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【结 构 式】 
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【药物名称】Sibenadet hydrochloride, AR-C68397XX(free base), FPL-68397, AR-C68397AA, Viozan 【化学名称】4-Hydroxy-7-[2-[2-[3-(2-phenylethoxy)propylsulfonyl]ethylamino]ethyl]benzothiazol-2(3H)-one hydrochloride 【CA登记号】154189-24-9, 154189-40-9 (free base) 【 分 子 式 】C22H29ClN2O5S2 【 分 子 量 】501.06783 |
【开发单位】AstraZeneca (Originator) 【药理作用】Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists, Dopamine D2 Agonists |
合成路线1
The reaction of 3-bromopropanol (I) with thiourea in refluxing water gives 3-sulfanylpropanol (II), which is cyclized with 2-phenylacetaldehyde (III) by means of p-toluenesulfonic acid in refluxing toluene yielding 2-benzyl-1,3-oxathiane (IV). The reductive cleavage of (IV) with Ca in liquid ammonia affords 3-(2-phenylethoxy)propanethiol (V), which is condensed with bromoacetic acid by means of NaH in DMF providing 2-[3-(2-phenylethoxy)propylsulfanyl]acetic acid (VI). The oxidation of (VI) with potassium peroxymonosulfate (oxone) gives the corresponding sulfonylacetic acid (VII), which is condensed with benzothiazolone (VIII) by means of DCC, HOBT and triethylamine in DMF yielding the correponding amide (IX). Finally, this compound is reduced with borane/THF yielding the target compound.
| 【1】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; Cheshire, D.R.; Dixon, J.; Ince, F.; Kinchin, E.C.; Lyons, A.J.; Davis, A.M.; Hallam, C.; Harper, S.T.; Unitt, J.F.; Dougall, I.G.; Jackson, D.M.; McKechnie, K.; Young, A.; Simpson, W.T.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airway diseases. 1. Discovery and biological evaluation of some 7-(2-aminoethyl)-4-hydroxybenzothiazol-2(3H)-one analogues. J Med Chem 1998, 41, 25, 4915. |
| 【2】 Bonnert, R.V.; Brown, R.C.; Cage, P.A.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.275. |
| 【3】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.276. |
| 【4】 Bonnert, R.V.; Brown, R.C.; Cheshire, D.R.; Ince, F. (AstraZeneca AB); 7-(2-Aminoethyl)-benzothiazolones. EP 0649418; JP 1996503923; US 5648370; WO 9324473 . |
| 【5】 Castañer, J.; Graul, A.; Viozan. Drugs Fut 2000, 25, 2, 165. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 | |
| 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 | |
| (I) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (II) | 25939 | 3-sulfanyl-1-propanol | 19721-22-3 | C3H8OS | 详情 | 详情 |
| (III) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (IV) | 25940 | 2-benzyl-1,3-oxathiane | C11H14OS | 详情 | 详情 | |
| (V) | 25941 | 3-(phenethyloxy)propylhydrosulfide; 3-(phenethyloxy)-1-propanethiol | C11H16OS | 详情 | 详情 | |
| (VI) | 25942 | 2-[[3-(phenethyloxy)propyl]sulfanyl]acetic acid | C13H18O3S | 详情 | 详情 | |
| (VII) | 25943 | 2-[[3-(phenethyloxy)propyl]sulfonyl]acetic acid | C13H18O5S | 详情 | 详情 | |
| (VIII) | 25944 | 7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one | C9H10N2O2S | 详情 | 详情 | |
| (IX) | 25945 | N-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]-2-[[3-(phenethyloxy)propyl]sulfonyl]acetamide | C22H26N2O6S2 | 详情 | 详情 |
合成路线2
The reaction of 3-bromopropanol (I) with thiourea in refluxing water gives 3-sulfanylpropanol (II), which is cyclized with 2-phenylacetaldehyde (III) by means of p-toluenesulfonic acid in refluxing toluene yielding 2-benzyl-1,3-oxathiane (IV). The reductive cleavage of (IV) with Ca in liquid ammonia affords 3-(2-phenylethoxy)propanethiol (V), which is condensed with bromoacetic acid by means of NaH in DMF providing 2-[3-(2-phenylethoxy)propylsulfanyl]acetic acid (VI). The oxidation of (VI) with potassium peroxymonosulfate (oxone) gives the corresponding sulfonylacetic acid (VII).The condensation of sulfonylacetic acid (VII) with dimethoxybenzothiazole derivative (X) by means of DCC, HOBT and triethylamine in DMF gives the corresponding amide (XI), which is reduced with borane/THF yielding intermediate (XII). Finally, this compound is demethylated with concentrated HBr or HCl.
| 【1】 Bonnert, R.V.; Brown, R.C.; Cage, P.A.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.275. |
| 【2】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.276. |
| 【3】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; Cheshire, D.R.; Dixon, J.; Ince, F.; Kinchin, E.C.; Lyons, A.J.; Davis, A.M.; Hallam, C.; Harper, S.T.; Unitt, J.F.; Dougall, I.G.; Jackson, D.M.; McKechnie, K.; Young, A.; Simpson, W.T.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airway diseases. 1. Discovery and biological evaluation of some 7-(2-aminoethyl)-4-hydroxybenzothiazol-2(3H)-one analogues. J Med Chem 1998, 41, 25, 4915. |
| 【4】 Bonnert, R.V.; Brown, R.C.; Cheshire, D.R.; Ince, F. (AstraZeneca AB); 7-(2-Aminoethyl)-benzothiazolones. EP 0649418; JP 1996503923; US 5648370; WO 9324473 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 | |
| 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 | |
| (I) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (II) | 25939 | 3-sulfanyl-1-propanol | 19721-22-3 | C3H8OS | 详情 | 详情 |
| (III) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (IV) | 25940 | 2-benzyl-1,3-oxathiane | C11H14OS | 详情 | 详情 | |
| (V) | 25941 | 3-(phenethyloxy)propylhydrosulfide; 3-(phenethyloxy)-1-propanethiol | C11H16OS | 详情 | 详情 | |
| (VI) | 25942 | 2-[[3-(phenethyloxy)propyl]sulfanyl]acetic acid | C13H18O3S | 详情 | 详情 | |
| (VII) | 25943 | 2-[[3-(phenethyloxy)propyl]sulfonyl]acetic acid | C13H18O5S | 详情 | 详情 | |
| (X) | 25946 | 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethylamine; 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)-1-ethanamine | C11H14N2O2S | 详情 | 详情 | |
| (XI) | 25947 | N-[2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethyl]-2-[[3-(phenethyloxy)propyl]sulfonyl]acetamide | C24H30N2O6S2 | 详情 | 详情 | |
| (XII) | 25948 | N-[2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethyl]-N-(2-[[3-(phenethyloxy)propyl]sulfonyl]ethyl)amine; 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)-N-(2-[[3-(phenethyloxy)propyl]sulfonyl]ethyl)-1-ethanamine | C24H32N2O5S2 | 详情 | 详情 |
合成路线3
The target compound can also be obtained by reductocondensation of benzothiazolone (VIII) with aldehyde (XIII) by means of sodium cynonoborohydride.
| 【1】 Bonnert, R.V.; Brown, R.C.; Cage, P.A.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.275. |
| 【2】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.276. |