Clentiazem maleate, TA-3090, Logna, -Drug Synthesis Database

【结构式】

【药物名称】Clentiazem maleate, TA-3090, Logna

【化学名称】(+)-(2S,3S)-3-Acetoxy-8-chloro-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one maleate

【CA登记号】96128-92-6, 96125-53-0 (free base)

【分子式】C₂₆H₂₉ClN₂O₈S

【分子量】565.04663

【开发单位】Tanabe Seiyaku (Originator), Aventis Pharma (Licensee)

【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Calcium Channel Blockers

合成路线1 合成路线2

合成路线1

A new synthesis of TA-3090 has been published: The cyclization of 2-amino-5-chlorothiophenol (I) with trans-2,3-epoxy-3-(4-methoxyphenyl)propanoic acid methyl ester (II) by heating at 160 C gives cis-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzo thiazepin-4-one (III), which is submitted to optical resolution with (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride. The (2S-cis)-isomer of (III) is then condensed with 2-(dimethylamino)ethyl chloride (IV) by means of K2CO3 in refluxing acetone - water, yielding (2S-cis)-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphen yl-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (V). Finally, this compound is acetylated with acetic anhydride in refluxing pyridine and converted into the maleate salt.

参考文献中间体

【1】 Inoue, H.; Konda, M.; Hashiyama, T.; et al.; Synthesis of halogen-substituted 1,5-benzothiazepine derivatives and their vasodilating and hypotensive activities. J Med Chem 1991, 34, 2, 675-87.

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)	11904	2-Amino-5-chlorobenzenethiol; 2-Amino-5-chlorophenylhydrosulfide		C₆H₆ClNS	详情	详情
(II)	11905	methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate		C₁₁H₁₂O₄	详情	详情
(III)	11906	(2S,3S)-8-Chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₁₆H₁₄ClNO₃S	详情	详情
(IV)	11907	Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine	107-99-3	C₄H₁₀ClN	详情	详情
(V)	11908	(2S,3S)-8-Chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₂₀H₂₃ClN₂O₃S	详情	详情

合成路线2

A new synthesis of racemic TA-3090 has been reported: The condensation of 5-chloro-2-nitrothiophenol (I) with 4-methoxybenzyl chloride (II) by means of sodium ethoxide in ethanol gives the thioether (III), which is reduced with SnCl2 in hot ethanol to afford 4-chloro-2-(4-methoxybenzylthio)aniline (IV). The acylation of (IV) with ethoxalyl chloride (V) by means of NaHCO3 in dichloromethane - water yields the oxamate (VI), which is condensed with 2-(dimethylamino)ethyl chloride (VII) by means of K2CO3 and 18-crown-6 in hot acetonitrile to afford the alkylated oxamate compound (VIII). The cyclization of (VIII) by means of lithium diisopropylamide in THF gives 8-chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiaze pine-3,4(2H,5H)-dione (IX), which is reduced with NaBH4 in aqueous ethanol to cis-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (X). Finally, this compound is acetylated in the usual manner.

参考文献中间体

【1】 Takeda, M.; Takamura, N.; Oh-ishi, T.; Harada, T.; Morimoto, M.; Inoue, H.; Nagasawa, M.; A new synthetic route to 1,5-benzothiazepines. Synthesis of derivatives of diltiazem. Chem Pharm Bull 1992, 40, 8, 1986.

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)	11909	5-Chloro-2-nitrophenylhydrosulfide; 5-Chloro-2-nitrobenzenethiol		C₆H₄ClNO₂S	详情	详情
(II)	11910	4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether	824-94-2	C₈H₉ClO	详情	详情
(III)	11911	4-[[(5-Chloro-2-nitrophenyl)sulfanyl]methyl]phenyl methyl ether; 4-Chloro-2-[(4-methoxybenzyl)sulfanyl]-1-nitrobenzene		C₁₄H₁₂ClNO₃S	详情	详情
(IV)	11912	4-Chloro-2-[(4-methoxybenzyl)sulfanyl]phenylamine; 4-Chloro-2-[(4-methoxybenzyl)sulfanyl]aniline		C₁₄H₁₄ClNOS	详情	详情
(V)	11043	Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride	4755-77-5	C₄H₅ClO₃	详情	详情
(VI)	11914	ethyl 2-[4-chloro-2-[(4-methoxybenzyl)sulfanyl]anilino]-2-oxoacetate		C₁₈H₁₈ClNO₄S	详情	详情
(VII)	11907	Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine	107-99-3	C₄H₁₀ClN	详情	详情
(VIII)	11916	ethyl 2-[4-chloro[2-(dimethylamino)ethyl]-2-[(4-methoxybenzyl)sulfanyl]anilino]-2-oxoacetate		C₂₂H₂₇ClN₂O₄S	详情	详情
(IX)	11917	(2S)-8-Chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione		C₂₀H₂₁ClN₂O₃S	详情	详情
(X)	11908	(2S,3S)-8-Chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₂₀H₂₃ClN₂O₃S	详情	详情

Extended Information