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【结 构 式】 
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【分子编号】14742 【品名】2,3-dichlorobenzaldehyde 【CA登记号】6334-18-5 |
【 分 子 式 】C7H4Cl2O 【 分 子 量 】175.01356 【元素组成】C 48.04% H 2.3% Cl 40.51% O 9.14% |
合成路线1
该中间体在本合成路线中的序号：(I)By cyclization of 2,3-dichlorobenzaldehyde (I) with 3-aminocrotonic acid ethyl ester (II) and acetylacetic acid methyl ester (III) in refluxing ethanol.
| 【1】 Bernston, P.B.; Carlsson, S.A.I.; Gaarder, J.O.; Ljung, B.R. (AstraZeneca AB); 2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same. CA 1117530; EP 0007293; JP 55009083; US 4264611 . |
合成路线2
该中间体在本合成路线中的序号：(I)The nitration of 2,3-dichlorobenzaldehyde (I) with HNO3/H2SO4 gives 2,3-dichloro-6-nitrobenzaldehyde (II), which is reduced with NaBH4 in methanol, yielding 2,3-dichloro-6-nitrobenzyl alcohol (III). The reaction of (III) with SOCl2 and TEA affords the benzyl chloride (IV), which is condensed with glycine ethyl ester (V) by means of TEA to provide the adduct (VI). The reduction of the nitro group of (VI) with SnCl2 in aq. HCl or H2 over PtO2/C in ethanol gives the expected amino derivative (VII), which is cyclized with CN-Br in toluene to yield the iminoquinazoline (VIII). Finally, this compound is further cyclized by means of TEA in water to afford the target imidazoquinazolinone.
| 【1】 Lang, P.C.; Spencer, R.P.; Yeh, W.-L.; Roth, M.J. (Shire Richwood Inc.); Method for the manufacture of anagrelide. WO 0208228 . |
| 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) | 14742 | 2,3-dichlorobenzaldehyde | 6334-18-5 | C7H4Cl2O | 详情 | 详情 |
| (II) | 52800 | 2,3-dichloro-6-nitrobenzaldehyde | C7H3Cl2NO3 | 详情 | 详情 | |
| (III) | 52801 | (2,3-dichloro-6-nitrophenyl)methanol | C7H5Cl2NO3 | 详情 | 详情 | |
| (IV) | 52802 | 1,2-dichloro-3-(chloromethyl)-4-nitrobenzene | C7H4Cl3NO2 | 详情 | 详情 | |
| (V) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (VI) | 29086 | ethyl 2-[(2,3-dichloro-6-nitrobenzyl)amino]acetate | C11H12Cl2N2O4 | 详情 | 详情 | |
| (VII) | 29087 | ethyl 2-[(6-amino-2,3-dichlorobenzyl)amino]acetate | C11H14Cl2N2O2 | 详情 | 详情 | |
| (VIII) | 29088 | ethyl 2-[5,6-dichloro-2-imino-1,4-dihydro-3(2H)-quinazolinyl]acetate | C12H13Cl2N3O2 | 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 condensation of 2,3-dichlorobenzaldehyde (I) with 2,2-dimethoxyethylamine (II) in refluxing toluene gives the corresponding Schiff base (III), which is reduced with H2 over PtO2 in ethyl acetate and acetylated with acetic anhydride yielding N-(2,3-dichlororobenzyl)-N-(2,2-dimethoxyethyl)acetamide (IV). The cyclization of (IV) with AlCl3 in dichloroethane affords 7,8-dichloro-2-acetyl-1,2-dihydroisoquinoline (V), which is submitted to cyclopropanation with CHCl3, NaOH and benzyltriethylammonium chloride giving 1,1,4,5-tetrachloro-2-acetyl-1a,2,3,7b-tetrahydro-1H-cycloprop[c]isoquinoline (VI). Ring opening of (VI) by refluxing with tert-butyl alcohol yields 2-acetyl-3-(tert-butoxy)-4,8,9-trichloro-2,3-dihydro-1H-2-benzazepine (VII), which is reduced with H2 over PtO2 in methanol affording 2-acetyl-8,9-dichloro 2,3,4,5-tetrahydro-1H-2-benzazepine (VIII). Finally, this compound is desacetylated by means of refluxing aqueous HCl.
| 【1】 Perchonock, C.D.; Lantos, I.; Holden, K.G.; Finkelstei, J.A.; Facile synthesis of halo-substituted tetrahydroisoquinolines and tetrahydro-2-benzazepines via N-acetyl-1,2-dihydroisoquinolines. J Org Chem 1980, 45, 10, 1950-53. |
| 【2】 Serradell, M.N.; Castaner, J.; LY-134046. Drugs Fut 1984, 9, 4, 268. |
| 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) | 14742 | 2,3-dichlorobenzaldehyde | 6334-18-5 | C7H4Cl2O | 详情 | 详情 |
| (II) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (III) | 34159 | N-[(Z)-(2,3-dichlorophenyl)methylidene]-2,2-dimethoxy-1-ethanamine; N-[(Z)-(2,3-dichlorophenyl)methylidene]-N-(2,2-dimethoxyethyl)amine | C11H13Cl2NO2 | 详情 | 详情 | |
| (IV) | 34160 | N-(2,3-dichlorobenzyl)-N-(2,2-dimethoxyethyl)acetamide | C13H17Cl2NO3 | 详情 | 详情 | |
| (V) | 34161 | 1-[7,8-dichloro-2(1H)-isoquinolinyl]-1-ethanone | C11H9Cl2NO | 详情 | 详情 | |
| (VI) | 34162 | 1-(1,1,4,5-tetrachloro-1,1a,3,7b-tetrahydro-2H-cyclopropa[c]isoquinolin-2-yl)-1-ethanone | C12H9Cl4NO | 详情 | 详情 | |
| (VII) | 34163 | 1-[3-(tert-butoxy)-4,8,9-trichloro-1,3-dihydro-2H-2-benzazepin-2-yl]-1-ethanone | C16H18Cl3NO2 | 详情 | 详情 | |
| (VIII) | 34164 | 1-(8,9-dichloro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-1-ethanone | C12H13Cl2NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)By cyclization of (II) with 2,3-dichlorobenzaldehyde (V) and methyl acetoacetate (VI).
| 【1】 Migano, T. et al. (Banyu Pharmaceutical Co., Ltd.); 2-N-Substd. or unsubstd.-carbamoyloxy-alkyl-1, 4-dihydropyridine-3,5-dicarboxylic acid symmetrical or asymmetrical diester deriv. and its preparation. JP 1984152373 . |
| 【2】 Prous, J.; Castaner, J.; NB-818. Drugs Fut 1989, 14, 4, 331. |
合成路线5
该中间体在本合成路线中的序号：(XVI)A synthesis of S-12968 has been published: The cyclization of 4-[2-(2-phthalimidoethoxy)ethoxy]-3-oxobutyric acid ethyl ester (I) with 2-(2,3-dichlorobenzylidene)-3-oxobutyric acid 2-cyanoethyl ester (II) and ammonium formate in hot ethanol gives the protected racemic 1,4-dihydropyridine (III), which is submitted to a chiral preparative HPLC to obtain the (R)-(-)-enantiomer (IV). The deprotection of (IV) with aqueous methylamine affords (S)-(-)-2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-1,4-di hydropyridine-3,5-dicarboxylic acid 3-monoethyl ester (V). Finally, this compound is methylated with diazomethane in ethyl ether/methanol. The starting compound, the dichlorobenzylidene derivative (II) has been obtained as follows: The condensation of Meldrum's acid (X) with acetic acid (XII) by means of CDI and pyridine as before gives 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (XIII), which is submitted to ring opening with 3-hydroxypropionitrile (XIV) in refluxing toluene yielding 2-cyanoethyl acetoacetate (XV). Finally, the condensation of (XV) with 2,3-dichlorobenzaldehyde (XVI) by means of piperidine and hexanoic acid in refluxing benzene affords the dichlorobenzylidene derivative (II) used as the second starting compound.
| 【1】 Dolle, F.; et al.; Highly efficient synthesis of [11C]S12968 and [11C]S12967, for the in vivo imaging of the cardiac calcium channels using PET. J Label Compd Radiopharm 2001, 44, 7, 481. |
| 【2】 Crouzel, C.; Duval, R.; Hinnen, F.; Fuseau, C.; Dollé, F.; Valette, H.; Péglion, J.-L.; Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging. Bioorg Med Chem 1997, 5, 4, 749. |
| 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) | 14743 | ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate | C18H21NO7 | 详情 | 详情 | |
| (II) | 14744 | 2-cyanoethyl (Z)-2-acetyl-3-(2,3-dichlorophenyl)-2-propenoate | C14H11Cl2NO3 | 详情 | 详情 | |
| (III) | 14745 | 5-(2-cyanoethyl) 3-ethyl 4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C32H31Cl2N3O8 | 详情 | 详情 | |
| (IV) | 14746 | 5-(2-cyanoethyl) 3-ethyl (4S)-4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C32H31Cl2N3O8 | 详情 | 详情 | |
| (V) | 14747 | (4R)-6-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-5-(ethoxycarbonyl)-2-methyl-1,4-dihydro-3-pyridinecarboxylic acid | C21H26Cl2N2O6 | 详情 | 详情 | |
| (X) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (XIII) | 12273 | 5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione | C8H10O5 | 详情 | 详情 | |
| (XIV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XV) | 13993 | 2-cyanoethyl 3-oxobutanoate | C7H9NO3 | 详情 | 详情 | |
| (XVI) | 14742 | 2,3-dichlorobenzaldehyde | 6334-18-5 | C7H4Cl2O | 详情 | 详情 |