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【结 构 式】 
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【分子编号】47677 【品名】2-Methyl-5-Hexanone; 5-Methyl-2-hexanone; 5-Methyl-2-oxohexane; iso-Amyl methyl ketone; Isopentyl methyl ketone; Methyl isoamyl ketone 【CA登记号】110-12-3 |
【 分 子 式 】C7H14O 【 分 子 量 】114.18756 【元素组成】C 73.63% H 12.36% O 14.01% |
合成路线1
该中间体在本合成路线中的序号：(VI)Condensation of 7-hydroxy-1,8-naphthyridin-2-amine (I) with phthalic anhydride (II) in refluxing acetic acid gives N-(7-hydroxy-1,8-naphthyridin-2-yl)phthalimide (III), which is treated with refluxing POCl3 to yield the 7-chloro derivative (IV). Reduction of compound (IV) with KBH4 in dioxane affords 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (V), which is condensed with 5-methyl-2-hexanone (VI) by means of NaH in DMF to give (±)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one (VII) (racemic pagoclone). The treatment of (VII) with NaOH in dioxane/water yields the racemic benzoic acid (VIII). Optical resolution of racemic (VIII) by means of (+)-ephedrine or cinchonine affords the (+)-isomer (IX), which is finally cyclized to the chiral (+)-indolinone derivative pagoclone by means of SOCl2 and imidazole in dichloromethane.
| 【1】 Silvestre, J.S.; Castaner, J.; Leeson, P.A.; Sorbera, L.A.; Pagoclone. Drugs Fut 2001, 26, 7, 651. |
| 【2】 Bourzat, J.-D.; Cotrel, C.; Roussel, G.; Capet, M.; Labaudiniere, R.; Pitchen, P. (Aventis SA); Isoindolinone derivs.. AU 8781911; EP 0274930; FR 2607503; JP 1988154681; US 4960779 . |
| 【3】 David-Comte, M.-T.; Roussel, G. (Aventis Pharma SA); Novel 2-aminonaphthyridine deriv., its preparation and its use. EP 0522969; FR 2678931 . |
| 【4】 David-Comte, M.-T. (Aventis Pharma SA); Dextrorotatory isomer of a deriv. of 2-amino naphthyridine and its preparation. EP 0522971; FR 2678933 . |
| 【5】 David-Comte, M.-T. (Aventis Pharma SA); Process for the preparation of a dextrorotatory isomer of an isoindolinone deriv.. EP 0522972; FR 2678934 . |
| 【6】 David-Comte, M.-T. (Aventis Pharma SA); Process for the preparation of the optical isomers of 2-aminonaphthyridine derivs.. EP 0522970; FR 2678932 . |
| 【7】 Cotrel, C.; Crisan, C.; Jeanmart, C.; Messer, M.N. (Aventis Pharma SA); Heterocyclic compounds. BE 0835325; DE 2550111; FR 2313060; FR 2322600; FR 2322601; FR 2322602; GB 1468497; JP 7670776; JP 7733685; JP 7998790; JP 8040671; JP 8051087; US 4220646 . |
| 【8】 (Aventis Pharma SA); Novel isoindoline derivs., their preparation and compsns. containing them. FR 2229400 . |
| 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) | 28994 | 7-amino[1,8]naphthyridin-2-ol | C8H7N3O | 详情 | 详情 | |
| (II) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (III) | 47675 | 2-(7-hydroxy[1,8]naphthyridin-2-yl)-1H-isoindole-1,3(2H)-dione | C16H9N3O3 | 详情 | 详情 | |
| (IV) | 47676 | 2-(7-chloro[1,8]naphthyridin-2-yl)-1H-isoindole-1,3(2H)-dione | C16H8ClN3O2 | 详情 | 详情 | |
| (V) | 11334 | 2-(7-Chloro[1,8]naphthyridin-2-yl)-3-hydroxy-1-isoindolinone | C16H10ClN3O2 | 详情 | 详情 | |
| (VI) | 47677 | 2-Methyl-5-Hexanone; 5-Methyl-2-hexanone; 5-Methyl-2-oxohexane; iso-Amyl methyl ketone; Isopentyl methyl ketone; Methyl isoamyl ketone | 110-12-3 | C7H14O | 详情 | 详情 |
| (VII) | 47678 | 2-(7-chloro[1,8]naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone | C23H22ClN3O2 | 详情 | 详情 | |
| (VIII) | 47679 | (rac)-2-[1-[(7-chloro[1,8]naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl]benzoic acid | C23H24ClN3O3 | 详情 | 详情 | |
| (IX) | 47680 | (+)-2-[1-[(7-chloro[1,8]naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl]benzoic acid | C23H24ClN3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)
| 【1】 Boldt KG, Biggers MS, Phifer SS, et al.2009.Synthesis of (+)- and (-)-tetrabenazine from the resolution of α-dihydrotetrabenazine. Synthetic Commun,39, 3574～3585. |
| 【2】 Gant TG, Shahbaz M.2010.Benzoquinoline inhibitors of vesicular monoamine transporter 2.WO 2010/044981 A2. |
| 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) | 47677 | 2-Methyl-5-Hexanone; 5-Methyl-2-hexanone; 5-Methyl-2-oxohexane; iso-Amyl methyl ketone; Isopentyl methyl ketone; Methyl isoamyl ketone | 110-12-3 | C7H14O | 详情 | 详情 |
| (II) | 67440 | 3-((dimethylamino)methyl)-5-methylhexan-2-one | 91342-74-4 | C10H21NO | 详情 | 详情 |
| (III) | 67441 | 2-acetyl-N,N,N,4-tetramethylpentan-1-aminium iodide | C11H24INO | 详情 | 详情 | |
| (IV) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (V) | 67442 | 6,7-dimethoxy-3,4-dihydroisoquinoline | 3382-18-1 | C11H13NO2 | 详情 | 详情 |
| (VII) | 67443 | (2S,3S,11bS)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol | C19H29NO3 | 详情 | 详情 |