Cevimeline hydrochloride, SNK-508, SNI-2011, FKS-508, SND-5008, AF-102B, Saligren, Evoxac, -Drug Synthesis Database

【结构式】

【药物名称】Cevimeline hydrochloride, SNK-508, SNI-2011, FKS-508, SND-5008, AF-102B, Saligren, Evoxac

【化学名称】(±)-cis-2-Methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride hemihydrate
　　　　　　(±)-cis-2'-Methylspiro[1-azabicyclo[2.2.2]octane-3,5'-[1,3]oxathiolane] hydrochloride hemihydrate

【CA登记号】153504-70-2, 107220-28-0 (anhydrous), 107233-08-9 (anhydrous free base)

【分子式】C₁₀H₂₀ClNO₂S

【分子量】253.7934

【开发单位】Israel Institute for Biological Research (Originator), Snow Brand (Licensee), Daiichi Pharmaceutical (Comarketer), Nippon Kayaku (Codevelopment), Ishihara Sangyo (Bulk Supplier)

【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, ONCOLYTIC DRUGS, Radioprotectants, Sjogren's Syndrome, Agents for, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Other Autoimmune Disorders, Muscarinic M1 Agonists, Muscarinic M3 Agonists

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

参考文献中间体

【1】 Bos M,Canesso R. 1994.Synthesis of enantionnerically pure (S)-3-hdroxy3-mercaptomethylquinuclidine.a chiral building block for the synthesisdthe muscarinic aganist AF 102B. Heterocydes,38:1889~1896

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	66180	2-hydroxy-1-(piperidin-4-yl)ethanone hydrochloride	C₇H₁₃NO₂.HCl	详情	详情
(II)	66181	tert-butyl 4-(2-methoxyacetyl)piperidine-1-carboxylate	C₁₃H₂₃NO₄	详情	详情
(III)	66182	tert-butyl 4-(2-hydroxyacetyl)piperidine-1-carboxylate	C₁₂H₂₁NO₄	详情	详情
(IV)	66183	tert-butyl 4-((R)-2-(hydroxymethyl)oxiran-2-yl)cyclohexanecarboxylate	C₁₄H₂₄O₄	详情	详情
(V)	66184	(R)-tert-butyl 4-(1-(benzylthio)-2,3-dihydroxypropan-2-yl)cyclohexanecarboxylate	C₂₁H₃₂O₄S	详情	详情
(VI)	66185	(R)-tert-butyl 4-(1-(benzylthio)-2-hydroxy-3-((methylsulfonyl)oxy)propan-2-yl)cyclohexanecarboxylate	C₂₂H₃₄O₆S₂	详情	详情
(VII)	66186	(S)-2-((benzylthio)methyl)bicyclo[2.2.2]octan-2-ol	C₁₆H₂₂OS	详情	详情
(VIII)	66187	(S)-2-(mercaptomethyl)bicyclo[2.2.2]octan-2-ol	C₈H₁₅NOS	详情	详情

合成路线2

参考文献中间体

【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

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)	37591	3-(sulfanylmethyl)-3-quinuclidinol		C₈H₁₅NOS	详情	详情
(II)	11974	Acetaldehyde	75-07-0	C₂H₄O	详情	详情
(III)	37593			C₁₀H₁₇NOS	详情	详情
(IV)	37592			C₁₀H₁₇NOS	详情	详情

合成路线3

参考文献中间体

【1】 Fisher A, Karton I.1989.Novel oxathiolane derivatives their preparation and their therapeutic use.EP 314444

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)	37590			C₈H₁₃NO	详情	详情

合成路线4

参考文献中间体

【1】 Fisher A,Kartonl.1989.Novel oxathiolane derivatives their preparation, and their therapeutic use. EP 314444

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)	66188	spiro[bicyclo[2.2.2]octane-2,2'-thiirane]		C₉H₁₄S	详情	详情

合成路线5

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.

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)