4-METHOXY-3-NITROBENZALDEHYDE -Drug Synthesis Database

【结构式】

【分子编号】18225

【品名】4-METHOXY-3-NITROBENZALDEHYDE

【CA登记号】31680-08-7

【分子式】C₈H₇NO₄

【分子量】181.14792

【元素组成】C 53.04% H 3.89% N 7.73% O 35.33%

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：(II)

Wittig reaction of 3,4,5-trimethoxybenzyl phosphonium bromide (I) with benzaldehyde (II) in the presence of NaH in toluene yielded a 1:1 mixture of E (III) and Z (IV) stilbenes, from which the Z isomer was separated by crystallization from EtOAc and then from EtOH. Then, nitro group of (IV) was reduced with Zn in AcOH at room temperature to give anilino compound (V), which was converted to the hydrochloride salt with HCl in dioxane-methylene chloride.

参考文献中间体

合成目标

【1】 Suga, Y.; Ohsumi, K.; Fukuda, Y.; Nihei, Y.; Hatanaka, T.; Tsuji, T.; Nakagawa, R.; Morrinaga, Y.; Ohishi, K.; Akiyama, Y.; Novel combretastatin analogue effective against murine solid tumors: Design and structure-activity relationships. J Med Chem 1998, 41, 16, 3022.

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)	18224	triphenyl(3,4,5-trimethoxybenzyl)phosphorane; 2,3-dimethoxy-5-[(triphenylphosphoranyl)methyl]phenyl methyl ether		C₂₈H₂₉O₃P	详情	详情
(II)	18225	4-METHOXY-3-NITROBENZALDEHYDE	31680-08-7	C₈H₇NO₄	详情	详情
(III)	18226	2,3-dimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene		C₁₈H₁₉NO₆	详情	详情
(IV)	28720	2,3-dimethoxy-5-[(Z)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(Z)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene		C₁₈H₁₉NO₆	详情	详情
(V)	18228	2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]aniline; 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenylamine		C₁₈H₂₁NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Wittig reaction of phosphonium bromide (I) with 4-methoxy-3-nitrobenzaldehyde (II) in the presence of NaOMe provided an approximately equimolecular mixture of Z- and E-stilbenes (III) and (IV), from which the E-isomer was isolated by crystallization. Stilbene (IV) was converted to bromohydrin (V) by treatment with N-bromosuccinimide in aqueous DMSO. Further Swern oxidation of (V) with DMSO-trifluoroacetic anhydride (TFAA) yielded bromoketone (VI), which was then cyclized with thiourea (VII) in the presence of K2CO3 in DMF to give aminothiazole (VIII). Finally, the nitro of (VIII) group was reduced to the target amine by treatment with Zn in AcOH.

参考文献中间体

合成目标

【1】 Ohsumi, K.; Hatanaka, T.; Fujita, K.; Nakagawa, R.; Fukuda, Y.; Nihei, Y.; Suga, Y.; Morinaga, Y.; Akiyama, Y.; Tsuji, T.; Syntheses and antitumor activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues. Bioorg Med Chem Lett 1998, 8, 22, 3153.
【2】 Suga, Y.; Ohsumi, K.; Fukuda, Y.; Nihei, Y.; Hatanaka, T.; Tsuji, T.; Nakagawa, R.; Morrinaga, Y.; Ohishi, K.; Akiyama, Y.; Novel combretastatin analogue effective against murine solid tumors: Design and structure-activity relationships. J Med Chem 1998, 41, 16, 3022.

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)	19866	triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide		C₂₈H₂₈BrO₃P	详情	详情
(II)	18225	4-METHOXY-3-NITROBENZALDEHYDE	31680-08-7	C₈H₇NO₄	详情	详情
(III)	28720	2,3-dimethoxy-5-[(Z)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(Z)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene		C₁₈H₁₉NO₆	详情	详情
(IV)	18226	2,3-dimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene		C₁₈H₁₉NO₆	详情	详情
(V)	18226	2,3-dimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene		C₁₈H₁₉NO₆	详情	详情
(V)	19870	2-bromo-2-(4-methoxy-3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)-1-ethanol		C₁₈H₂₀BrNO₇	详情	详情
(VI)	19871	2-bromo-2-(4-methoxy-3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)-1-ethanone		C₁₈H₁₈BrNO₇	详情	详情
(VII)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VIII)	19873	5-(4-methoxy-3-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-amine; 5-(4-methoxy-3-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-ylamine		C₁₉H₁₉N₃O₆S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

The condensation between 3,4,5-trimethoxybenzaldehyde (I), 4-methylbenzenesulfinic acid (II) and formamide in the presence of camphorsulfonic acid gave tosyl-(3,4,5-trimethoxyphenyl)methylformamide (III), which was subsequently dehydrated to the isonitrile (IV) by treatment with POCl3 and Et3N. After conversion of 4-methoxy-3-nitrobenzaldehyde (V) to the corresponding imine with methylamine, its reaction with the tosylmethyl isonitrile (IV) gave rise to the diaryl imidazole (VI). The nitro group of (VI) was finally reduced to amine by using SnCl2 and HCl or ammonium formiate and Pd/C

参考文献中间体

合成目标

【1】 Wang, L.; Woods, K.W.; Li, Q.; Barr, K.J.; McCroskey, R.M.; Hannick, S.M.; Gherke, L.; Credo, R.B.; Hui, Y.H.; Marsch, K.; Warner, R.; Lee, J.Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S.H.; Sham, H.L.; Potent, orally active heterocycle-based combretastatin A-4 analogues: Synthesis, structure-activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation. J Med Chem 2002, 45, 8, 1697.
【2】 Wang, L.; Woods, K.W.; Li, Q.; Sham, H.L. (Abbott Laboratories Inc.); Imidazole antiproliferative agents. WO 0109103 .

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)	11136	3,4,5-Trimethoxybenzaldehyde	86-81-7	C₁₀H₁₂O₄	详情	详情
(II)	25593	4-methylbenzenesulfinic acid		C₇H₈O₂S	详情	详情
(III)	49071	[(4-methylphenyl)sulfonyl](3,4,5-trimethoxyphenyl)methylformamide		C₁₈H₂₁NO₆S	详情	详情
(IV)	49072	2-[(4-methylphenyl)sulfonyl]-2-(3,4,5-trimethoxyphenyl)acetonitrile		C₁₈H₁₉NO₅S	详情	详情
(V)	18225	4-METHOXY-3-NITROBENZALDEHYDE	31680-08-7	C₈H₇NO₄	详情	详情
(VI)	49073	2,3-dimethoxy-5-[5-(4-methoxy-3-nitrophenyl)-1-methyl-1H-imidazol-4-yl]phenyl methyl ether; 5-(4-methoxy-3-nitrophenyl)-1-methyl-4-(3,4,5-trimethoxyphenyl)-1H-imidazole		C₂₀H₂₁N₃O₆	详情	详情

Extended Information