4-aminobenzamide; p-aminobenzamide -Drug Synthesis Database

【结构式】

【分子编号】16778

【品名】4-aminobenzamide; p-aminobenzamide

【CA登记号】2835-68-9

【分子式】C₇H₈N₂O

【分子量】136.1534

【元素组成】C 61.75% H 5.92% N 20.57% O 11.75%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIII)

1) The cyclization of 4-hydrazinobenzonitrile (I) with 4-(benzoyloxy)cyclohexanone (II) in refluxing acetic acid gives 3-(benzoyloxy)-1,2,3,4-tetrahydro-9H-carbazole-6-carbonitrile (III), which is hydrolyzed with aqueous KOH to the corresponding alcohol (IV). The tosylation of (IV) with tosyl chloride in pyridine yields the tosylate (V), which by treatment with methylamine in hot ethanol is converted into 3-(methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carbonitrile (VI). The partial hydrolysis of the nitrile group with NaOH/H2O2, with previous protection of the amino group with di-tert-butyl dicarbonate, affords 3-(methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide (VII) as a racemic mixture. The reaction of (VII) with di-tert-butyl dicarbonate gives the carbamate (VIII), which is submitted to chiral HPLC in hexane/ethanol giving the (R)-isomer (IX). Finally, this carbamate is hydrolyzed with aqueous HCl/methanol. 2) The optical resolution can also be performed with the benzoyloxycarbonyl derivative of (VII) in a similar way. 3) The optical resolution of (VII) can also be performed directly with (1S)-(+)-camphorsulfonic acid in methanol. 4) The reaction of cyclohexane-1,4-dione mono 2,2-dimethyltrimethylene ketal (X) with methylamine in toluene gives the corresponding methylimine (XI), which is reduced with H2 over Pd/C in ethanol to the expected methylamine (XII). Finally, this compound is cyclized with 4-aminobenzamide (XIII) by treatment first with NaNO2/HCl and then with sodium dithionite affording the racemic mixture (VII) already described.

参考文献中间体

合成目标

【1】 Graul, A.; Leeson, P.; Castañer, J.; SB-209509/VML-251. Drugs Fut 1997, 22, 7, 725.
【2】 King, F.D.; Gaster, L.M.; Kaumann, A.J.; Young, R.C. (SmithKline Beecham plc); Use of tetrahydrocarbazole derivs. as 5HT1 receptor agonists. EP 0591280; JP 1994508827; US 5464864; US 5827871; WO 9300086 .
【3】 Borrett, G.T.; Kitteringham, J.; Porter, R.A.; Shipton, M.R.; Vimal, M.; Young, R.C. (SmithKline Beecham plc); Enantiomers of carbazole derivs. as 5-HT1-like agonists. EP 0674621; JP 1996504790; US 5650426; US 5962501; WO 9414772 .
【4】 King, F.D.; Gaster, L.M.; Kuamann, A.J.; Young, R.C. (SmithKline Beecham plc); Tetrahydrocarbazole derivs. for the manufacture of a medicament for the treatment of a disease where a 5-HT1-like agonist is indicated. EP 0603432 .

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)	16766	4-hydrazinobenzonitrile		C₇H₇N₃	详情	详情
(II)	16767	4-oxocyclohexyl benzoate		C₁₃H₁₄O₃	详情	详情
(III)	16768	6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl benzoate		C₂₀H₁₆N₂O₂	详情	详情
(IV)	16769	3-hydroxy-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile		C₁₃H₁₂N₂O	详情	详情
(V)	16770	6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl 4-methylbenzenesulfonate		C₂₀H₁₈N₂O₃S	详情	详情
(VI)	16771	3-(methylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile		C₁₄H₁₅N₃	详情	详情
(VII)	16772	3-(methylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide		C₁₄H₁₇N₃O	详情	详情
(VIII)	16773	tert-butyl N-[6-(aminocarbonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-methylcarbamate		C₁₉H₂₅N₃O₃	详情	详情
(IX)	16774	tert-butyl N-[(3R)-6-(aminocarbonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-methylcarbamate		C₁₉H₂₅N₃O₃	详情	详情
(X)	16775	3,3-Dimethyl-1,5-dioxaspiro[5.5]undecan-9-one; 1,4-Cyclohexanedione mono-2,2-dimethyltrimethylene ketal	69225-59-8	C₁₁H₁₈O₃	详情	详情
(XI)	16776	N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-ylidene)-N-methylamine; N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-ylidene)methanamine		C₁₂H₂₁NO₂	详情	详情
(XII)	16777	N,3,3-trimethyl-1,5-dioxaspiro[5.5]undecan-9-amine; N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-N-methylamine		C₁₂H₂₃NO₂	详情	详情
(XIII)	16778	4-aminobenzamide; p-aminobenzamide	2835-68-9	C₇H₈N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The condensation of 4-aminobenzamide (I) with N-(tert-butoxycarbonyl)-L-methionine (II) by means of 2-chloro-1-methylpyridinium iodide (CMPI) and N-methylmorpholine (NMM) in DMF gives the corresponding methioninamide (III), which is cyclized by means of trimethylsulfonium iodide and K2CO3 in hot DMSO yielding the pyrrolidinone (IV). The dehydration of (IV) with trifluoroacetic anhydride in THF affords the corresponding nitrile (V), which is deprotected with dry HCl in ethyl acetate giving the amine (VI). The condensation of (VI) with beta-alanine ethyl ester (VII) and carbonyl diimidazole (CDI) in pyridine yields the substituted urea (VIII), which is treated with hydroxylamine hydrochloride and triethylamine in ethyl acetate to afford the N-hydroxybenzamidine (IX). Finally, this compound is hydrogenated with H2 over Pd/C in acetic acid.

参考文献中间体

合成目标

【1】 Castañer, J.; Merlos, M.; Leeson, P.A.; Orbofiban Acetate. Drugs Fut 1998, 23, 11, 1190-1198.
【2】 Abood, N.A.; Flynn, D.L.; Laneman, S.A.; Nosal, R.; Schretzman, L.A. (Pharmacia Corp.); Process for the preparation of amidino phenyl pyrrolidine betal-alanine urea analogs. US 5484946 .

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)	16778	4-aminobenzamide; p-aminobenzamide	2835-68-9	C₇H₈N₂O	详情	详情
(II)	17634	(2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine	2488-15-5	C₁₀H₁₉NO₄S	详情	详情
(III)	17635	tert-butyl (1S)-1-[[4-(aminocarbonyl)anilino]carbonyl]-3-(methylsulfanyl)propylcarbamate		C₁₇H₂₅N₃O₄S	详情	详情
(IV)	17636	tert-butyl (3S)-1-[4-(aminocarbonyl)phenyl]-2-oxopyrrolidinylcarbamate		C₁₆H₂₁N₃O₄	详情	详情
(V)	17637	tert-butyl (3S)-1-(4-cyanophenyl)-2-oxopyrrolidinylcarbamate		C₁₆H₁₉N₃O₃	详情	详情
(VI)	17638	4-[(3S)-3-amino-2-oxopyrrolidinyl]benzonitrile		C₁₁H₁₁N₃O	详情	详情
(VII)	17639	beta-Alanine, ethyl ester; ethyl 3-aminopropanoate	924-73-2	C₅H₁₁NO₂	详情	详情
(VIII)	17640	ethyl 3-[([[(3S)-1-(4-cyanophenyl)-2-oxopyrrolidinyl]amino]carbonyl)amino]propanoate		C₁₇H₂₀N₄O₄	详情	详情
(IX)	17641	ethyl 3-([[((3S)-1-[4-[amino(hydroxyimino)methyl]phenyl]-2-oxopyrrolidinyl)amino]carbonyl]amino)propanoate		C₁₇H₂₃N₅O₅	详情	详情

Extended Information