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【结 构 式】 
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【药物名称】Pramipexole hydrochloride, SND-919, PNU-98528E, SND-919CL2Y(free base), U-98528E(free base), SND-919Y, Mirapexin, Sifrol, Mirapex 【化学名称】(S)-(-)-2-Amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole dihydrochloride 【CA登记号】104632-25-9, 104632-28-2 ((R)-isomer), 104632-27-1 ((R)-isomer; diHCl), 104632-26-0 (free base) 【 分 子 式 】C10H19Cl2N3S 【 分 子 量 】284.25303 |
【开发单位】Boehringer Ingelheim (Originator), Nippon Boehringer Ingelheim (Originator), National Institutes of Health (Not Determined), Pfizer (Licensee) 【药理作用】Antiparkinsonian Drugs, Bipolar Disorder, Treatment of, Extrapyramidal Disorders, Treatment of, Fibromyalgia, Treatment of, Mood Disorders, Treatment of, Myoclonus, Treatment of, NEUROLOGIC DRUGS, Neurologic Drugs (Miscellaneous), PSYCHOPHARMACOLOGIC DRUGS, Restless Legs Syndrome, Treatment of, Sensation Disorders, Treatment of, Dopamine D3 Agonists |
合成路线1
This compound can be obtained in two related ways: 1) The cyclization of 4-acetamidocyclohexanone (I) with thiourea (II) by means of Br2 in hot acetic acid gives 6-acetamido-2-amino-4,5,6,7-tetrahydrobenzothiazole (III), which by hydrolysis with refluxing aqueous HBr yields racemic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (racemic IV). Optical resolution with L-(+)-tartaric acid affords the (S)-(-)-isomer (IV), which is finally treated with propionaldehyde and LiBH4. 2) The reaction of 4-aminocyclohexanol (V) with phthalic anhydride (VI) in toluene gives the phthalimido derivative (VII), which is oxidized with potassium dichromate - H2SO4 to the corresponding cyclohexanone (VIII). The cyclization of (VIII) with thiourea (II) and Br2 as before affords 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzothiazole (IX), which is deprotected with hydrazine in refluxing ethanol yielding racemic (IV), already obtained.
| 【1】 Griss, G. et al. (Dr. Karl Thomae GmbH); Tetrahydrobenzothiazoles, their preparation and their use as intermediates or as medicines. AU 8551544; DE 3447075; DE 3508947; EP 0186087; ES 8707513; ES 8707514; ES 8707515; JP 1986155377; US 4731374 . |
| 【2】 Schneider, C.S.; Mierau, J.; J. Dopamine autoreceptor agonists: Resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analogue of apomorphine. J Med Chem 1987, 30, 3, 494. |
| 【3】 De Angelis, L.; Pramipexole Hydrochloride. Drugs Fut 1992, 17, 4, 291. |
| 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) | 11895 | N-(4-Oxocyclohexyl)acetamide | 27514-08-5 | C8H13NO2 | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 11897 | N-(2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)acetamide | 104617-51-8 | C9H13N3OS | 详情 | 详情 |
| (IV) | 11898 | (6S)-2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-ylamine; (6S)-4,5,6,7-Tetrahydro-1,3-benzothiazole-2,6-diamine | C7H11N3S | 详情 | 详情 | |
| (V) | 11899 | 4-Aminocyclohexanol; trans-4-Aminocyclohexanol | 27489-62-9 | C6H13NO | 详情 | 详情 |
| (VI) | 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 |
| (VII) | 11901 | 2-(4-Hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione | 104618-31-7 | C14H15NO3 | 详情 | 详情 |
| (VIII) | 11902 | 2-(4-Hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione | C14H13NO3 | 详情 | 详情 | |
| (IX) | 11903 | 2-(2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)-1H-isoindole-1,3(2H)-dione | C15H13N3O2S | 详情 | 详情 |