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【结 构 式】

【分子编号】11041

【品名】4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone

【CA登记号】100-06-1

【 分 子 式 】C9H10O2

【 分 子 量 】150.1772

【元素组成】C 71.98% H 6.71% O 21.31%

与该中间体有关的原料药合成路线共 11 条

合成路线1

该中间体在本合成路线中的序号:(I)

The bromination of labeled 4'-methoxyacetophenone (I) with CuBr2 gives 4'-methoxyphenacyl bromide (II), which is reduced with NaBH4, yielding the carbinol (III). The protection of (III) with DHP affords the tetrahydropyranyl ether (IV), which is condensed with 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (V) and acidified to provide the aminoalcohol (VI). The cyclization of (VI) with MsOH and trifluoroacetic acid furnishes labeled 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (VII), which is finally demethylated with BBr3 and MsOH.

1 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645.
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) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(I) 44616 1-(4-methoxyphenyl)-1-ethanone C9H10O2 详情 详情
(II) 21991 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone 2632-13-5 C9H9BrO2 详情 详情
(II) 44617 2-bromo-1-(4-methoxyphenyl)-1-ethanone C9H9BrO2 详情 详情
(III) 44053 2-bromo-1-(4-methoxyphenyl)-1-ethanol C9H11BrO2 详情 详情
(III) 44618 2-bromo-1-(4-methoxyphenyl)-1-ethanol C9H11BrO2 详情 详情
(IV) 44054 2-bromo-1-(4-methoxyphenyl)ethyl tetrahydro-2H-pyran-2-yl ether; 2-[2-bromo-1-(4-methoxyphenyl)ethoxy]tetrahydro-2H-pyran C14H19BrO3 详情 详情
(IV) 44619 2-bromo-1-(4-methoxyphenyl)ethyl tetrahydro-2H-pyran-2-yl ether; 2-[2-bromo-1-(4-methoxyphenyl)ethoxy]tetrahydro-2H-pyran C14H19BrO3 详情 详情
(V) 42037 2-chloro-3,4-dimethoxyphenethylamine; 2-(2-chloro-3,4-dimethoxyphenyl)-1-ethanamine 67287-36-9 C10H14ClNO2 详情 详情
(VI) 31702 2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol C19H24ClNO4 详情 详情
(VI) 44620 2-[(2-chloro-3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-ethanol C19H24ClNO4 详情 详情
(VII) 31704 4-(6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether; 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine C19H22ClNO3 详情 详情
(VII) 44621 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 4-(6-chloro-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)phenyl methyl ether C19H22ClNO3 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 cyclization of p-methoxyacetophenone (I) with thiourea (II) by means of SO2Cl2 gives 4-(p-methoxyphenyl)-2-aminothiazole (III), which is then reacted with ethoxalyl chloride (IV) in presence of a base to afford F-1865.

1 Casadio, S.; Cousse, H.; Tarayre, J.P.; Mouzin, G. (Pierre Fabre SA.); 4-Phenyl-2-thiazolyloxamate derivs., method for their preparation and their application in the treatment of asthma. EP 0006368; ES 481633; FR 2429210; JP 55002684; US 4246271 .
2 Tarayre, J.P.; Bonnaud, B.; TIOXAMAST. Drugs Fut 1990, 15, 5, 469.
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) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 11042 4-(4-Methoxy-phenyl)-thiazol-2-ylamine; 4-(4-methoxyphenyl)-1,3-thiazol-2-ylamine; 4-(4-methoxyphenyl)-1,3-thiazol-2-amine 2104-04-3 C10H10N2OS 详情 详情
(IV) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(XVI)

Condensation of 1,3-benzodioxole-5-carbaldehyde (XV) with nitromethane by means of ammonium acetate in HOAc gives the nitrostyrene (I), which is condensed with ethyl 2-(4-methoxybenzoyl)acetate (II) [obtained by reaction of acetophenone (XVI), diethyl carbonate and potassium tert-amyloxide] by means of NaOEt in THF to yield the 4-nitrobutyrate (III). Reductive cyclization of (III) with H2 over Raney-Ni in THF affords the (cis, cis)-pyrrolidine (VI), which is isomerized to the (trans,trans)-isomer (V) by means of NaOEt in refluxing ethanol. This racemic ester (V) is submitted to optical resolution with (S)-(+)-mandelic acid to provide the pure chiral ester (XVII). This compound is condensed with 2-bromo-N,N-dibutylacetamide (XIII) [obtained by reaction of 2-bromoacetyl bromide (XVIII) with dibutylamine (XIX) in toluene] by means of DIEA in acetonitrile to give the ethyl ester (XX), which is finally hydrolyzed with NaOH in hot ethanol.

1 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939.
2 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 .
3 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 .
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) 20675 5-[(E)-2-nitroethenyl]-1,3-benzodioxole 1485-00-3 C9H7NO4 详情 详情
(II) 20676 ethyl 3-(4-methoxyphenyl)-3-oxopropanoate C12H14O4 详情 详情
(III) 20677 ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate C21H21NO8 详情 详情
(VI) 20679 ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C21H23NO5 详情 详情
(XIII) 20685 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide C10H20BrNO 详情 详情
(XV) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(XVI) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(XVII) 20680 ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C21H23NO5 详情 详情
(XVIII) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XIX) 33492 N,N-dibutylamine; N-butyl-1-butanamine 111-92-2 C8H19N 详情 详情
(XX) 48687 ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C31H42N2O6 详情 详情

合成路线4

该中间体在本合成路线中的序号:(I)

Title compound has been prepared by several routes: Condensation of 4'-methoxyacetophenone (I) with diethyl oxalate in the presence of lithium hexamethyldisilazide provided lithium ethyl 4-methoxybenzoylpyruvate (II). Subsequent condensation of (II) with 4-methoxyphenylhydrazine hydrochloride (III) yielded diarylpyrazole (IV). This was coupled with bromide (V) in the presence of n-BuLi to afford ketone (VI). The oxazoline ring of (VI) was then hydrolyzed to carboxylic acid (VII) by successive treatments with HCl and with NaOH. Activation of the carboxylic acid of (VII) as the mixed anhydride with ethyl chloroformate, followed by treatment with gaseous ammonia provided amide (VIII). The required dimethyl ketal was finally introduced in (VIII) by means of trimethyl orthoformate in MeOH in the presence of p-TsOH.

1 Lamari, L.; Zitouni, A.; Boudjella, H.; et al.; J Heterocycl Chem 1989, 26, 8, 1389-1392.
2 Numata, H.; Okamoto, Y.; Shinoda, M.; Kobayashi, N.; Miyazawa, S.; Kawahara, T.; Shirota, H.; Nagakura, N.; Horizoe, T.; Abe, S.; Kobayashi, S.; Yamanaka, T. (Eisai Co., Ltd.); Pyrazole derivs. exhibiting anti-inflammatory and analgesic effects. JP 1998509140; WO 9614302 .
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) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(II) 25533 2-Hydroxy-4-(4-methoxyphenyl)-3-oxo-2(E)-butenoic acid ethyl ester lithium salt C13H13LiO5 详情 详情
(III) 12688 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine 3471-32-7 C7H10N2O 详情 详情
(IV) 25534 ethyl 1,5-bis(4-methoxyphenyl)-1H-pyrazole-3-carboxylate C20H20N2O4 详情 详情
(V) 25535 2-(5-bromo-2-chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole C11H11BrClNO 详情 详情
(VI) 25536 [1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl][4-chloro-3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]methanone C29H26ClN3O4 详情 详情
(VII) 25537 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzoic acid C25H19ClN2O5 详情 详情
(VIII) 25538 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzamide C25H20ClN3O4 详情 详情

合成路线5

该中间体在本合成路线中的序号:(II)

Aldol condensation of piperonal (I) with 4-methoxyacetophenone (II) afforded chalcone (III). Subsequent addition of KCN to (III) in the presence of AcOH gave nitrile (IV), which was hydrolyzed in methanol in the presence of p-TsOH to provide ketoester (V). Subsequent base-catalyzed condensation of (V) with aldehyde (VI), followed by cyclization in refluxing AcOH furnished the target butenolide.

1 Repine, J.T.; Patt, W.C.; Cheng, X.-M.; et al.; Butenolide endothelin antagonists with improved aqueous solubility. J Med Chem 1999, 42, 12, 2162.
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) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(II) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(III) 25775 (E)-3-(1,3-benzodioxol-5-yl)-1-(4-methoxyphenyl)-2-propen-1-one C17H14O4 详情 详情
(IV) 25776 2-(1,3-benzodioxol-5-yl)-4-(4-methoxyphenyl)-4-oxobutanenitrile C18H15NO4 详情 详情
(V) 25777 ethyl 2-(1,3-benzodioxol-5-yl)-4-(4-methoxyphenyl)-4-oxobutanoate C20H20O6 详情 详情
(VI) 25778 3-(5-formyl-2,3-dimethoxyphenoxy)-1-propanesulfonate C12H15O7S 详情 详情

合成路线6

该中间体在本合成路线中的序号:(IV)

Dimethyl 3-nitrophthalate (I) was hydrogenated in the presence of Pd/C to give aminophthalate (II), which was acylated with Ac2O in pyridine, yielding acetamidophthalate (III). Condensation of phthalate ester (III) with 4'-methoxyacetophenone (IV) using NaH in DMF produced triketone (V). After acid hydrolysis of the amide function of (V), the resulting aminoindenetrione (VI) was cyclized with hydrazine hydrate to generate the indenopyrazolone system (VII). Condensation of (VII) with phenyl chloroformate afforded the phenyl carbamate (VIII). This was finally treated with concentrated ammonia to furnish the target urea derivative.

1 Yue, E.W.; Carini, D.J.; Nugiel, D.A.; Dimeo, S.V. (DuPont Pharmaceuticals Co.); 5-Aminoindeno(1,2-c)pyrazol-4-ones as anti-cancer and anti-proliferative agents. WO 9954308 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13580 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate 1885-14-9 C7H5ClO2 详情 详情
(I) 34481 dimethyl 3-nitrophthalate 13365-26-9 C10H9NO6 详情 详情
(II) 34482 dimethyl 3-aminophthalate C10H11NO4 详情 详情
(III) 34483 dimethyl 3-(acetamido)phthalate C12H13NO5 详情 详情
(IV) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(V) 34484 N-[2-(4-methoxybenzoyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl]acetamide C19H15NO5 详情 详情
(VI) 34485 4-amino-2-(4-methoxybenzoyl)-1H-indene-1,3(2H)-dione C17H13NO4 详情 详情
(VII) 34486 5-amino-3-(4-methoxyphenyl)indeno[1,2-c]pyrazol-4(2H)-one C17H13N3O2 详情 详情
(VIII) 34487 phenyl 3-(4-methoxyphenyl)-4-oxo-2,4-dihydroindeno[1,2-c]pyrazol-5-ylcarbamate C24H17N3O4 详情 详情

合成路线7

该中间体在本合成路线中的序号:(IV)

Catalytic hydrogenation of dimethyl 3-nitrophthalate (I) in the presence of Pd/C afforded the corresponding amino derivative (II), which was subsequently acetylated with Ac2O in pyridine yielding amide (III). Claisen condensation of diester (III) with 4'-methoxyacetophenone (IV) using NaH in hot DMF furnished the indandione (V). The tricarbonyl intermediate (V) was then treated with hydrazine to give the indenopyrazole (VI) as a single regioisomer. Acidic hydrolysis of the acetamide function of (VI) provided amine (VII). This was finally converted to the target formamide derivative upon heating with neat formic acid.

1 Nugiel, D.A.; et al.; Indenopyrazoles as novel cyclin dependen kinase (CDK) inhibitors. J Med Chem 2001, 44, 9, 1334.
2 Yue, E.W.; Carini, D.J.; Nugiel, D.A.; Dimeo, S.V. (DuPont Pharmaceuticals Co.); 5-Aminoindeno(1,2-c)pyrazol-4-ones as anti-cancer and anti-proliferative agents. WO 9954308 .
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) 34481 dimethyl 3-nitrophthalate 13365-26-9 C10H9NO6 详情 详情
(II) 34482 dimethyl 3-aminophthalate C10H11NO4 详情 详情
(III) 34483 dimethyl 3-(acetamido)phthalate C12H13NO5 详情 详情
(IV) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(V) 34484 N-[2-(4-methoxybenzoyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl]acetamide C19H15NO5 详情 详情
(VI) 49762 N-[3-(4-methoxyphenyl)-4-oxo-2,4-dihydroindeno[1,2-c]pyrazol-5-yl]acetamide C19H15N3O3 详情 详情
(VII) 34486 5-amino-3-(4-methoxyphenyl)indeno[1,2-c]pyrazol-4(2H)-one C17H13N3O2 详情 详情

合成路线8

该中间体在本合成路线中的序号:(I)

 

1 Hu GY.Xue JW,Dong YH,et aL 2007.Ptepanttion of 4-tert-butyl-4’-metho:qndibenzqdmethane发明专 利申请公开说明书,CN1958549
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) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(II) 66138 4-tert-Butylbenzoic acid;PTBBA 98-73-7 C11H14O2 详情 详情

合成路线9

该中间体在本合成路线中的序号:(VI)

 

1 Zheng CY,ZherigJ,FanL.et aL 2006. Synthesis of.diketone compoundN for UV-A ultraviolet absorbent 化学世界,28 (9): 538~540
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 66140 Benzoic acid,4-(1,1-dimethylethyl)-, ethyl ester;Benzoicacid, p-tert-butyl-, ethyl ester (6CI,7CI,8CI);4-t-Butylbenzoic acid ethylester;Ethyl 4-tert-butylbenzoate;Ethyl p-tert-butylbenzoate; 5406-57-5 C13H18O2 详情 详情
(VI) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情

合成路线10

该中间体在本合成路线中的序号:(VI)

 

1 Habeck T, Prechtl F. 2000. Preparation of dibenzoylmethanes EP 994092
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 66140 Benzoic acid,4-(1,1-dimethylethyl)-, ethyl ester;Benzoicacid, p-tert-butyl-, ethyl ester (6CI,7CI,8CI);4-t-Butylbenzoic acid ethylester;Ethyl 4-tert-butylbenzoate;Ethyl p-tert-butylbenzoate; 5406-57-5 C13H18O2 详情 详情
(VI) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(VII) 66141 (E)-3-(4-(tert-butyl)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one   C20H22O2 详情 详情

合成路线11

该中间体在本合成路线中的序号:(I)

 

1 Murillo Gamdo JV, Armengol Montserrat M, Juarez J. 2007. Method of obtaining phenyl carbamates. WO 2007014973(本专利属于Ragactives,S L,Spain; Interquim,S. A.)
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) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(II) 66628 1-(3-methoxyphenyl)-N-methylethanamine   C10H15NO 详情 详情
(III) 66629 3-(1-(methylamino)ethyl)phenol   C9H13NO 详情 详情
(IV) 66630     C10H15BrO4S.C9H13NO 详情 详情
(V) 66631 (S)-3-(1-(methylamino)ethyl)phenol   C9H13NO 详情 详情
(VI) 66632 (S)-3-(1-(methylamino)ethyl)phenyl ethyl(methyl)carbamate   C13H20N2O2 详情 详情
Extended Information