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【结 构 式】 
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【分子编号】13620 【品名】4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid 【CA登记号】56-12-2 |
【 分 子 式 】C4H9NO2 【 分 子 量 】103.121 【元素组成】C 46.59% H 8.8% N 13.58% O 31.03% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of 4-aminobutyric acid (VI) with acid chloride (IV) by means of NaOH in water gives 4-(4-methoxybenzoylamino)butyric acid (VII), which is then cyclized by means of P2O5 in phosphoric acid.
| 【1】 Kyburz, E.; Aschwanden, W. (F. Hoffmann-La Roche AG); 1-(p-Methoxy-p-hydroxy, and p-benzyloxybenzoyl)-2-pyrrolidinones. DD 141828; EP 0005143; EP 0044088; ES 477587; ES 483756; JP 54117468 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 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) | 29099 | 4-[(4-methoxybenzoyl)amino]butyric acid | C12H15NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)1) The cyclization of 4-cyanophenol (I) with 3-chloro-3-methylbutine (II) by means of benzyltrimethylammonium hydroxide in methanol-CH2Cl2 gives 6-cyano-2,2-dimethyl-2H-benzo[b]pyran (III), which is treated with N-bromosuccinimide in DMSO to afford 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl 2H benzo[b]pyran-4-ol (IV). Epoxidation of (IV) by means of NaOH in dioxane-water yields 6-cyano-3-(4-dihydro-3,4-epoxy-2,2-dimethyl-2H-benzo[b]pyran (V), which is finally treated with 4-aminobutyric acid (VI) and NaHCO3 in refluxing ethanol. 2) By reaction of epoxide (V) with 2-pyrrolidone (X) by means of NaH in DMSO.
| 【1】 Evans, J.M.; Buckingham, R.E.; Willcocks, K. (SmithKline Beecham plc); Benzopyrans. EP 0076075; JP 3014573; JP 5202034; US 4446113 . |
| 【2】 Faruk, E.A. (SmithKline Beecham plc); Antihypertensive chromenes and chromans. EP 0093535; US 4510152 . |
| 【3】 Castaner, J.; Mannhold, R.; BRL-34915. Drugs Fut 1986, 11, 3, 175. |
| 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) | 27394 | Trimethylbenzylammonium Hydroxide; N,N,N-trimethyl(phenyl)methanaminium hydroxide; Triton B; Benzyltrimethylammonium hydroxide | 100-85-6 | C10H17NO | 详情 | 详情 |
| (I) | 25109 | 4-hydroxybenzonitrile | 767-00-0 | C7H5NO | 详情 | 详情 |
| (II) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (III) | 27395 | 2,2-dimethyl-2H-chromene-6-carbonitrile | C12H11NO | 详情 | 详情 | |
| (IV) | 27396 | 3-bromo-4-hydroxy-2,2-dimethyl-6-chromanecarbonitrile | C12H12BrNO2 | 详情 | 详情 | |
| (V) | 12861 | 2,2-Dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile | C12H11NO2 | 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 |
| (X) | 27397 | 2-Pyrrolidinone | 616-45-5 | C4H7NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)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4
该中间体在本合成路线中的序号：Z-4105 was prepared according to the reaction sequence as follows: The isoxazole intermediate (III) was obtained by one-pot 1,3-dipolar cycloaddition between acetonitrile oxide, in situ generated from chlorooxime (II), and propargyl alcohol. The oxidation of compound (III) with potassium permanganate gave the acid (IV), which was subsequently converted into the acid chloride (V) by Burdett's method. Finally, Z-4105 was synthesized from (V) and gamma-aminobutyric acid by means of Schotten-Baumann procedure.
| 【1】 Burdett, K.A.; An improved acid chloride preparation via phase transfer catalysis. Synthesis 1991, 441-2. |
| 【2】 Casnati, G.; Ricca, A.; Aliphatic chloro oximes and their application in the synthesis of isoxazole and beta-furanone systems. Tetrahedron Lett 1967, 4, 327-30. |
| 【3】 Fusi, R.; Luperi, L.; Napoletano, M.; Ricciardi, S.; Masotto, C.; Z-4105. Drugs Fut 1995, 20, 6, 584. |
| 【4】 Carenzi, A.; Chiarino, D.; Della Bella, D.; Napoletano, M.; Sala, A. (Zambon Group SpA); Isoxazoles with nootropic activity. AU 8817869; EP 0317588; JP 1990500365; US 4985428; WO 8809330 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13620 | 4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid | 56-12-2 | C4H9NO2 | 详情 | 详情 | |
| 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 | |
| (I) | 13341 | Acetaldehyde oxime | 107-29-9 | C2H5NO | 详情 | 详情 |
| (II) | 13342 | N-Hydroxyethanimidoyl chloride | C2H4ClNO | 详情 | 详情 | |
| (III) | 13343 | (3-Methyl-5-isoxazolyl)methanol | C5H7NO2 | 详情 | 详情 | |
| (IV) | 13344 | 3-Methyl-5-isoxazolecarboxylic acid | C5H5NO3 | 详情 | 详情 | |
| (V) | 13345 | 3-Methyl-5-isoxazolecarbonyl chloride | C5H4ClNO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Nicotinic acid azide (I) is mixed with a solution of gamma-aminobutyric acid (II) in 1 N NaOH (pH 8-9). The mixture is stirred for 24 hours, evaporated and the residue is washed with methanol. The resultant sodium salt of nicotinoyl-gamma-aminobutyric acid is then dried. It can be further converted to nicotinoyl-gamma-aminobutyric acid (III) by dissolving in a minimum amount of water and adjusting pH to 3.5.
| 【1】 Kopelevich, V.M.; Trubnikov, V.I.; Shmvilovich, L.M.; et al. (USSR Res. Inst. Vitamins); Process for the preparation of N-nicotinoyl-gamma-aminoaliphatic acids or its esters. SU 325232 . |
| 【2】 Rejholec, V.; PIKAMILONE. Drugs Fut 1990, 15, 2, 133. |
合成路线6
该中间体在本合成路线中的序号：(II)Pivagabine is prepared by reacting pivaloyl chloride (I) and 4-aminobutyric acid (II) in aqueous sodium hydroxide solution; by adding dilute hydrochloric acid the crude product is isolated and then purified by crystallization from water.
| 【1】 Mezzich, J.E.; Mezzich, A.C.; Fabrega, H.; Adjustment disorder as a marginal or transitional illness category in DSM-III. Arch Gen Psychiatry 1987, 44, 6, 567-72. |
| 【2】 Esposito, G.; Lazzarini, R.; Pivagabine. Drugs Fut 1998, 23, 4, 390. |
合成路线7
该中间体在本合成路线中的序号：(I)The condensation of gamma-aminobutylic acid (I) with 3,4-methylenedioxyphenylisothiocyanate (II) in ethanol-H2O gives 1-[3-(carboxy)propyl]-3-(3,4-methylenedioxyphenyl)thiourea (III), which is allowed to react with 3-[3-(piperidinomethyl)phenoxy]propylamine (IV) by means of ethyl chloroformate and triethylamine in dichloromethane to afford TRM-115.
| 【1】 Nakazawa, K.; Isozaki, M.; Koyama, S. (Terumo Corp.); Thiourea derivs. JP 93059038 . |
| 【2】 Isozaki, M.; Nakazawa, K.; Nanba, R.; Matsushima, H.; Koyama, S.; Synthesis of TRM-115. Terumo Co., Ltd. Internal Report . |
| 【3】 Matsushima, H.; Nanba, R.; Isozaki, M.; Nakazawa, K.; Koyama, S.; Synthesis of TRM-115, a new antiulcer agent, and its pharmacological action. 113th Annu Meet Pharmaceut Soc Jpn (March 29-31, Osaka) 1993, Abst 29PB 13-04.. |
| 【4】 Takenaga, T.; Isozaki, M.; TRM-115. Drugs Fut 1993, 18, 10, 909. |
| 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) | 13620 | 4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid | 56-12-2 | C4H9NO2 | 详情 | 详情 |
| (II) | 16103 | 1,3-benzodioxol-5-yl isothiocyanate; 5-isothiocyanato-1,3-benzodioxole | 113504-93-1 | C8H5NO2S | 详情 | 详情 |
| (III) | 16104 | 4-[[(1,3-benzodioxol-5-ylamino)carbothioyl]amino]butyric acid | C12H14N2O4S | 详情 | 详情 | |
| (IV) | 16105 | 3-[3-(piperidinomethyl)phenoxy]-1-propanamine; 3-[3-(piperidinomethyl)phenoxy]propylamine | C15H24N2O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)N-Protection of 4-aminobutyric acid with Boc2O gives N-Boc-4-aminobutyric acid (II) , which by esterification with perphenazine (III) by means of either CDI in DMF or DCC and DMAP in CH2Cl2 affords the N-Boc-amino ester (IV). Alternatively, treatment of N-Boc-GABA (II) with t-BuCOCl in the presence of of Et3N in THF gives the mixed anhydride (V), which by reaction with perphenazine (III) in THF yields amino ester (IV) . Finally, compound (IV) is deprotected by means of MsOH in acetonitrile .
| 【1】 Nudelman, A., Gil-Ad, I., Shpaisman, N. et al. A mutual prodrug ester of GABA and perphenazine exhibits antischizophrenic efficacy with diminished extrapyramidal effects. J Med Chem 2008, 51(9): 2858-62. |
| 【2】 Nudelman, A., Weizman, A., Rephaeli, A., Gil-Ad, I. (Ramot at Tel Aviv University, Ltd.; Bar-Ilan University). Conjugated anti-psychotic drugs and uses thereof. CA 2461663, EP 1429844, EP 2275143, JP 2005503423, JP 2010090170, KR 201009724, WO 2003026563. |
| 【3】 Nudelman, A., Rephaeli, A., Gil-Ad, I., Weizman, A., Halachmi, S., Benjamin, E.J. (Ramot at Tel Aviv University, Ltd.; Bar-Ilan University; BioLineRx, Ltd.). Novel salts of conjugated psychotropic drugs and processes of preparing same. EP 1888120, EP 2272537, JP 2008545777, US 2009298814, WO 2006131923. |
| 【4】 Gil-Ad, I., Rephaeli, A., Weizman, A., Nudelman, A. (Bar-Ilan University; Ramot at Tel Aviv University, Ltd.). Conjugated psychotropic drugs and uses thereof. CA 2560905, EP 1727566, JP 200753029, JP 2011121971, US 2004242570, US 7544681, WO 2005092392. |
| 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) | 13620 | 4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid | 56-12-2 | C4H9NO2 | 详情 | 详情 |
| (II) | 39226 | 4-[(tert-butoxycarbonyl)amino]butyric acid;4-((tert-butoxycarbonyl)amino)butanoic acid | 57294-38-9 | C9H17NO4 | 详情 | 详情 |
| (III) | 68568 | 2-(4-(3-(2-chloro-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethanol | 58-39-9 | C21H26ClN3OS | 详情 | 详情 |
| (IV) | 68569 | 2-(4-(3-(2-chloro-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethyl 4-((tert-butoxycarbonyl)amino)butanoate | C30H41ClN4O4S | 详情 | 详情 | |
| (V) | 68570 | 4-((tert-butoxycarbonyl)amino)butanoic pivalic anhydride | C14H25NO5 | 详情 | 详情 |