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
|