盐酸西维美林 ((+/-)-顺式-2-甲基螺[1,3-氧硫杂环戊烷-5,3'-奎宁环]盐酸半水合物 西维美林Chemical Name: (?-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
CAS No. 153504-70-2, 107220-28-0 (anhydrous), 107233-08-9 (anhydrous free base)
项目整合开发状态: Launched-2000
项目研究机构: Israel Institute for Biological Research (Originator), Snow Brand (Licensee), Daiichi Pharmaceutical (Comarketer), Nippon Kayaku (Codevelopment), Ishihara Sangyo (Bulk Supplier)
合成路线: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.
📄 详细内容
合成路线: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.
参考文献标题:Preparation method of cis-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine hydrochloride.1/2 hydrate capable of disgregating easily
文献作者:Honda,N.; Saito,K.; Ono,T.(Snow Brand Milk Products Co.,Ltd.)
参考来源:JP 1992108792
合成路线: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.
参考文献标题:Method for isomerization of trans-form 2-methylspiro-(1,3-oxothiolane-5,3')-quinuclidine or acid addition salts thereof
文献作者:Hara,K.; Koyanagi,T.; Shigehara,I.; Maeda,M.; Haga,T.(Ishihara Sangyo Kaisha,Ltd.)
参考来源:EP 0298491; US 4861886
合成路线: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.
参考文献标题:Method for producing 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine
文献作者:Hayashi,K.; Isogai,T.; Tokumoto,S.; Yoshizawa,H.(Ishihara Sangyo Kaisha,Ltd.)
参考来源:EP 0683168; US 5571918
合成路线: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.
参考文献标题:Cevimeline Hydrochloride
文献作者:Sorbera,L.A.; Castar,J.
参考来源:Drugs Fut 2000,25(6),558