Maleic acid; (Z)-2-Butenedioic acid -Drug Synthesis Database

【结构式】

【分子编号】37495

【品名】Maleic acid; (Z)-2-Butenedioic acid

【CA登记号】110-16-7

【分子式】C₄H₄O₄

【分子量】116.07336

【元素组成】C 41.39% H 3.47% O 55.14%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(B)

The reaction of p-chlorobenzaldehyde (I) sodium cyanide and ethyl acetate gives ethyl 4-(p-chlorophenyl)-4-oxobutyrate (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reduction of (III) with Zn and aqueous HCl affords 4-(p-chlorophenyl)butyric acid (IV), which is condensed with heptylamine (B) by means of oxalyl chloride (A) in refluxing benzene to yield N-heptyl-4-(p-chlorophenyl)butyramide (V), which is reduced with diborane in refluxing THF to afford N-heptyl-4-(p-chlorophenyl)butylamine (VI). The acetylation of (VI) with acetyl chloride (C) by means of Na2CO3 in acetone gives N-acetyl-N-heptyl-4-(p-chlorophenyl)butylamine (VII), which is reduced with diborane as before to yield N-ethyl-N-heptyl-4-(p-chlorophenyl)butylamine (VIII). The quaternization of (VIII) with refluxing ethyl bromide (D) gives N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butylammonium bromide (IX), which by elution through a column with Dowex 1-X8, hydroxide form, resin is converted into N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butyl ammonium hydroxide (X). Finally, this compound is salified with diluted aqueous phosphoric acid.

参考文献中间体

合成目标

【1】 Fukuzawa, S.; et al.; JP 76131883 .
【2】 Muro, T.; et al.; US 4005084 .
【3】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Y-8894. Drugs Fut 1981, 6, 7, 423.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(B)	37495	Maleic acid; (Z)-2-Butenedioic acid	110-16-7	C₄H₄O₄	详情	详情
(I)	37488	1-(benzylamino)-3-[2-(2-thienylmethyl)phenoxy]-2-propanol		C₂₁H₂₃NO₂S	详情	详情
(II)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(III)	37489	N-benzyl-2-chloro-N-[2-hydroxy-3-[2-(2-thienylmethyl)phenoxy]propyl]acetamide		C₂₃H₂₄ClNO₃S	详情	详情
(IV)	37490	4-benzyl-6-[[2-(2-thienylmethyl)phenoxy]methyl]-3-morpholinone		C₂₃H₂₃NO₃S	详情	详情
(V)	37491	4-benzyl-2-[[2-(2-thienylmethyl)phenoxy]methyl]morpholine; (4-benzyl-2-morpholinyl)methyl 2-(2-thienylmethyl)phenyl ether		C₂₃H₂₅NO₂S	详情	详情
(VI)	37492	ethyl 2-[[2-(2-thienylmethyl)phenoxy]methyl]-4-morpholinecarboxylate		C₁₉H₂₃NO₄S	详情	详情
(VII)	37493	2-[[2-(2-thienylmethyl)phenoxy]methyl]oxirane; 2-oxiranylmethyl 2-(2-thienylmethyl)phenyl ether		C₁₄H₁₄O₂S	详情	详情
(VIII)	37494	2-aminoethyl hydrogen sulfate	926-39-6	C₂H₇NO₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：

The condensation of epichlorohydrin (I) with 7-hydroxyflavone (II) by means of NaOH in ethanol - water gives 7-(2,3-epoxypropoxy)fIavone (III), which is then treated with propylamine (IV) in methanol, and neutralized with maleic acid.

参考文献中间体

合成目标

【1】 Wu, E.S.-C. (Pennwalt Corp.); Antihypertensive agents. EP 0064165; US 4501755 .
【2】 Castaner, J.; Prous, J.; Flavodilol maleate. Drugs Fut 1986, 11, 10, 837.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	37495	Maleic acid; (Z)-2-Butenedioic acid	110-16-7	C₄H₄O₄	详情	详情
(I)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(II)	23921	7-hydroxy-2-phenyl-4H-chromen-4-one	6665-86-7	C₁₅H₁₀O₃	详情	详情
(III)	23922	7-(2-oxiranylmethoxy)-2-phenyl-4H-chromen-4-one		C₁₈H₁₄O₄	详情	详情
(IV)	23923	1-propanamine	107-10-8	C₃H₉N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Condensation of 2-formylcycloheptanone (I) with ethyl 3-aminocrotonate (II) provides ethyl carboxylate (III), which is then converted into carbonylguanidine (VI) by reaction with free guanidine (V) (obtained from guanidine hydrochloride (IV) by treatment with Na/MeOH) in refluxing isopropanol. Alternatively, carbonylguanidine (VI) can also be obtained by saponification of ethyl ester (III) with refluxing NaOH to yield carboxylic acid (VII), which is then activated with oxalyl chloride (A) in CH2Cl2 or with CDI in THF to allow condensation with guanidine (V) in THF. Finally, the corresponding maleate can be obtained by reaction of carbonylguanidine (VI) with maleic acid (VIII) in MeOH.

参考文献中间体

合成目标

【1】 Kogi, K.; Takahashi, A.; Gengyou, K.; Aihara, K.; Yoneyama, F.; Sasamori, J.; Yoneyama, S.; Satoh, T.; Yamada, S.; Kimura, T. (Toa Eiyo Ltd.); Cycloalka[b]pyridine-3-carbonylguanidine derivs., process for producing the same, and drugs containing the same. EP 0972767; WO 9839300 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV),(V)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(A)	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情
(I)	45624	2-oxocycloheptanecarbaldehyde	641-70-3	C₈H₁₂O₂	详情	详情
(II)	45628	Ethyl (Z)-3-amino-2-butenoate; 3-amino-2-butenoic acid ethyl ester; Ethyl 3-aminocrotonate; 3-Aminocrotonic acid ethyl ester	626-34-6	C₆H₁₁NO₂	详情	详情
(III)	45625	ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate		C₁₄H₁₉NO₂	详情	详情
(VI)	45626	N-[(2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl)carbonyl]guanidine		C₁₃H₁₈N₄O	详情	详情
(VII)	45627	2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylic acid		C₁₂H₁₅NO₂	详情	详情
(VIII)	37495	Maleic acid; (Z)-2-Butenedioic acid	110-16-7	C₄H₄O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

The reaction of N-benzoyl-N',N'-di-n-propyl-DL-isoglutamine (I) with N-3-chloropropyl-N'-2-hydroxyethylpiperazine (II) by means of sodium methoxide in DMSO at 105 C gives N-[3-(N-benzoyl-N',N'-di-n-propyl-DL-isoglutaminyl)oxypropyl]-N'-(2-hydroxyethyl)piperazine (III), which is then condensed with 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (IV) by means of dicyclohexylcarbodiimide and NaHCO3 in ethyl acetate, and treated finally with maleic acid (V)

参考文献中间体

合成目标

【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; de Angelis, L.; Proglumetacin maleate. Drugs Fut 1980, 5, 3, 142.
【2】 Makovec, F.; et al. (Rotta Research Laboratorium SpA); BE 830880; CA 1053663; DE 2535799; FR 2281755; GB 1467568; JP 7643773; JP 7643774; JP 7916511; JP 7916512; NL 7509091; SA 7509091; US 3985878 .

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)	60631	4-(benzoylamino)-5-(dipropylamino)-5-oxopentanoic acid		C₁₈H₂₆N₂O₄	详情	详情
(II)	60632	2-[4-(3-chloropropyl)-1-piperazinyl]-1-ethanol		C₉H₁₉ClN₂O	详情	详情
(III)	60633	3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl 4-(benzoylamino)-5-(dipropylamino)-5-oxopentanoate		C₂₇H₄₄N₄O₅	详情	详情
(IV)	22930	2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid		C₁₉H₁₆ClNO₄	详情	详情
(V)	37495	Maleic acid; (Z)-2-Butenedioic acid	110-16-7	C₄H₄O₄	详情	详情

Extended Information