E-6123, -Drug Synthesis Database

【结构式】

【药物名称】E-6123

【化学名称】(+)-6-(2-Chlorophenyl)-9-(cyclopropylcarbonyl)-1,4(S)-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

【CA登记号】131614-02-3

【分子式】C₂₃H₂₂ClN₅OS

【分子量】451.98169

【开发单位】Eisai (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Platelet-Activating Factor (PAF) Antagonists

合成路线1 合成路线2

合成路线1

1-Acetyl-4-piperidone (I) is condensed with 2-chlorocyanoacetophenone in the presence of sulfur and base to give the thiophene (II). Treatment of (II) with 2-bromopropionyl bromide gives the amide (III), which on reaction with ammonia gives the amine (IV). Cyclization of (IV) with acetic acid/pyridine gives the diazepine (V). Reaction of the amide of (V) with phosphorus pentasulfide or Lawesson's reagent produces the thioamide (VI), which is reacted with acetic hydrazide to give the triazole (VII). Basic hydrolysis of the amide of (VII) produces the amine (VIII), which is resolved to give the S-enantiomer (IX). Reaction of (IX) with cyclopropanecarbonyl chloride gives the amide (X).

参考文献中间体

【1】 1,4-Diazepine deriv. and its pharmaceutical use. AU 8943761; EP 0367110; EP 0606103; EP 0677524; JP 1990256682; US 5221671; US 5304553; US 5382579; US 5409909; US 5438045; US 5468740; US 5482937 .
【2】 Clark, R.S.J.; E6123. Drugs Fut 1991, 16, 4, 310.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12923	3-(2-Chlorophenyl)-3-oxopropanenitrile	40018-25-5	C₉H₆ClNO	详情	详情
	14061	Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride	4023-34-1	C₄H₅ClO	详情	详情
(I)	14050	N-Acetyl-4-piperidone; 1-Acetyltetrahydro-4(1H)-pyridinone	32161-06-1	C₇H₁₁NO₂	详情	详情
(II)	14051	1-[2-Amino-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl]-1-ethanone		C₁₆H₁₅ClN₂O₂S	详情	详情
(III)	14052	N-[6-Acetyl-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]-2-bromopropanamide		C₁₉H₁₈BrClN₂O₃S	详情	详情
(IV)	14053	N-[6-Acetyl-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]-2-aminopropanamide		C₁₉H₂₀ClN₃O₃S	详情	详情
(V)	14054	8-Acetyl-5-(2-chlorophenyl)-3-methyl-1,3,6,7,8,9-hexahydro-2H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepin-2-one		C₁₉H₁₈ClN₃O₂S	详情	详情
(VI)	14055	5-(2-Chlorophenyl)-8-ethanethioyl-3-methyl-1,3,6,7,8,9-hexahydro-2H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-2-thione		C₁₉H₁₈ClN₃S₃	详情	详情
(VII)	14056	1-[6-(2-Chlorophenyl)-1,4-dimethyl-7,10-dihydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-9(8H)-yl]-1-ethanethione		C₂₁H₂₀ClN₅S₂	详情	详情
(VIII)	14057	6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine		C₁₉H₁₈ClN₅S	详情	详情
(IX)	14058	(4S)-6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine		C₁₉H₁₈ClN₅S	详情	详情

合成路线2

A large-scale production method (kg scale) for E-6123 has been reported: The optical resolution of racemic 6-(2-chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (I), prepared by the previously reported method, by crystallization of its salt with (+)-(D)-dibenzoyltartaric acid in ethanol and treatment with aqueous NaHCO3 gives the corresponding (S)-isomer (II), which is then acylated with cyclopropanecarbonyl chloride (III) and pyridine in dichloromethane.

参考文献中间体

【1】 Miyazawa, S.; Shimomura, N.; Okano, K.; et al.; A practical synthesis of optically active platelet-activating factor antagonist, E6123, and its absolute configuration. Chem Pharm Bull 1992, 40, 2, 521.

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)	14057	6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine		C₁₉H₁₈ClN₅S	详情	详情
(II)	14058	(4S)-6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine		C₁₉H₁₈ClN₅S	详情	详情
(III)	14061	Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride	4023-34-1	C₄H₅ClO	详情	详情

Extended Information