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 -Drug Synthesis Database

【结构式】

【分子编号】14057

【品名】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

【CA登记号】

【分子式】C₁₉H₁₈ClN₅S

【分子量】383.90432

【元素组成】C 59.44% H 4.73% Cl 9.23% N 18.24% S 8.35%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(VIII)

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

合成目标

【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

该中间体在本合成路线中的序号：(I)

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

合成目标

【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

合成路线3

该中间体在本合成路线中的序号：(VII)

Ketone (I) was converted to the corresponding oxime (II) by treatment with hydroxylamine hydrochloride and pyridine. Subsequent alkylation of the oxime (II) with ethyl 5-bromovalerate (III) in the presence of NaH provided (IV). After desilylation of (IV) by means of tetrabutylammonium fluoride, the liberated alcohol (V) was converted to mesylate (VI). The title compound was then obtained by condensation of mesylate (VI) with the pyridothienotriazolodiazepine derivative (VII).

参考文献中间体

合成目标

【1】 Sano, T.; Seki, T.; Fujita, M.; Inada, H. (Nikken Chemicals Co., Ltd.); Triazolo-1,4-diazepine cpds. and medicinal compsn. containing the same. EP 0995752; JP 1999071378; US 6433167; WO 9858930 .

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)	56588	[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone		C₂₉H₂₉NO₂Si	详情	详情
(II)	56589	[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone oxime		C₂₉H₃₀N₂O₂Si	详情	详情
(III)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(IV)	56590	ethyl 5-({[(E)-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methylidene]amino}oxy)pentanoate		C₃₆H₄₂N₂O₄Si	详情	详情
(V)	56591	ethyl 5-({[(E)-[3-(hydroxymethyl)phenyl](3-pyridinyl)methylidene]amino}oxy)pentanoate		C₂₀H₂₄N₂O₄	详情	详情
(VI)	56592	ethyl 5-({[(E)-(3-{[(methylsulfonyl)oxy]methyl}phenyl)(3-pyridinyl)methylidene]amino}oxy)pentanoate		C₂₁H₂₆N₂O₆S	详情	详情
(VII)	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

合成路线4

该中间体在本合成路线中的序号：(VI)

The Wittig condensation of 1-[4-(tert-butyldiphenylsilyloxymethyl)phenyl]-1-(3-pyridyl)methanone (I) with phosphonium bromide (II) by means of NaH in tert-butanol gives the heptenoic ester (III), which is desilylated with TBAF in THF to yield 7-[4-(hydroxymethyl)phenyl]-7-(3-pyridyl)-6-heptenoic acid ethyl ester (IV). The reaction of (IV) with Ms-Cl and TEA affords the corresponding mesylate (V), which is finally condensed with the triazolodiazepine (VI) by means of K2CO3 and 18-crown-6 in DMF.

参考文献中间体

合成目标

【1】 Fujita, M.; et al.; Novel agents combining platelet activating factor (PAF) receptor antagonist with thromboxane synthase inhibitor (TxSI). Bioorg Med Chem Lett 2002, 12, 5, 771.
【2】 Sano, T.; Seki, T.; Fujita, M.; Inada, H. (Nikken Chemicals Co., Ltd.); Triazolo-1,4-diazepine cpds. and medicinal compsn. containing the same. EP 0995752; JP 1999071378; US 6433167; WO 9858930 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	54466	[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone	C₂₉H₂₉NO₂Si	详情	详情
(II)	54467	(6-ethoxy-6-oxohexyl)(triphenyl)phosphonium bromide	C₂₆H₃₀BrO₂P	详情	详情
(III)	54468	ethyl (E)-7-[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl]-7-(3-pyridinyl)-6-heptenoate	C₃₇H₄₃NO₃Si	详情	详情
(IV)	54469	ethyl (E)-7-[4-(hydroxymethyl)phenyl]-7-(3-pyridinyl)-6-heptenoate	C₂₁H₂₅NO₃	详情	详情
(V)	54470	ethyl (E)-7-(4-{[(methylsulfonyl)oxy]methyl}phenyl)-7-(3-pyridinyl)-6-heptenoate	C₂₂H₂₇NO₅S	详情	详情
(VI)	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

合成路线5

该中间体在本合成路线中的序号：(VII)

Treatment of 4-(t-butyldiphenylsilyloxymethyl)phenyl-(3-pyridyl)ketone (I) with hydroxylamine hydrochloride in pyridine affords oxime (II) as a mixture of geometric isomers. Then, alkylation of oxime (II) with ethyl 5-bromovalerate (III) in the presence of NaH provides ester (IV). After desilylation of (IV) with tetrabutylammonium fluoride, the deprotected primary alcohol (V) is oxidized by KMnO4 to furnish carboxylic acid (VI). Finally, DCC-mediated coupling of acid (VI) with the known tetracyclic precursor (VII) gives rise to the corresponding amide.

参考文献中间体

合成目标

【1】 Sano, T.; Seki, T.; Fujita, M.; Inada, H. (Nikken Chemicals Co., Ltd.); Triazolo-1,4-diazepine cpds. and medicinal compsn. containing the same. EP 0995752; JP 1999071378; US 6433167; WO 9858930 .

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)	54466	[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone		C₂₉H₂₉NO₂Si	详情	详情
(II)	61007	[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone oxime		C₂₉H₃₀N₂O₂Si	详情	详情
(III)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(IV)	61008	ethyl 5-({[(E)-[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methylidene]amino}oxy)pentanoate		C₃₆H₄₂N₂O₄Si	详情	详情
(V)	61009	ethyl 5-({[(E)-[4-(hydroxymethyl)phenyl](3-pyridinyl)methylidene]amino}oxy)pentanoate		C₂₀H₂₄N₂O₄	详情	详情
(VI)	61010	4-[{[(5-ethoxy-5-oxopentyl)oxy]imino}(3-pyridinyl)methyl]benzoic acid		C₂₀H₂₂N₂O₅	详情	详情
(VII)	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

Extended Information