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【结 构 式】 
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【分子编号】18359 【品名】p-chlorobenzoic acid; 4-chlorobenzoic acid 【CA登记号】74-11-3 |
【 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：(I)The reaction of p-chlorobenzoic acid (I) with SOCl2 gives p-chlorobenzoyl chloride (II), which is esterified with 4-fluorophenol (III) affording 4-fluorophenyl-4-chlorobenzoate (IV). The isomerization of (IV) with AlCl3 yields 4-chloro-2'-hydroxy-5'-fluorobenzophenone (V), which is condensed with 4-aminobutyric acid (VI) by means of sodium methoxide in ethanol giving 4-[[alpha-(p-chlorophenyl)-5-fluoro-2-hydroxybenzylidene]amino]butyric acid (VII). The reaction of (VII) with SOCl2 in THF affords the corresponding acyl chloride (VIII), which is then treated with NH3. An alternative way of converting the acid (VII) into its amide is by treatment with carbonyldiimidazole (A) and liquid NH3 in THF.
| 【1】 Kaplan, J.P.; et al.; Derives alpha-phenyl-benzylideniques des acides amines. FR 2358887 . |
| 【2】 Kaplan, J.P.; et al. (Sanofi-Synthelabo); Benzylidene derivatives. ES 450300; FR 2319338; GB 1506808; JP 52019644; US 4094992 . |
| 【3】 Kaplan, J.P.; et al. (Sanofi-Synthelabo); Preparation of benzylidene derivatives. DE 2830034; ES 471606; FR 2397397; GB 2001066; JP 54019953 . |
| 【4】 Serradell, M.N.; Owen, R.T.; Blancafort, P.; Castaner, J.; Progabide. Drugs Fut 1980, 5, 9, 445. |
| 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) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (I) | 18359 | p-chlorobenzoic acid; 4-chlorobenzoic acid | 74-11-3 | C7H5ClO2 | 详情 | 详情 |
| (II) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (III) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
| (IV) | 32698 | 4-Fluorophenyl 4-chlorobenzoate | C13H8ClFO2 | 详情 | 详情 | |
| (V) | 32699 | (4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methanone | 62433-26-5 | C13H8ClFO2 | 详情 | 详情 |
| (VI) | 13620 | 4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid | 56-12-2 | C4H9NO2 | 详情 | 详情 |
| (VII) | 32700 | 4-[[(Z)-(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylidene]amino]butyric acid | C17H15ClFNO3 | 详情 | 详情 | |
| (VIII) | 32701 | 4-[[(Z)-(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylidene]amino]butanoyl chloride | C17H14Cl2FNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)This compound can be prepared in several different ways: 1) By reaction of p-chlorobenzoyl chloride (I) with N-(2-aminoethyl)morpholine (II) in pyridine. 2) By reaction of p-chlorobenzoyl anhydride (III) with N-(2-aminoethyl)morpholine (II) in pyridine. 3) By reaction of methyl p-chlorobenzoate (IV) with N-(2-aminoethyl)morpholine (II) at 120 C. 4) By reaction of N-(p-chlorobenzoyl)succinimide (V) with N-(2-aminoethyl)morpholine (II) in dioxane. 5) By reaction of p-nitrophenyl p-chlorobenzoate (VI) with N-(2-aminoethyl)morpholine (II) in THF. 6) By reaction of p-chloro-N-(2-chloroethyl)benzamide (VII) with morpholine (VIII) at 100 C. 7) By reaction of p-chlorobenzoylaziridine (IX) with morpholine (VIII) in refluxing toluene. 8) By reaction of p-chlorobenzaldehyde (X) with N-(2-aminoethyl)morpholine (II) in refluxing benzene to give 4-[2-[(p-chlorobenzylidene)amino]ethyl]morpholine (XI), followed by an oxidation with H2O2 in methanol. 9) By reaction of p-chloro-N-(2-morpholinoethyl)thiobenzamide (XII) with lead tetraacetate in refluxing water. 11) By reaction of p-chlorobenzoic acid (XIV) with N-(2-aminoethyl)morpholine (II) by means of dicyclohexylcarbodiimide in pyridine, or by means of chloroformic acid ethyl ester and triethylamine in acetone. 10) By isomerization of (alpha-(p-chlorophenyl)-N-(2-morpholinoethyl)nitrone (XIII) in hot acetic acid - acetic anhydride, followed by a treatment with NaOH.
| 【1】 Bukard, W.; Wyss, P.C. (F. Hoffmann-La Roche AG); Benzamides. BE 0851422; CA 1076112; DE 2706179; FR 2340940; GB 1512194; JP 52100476; NL 7701144; US 4210754; ZA 7700488 . |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Grau, M.; Moclobemide. Drugs Fut 1983, 8, 2, 124. |
| 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) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (II) | 12880 | 4-(2-Aminoethyl)morpholine; 2-(4-Morpholinyl)ethylamine; 2-(4-Morpholinyl)-1-ethanamine; N-(2-Aminoethyl)morpholine; N-Morpholine ethanamide | 2038-03-1 | C6H14N2O | 详情 | 详情 |
| (III) | 30702 | 4-chloro-1-benzenecarboxylic anhydride | C14H8Cl2O3 | 详情 | 详情 | |
| (IV) | 30703 | methyl 4-chlorobenzoate | 1126-46-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 30704 | 1-(4-chlorobenzoyl)-2,5-pyrrolidinedione | C11H8ClNO3 | 详情 | 详情 | |
| (VI) | 30705 | 4-nitrophenyl 4-chlorobenzoate | C13H8ClNO4 | 详情 | 详情 | |
| (VII) | 30706 | 4-chloro-N-(2-chloroethyl)benzamide | C9H9Cl2NO | 详情 | 详情 | |
| (VIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (IX) | 30707 | 1-aziridinyl(4-chlorophenyl)methanone | C9H8ClNO | 详情 | 详情 | |
| (X) | 29029 | 4-chlorobenzaldehyde | 104-88-1 | C7H5ClO | 详情 | 详情 |
| (XI) | 30708 | N-[(E)-(4-chlorophenyl)methylidene]-2-(4-morpholinyl)-1-ethanamine; N-[(E)-(4-chlorophenyl)methylidene]-N-[2-(4-morpholinyl)ethyl]amine | C13H17ClN2O | 详情 | 详情 | |
| (XII) | 30709 | 4-chloro-N-[2-(4-morpholinyl)ethyl]benzenecarbothioamide | C13H17ClN2OS | 详情 | 详情 | |
| (XIII) | 30710 | [(Z)-(4-chlorophenyl)methylidene][2-(4-morpholinyl)ethyl]ammoniumolate | C13H17ClN2O2 | 详情 | 详情 | |
| (XIV) | 18359 | p-chlorobenzoic acid; 4-chlorobenzoic acid | 74-11-3 | C7H5ClO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Romazarit (sodium salt) is prepared by a 7-step process from 4-chlorobenzoic acid, ethyl 2-chloroacetoacetate (VIII) and ethyl 2-methyl 2-hydroxypropionate (X). Reaction of the sodium salt of 4-chlorobenzoic acid (I) with ethyl 2-chloroacetoacetate (VIII) affords ethyl 3-oxo-2-(4-chlorophenylcarboxy)butyrate (II). Cyclization of (II) to ethyl 2-(4-chlorophenyl)-4-methyloxazole-5-carboxylate (III) is accomplished by treatment with formamide (IX)/sulfuric acid. Reduction of the ester (III) with lithium aluminum hydroxide in tetrahydrofuran yields 2-(4-chlorophenyl)-4-methyl-5-oxazolemethanol (IV). Chlorination of alcohol (IV) with thionyl chloride followed by reaction of crude chloromethyloxazole (V) with the sodium alkoxide derivative of ethyl 2-methyl-2-hydroxypropionate (X) yields ethyl [2-[(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionate (VI). Hydrolysis of the ester (VI), acidification and recrystallization affords Ro 31-3948 (VII) as a white solid, which is converted to the sodium salt by treatment with sodium isopropoxide in isopropanol.
| 【1】 Self, C.R.; Machin, P.J.; Osbond, J.M.; Smithen, C.E.; Tong, B.P. (Hoffmann-La Roche, Inc.); Oxazole and isoxazole derivatives having anti-arthritic activity.. EP 0220573; ES 2002420; ES 2010537; US 4774253 . |
| 【2】 Bradshaw, D.; Sedgwick, A.D.; Self, C.R.; ROMAZARIT SODIUM < Prop INNM; BAN >. Drugs Fut 1989, 14, 9, 867. |
| 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) | 18359 | p-chlorobenzoic acid; 4-chlorobenzoic acid | 74-11-3 | C7H5ClO2 | 详情 | 详情 |
| (II) | 21331 | 1-(ethoxycarbonyl)-2-oxopropyl 4-chlorobenzoate | C13H13ClO5 | 详情 | 详情 | |
| (III) | 21332 | ethyl 2-(4-chlorophenyl)-4-methyl-1,3-oxazole-5-carboxylate | C13H12ClNO3 | 详情 | 详情 | |
| (IV) | 13450 | [2-(4-Chlorophenyl)-4-methyl-1,3-oxazol-5-yl]methanol | C11H10ClNO2 | 详情 | 详情 | |
| (V) | 21334 | 5-(chloromethyl)-2-(4-chlorophenyl)-4-methyl-1,3-oxazole | C11H9Cl2NO | 详情 | 详情 | |
| (VI) | 21335 | ethyl 2-[[2-(4-chlorophenyl)-4-methyl-1,3-oxazol-5-yl]methoxy]-2-methylpropanoate | C17H20ClNO4 | 详情 | 详情 | |
| (VII) | 21336 | 2-[[2-(4-chlorophenyl)-4-methyl-1,3-oxazol-5-yl]methoxy]-2-methylpropionic acid | C15H16ClNO4 | 详情 | 详情 | |
| (VIII) | 21337 | ethyl 2-chloro-3-oxobutanoate | 609-15-4 | C6H9ClO3 | 详情 | 详情 |
| (IX) | 16595 | 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate | 144163-97-3 | C11H8N2O5S | 详情 | 详情 |
| (X) | 21339 | ethyl 2-hydroxy-2-methylpropanoate | 80-55-7 | C6H12O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Ortho metalation of 4-chlorobenzoic acid (I) with 2 equivalents of sec-butyllithium in the presence of tetramethylethylenediamine (TMEDA) in THF at -90 C, followed by addition of methyl iodide at -80 C afforded 4-chloro-2-methylbenzoic acid (II). Chlorosulfonation of (II) with ClSO3H at 135 C provided (III), which was reduced to sulfinic acid (IV) by means of Na2SO3. Alkylation of the sodium salt of (IV) with methyl iodide in aqueous methanol yielded sulfone (V). Subsequent reaction with an excess of benzylamine at 160 C gave benzylaniline (VI), from which the benzyl group was removed by hydrogenolysis in the presence of Pd/C to afford primary amine (VII). Further esterification with a methanolic solution of HCl provided methyl ester (VIII). Conversion of amine (VIII) to pyrrolyl compound (X) was effected by treatment with 2,5-dimethoxytetrahydrofuran (IX) in the presence of 4-chloropyridine hydrochloride in refluxing dioxan. Finally, condensation with guanidine in methanol at 50 C furnished the title compound.
| 【1】 Baumgarth, M.; et al.; (2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ antiporter inhibitors. J Med Chem 1997, 40, 13, 2017. |
| 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) | 18359 | p-chlorobenzoic acid; 4-chlorobenzoic acid | 74-11-3 | C7H5ClO2 | 详情 | 详情 |
| (II) | 18360 | 4-chloro-2-methylbenzoic acid | 7499-07-2 | C8H7ClO2 | 详情 | 详情 |
| (III) | 18361 | 4-chloro-5-(chlorosulfonyl)-2-methylbenzoic acid | C8H6Cl2O4S | 详情 | 详情 | |
| (IV) | 18362 | 4-chloro-2-methyl-5-sulfinobenzoic acid | C8H7ClO4S | 详情 | 详情 | |
| (V) | 18363 | 4-chloro-2-methyl-5-(methylsulfonyl)benzoic acid | C9H9ClO4S | 详情 | 详情 | |
| (VI) | 18364 | 4-(benzylamino)-2-methyl-5-(methylsulfonyl)benzoic acid | C16H17NO4S | 详情 | 详情 | |
| (VII) | 18365 | 4-amino-2-methyl-5-(methylsulfonyl)benzoic acid | C9H11NO4S | 详情 | 详情 | |
| (VIII) | 18366 | methyl 4-amino-2-methyl-5-(methylsulfonyl)benzoate | C10H13NO4S | 详情 | 详情 | |
| (IX) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (X) | 18368 | methyl 2-methyl-5-(methylsulfonyl)-4-(1H-pyrrol-1-yl)benzoate | C14H15NO4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)Cyclization of 3-(3-chlorophenyl)-N-phenyl-2-propenamide (I) by means of polyphosphoric acid (PPA) at 100 C gives 4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-2-one (II), which is condensed with 4-chlorobenzoic acid (III) by means of PPA at 140 C to yield 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1,2,3,4-tetrahydroquinolin-2-one (IV). The dehydrogenation of (IV) by means of Br2 in bromobenzene at 160 C affords 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)quinolin-2(1H)-one (V), which is methylated with iodomethane and NaOH/benzyltrimethylammonium chloride in THF to provide 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one (VI). Condensation of compound (VI) with 1-methylimidazole (VII) by means of butyllithium in THF gives the triaryl carbinol (VIII), which is finally treated with ammonia in THF to afford R-115777.
| 【1】 Sorbera, L.A.; Castaner, J.; Fernandez, R.; R-115777. Drugs Fut 2001, 26, 5, 453. |
| 【2】 Venet, M.G.; Angibaud, P.R.; Muller, P.; Sanz, G.C. (Janssen Pharmaceutica NV); Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivs.. EP 0865440; JP 1998511405; US 6037350; WO 9721701 . |
| 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) | 46720 | (E)-3-(3-chlorophenyl)-N-phenyl-2-propenamide | C15H12ClNO | 详情 | 详情 | |
| (II) | 46721 | 4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone | C15H12ClNO | 详情 | 详情 | |
| (III) | 18359 | p-chlorobenzoic acid; 4-chlorobenzoic acid | 74-11-3 | C7H5ClO2 | 详情 | 详情 |
| (IV) | 46722 | 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone | C22H15Cl2NO2 | 详情 | 详情 | |
| (V) | 46723 | 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone | C22H13Cl2NO2 | 详情 | 详情 | |
| (VI) | 46724 | 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone | C23H15Cl2NO2 | 详情 | 详情 | |
| (VII) | 38630 | 1-methyl-1H-imidazole | 616-47-7 | C4H6N2 | 详情 | 详情 |
| (VIII) | 46725 | 4-(3-chlorophenyl)-6-[(4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone | C27H21Cl2N3O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)By Ullmann condensation of 4-chlorobenzoic acid (I) with 3-hydroxybenzonitrile (II) by means of Cu or CuI and K2CO3 in DMF at 170 C. The same reaction can also be performed with 4-bromo- or 4-iodobenzoic acids instead of 4-chlorobenzoic acid (I).
| 【1】 Nimura, M.; et al.; Synthesis and structure-activity relationships of substituted biaryl, biaryl ether derivatives as uricosuric agents. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 169. |
合成路线7
该中间体在本合成路线中的序号：(I)The title hydrazide was prepared from 4-chlorobenzoic acid (I) via conversion to the corresponding acid chloride (II), followed by condensation with 4-methylphenylhydrazine (III).
| 【1】 Sui, Z.; et al.; 1,3-Diarylcycloalkano-[1,2-d]-pyrazoles and diphenyl hydrazides as selective inhibitors of cyclooxygenase-2. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 202. |
| 【2】 Ferro, M.P.; Sui, Z.; Guan, J.; et al.; 1,3-Diarylcycloalkanopyrazoles and diphenyl hydrazides as selective inhibitors of cyclooxygenase-2. Bioorg Med Chem Lett 2000, 10, 6, 601. |