of 6-methylbenzoic acid (I) with 2-aminobenzoic acid (II); and 2. By the same type of condensation, but using 2-amino-3-methylbenzoic acid (III) and 2-chlorobenzoic acid (IV). The cyclization of the intermediate dicarboxylic acid (V) under acidic conditions gives 5-methyl-9-oxo-9,10-dihydroacridine-4-carboxylic acid (VI), which is treated with hot SOCl2 and DMF to yield 9-choloro-5-methylacridine-4-carbonyl chloride (VII). The reaction of (VII) with N,N-dimethylethylenediamine (VIII) in dichloromethane affords the corresponding amide (IX), which is finally treated first with phenol at 100 C and then with a stream of dry ammonia at 110-20 C to obtain the target 9-aminoacridine derivative.
| 【1】 Rewcastle, G.W.; et al.; Potential antitumor agents. 46. Structure-activity relationships for acridine monosubstituted derivatives of the antitumor agent N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide. J Med Chem 1986, 29, 4, 472. |
| 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) | 51949 | 2-Chloro-3-methylbenzoic acid | 15068-35-6 | C8H7ClO2 | 详情 | 详情 |
| (II) | 11661 | 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid | 118-92-3 | C7H7NO2 | 详情 | 详情 |
| (III) | 48130 | 2-amino-3-methylbenzoic acid | 4389-45-1 | C8H9NO2 | 详情 | 详情 |
| (IV) | 10203 | o-Chlorobenzoic acid; 2-Chlorobenzoic acid | 118-91-2 | C7H5ClO2 | 详情 | 详情 |
| (V) | 51950 | 2-(2-carboxyanilino)-3-methylbenzoic acid | C15H13NO4 | 详情 | 详情 | |
| (VI) | 30493 | 5-methyl-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | C15H11NO3 | 详情 | 详情 | |
| (VII) | 30494 | 9-chloro-5-methyl-4-acridinecarbonyl chloride | C15H9Cl2NO | 详情 | 详情 | |
| (VIII) | 14481 | (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid | C21H26F2O4S | 详情 | 详情 | |
| (IX) | 51951 | 9-chloro-N-[2-(dimethylamino)ethyl]-5-methyl-4-acridinecarboxamide | C19H20ClN3O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Ullmann condensation between o-chlorobenzoic acid (I) and p-anisidine (II) produces the diphenylamine carboxylic acid (III), which is further cyclized to the 2-methoxyacridone (IV) by heating in polyphosphoric acid. N-Alkylation of acridone (IV) with 1-bromo-4-chlorobutane (V) in the presence of KOH under phase-transfer conditions furnishes the N-(chlorobutyl)acridone (VI). Finally, nucleophilic substitution of the chloro group of (VI) with N-(2-hydroxyethyl)piperazine (VII) gives rise to the title compound.
| 【1】 Krishnegowda, G.; et al.; Synthesis and chemical characterization of 2-methoxy-N10-substituted acridones needed to reverse vinblastine resistance in multidrug resistant (MDR) cancer cells. Bioorg Med Chem 2002, 10, 7, 2367. |
| 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) | 10203 | o-Chlorobenzoic acid; 2-Chlorobenzoic acid | 118-91-2 | C7H5ClO2 | 详情 | 详情 |
| (II) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (III) | 57755 | 2-(4-methoxyanilino)benzoic acid | C14H13NO3 | 详情 | 详情 | |
| (IV) | 57756 | 2-Methoxy-9(10H)-acridone | C14H11NO2 | 详情 | 详情 | |
| (V) | 16141 | 1-bromo-4-chlorobutane | 6940-78-9 | C4H8BrCl | 详情 | 详情 |
| (VI) | 57757 | 10-(4-chlorobutyl)-2-methoxy-9(10H)-acridinone | C18H18ClNO2 | 详情 | 详情 | |
| (VII) | 21893 | 2-(1-piperazinyl)-1-ethanol; 1-piperazineethanol; 1-(2-Hydroxyethyl)piperazine | 103-76-4 | C6H14N2O | 详情 | 详情 |