5-hydroxy-2-nitrobenzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】14942

【品名】5-hydroxy-2-nitrobenzaldehyde

【CA登记号】42454-06-8

【分子式】C₇H₅NO₄

【分子量】167.12104

【元素组成】C 50.31% H 3.02% N 8.38% O 38.29%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Alkylation of 5-hydroxy-2-nitrobenzaldehyde (I) with ethyl 4-bromobutyrate (II) in the presence of potassium carbonate at 110 C in DMF provided the aldehyde (III). Coupling of (III) with the phosphonate (IV) using triethylamine as the base afforded the unsaturated hydantoin derivative (V) as a mixture of geometrical isomers. Exhaustive catalytic hydrogenation of (V) over palladium on charcoal in DMF furnished the saturated aniline (VI), which underwent acid-catalyzed cyclization-dehydration in methanol at reflux, followed by oxidation upon addition of a molar equivalent of iodine to give the imidazo[4,5-b]quinoline derivative (VII). Alkaline hydrolysis of (VII) provided acid (VIII), which was coupled with N-cyclohexylmethylpiperazine, using diphenylphosphoryl azide in DMF at room temperature, to furnish BMY 43351 (IX). The dihydrochloride salt of (IX) was prepared by dissolution of the free base in a solution of 10% hydrogen chloride in methanol and subsequent precipitation with diethyl ether.

参考文献中间体

合成目标

【1】 Wedding, D.L.; Meanwell, N.A.; Roth, H.R.; Wright, J.J.K.; Smith, E.C.R.; Diethyl 2,4-dioxoimidazolidine-5-phosphonates: Horner-Wadsworth-Emmons reagents for the mild and efficient preparations of C-5 unsaturated hydantoin derivatives. J Org Chem 1991, 56, 6897-904.
【2】 Russell, J.W.; Seiler, S.M.; Meanwell, N.A.; Fleming, J.S.; BMY 43351. Drugs Fut 1992, 17, 1, 15.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	63929	1-(cyclohexylmethyl)piperazine		C₁₁H₂₂N₂	详情	详情
(I)	14942	5-hydroxy-2-nitrobenzaldehyde	42454-06-8	C₇H₅NO₄	详情	详情
(II)	11263	ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate	2969-81-5	C₆H₁₁BrO₂	详情	详情
(III)	14944	ethyl 4-(3-formyl-4-nitrophenoxy)butanoate		C₁₃H₁₅NO₆	详情	详情
(IV)	14945	Diethyl 5-hydantoylphosphonate; diethyl 2,5-dioxo-4-imidazolidinylphosphonate	95378-36-2	C₇H₁₃N₂O₅P	详情	详情
(V)	14946	ethyl 4-[3-[(2,5-dioxotetrahydro-4H-imidazol-4-ylidene)methyl]-4-nitrophenoxy]butanoate		C₁₆H₁₇N₃O₇	详情	详情
(VI)	14947	ethyl 4-[4-amino-3-[(2,5-dioxo-4-imidazolidinyl)methyl]phenoxy]butanoate		C₁₆H₂₁N₃O₅	详情	详情
(VII)	14948	methyl 4-[(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoate		C₁₅H₁₅N₃O₄	详情	详情
(VIII)	14949	4-[(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid		C₁₄H₁₃N₃O₄	详情	详情
(IX)	14950	7-[4-[4-(cyclohexylmethyl)piperazino]-4-oxobutoxy]-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one		C₂₅H₃₃N₅O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The esterification of myricerone (I) with 2-(diethoxyphosphoryl)acetic acid (II) by means of CDI gives the corresponding ester (III), which is condensed with the benzaldehyde (IV) by means of DBU and LiCl in DMF yielding the expected condensation product (V). Finally, this compound is hydrolyzed with LiOH in aqueous DME, and treated with aqueous NaOH to obtain the target sodium salt. The intermediate benzaldehyde (IV) has been obtained as follows: The reduction of 5-hydroxy-2-nitrobenzaldehyde (VI) with TiCl3 gives 2-amino-5-hydroxybenzaldehyde (VII), which is then condensed with maleic acid monomethyl ester monochloride (VIII).

参考文献中间体

合成目标

【1】 Konoike, T.; et al.; Practical large-scala synthesis of endothelin receptor antagonist S-0139. Org Process Res Dev 1999, 3, 5, 347.

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)	36511	(6aR,6bR,12aR)-6a-(hydroxymethyl)-2,2,6b,9,9,12a-hexamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylic acid		C₃₀H₄₆O₄	详情	详情
(II)	36512	2-(diethoxyphosphoryl)acetic acid	3095-95-2	C₆H₁₃O₅P	详情	详情
(III)	36513	(6aR,6bR,12aR)-6a-([[2-(diethoxyphosphoryl)acetyl]oxy]methyl)-2,2,6b,9,9,12a-hexamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylic acid		C₃₆H₅₇O₈P	详情	详情
(IV)	36514	methyl (E)-4-(2-formyl-4-hydroxyanilino)-4-oxo-2-butenoate		C₁₂H₁₁NO₅	详情	详情
(V)	36515	(6aR,6bR,12aR)-6a-([[(E)-3-(5-hydroxy-2-[[(E)-4-methoxy-4-oxo-2-butenoyl]amino]phenyl)-2-propenoyl]oxy]methyl)-2,2,6b,9,9,12a-hexamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydro-4a(2H)-picenecarboxylic acid		C₄₄H₅₇NO₉	详情	详情
(VI)	14942	5-hydroxy-2-nitrobenzaldehyde	42454-06-8	C₇H₅NO₄	详情	详情
(VII)	36516	2-amino-5-hydroxybenzaldehyde		C₇H₇NO₂	详情	详情
(VIII)	36517	methyl (E)-4-chloro-4-oxo-2-butenoate		C₅H₅ClO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXIII)

The precursor aminopropiophenone (XXVII) was synthesized as follows: 3-Amino-1-propanol (XX) was converted to the N-Boc derivative (XXI) and subsequently sulfonylated with p-toluenesulfonyl chloride to afford tosylate (XXII). Addition of vinylmagnesium bromide to 5-hydroxy-2-nitrobenzaldehyde (XXIII) provided the allyl alcohol (XXIV). The phenolic hydroxyl of (XXIV) was then alkylated with tosylate (XXII), yielding ether (XXV). The oxidation of the OH group of (XXV) with MnO2 gave the unsaturated ketone (XXVI). Catalytic hydrogenation of the olefin and nitro groups of (XXVI) provided the aminopropiophenone (XXVII).

参考文献中间体

合成目标

【1】 Tsujihara, K.; Kawaguchi, T.; Okuno, S.; Yano, T. (Tanabe Seiyaku Co., Ltd.); Camptothecin derivs.. CA 2182244; EP 0757049; JP 1998072467; US 5837673 .
【2】 Nomura, S.; Tsujihara, K.; Kawaguchi, T. (Tanabe Seiyaku Co., Ltd.); S type 2-substd. hydroxy-2-indolidinylbutyric ester cpds. and process for preparation thereof. US 6277992 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XX)	18522	3-amino-1-propanol	156-87-6	C₃H₉NO	详情	详情
(XXI)	10260	tert-butyl N-(3-hydroxypropyl)carbamate	58885-58-8	C₈H₁₇NO₃	详情	详情
(XXII)	49950	3-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate		C₁₅H₂₃NO₅S	详情	详情
(XXIII)	14942	5-hydroxy-2-nitrobenzaldehyde	42454-06-8	C₇H₅NO₄	详情	详情
(XXIV)	49951	3-(1-hydroxy-2-propenyl)-4-nitrophenol		C₉H₉NO₄	详情	详情
(XXV)	49952	tert-butyl 3-[3-(1-hydroxy-2-propenyl)-4-nitrophenoxy]propylcarbamate		C₁₇H₂₄N₂O₆	详情	详情
(XXVI)	49953	tert-butyl 3-(3-acryloyl-4-nitrophenoxy)propylcarbamate		C₁₇H₂₂N₂O₆	详情	详情
(XXVII)	49954	tert-butyl 3-(4-amino-3-propionylphenoxy)propylcarbamate		C₁₇H₂₆N₂O₄	详情	详情

Extended Information