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【结 构 式】 
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【药物名称】Terbinafine hydrochloride, SF-86327, Lamisil AT, Daskil, Afogan, Lamisil 【化学名称】(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine hydrochloride 【CA登记号】78628-80-5, 91161-71-6 (free base) 【 分 子 式 】C21H26ClN 【 分 子 量 】327.90107 |
【开发单位】Novartis (Originator), LPB (Not Determined), Galderma (Licensee), Samil (Licensee) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY |
合成路线1
1) The Grignard reaction of 1-bromonaphthalene (I) with Mg in THF and then with [14C]-labeled CO2 gives the corresponding 1-naphthoic acid (II), which by reaction with SO2Cl2 and then with methylamine yields [14C]-N-methyl-1-naphthalenecarboxamide (III). The reduction of (III) with LiAlH4 in refluxing THF affords the corresponding amine (IV). Finally, this compound is condensed with 1-bromo-6,6-dimethylhept-2-en-4-yne (V) by means of Na2CO3 in DMF, and treated with ethanolic HCl.
| 【1】 Andres, H.; Carbon-14 labelling of terbinafine, an antimycotic agent. J Label Compd Radiopharm 1989, 27, 11, 1307. |
| 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) | 10105 | 1-Bromonaphthalene | 90-11-9 | C10H7Br | 详情 | 详情 |
| (II) | 10106 | 1-Naphthoic acid | 86-55-5 | C11H8O2 | 详情 | 详情 |
| (II) | 44581 | 1-naphthoic acid | C11H8O2 | 详情 | 详情 | |
| (III) | 10107 | N-Methyl-1-naphthamide | 3400-33-7 | C12H11NO | 详情 | 详情 |
| (III) | 44582 | N-methyl-1-naphthamide | C12H11NO | 详情 | 详情 | |
| (IV) | 10108 | N-Methyl(1-naphthyl)methanamine; N-Methyl-N-(1-naphthylmethyl)amine; 1-Methyl-1-naphthalenemethylamine | 65473-13-4 | C12H13N | 详情 | 详情 |
| (IV) | 44583 | N-methyl(1-naphthyl)methanamine; N-methyl-N-(1-naphthylmethyl)amine | C12H13N | 详情 | 详情 | |
| (V) | 10109 | (E)-1-Bromo-6,6-dimethyl-2-hepten-4-yne | 78629-21-7 | C9H13Br | 详情 | 详情 |
合成路线2
2) By condensation of (E)-N-methyl-N-(1-naphthylmethyl)-N-(pent-2-en-4-ynyl)amine (I) with [14C]-tert-butyl-chloride (II) by means of butyllithium and diethylaluminum chloride in hexane-dichloromethane.
| 【1】 Andres, H.; Carbon-14 labelling of terbinafine, an antimycotic agent. J Label Compd Radiopharm 1989, 27, 11, 1307. |
合成路线3
The condensation of N-methyl-N-(1-naphthylmethyl)propargylamine (I) with 1-bromo-2-tert-butylacetylene (II) by means of Cu2Cl2 gives N-methyl-N-(1-naphthylmethyl)-6,6-dimethylhept-2,4-diynylamine (III), which is then reduced selectively with diisobutylaluminurn hydride in toluene.
| 【1】 Stutz, A.; SF-86327 and related compounds: Synthetic methods. Int Con Chemother 1983, 116, 5-8. |
| 【2】 Stutz, A. (Novartis AG); Propenylamines, pharmaceutical compositions containing them and their use as pharmaceuticals. EP 0024587; JP 56032440; JP 63313753; Us 4755534 . |
| 【3】 Serradell, M.N.; Castaner, J.; SF-86327. Drugs Fut 1984, 9, 6, 425. |
| 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) | 30533 | N-methyl-N-(1-naphthylmethyl)-N-(2-propynyl)amine; N-methyl-N-(1-naphthylmethyl)-2-propyn-1-amine | C15H15N | 详情 | 详情 | |
| (II) | 30534 | 1-bromo-3,3-dimethyl-1-butyne | C6H9Br | 详情 | 详情 | |
| (III) | 30535 | N-(6,6-dimethyl-2,4-heptadiynyl)-N-methyl-N-(1-naphthylmethyl)amine; N,6,6-trimethyl-N-(1-naphthylmethyl)-2,4-heptadiyn-1-amine | C21H23N | 详情 | 详情 |
合成路线4
The condensation of N-(1-naphthylmethyl)methylamine (IV) with formaldehyde and 5,5-dimethylhexadiine (V) by means of Cu2Cl2 also gives (III), which is then reduced selectively with diisobutylaluminum hydride in toluene.
| 【1】 Stutz, A.; SF-86327 and related compounds: Synthetic methods. Int Con Chemother 1983, 116, 5-8. |
| 【2】 Serradell, M.N.; Castaner, J.; SF-86327. Drugs Fut 1984, 9, 6, 425. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 30535 | N-(6,6-dimethyl-2,4-heptadiynyl)-N-methyl-N-(1-naphthylmethyl)amine; N,6,6-trimethyl-N-(1-naphthylmethyl)-2,4-heptadiyn-1-amine | C21H23N | 详情 | 详情 | |
| (IV) | 10108 | N-Methyl(1-naphthyl)methanamine; N-Methyl-N-(1-naphthylmethyl)amine; 1-Methyl-1-naphthalenemethylamine | 65473-13-4 | C12H13N | 详情 | 详情 |
| (V) | 30536 | 5,5-dimethyl-1,3-hexadiyne | C8H10 | 详情 | 详情 |
合成路线5
By reductocondensation of amino (IV) with 6,6-dimethylhept-2-en-4-ynal (VI) by means of NaBH4 in methanol.
| 【1】 Stutz, A. (Novartis AG); Propenylamines, pharmaceutical compositions containing them and their use as pharmaceuticals. EP 0024587; JP 56032440; JP 63313753; Us 4755534 . |
| 【2】 Serradell, M.N.; Castaner, J.; SF-86327. Drugs Fut 1984, 9, 6, 425. |
合成路线6
The condensation of propenal (VII) with tert-butylacetylene (VIII) by means of butyllithium gives 6,6-dimethylhept-1-en-4-yn-3-ol (IX), which is rearranged with HBr to the allyl isomer 6,6-dimethylhept-2-en-4-yn-1-yl bromide (X). Finally, this compound is condensed with amine (IV) by means of Na2CO3 in DMF.
| 【1】 Stutz, A.; SF-86327 and related compounds: Synthetic methods. Int Con Chemother 1983, 116, 5-8. |
| 【2】 Stutz, A. (Novartis AG); Propenylamines, pharmaceutical compositions containing them and their use as pharmaceuticals. EP 0024587; JP 56032440; JP 63313753; Us 4755534 . |
| 【3】 Serradell, M.N.; Castaner, J.; SF-86327. Drugs Fut 1984, 9, 6, 425. |
| 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) | 10108 | N-Methyl(1-naphthyl)methanamine; N-Methyl-N-(1-naphthylmethyl)amine; 1-Methyl-1-naphthalenemethylamine | 65473-13-4 | C12H13N | 详情 | 详情 |
| (VII) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (VIII) | 30538 | 4,4-dimethyl-2-pentyne | 999-78-0 | C7H12 | 详情 | 详情 |
| (IX) | 30539 | 6,6-dimethyl-1-hepten-4-yn-3-ol | C9H14O | 详情 | 详情 | |
| (X) | 30540 | (E)-1-bromo-5,5-dimethyl-1-hexen-3-yne | C8H11Br | 详情 | 详情 |
合成路线7
The rearrangement of 6,6-dimethylhept-1-en-4-yn-3-ol (I) (scheme 09027805a, intermediate (IX)) to 1-bromo-6,6-dimethylhept-2(E)-en-4-yne (scheme 09027805a, intermediate (X)) with HBr reports a stereoselectivity E/Z of only 3/1. An exhaustive study of this halogenation/rearrangement reaction has been performed. This reaction ((I) to chloride (II)) has been improved up to and E/Z ratio of 9/1 with reaction yields of 95%, the reaction conditions being BCl3 (1.25 molar ratio) in hexane, with a reaction temperature of 25 C.
| 【1】 Chou, S.Y.; et al.; A stereoselective synthesis of (E)-1-halo-6,6-dimethyl-2-hepten-4-yne: A key intermediate for terbinafine. Tetrahedron Lett 2000, 41, 20, 3895. |
合成路线8
A new method for the short preparation of terbinafine has been described: Condensation of (E)-N-(3-bromoallyl)-N-methyl-N-(1-naphthyl)amine (I) with lithium tert-butylethynyl(triisopropoxy)borate (II) by means of Pd(PPh3)4, and CuI in hot DMF.
| 【1】 Oh, C.H.; Jung, S.H.; Efficient coupling reactions of lithium alkynyl(triisopropoxy)borates with aryl halides: Application to the antifungal terbinafine synthesis. Tetrahedron Lett 2000, 41, 44, 8513. |