|
【结 构 式】 
|
【分子编号】29856 【品名】2-hydroxyacetic acid;glycolic acid 【CA登记号】79-14-1 |
【 分 子 式 】C2H4O3 【 分 子 量 】76.05196 【元素组成】C 31.59% H 5.3% O 63.11% |
合成路线1
该中间体在本合成路线中的序号：(VII)The reductocondensation of piperidine (I) with 3-hydroxybenzaldehyde (II) by means of sodium borohydride in ethanol gives 3-(1-piperidylmethyl)phenol (III), which is then condensed with N-(3-bromopropyl)phthalimide (IV) by means of NaH in DMF yielding N-[3-[3-(1-piperidylmethyl)phenoxy]propyl]phthalimide (V). The hydrolysis of (V) with hydrazine in ethanol affords 3-[3-(1-piperidylmethyl)phenoxy]propylamine (VI), which is acylated with hydroxyacetic acid (VII) at 200 C giving N-[3-[3-(1-piperidylmethyl)phenoxy]propyl]hydroxyacetamide (VIII). Finally, this compound is acetylated with acetic anhydride at 100 C.
| 【1】 Shibata, K.; et al. (Teikoku Hormone Manufacturing Co., Ltd.); Antiulcer phenoxypropylamine derivatives. EP 0024510; JP 81115750; US 4293557 . |
| 【2】 Castaner, J.; Serradell, M.N.; TZU-0460. Drugs Fut 1985, 10, 12, 995. |
| 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) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (II) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (III) | 29854 | 3-(1-piperidinylmethyl)phenol | C12H17NO | 详情 | 详情 | |
| (IV) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (V) | 29855 | 2-[2-[3-(1-piperidinylmethyl)phenoxy]ethyl]-1H-isoindole-1,3(2H)-dione | C22H24N2O3 | 详情 | 详情 | |
| (VI) | 16105 | 3-[3-(piperidinomethyl)phenoxy]-1-propanamine; 3-[3-(piperidinomethyl)phenoxy]propylamine | C15H24N2O | 详情 | 详情 | |
| (VII) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (VIII) | 29857 | 2-hydroxy-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide | C17H26N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)An aqueous solution of diamineplatinum nitrate (I) is passed through an anion exchange resin to give diamineplatinum hydroxide (II), which is then treated with glycolic acid (III) in hot water.
| 【1】 Satoi, Y.; Jaracz, E.; Ling, M.; Rico, M.J.; Maher, R.M.; Eichenfield, L.; Fleischer, A.B.; 5th Inter Symp Platinum Other Metal Coordin Comp Cancer Chemother (June,29-July,2, Abano Terme) 1987, 47, 4, E44. |
| 【2】 Shiratori, O.; Toya, T.; Aono, K. (Shionogi & Co. Ltd.); Novel glycolic acid platinum complex and antineoplasticagent. JP 1984222497 . |
| 【3】 Castaner, J.; Castaner, R.M.; Serradell, M.N.; 254-S. Drugs Fut 1987, 12, 11, 1029. |
合成路线3
该中间体在本合成路线中的序号：(VI)The reaction of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (I) with hydroxylamine and pyridine in refluxing ethanol gives the oxime (II), which is reduced with LiAlH4 in refluxing 10% H2SO4 yielding endo-methyl-8-azabicyclo[3.2.1]octan-3-amine (III). Finally, this compound is condensed with 1-isopropylbenzimidazole-2-carboxylic acid isopropyl ester (IV) by means of Al(CH3)3 in refluxing toluene. The intermediate 1-isopropylbenzimidazole-2-carboxylic acid isopropyl ester (IV) has been obtained as follows: The cyclization of o-phenylenediamine (V) with 2-hydroxyacetic acid (VI) in refluxing 4N HCl gives 1H-benzyldazole-2-ylmethanol (VII), which is oxidized with KMnO4 to the corresponding carboxylic acid (VIII). Finally, this compound is alkylated and esterified with isopropyl chloride and NaH in DMF.
| 【1】 Labeaga, L.; Alonso-Cires, L.; Tapia, I.; Mosquera, R.; Orjales, A.; Lopez-Tudanca, P.; Benzimidazole-2-carboxylic acid amides and esters: A new structural class of 5-HT3 ligands. Eur J Med Chem 1999, 34, 5, 415. |
| 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) | 38416 | Tropinone; 3-Tropanone; Tropionone; 8-methyl-8-azabicyclo[3.2.1]octan-3-one | 532-24-1 | C8H13NO | 详情 | 详情 |
| (II) | 38412 | 8-methyl-8-azabicyclo[3.2.1]octan-3-one oxime | C8H14N2O | 详情 | 详情 | |
| (III) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 | |
| (IV) | 38413 | isopropyl 1-isopropyl-1H-benzimidazole-2-carboxylate | C14H18N2O2 | 详情 | 详情 | |
| (V) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (VI) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (VII) | 38414 | 1H-benzimidazol-2-ylmethanol | 4856-97-7 | C8H8N2O | 详情 | 详情 |
| (VIII) | 38415 | 1H-benzimidazole-2-carboxylic acid | C8H6N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Synthesis of benzimidazole intermediate (VIII) was achieved as follows. The reaction of 2,5-difluoronitrobenzene (I) with 3-methoxypropylamine (II) by means of K2CO3 in acetonitrile gives the aniline (III), which is reduced with Fe and NH4Cl in water to yield the phenylenediamine (IV). The cyclization of (IV) with glycolic acid (V) in refluxing 4N HCl affords the benzimidazolylmethanol (VI). Finally, this compound is brominated with (bromomethylene)dimethylammonium bromide (VII) in acetonitrile to provide the target bromomethylbenzimidazole intermediate (VIII). The reaction of 4-methoxy-3-nitropyridine (IX) with cyclopropylamine (X) in refluxing ethanol gives the N-cyclopropyl-3-nitropyridine-4-amine (XI), which is reduced with H2 over Pd/C in methanol to yield the pyridinediamine (XII). The cyclization of (XII) with phosgene in acetonitrile affords 1-cyclopropyl-2,3-dihydro-1H-imidazol[4,5-c]pyridin-2-one (XIII), which is condensed with bromomethyl intermediate (VIII) by means of NaH in THF, DMF or acetonitrile to provide the adduct (XIV). Finally, this compound is demethylated by means of BBr3 in dichloromethane to furnish the target 3-hydroxypropyl compound.
| 【1】 Meanwell, N.A.; Yu, K.-L.; Combrink, K.D.; Wang, X.; Civiello, R.L.; Gulgeze, H.B.; Sin, N.; Venables, B.L. (Bristol-Myers Squibb Co.); Imidazopyridine and imidazopyrimidine antiviral agents. EP 1311268; US 2002016309; US 6489338; WO 0195910 . |
| 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) | 28544 | 1,4-difluoro-2-nitrobenzene | 364-74-9 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 61531 | Carbo-trap(TM) 2; 3-Methoxypropylamine; 1-Propanamine, 3-methoxy-; 3-Methoxy-1-aminopropane; 3-Methoxypropane-1-amine; 1-Amino-3-methoxypropane; 3-Methoxypropylamine; 3-Methoxypropyl-1-amine; 3-Aminopropyl Methyl Ether; 3-Methoxypropylamine with G.C.; 3-Methoxy Propylamine; 3-Methoxy-1-propanamine; 3MOPA | 5332-73-0 | C4H11NO | 详情 | 详情 |
| (III) | 61532 | 4-fluoro-N-(3-methoxypropyl)-2-nitroaniline; N-(4-fluoro-2-nitrophenyl)-N-(3-methoxypropyl)amine | C10H13FN2O3 | 详情 | 详情 | |
| (IV) | 61533 | N-(2-amino-4-fluorophenyl)-N-(3-methoxypropyl)amine; 4-fluoro-N~1~-(3-methoxypropyl)-1,2-benzenediamine | C10H15FN2O | 详情 | 详情 | |
| (V) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (VI) | 61534 | [1-(3-methoxypropyl)-1H-benzimidazol-2-yl]methanol | C12H16N2O2 | 详情 | 详情 | |
| (VII) | 61535 | N-(bromomethylene)-N-methylmethanaminium bromide | C3H7Br2N | 详情 | 详情 | |
| (VIII) | 61536 | 2-(bromomethyl)-1-(3-methoxypropyl)-1H-benzimidazole; 3-[2-(bromomethyl)-1H-benzimidazol-1-yl]propyl methyl ether | C12H15BrN2O | 详情 | 详情 | |
| (IX) | 61537 | 4-methoxy-3-nitropyridine; methyl 3-nitro-4-pyridinyl ether | C6H6N2O3 | 详情 | 详情 | |
| (X) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XI) | 61538 | N-cyclopropyl-3-nitro-4-pyridinamine; N-cyclopropyl-N-(3-nitro-4-pyridinyl)amine | C8H9N3O2 | 详情 | 详情 | |
| (XII) | 61539 | N-(3-amino-4-pyridinyl)-N-cyclopropylamine; N~4~-cyclopropyl-3,4-pyridinediamine | C8H11N3 | 详情 | 详情 | |
| (XIII) | 61540 | 1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one | C9H9N3O | 详情 | 详情 | |
| (XIV) | 61541 | 1-cyclopropyl-3-{[1-(3-methoxypropyl)-1H-benzimidazol-2-yl]methyl}-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one | C21H23N5O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXXII)The triazolopyrimidine intermediate (IX) is prepared as follows. Cyclization of glycolic acid (XXXII) with aminoguanidine bicarbonate (XXXIII) in the presence of HNO3 at reflux yields 3-amino-5-(hydroxymethyl)-1,2,4-triazole (XXXIV) (1), optionally isolated as its glycolate salt , which then cyclizes with acetylacetone (XXXV) in refluxing AcOH/EtOH to afford the [1,2,4]triazolo[1,5-a]pyrimidine derivative (XXXVI) . Finally, alcohol (XXXVI) is oxidized by means of o-iodoxybenzoic acid (IBX) in DCE at 80 °C or with PhI(OAc)2 in the presence of TEMPO in CH2Cl2 .
| 【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725. |
| 【2】 Matthews, C.F., Scott, R.W., Tucker, J.L. (Pfizer, Inc.). CN 102336758, EP 1928878, JP 2007056022, US 2009023921, US 7807838, WO 2007023381. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 68338 | 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde | C8H8N4O | 详情 | 详情 | |
| (XXXII) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (XXXIII) | 68355 | aminoguanidine bicarbonate;aminoguanidine carbonate;1-aminoguanidine bicarbonate;aminoguanidine hydrogen carbonate | 2200-97-7 | CH6N4.CH2O3 | 详情 | 详情 |
| (XXXIV) | 68356 | 5-amino-1H-1,2,4-Triazole-3-methanol;3-amino-5-(hydroxymethyl)-1,2,4-triazole;5-amino-s-Triazole-3-methanol;(5-Amino-1H-[1,2,4]triazol-3-yl)methanol | 27277-03-8 | C3H6N4O | 详情 | 详情 |
| (XXXV) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (XXXVI) | 68357 | (5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol | C8H10N4O | 详情 | 详情 |