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【结 构 式】 
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【分子编号】37591 【品名】3-(sulfanylmethyl)-3-quinuclidinol 【CA登记号】 |
【 分 子 式 】C8H15NOS 【 分 子 量 】173.27924 【元素组成】C 55.45% H 8.73% N 8.08% O 9.23% S 18.51% |
合成路线1
该中间体在本合成路线中的序号：(III)Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid affords a mixture of two diastereomeric spiroracemates, the (±)-trans (V) and (±)-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid. The (±)-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3. Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane.
| 【1】 Fisher, A.; Grunfeld, Y.; Heldman, E.; Karton, I.; Levy, A. (Israel Institute for Biological Research); Derivs of quinuclidine. EP 0205247; JP 1986280497; US 4855290 . |
| 【2】 Sorbera, L.A.; Castaner, J.; Cevimeline Hydrochloride. Drugs Fut 2000, 25, 6, 558. |
| 【3】 Hayashi, K.; Isogai, T.; Tokumoto, S.; Yoshizawa, H. (Ishihara Sangyo Kaisha, Ltd.); Method for producing 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine. EP 0683168; US 5571918 . |
| 【4】 Hara, K.; Koyanagi, T.; Shigehara, I.; Maeda, M.; Haga, T. (Ishihara Sangyo Kaisha, Ltd.); Method for isomerization of trans-form 2-methylspiro-(1,3-oxothiolane-5,3')-quinuclidine or acid addition salts thereof. EP 0298491; US 4861886 . |
| 【5】 Honda, N.; Saito, K.; Ono, T. (Snow Brand Milk Products Co., Ltd.); Preparation method of cis-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine hydrochloride.1/2 hydrate capable of disgregating easily. JP 1992108792 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| cis-(V) | 37592 | C10H17NOS | 详情 | 详情 | ||
| trans-(V) | 37593 | C10H17NOS | 详情 | 详情 | ||
| (I) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
| (II) | 37590 | C8H13NO | 详情 | 详情 | ||
| (III) | 37591 | 3-(sulfanylmethyl)-3-quinuclidinol | C8H15NOS | 详情 | 详情 | |
| (IV) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 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】 Hayashi K, Tokumoto S,Yoshizawa H,et aL. 1995,Method and catalysts {or producing cis-2-methylspiro(1,3-oxthiolane-5,3’)quinuclidinefrom 3-hydroxy-3-mercaptomethylquinuclidine and acarbonyl com pound. EP 683168 |