Bepotastine besilate, Betotastine besilate, TAU-284DS, TAU-284, Talion, -Drug Synthesis Database

【结构式】

【药物名称】Bepotastine besilate, Betotastine besilate, TAU-284DS, TAU-284, Talion

【化学名称】(+)-(S)-4-[4-[1-(4-Chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]butyric acid monobenzenesulfonate
　　　　　　(+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidin-1-yl]butyric acid monobenzenesulfonate

【CA登记号】190786-44-8, 190786-43-7 (free base), 125602-71-3 (free base undefined isomer)

【分子式】C₂₇H₃₁ClN₂O₆S

【分子量】547.07492

【开发单位】Ube (Originator), Senju (Licensee), Tanabe Seiyaku (Licensee)

【药理作用】Allergic Skin Disorders, Treatment for, Antiallergic Ophthalmic Agents, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Urticaria, Treatment for, Histamine H1 Antagonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The reaction of 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) with ethyl 4-bromobutyrate (II) by means of K2CO3 in refluxing acetone gives the corresponding condensation product (III), which is then hydrolyzed with NaOH in ethanol/water yielding compound (IV).

参考文献中间体

【1】 Castaner, J.; Graul, A.; Betotastine besilate. Drugs Fut 1998, 23, 3, 256.
【2】 Koda, A.; Kuroki, Y.; Fujiwara, H.; Takamura, S.; Yamano, K. (Ube Industries, Ltd.); Piperidine and piperazine derivs., process for preparing the same and pharmaceutical compsns. containing them. EP 0335586; JP 1989242574; JP 1990025465; JP 1993294929; US 4929618 .

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)	16053	2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether		C₁₇H₁₉ClN₂O	详情	详情
(II)	11263	ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate	2969-81-5	C₆H₁₁BrO₂	详情	详情
(III)	16055	ethyl 4-[4-[(4-chlorophenyl)(2-pyridinyl)methoxy]piperidino]butanoate		C₂₃H₂₉ClN₂O₃	详情	详情
(IV)	16056	4-[4-[(4-chlorophenyl)(2-pyridinyl)methoxy]piperidino]butyric acid		C₂₁H₂₅ClN₂O₃	详情	详情

合成路线2

A new synthesis of betotastine has been developed: The racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) is submitted to optical resolution with N-acyl amino acids such as N-acetyl-L-phenylalanine (preferred), N-acetyl-L-leucine, N-(benzyloxycarbonyl)-L-phenylalanine, N-(benzyloxycarbonyl)-L-valine, N-(benzyloxycarbonyl)-L-threonine, N-(benzyloxycarbonyl)-L-serine or with (2R,3R)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (S)-isomer (II). The condensation of (II) with ethyl 4-bromobutyrate (III) by means of a base such as Na2CO3, NaHCO3, K2CO3 or KHCO3 gives the expected 4-(1-piperidinyl)butyric acid ester (IV), which is finally hydrolyzed with NaOH or KOH in aqueous ethanol or methanol.

参考文献中间体

【1】 Kita, J.; Yoshioka, R.; Ozaki, Y.; Takemura, S.; Fujiwara, H.; Yamada, S. (Tanabe Seiyaku Co., Ltd.; Ube Industries, Ltd.); Acid-addition salts of optically active piperidine cpd. and process for producing the same. JP 1998237070; JP 2000198784; WO 9829409 .

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)	16053	2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether		C₁₇H₁₉ClN₂O	详情	详情
(II)	22441	(S)-(4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether		C₁₇H₁₉ClN₂O	详情	详情
(III)	11263	ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate	2969-81-5	C₆H₁₁BrO₂	详情	详情
(IV)	22443	ethyl 4-(4-[[(S)-(4-chlorophenyl)(2-pyridinyl)methyl]oxy]-1-piperidinyl)butanoate		C₂₃H₂₉ClN₂O₃	详情	详情

合成路线3

参考文献中间体

【1】 Ha TH, Parks CH, Kim WJ, et al. 2008. Process for preparing bepotastine and intermediates used therein. WO 2008153289 (Hanmi Pharm Co Ltd, S Korea). Krueger W, Krueger G. 1983. 4-[1-methyl-5-bis[(2-chloroethyl) amino] -2-benzimidazolyl] butyric acid. Ger, (East)DD 159877.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	67057	(2R,5R)-2-isopropyl-5-methylcyclohexyl 4-(4-((S)-(4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)butanoate (R)-2-(((benzyloxy)carbonyl)amino)succinate		C₃₁H₄₃ClN₂O₃.C₁₂H₁₃NO₆	详情	详情
(I)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(II)	67053	(1R,5R)-2-isopropyl-5-methylcyclohexanol		C₁₀H₂₀O	详情	详情
(III)	67054	(1S,5S)-2-isopropyl-5-methylcyclohexyl 4-chlorobutanoate		C₁₄H₂₅ClO₂	详情	详情
(IV)	16053	2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether		C₁₇H₁₉ClN₂O	详情	详情
(V)	67055	(1S,2R)-2-isopropyl-5-methylcyclohexyl 4-(4-((4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)butanoate		C₃₁H₄₃ClN₂O₃	详情	详情
(VI)	67056	(S)-2-(((benzyloxy)carbonyl)amino)succinic acid		C₁₂H₁₃NO₆	详情	详情
(VIII)	67058	(2R,5R)-2-isopropyl-5- methylcyclohexyl 4-(4-((S)-(4-chlorophenyl)(pyridin-2 -yl)methoxy)piperidin-1-yl)butanoate		C₃₁H₄₃ClN₂O₃	详情	详情
(IX)	67059			C₂₁H₂₅ClN₂O₃	详情	详情

合成路线4

参考文献中间体

【1】 Zhan ZQ, Zhou ZY, Peng LZ. 2006. Asymmetry synthesis of bepotastine besilate. Zhongguo Yiyao Gongye Zazhi, 37(11): 726～727. Krueger W, Krueger G. 1983. 4-[1-methyl-5-bis[(2-chloroethyl) amino] -2-benzimidazolyl] butyric acid. Ger, (East)DD 159877.

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)	57809	4-(4-Chlorobenzoyl)pyridine; 4-Chlorophenyl 4-pyridyl ketone	14548-48-2	C₁₂H₈ClNO	详情	详情
(II)	67060	(S)-(4-chlorophenyl)(pyridin-2-yl)methanol		C₁₂H₁₀ClNO	详情	详情
(III)	67061	ethyl 3-(4-bromopiperidin-1-yl)propanoate		C₁₀H₁₈BrNO₂	详情	详情
(IV)	22443	ethyl 4-(4-[[(S)-(4-chlorophenyl)(2-pyridinyl)methyl]oxy]-1-piperidinyl)butanoate		C₂₃H₂₉ClN₂O₃	详情	详情
(V)	67062			C₂₁H₂₅ClN₂O₃	详情	详情

Extended Information