Sibenadet hydrochloride, AR-C68397XX(free base), FPL-68397, AR-C68397AA, Viozan, -Drug Synthesis Database

【结构式】

【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 合成路线2 合成路线3

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.

参考文献中间体

【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.

参考文献中间体

【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.

参考文献中间体

【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	25944	7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one		C₉H₁₀N₂O₂S	详情	详情
(XIII)	25949	2-[[3-(phenethyloxy)propyl]sulfonyl]acetaldehyde		C₁₃H₁₈O₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)