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【结 构 式】 
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【分子编号】14625 【品名】4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutyric acid 【CA登记号】 |
【 分 子 式 】C11H13NO5S 【 分 子 量 】271.29396 【元素组成】C 48.7% H 4.83% N 5.16% O 29.49% S 11.82% |
合成路线1
该中间体在本合成路线中的序号：(V)The acylation of aniline (I) with methanesulfonyl chloride (II) in pyridine gives the corresponding sulfonamide (III), which is submitted to a Friedel-Crafts condensation with succinic anhydride (IV) and AlCl3 in hot carbon disulfide to afford 4-[4-(methanesulfonyl)phenyl]-4-oxobutyric acid (V). The amidation of (V) with N-ethylheptylamine (VI) yields the corresponding amide (VII), which is finally reduced with LiAlH4 in THF and treated with an ethanolic solution of fumaric acid in order to precipitate the corresponding salt.
| 【1】 Stolle, W.T.; Stelzer, L.S.; Hester, J.B.; Perricone, S.C.; Hsi, R.S.P.; Synthesis of radiolabeled racemic and enantiomeric antiarrhythmic agents. J Label Compd Radiopharm 1994, 34, 10, 929. |
| 【2】 Robinson, C.; Robinson, K.; Castaner, J.; Ibutilide Fumarate. Drugs Fut 1996, 21, 9, 894. |
| 【3】 Hester, J.B. Jr. (Pharmacia Corp.); N-(Aminoalkylphenyl)sulfonamides their preparation and therapeutic use. EP 0164865; JP 1985239458; US 5155268 . |
| 【4】 Hester, J.B.; Gibson, J.K.; Cimini, M.G.; Emmert, D.E.; Locker, P.K.; Perricone, S.C.; Skaletzky, L.L.; Sykes, J.K.; West, B.E.; N-[(omega-Amino-1-hydroxyalkyl)phenyl]methanesulfonamide derivatives with Class III antiarrhythmic activity. J Med Chem 1991, 34, 1, 308-15. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (III) | 13699 | N-Phenylmethanesulfonamide; N-Phenyl methanesulfonamide | 1197-22-4 | C7H9NO2S | 详情 | 详情 |
| (IV) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (V) | 14625 | 4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutyric acid | C11H13NO5S | 详情 | 详情 | |
| (VI) | 14626 | N-ethyl-1-heptanamine; N-ethyl-N-heptylamine | C9H21N | 详情 | 详情 | |
| (VII) | 14627 | N-ethyl-N-heptyl-4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutanamide | C20H32N2O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Activation of butyric acid derivative (I) with isobutyl chloroformate (II) by means of Et3N in THF, followed by coupling with ethylamine (III) in THF in the presence of Et3N, yields butyramide derivative (IV). Reduction of (IV) by means of (-)-B-chlorodiisopinocampheylborane (Ipc2BCl) in THF, followed by reaction with diethanolamine (A), affords hydroxy derivative (V), whose carbonyl group is removed by means of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in toluene/THF, followed by treatment with H2SO4 to provide compound (VI) . Separately, the synthesis of intermediate (XIV) is performed as follows: condensation of pentamethylene chlorohydrin (VII) with 3,4-dihydro-2H-pyran (VIII) by means of p-toluenesulfonic acid in Et2O furnishes 5-chloropentyl-2-tetrahydropyranyl ether (IX), which is then subjected to reaction with acetone (X) in THF by means of Mg in the presence of 1,2-dibromoethane (B) to provide tetrahydropyranyl ether (XI). Conversion of hydroxy derivative (XI) into the corresponding fluoro derivative (XII) is performed by reaction with diethylaminosulfur trifluoride (DAST) in CH2Cl2, and posterior reaction of (XII) with pyridinium p-toluenesulfonate in EtOH furnishes 6-fluoro-6-methyl-1-heptanol (XIII). Finally, intermediate (XIV) is obtained by reaction of (XIII) with NBS and PPh3 in benzene. Condensation of secondary amine (VI) with intermediate (XIV) by means of NaHCO3 in refluxing acetonitrile provides methanesulfonamide (XV), which is finally converted into the target product by formation of the hemifumarate salt by treatment with fumaric acid (XVI) in acetone.
| 【1】 Hester, J.B.; Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: Synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential. J Med Chem 2001, 44, 7, 1099. |
| 【2】 Hester, J.B. Jr.; Gibson, J.K. (Pharmacia Corp.); Antiarrhythmic (S)-enantiomers of methanesulfonamides. EP 0802900; JP 1999500418; WO 9621643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (A) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (I) | 14625 | 4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutyric acid | C11H13NO5S | 详情 | 详情 | |
| (II) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (III) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
| (IV) | 48114 | N-ethyl-4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutanamide | C13H18N2O4S | 详情 | 详情 | |
| (V) | 48115 | (4S)-N-ethyl-4-hydroxy-4-[4-[(methylsulfonyl)amino]phenyl]butanamide | C13H20N2O4S | 详情 | 详情 | |
| (VI) | 48116 | N-[4-[(1S)-4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide | C13H22N2O3S | 详情 | 详情 | |
| (VII) | 48117 | 5-chloro-1-pentanol | C5H11ClO | 详情 | 详情 | |
| (VIII) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (IX) | 48118 | 2-[(5-chloropentyl)oxy]tetrahydro-2H-pyran; 5-chloropentyl tetrahydro-2H-pyran-2-yl ether | C10H19ClO2 | 详情 | 详情 | |
| (X) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (XI) | 48119 | 2-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-2-hexanol | C12H24O3 | 详情 | 详情 | |
| (XII) | 48120 | 5-fluoro-5-methylhexyl tetrahydro-2H-pyran-2-yl ether; 2-[(5-fluoro-5-methylhexyl)oxy]tetrahydro-2H-pyran | C12H23FO2 | 详情 | 详情 | |
| (XIII) | 48121 | 6-fluoro-6-methyl-1-heptanol | C8H17FO | 详情 | 详情 | |
| (XIV) | 48122 | 1-bromo-6-fluoro-6-methylheptane | C8H16BrF | 详情 | 详情 | |
| (XV) | 48123 | N-(4-[(1S)-4-[ethyl(6-fluoro-6-methylheptyl)amino]-1-hydroxybutyl]phenyl)methanesulfonamide | C21H37FN2O3S | 详情 | 详情 | |
| (XVI) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |