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【结 构 式】 
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【分子编号】29654 【品名】2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone 【CA登记号】118-93-4 |
【 分 子 式 】C8H8O2 【 分 子 量 】136.15032 【元素组成】C 70.57% H 5.92% O 23.5% |
合成路线1
该中间体在本合成路线中的序号：(I)This 1-vinyl derivative (II) is obtained by reaction of N,N'-thionyldiimidazole (A) with o-hydroxyacetophenone (I) in dichloromethane at room temperature. Treatment of (II) with m-chlorobenzyl chloride (B) in the presence of KOH in DMF gives the m-chlorobenzyl ether (III). The hydrochloride can be prepared by treatment of (III) with HCl in AcOEt.
| 【1】 Ogata, M.; Hamada, Y.; Takehara, M.; Tawara, K.; Matsumoto, H.; 1-[1-[2-[(3-Chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole hydrochloride, a new potent antifungal agent. J Med Chem 1983, 26, 5, 768-770. |
| 【2】 Ogata, M.; Tawara, K.; Cloconazole Hydrochloride. Drugs Fut 1985, 10, 6, 451. |
| 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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 26955 | 3-phenyl-1,1-cyclobutanedicarboxylic acid | C12H12O4 | 详情 | 详情 | |
| (III) | 26956 | 3-phenylcyclobutanecarboxylic acid | C11H12O2 | 详情 | 详情 | |
| (IV) | 20642 | 1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride | 620-20-2 | C7H6Cl2 | 详情 | 详情 |
| (V) | 29657 | 1-(1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl)-1H-imidazole; 3-chlorobenzyl 2-[1-(1H-imidazol-1-yl)vinyl]phenyl 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：(A)The synthesis of bervastatin is outlined: Heating of 2-hydroxyacetophenone (A) with cyclopentanone (B) and pyrrolidine in toluene gave 3,4-dihydrospiro[1-benzopyran-2(2H),1'-cyclopentan]-4-one (I). 1,2-Addition of 4-fluorophenylmagnesium bromide (D) on (I) followed by dehydration of the intermediate alcohol (II) upon treatment with p-toluenesulfonic acid yielded 4-(4-fluorophenyl)spiro[1-benzopyran-2(2H),1'-cyclopentane] (III). Vilsmeier reaction on (III) using 3-morpholinoacrolein (E) gave the corresponding prop-2-enal (IV). Addition of the dianion of ethyl acetoacetate to aldehyde (IV) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (V) with diethylmethoxyborane and sodium borohydride yielded bervastatin.
| 【1】 Festal, D.; Bervastatin. Drugs Fut 1995, 20, 12, 1217. |
| 【2】 Festal, D.; Nioche, J.-Y.; Descours, D.; Bellemin, R.; Decerprit, J. (Lipha Santé); Derivs. of benzocycloalkenyldihydroxyalkanoic acids, inhibitors of HMG-CoA reductase, antagonists of thromboxane A2 receptors and antifungals. AU 9048797; EP 0380392; FR 2642065; JP 1990258738; US 5082859; US 5183924 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (B) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (A) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (E) | 44198 | (E)-3-(4-morpholinyl)-2-propenal | C7H11NO2 | 详情 | 详情 | |
| (I) | 14114 | 3,4-Dihydro-2H-spiro[1-benzopyran-2,1'-cyclopentan]-4-one | C13H14O2 | 详情 | 详情 | |
| (II) | 14115 | 4-(4-Fluorophenyl)-3,4-dihydro-2H-spiro[1-benzopyran-2,1'-cyclopentan]-4-ol | C19H19FO2 | 详情 | 详情 | |
| (III) | 14116 | 4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentane] | C19H17FO | 详情 | 详情 | |
| (IV) | 14117 | 3-[4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentan]-3-yl]-2(E)-propenal | C22H19FO2 | 详情 | 详情 | |
| (V) | 14118 | 5-Hydroxy-7-[4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentan]-3-yl]-3-oxo-6(E)-heptenoic acid ethyl ester | C28H29FO5 | 详情 | 详情 | |
| (C) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The cyclization of 2-hydroxyacetophenone (I) with pyruvic aldehyde dimethylacetal (II) by means of pyridine in refluxing toluene gives 2-(dimethoxymethyl)-2-methyl-3,4-dihydro-2H-1-benzopyran-4-one (III), which is nitrated with ammonium nitrate and TFA yielding the 6-nitro derivative (IV). The reduction of (IV) with NaBH4 in methanol affords the benzopyranol (V), which is treated with MsCl and DIEA to provide the mesylate (VI). The reaction of (VI) with DBU in refluxing toluene gives 2-(dimethoxymethyl)-2-methyl-6-nitro-2H-1-benzopyran (VII), which is treated with NBS in DMSO to yield the bromohydrin (VIII). Epoxidation of (VIII) with NaOH in dioxane/water affords the epoxide (IX), which is treated with 2-pyrrolidinone (X) and potassium tert-butoxide in tert-butanol to furnish 1-[2-(dimethoxymethyl)-3-hydroxy-2-methyl-3,4-dihydro-2H-1-benzpyran-4-yl]pyrrolidin-2-one (XI). The trans-acetalization of (XI) with ethylene glycol (XII) and TsOH in refluxing toluene gives the 1,3-dioxolanyl derivative (XIII), which is finally dehydrated to the target compound with NaOH in refluxing dioxane.
| 【1】 Yoo, S.-E.; Yi, K.Y.; Jeong, N.C.; Suh, J.H.; Kim, S.-J.; Shin, H.-S.; Lee, B.H.; Jung, K.S. (Korea Research Institute of Chemical Technology); Spiro-benzopyran derivs. and useful for treating asthma and hypertension. EP 0514935; US 5300511; US 5493029 . |
| 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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (III) | 38906 | 2-(dimethoxymethyl)-2-methyl-2,3-dihydro-4H-chromen-4-one | C13H16O4 | 详情 | 详情 | |
| (IV) | 38907 | 2-(dimethoxymethyl)-2-methyl-6-nitro-2,3-dihydro-4H-chromen-4-one | C13H15NO6 | 详情 | 详情 | |
| (V) | 38908 | 2-(dimethoxymethyl)-2-methyl-6-nitro-4-chromanol | C13H17NO6 | 详情 | 详情 | |
| (VI) | 38909 | 2-(dimethoxymethyl)-2-methyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-nitrochromane; methoxy(2-methyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-nitro-3,4-dihydro-2H-chromen-2-yl)methyl methyl ether | C16H23NO6S | 详情 | 详情 | |
| (VII) | 38910 | methoxy(2-methyl-6-nitro-2H-chromen-2-yl)methyl methyl ether; 2-(dimethoxymethyl)-2-methyl-6-nitro-2H-chromene | C13H15NO5 | 详情 | 详情 | |
| (VIII) | 38911 | 3-bromo-2-(dimethoxymethyl)-2-methyl-6-nitro-4-chromanol | C13H16BrNO6 | 详情 | 详情 | |
| (IX) | 38912 | methoxy(2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-2-yl)methyl methyl ether; 2-(dimethoxymethyl)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromene | C13H15NO6 | 详情 | 详情 | |
| (X) | 27397 | 2-Pyrrolidinone | 616-45-5 | C4H7NO | 详情 | 详情 |
| (XI) | 38913 | 1-[2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]-2-pyrrolidinone | C17H22N2O7 | 详情 | 详情 | |
| (XII) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XIII) | 38914 | 1-[2-(1,3-dioxolan-2-yl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]-2-pyrrolidinone | C17H20N2O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The reaction of labeled 2-hydroxyacetophenone (I) with dimethyl oxalate and NaOMe gives 4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester (II), which is hydrogenated with H2 over Pd/C to yield 3,4-dihydro-2H-1-benzopyran-2(R)-carboxylic acid methyl ester (III). The optical resolution of (III) by chiral chromatography affords the labeled (R)-enantiomer (IV), which is condensed with benzylamine (V) to provide the corresponding amide (VI). The reduction of (VI) by means of NaAlH2(OC2H4OMe)2 gives the labeled chiral amine (VII), which is condensed with the butyl bromide derivative (VIII) to yield the tertiary amine (IX). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C to afford the target labeled Repinotan.
| 【1】 Seidel, D.; et al.; Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6. J Label Compd Radiopharm 2002, 45, 13, 1115. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 | |
| (I) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 62016 | methyl 4-oxo-4H-chromene-2-carboxylate | C11H8O4 | 详情 | 详情 | |
| (III) | 62017 | methyl 2-chromanecarboxylate | C11H12O3 | 详情 | 详情 | |
| (IV) | 62018 | methyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate | C11H12O3 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 62019 | (2R)-N-benzyl-3,4-dihydro-2H-chromene-2-carboxamide | C17H17NO2 | 详情 | 详情 | |
| (VII) | 62020 | N-benzyl-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amine; N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine | C17H19NO | 详情 | 详情 | |
| (VIII) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 | |
| (IX) | 62021 | 2-(4-{benzyl[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C28H30N2O4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)3-Formylchromen-4-one (II) was prepared by Vilsmeier formylation of 2'-hydroxyacetophenone (I) with POCl3 and DMF. Cyclization of (II) with guanidine carbonate (III) in refluxing EtOH gave rise to the benzopyranopyrimidine (IV). This was finally condensed with piperidine (V) in the presence of TiCl4 to furnish the title compound.
| 【1】 Barocelli, E.; Bertoni, S.; Bruno, O.; Ranise, A.; Schenone, S.; Chiavarini, M.; Ballabeni, V.; Synthesis and pharmacological screening of novel non-acidic gastroprotective antipyretic anti-inflammatory agents with anti-platelet properties. 5-Alkyl/cycloalkylamino substituted 2-amino-5H-[1]benzopyrano[4,3-d]pyrimidines. Arzneim-Forsch Drug Res 2000, 50, 2, 140. |
| 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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 47086 | 4-oxo-4H-chromene-3-carbaldehyde | 17422-74-1 | C10H6O3 | 详情 | 详情 |
| (III) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (IV) | 47087 | 2-amino-5H-chromeno[4,3-d]pyrimidin-5-ol | C11H9N3O2 | 详情 | 详情 | |
| (V) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Claisen condensation between 2'-hydroxyacetophenone (I) and 3,4-dibenzyloxybenzaldehyde (II) afforded chalcone (III) which was further subjected to the Agar-Flynn-Oyamada reaction to give flavonol (IV). The silver oxide-assisted glycosylation of (IV) with acetobromoglucose (V) in pyridine furnished the protected glucoside (VI). Removal of the acetyl protecting groups of (VI) was effected by methanolysis in the presence of potassium tert-butoxide to yield (VII). Subsequent catalytic hydrogenolysis of the benzyl groups of (VII) provided the title compound.
| 【1】 Frederique, A.; et al.; Synthesis of novel 3,7-substituted-2-(3',4'-dihydroxyphenyl) flavones with improved antioxidant activity. J Med Chem 2000, 43, 20, 3752. |
| 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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 49829 | 3,4-Dibenzyloxybenzaldehyde; 3,4-Bis(benzyloxy)benzaldehyde | 5447-02-9 | C21H18O3 | 详情 | 详情 |
| (III) | 49830 | (E)-3-[3,4-bis(benzyloxy)phenyl]-1-(2-hydroxyphenyl)-2-propen-1-one | C29H24O4 | 详情 | 详情 | |
| (IV) | 49831 | 2-[3,4-bis(benzyloxy)phenyl]-3-hydroxy-4H-chromen-4-one | C29H22O5 | 详情 | 详情 | |
| (V) | 27260 | (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate | 572-09-8 | C14H19BrO9 | 详情 | 详情 |
| (VI) | 49832 | (2R,3R,4S,5R)-3,5-bis(acetoxy)-2-[(acetoxy)methyl]-6-([2-[3,4-bis(benzyloxy)phenyl]-4-oxo-4H-chromen-3-yl]oxy)tetrahydro-2H-pyran-4-yl acetate | C43H40O14 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)2'-Hydroxyacetophenone (I) is protected as the silyl ether (II) employing t-butyldimethylsilyl chloride and imidazole. Condensation of acetophenone (II) with 3-nitrobenzaldehyde (III) and malononitrile in the presence of ammonium acetate gives rise to the cyanopyridine (IV). The nitro group of (IV) is then reduced to the corresponding amine (V) by catalytic hydrogenation over Pd/C. 3-Piperidinylpropionic acid (VI) is then activated as the acid chloride (VII) upon treatment with oxalyl chloride. Subsequent coupling of acid chloride (VII) with amine (V) furnishes amide (VIII). Finally, desilylation of (VIII) by means of either tetrabutylammonium fluoride or HCl in dioxane leads to the title compound. (1,2)
| 【1】 Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Kadono, H.; Masuda, T.; Shimazaki, M.; Shintani, T.; Fuchikami, K.; Sakai, K.; Inbe, H.; Takeshita, K.; Niki, T.; Umeda, M.; Bacon, K.B.; Ziegelbauer, K.B.; Lowinger, T.B.; Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1. Bioorg Med Chem Lett 2003, 13, 5, 913. |
| 【2】 Yoshida, N.; Masuda, T.; Sakakibara, S.; Murata, T.; Yoshino, T.; Umeda, M.; Shimada, M.; Lowinger, T.B.; Komura, H.; Shintani, T.; Ziegelbauer, K.B.; Fuchikami, K.; Ikegami, Y.; Shimazaki, M. (Bayer AG); 4-Aryl pyridine derivs.. EP 1339687; JP 2002193938; WO 0244153 . |
| 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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 64006 | 1-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanone | C14H22O2Si | 详情 | 详情 | |
| (III) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IV) | 64007 | 2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(3-nitrophenyl)nicotinonitrile | C24H26N4O3Si | 详情 | 详情 | |
| (V) | 64008 | 2-amino-4-(3-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)nicotinonitrile | C24H28N4OSi | 详情 | 详情 | |
| (VI) | 64010 | 3-(1-piperidinyl)propanoic acid | C8H15NO2 | 详情 | 详情 | |
| (VII) | 64011 | 3-(1-piperidinyl)propanoyl chloride | C8H14ClNO | 详情 | 详情 | |
| (VIII) | 64009 | N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide | C32H41N5O2Si | 详情 | 详情 |