1-(4-Methoxyphenyl)diazonium chloride -Drug Synthesis Database

【结构式】

【分子编号】12149

【品名】1-(4-Methoxyphenyl)diazonium chloride

【CA登记号】

【分子式】C₇H₇ClN₂O

【分子量】170.59816

【元素组成】C 49.28% H 4.14% Cl 20.78% N 16.42% O 9.38%

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)

The nitrosation of p-anisidine (I) with NaNO2 and HCl in water gives 4-methoxyphenyldiazonium chloride (II), which is condensed with 4-(4-methyl-1-cyclohexenyl)morpholine (III) yielding 2-(4-methoxyphenylhydrazono)-4-methylcyclohexanone (IV). The cyclization of (IV) by means of H2SO4 in refluxing ethanol affords 6-methoxy-4-methyl-1,2,3,4-tetrahydro-9H-carbazol-1-one (V), which is condensed with refluxing ethyl formate and NaH to give the corresponding 2-(hydroxymethylene) derivative (VI). The alkylation of (VI) with isopropyl iodide and K2CO3 yields the corresponding 2-(isopropoxymethylene) derivative (VII), which is methylated with CH3Li in ether to afford 6-methoxy-1,4-dimethyl-3,4-dihydrocarbazole-2-carboxaldehyde (VIII). The aromatization of (VIII) with MnO2 in refluxing benzene gives the corresponding carbazole (IX), which is condensed with malonic acid by means of piperidine in refluxing pyridine to afford 3-(6-methoxy-1,4-dimethylcarbazol-2-yl)-2-propenoic acid (X). The reaction of (X) with ethylchloroformate and sodium azide and acetone gives the corresponding azide (XI), which is cyclized by means of tributylamine in diphenyl ether at 250 C yielding 9-methoxy-5,11-dimethyl-1,2-dihydro-6H-pyrido[4,3-b]carbazol-1-one (XII). The reaction of (XII) with refluxing POCl3 affords 1-chloro-9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (XIII), which is finally treated with refluxing 2-(diethylamino)propylamine (XIV).

参考文献中间体

合成目标

【1】 Lhoste, J.-M.; Bisagni, E.; Rivalle, C.; Ducrocq, C.; Civier, A.; Synthesis of 1-substituted ellipticines by a new route to pyrido[4,3-b]carbazoles. J Chem Soc - Perkins Trans I 1979, 1706.
【2】 Bisagni, E.; Ducrocq, C.; Rivalle, C.; Tambourin, P.; Wendling, F.; Civier, A.; Montagnier, L.; Chermann, J.-C.; Gruest, J.; Lidereau, R. (ANVAR (Agence Natl. Valor. Rech.)); Substd. ellipticines in position 1 by a polyaminated chain, their synthesis and medicaments containing them. EP 0010029 .
【3】 Castaner, J.; Hoshi, A.; Retelliptine. Drugs Fut 1994, 19, 2, 122.
【4】 Tourbez-Perrin, M.; Ducrocq, C.; Wendling, F.; et al.; Structure-activity relationships in a series of newly synthesized 1-aminosubstituted ellipticine derivatives. J Med Chem 1980, 23, 1212.

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)	10478	p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine	104-94-9	C₇H₉NO	详情	详情
(II)	12149	1-(4-Methoxyphenyl)diazonium chloride		C₇H₇ClN₂O	详情	详情
(III)	12150	4-(4-Methyl-1-cyclohexen-1-yl)morpholine		C₁₁H₁₉NO	详情	详情
(IV)	12151	4-Methyl-1,2-cyclohexanedione 2-[N-(4-methoxyphenyl)hydrazone]		C₁₄H₁₈N₂O₂	详情	详情
(V)	12152	6-Methoxy-4-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one		C₁₄H₁₅NO₂	详情	详情
(VI)	12153	2-[(E)-Hydroxymethylidene]-6-methoxy-4-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one		C₁₅H₁₅NO₃	详情	详情
(VII)	12154	2-[(E)-Isopropoxymethylidene]-6-methoxy-4-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one		C₁₈H₂₁NO₃	详情	详情
(VIII)	12155	6-Methoxy-1,4-dimethyl-4,9-dihydro-3H-carbazole-2-carbaldehyde		C₁₆H₁₇NO₂	详情	详情
(IX)	12156	6-Methoxy-1,4-dimethyl-9H-carbazole-2-carbaldehyde		C₁₆H₁₅NO₂	详情	详情
(X)	12157	(Z)-3-(6-Methoxy-1,4-dimethyl-9H-carbazol-2-yl)-2-propenoic acid		C₁₈H₁₇NO₃	详情	详情
(XI)	12158	(Z)-1-Azido-3-(6-methoxy-1,4-dimethyl-9H-carbazol-2-yl)-2-propen-1-one		C₁₈H₁₆N₄O₂	详情	详情
(XII)	12159	9-Methoxy-5,11-dimethyl-2,6-dihydro-1H-pyrido[4,3-b]carbazol-1-one		C₁₈H₁₆N₂O₂	详情	详情
(XIII)	12160	1-Chloro-9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole; 1-Chloro-5,11-dimethyl-6H-pyrido[4,3-b]carbazol-9-yl methyl ether		C₁₈H₁₅ClN₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Diazotization of p-anisidine (I), followed by coupling of the resulting diazonium salt (II) with 3-tert-butyl-4-hydroxyanisole (III) produced azobenzene (IV). Subsequent protection of the hydroxyl group of (IV) with chloromethyl methyl ether in the presence of NaH afforded the methoxymethyl derivative (V). Aniline (VI) was then obtained by catalytic hydrogenation of (V) over Pd/C. Condensation of aniline (VI) with triphosgene, followed by reaction with 3-picolylamine (VII) gave rise to urea (VIII). The methoxymethyl protecting group of (VIII) was finally removed by treatment with methanolic HCl.

参考文献中间体

合成目标

【1】 Nakao, K.; et al.; Quantitative structure-activity analyses of novel hydroxyphenylurea derivatives as antioxidants. Bioorg Med Chem 1998, 6, 6, 849.
【2】 Suzuki, T.; Ohmizu, H.; Hashimura, Y.; Kubota, H.; Tanaka, K. (Tanabe Seiyaku Co., Ltd.); Phenol-derivs. having pharmaceutical activity and process for preparing the same. EP 0790240; JP 1998195037; US 5849732 .

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)	10478	p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine	104-94-9	C₇H₉NO	详情	详情
(II)	12149	1-(4-Methoxyphenyl)diazonium chloride		C₇H₇ClN₂O	详情	详情
(III)	40700	2-(tert-butyl)-4-methoxyphenol		C₁₁H₁₆O₂	详情	详情
(IV)	40701	2-(tert-butyl)-4-methoxy-6-[(Z)-2-(4-methoxyphenyl)diazenyl]phenol		C₁₈H₂₂N₂O₃	详情	详情
(V)	40702	(Z)-1-[3-(tert-butyl)-5-methoxy-2-(methoxymethoxy)phenyl]-2-(4-methoxyphenyl)diazene; 3-(tert-butyl)-4-(methoxymethoxy)-5-[(Z)-2-(4-methoxyphenyl)diazenyl]phenyl methyl ether		C₂₀H₂₆N₂O₄	详情	详情
(VI)	40703	3-(tert-butyl)-5-methoxy-2-(methoxymethoxy)phenylamine; 3-(tert-butyl)-5-methoxy-2-(methoxymethoxy)aniline		C₁₃H₂₁NO₃	详情	详情
(VII)	18731	3-pyridinylmethanamine; 3-pyridinylmethylamine	3731-52-0	C₆H₈N₂	详情	详情
(VIII)	40704	N-[3-(tert-butyl)-5-methoxy-2-(methoxymethoxy)phenyl]-N'-(3-pyridinylmethyl)urea		C₂₀H₂₇N₃O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

The intermediate chloro hydrazone (I) is prepared by he following method. Diazotization of p-anisidine (XII) employing sodium nitrite in cold aqueous HCl yields the ntermediate diazonium salt (XIII), which undergoes Japp-Klingemann reaction with ethyl 2-chloroacetoacetate (XIV) in the presence of NaOAc to produce the target hydrazone (I) (1, 2). Scheme 2.

参考文献中间体

合成目标

【1】 Shapiro, R., Rossano, L.T., Mudryk, B.M. et al. (Bristol-Myers Squibb Co.). Process for preparing 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones. WO 2007001385.
【2】 Pinto, D., Quan, M., Orwat, M. et al. (Bristol-Myers Squibb Co.). Lactam-containing compounds and derivatives thereof as factor Xa inhibitors. EP 1427415, JP 2005507889, WO 03026652.

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)	65609	Ethyl chloro[(4-methoxyphenyl)hydrazono]acetate; Chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester	27143-07-3	C₁₁H₁₃ClN₂O₃	详情	详情
(XII)	10478	p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine	104-94-9	C₇H₉NO	详情	详情
(XIII)	12149	1-(4-Methoxyphenyl)diazonium chloride		C₇H₇ClN₂O	详情	详情
(XIV)	21337	ethyl 2-chloro-3-oxobutanoate	609-15-4	C₆H₉ClO₃	详情	详情

Extended Information