|
【结 构 式】 
|
【分子编号】34458 【品名】Cyanoacetic acid methyl ester; methyl 2-cyanoacetate 【CA登记号】105-34-0 |
【 分 子 式 】C4H5NO2 【 分 子 量 】99.08924 【元素组成】C 48.49% H 5.09% N 14.14% O 32.29% |
合成路线1
该中间体在本合成路线中的序号：An improved procedure for the large-scale preparation of (R)-aminoglutethimide has been reported. Nucleophilic substitution of 1-chloro-4-nitrobenzene (I) with methyl cyanoacetate afforded the (nitrophenyl)cyanoacetate (II), which was alkylated with diethyl sulfate in the presence of Et3N, yielding (III). Hydrolysis and decarboxylation of the cyano ester (III) by means of K2CO3 in aqueous MeOH provided the arylbutyronitrile (IV). Subsequent Michael addition with methyl acrylate gave adduct (V). This was hydrolyzed to the cyano acid (VI), which was further resolved with (-)-cinchonidine, yielding the desired (R)-enantiomer (VII). Acid-catalyzed cyclization of (VII) in boiling toluene generated the glutarimide derivative (VIII). The nitro group of (VIII) was finally reduced to the title amino derivative by hydrogenation over Pd/C.
| 【1】 Bunegar, M.J.; et al.; Production of (R)-aminogluthimide: A new route from 1-chloro-4-nitrobenzene. Org Process Res Dev 1999, 3, 6, 442. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 | |
| 34458 | Cyanoacetic acid methyl ester; methyl 2-cyanoacetate | 105-34-0 | C4H5NO2 | 详情 | 详情 | |
| (I) | 13909 | 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene | 100-00-5 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 34928 | methyl 2-cyano-2-(4-nitrophenyl)acetate | C10H8N2O4 | 详情 | 详情 | |
| (III) | 34929 | methyl 2-cyano-2-(4-nitrophenyl)butanoate | C12H12N2O4 | 详情 | 详情 | |
| (IV) | 34930 | 2-(4-nitrophenyl)butanenitrile | C10H10N2O2 | 详情 | 详情 | |
| (V) | 34931 | methyl 4-cyano-4-(4-nitrophenyl)hexanoate | C14H16N2O4 | 详情 | 详情 | |
| (VI) | 34932 | 4-cyano-4-(4-nitrophenyl)hexanoic acid | C13H14N2O4 | 详情 | 详情 | |
| (VII) | 34933 | (4R)-4-cyano-4-(4-nitrophenyl)hexanoic acid | C13H14N2O4 | 详情 | 详情 | |
| (VIII) | 34934 | (3R)-3-ethyl-3-(4-nitrophenyl)-2,6-piperidinedione | C13H14N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The nitration of 2,5-dichlorotoluene (I) with HNO3 in H2SO4/AcOH gives 2,5-dichloro-4-methylnitrobenzene (II), which is treated with t-butoxybis(dimethylamino)methane (III) in refluxing THF to yield 2,5-dichloro-4-[2-(dimethylamino)vinyl]nitrobenzene (IV). The condensation of (IV) with 1-(1,2-benzoisothiazol-3-yl)piperazine (V) in AcOH affords the disubstituted piperazine (VI), whose double bond is reduced by means of NaBH(OAc)3 in dichloroethane/AcOH to provide the saturated compound (VII). The condensation of (VII) with dimethyl malonate (VIII) by means of KOH in NMP gives the alkylated malonic ester (IX), which is hydrolyzed and monodecarboxylated with refluxing 3N HCl to yield the phenylacetic acid (X). The esterification of (X) with SOCl2 and methanol affords the methyl ester (XI), which is finally cyclized to the target indolone by reduction of its nitro group with sodium hydrosulfite in refluxing THF/ethanol. Alternatively, compound (VII) can be condensed with methyl cyanacetate (XII) by means of KOH in NMP to give the alkylated cyanacetic ester (XIII), which is hydrolyzed with refluxing 3N HCl to afford the already reported phenylacetic acid (X).
| 【1】 Urban, F.J.; et al.; A novel synthesis of the antipsychotic agent ziprasidone. Synth Commun 1996, 26, 8, 1629. |
| 【2】 Urban, F.J. (Pfizer Inc.); Processes and intermediates for the preparation of 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one. WO 9500510 . |
| 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) | 62890 | 1,4-dichloro-2-methylbenzene | C7H6Cl2 | 详情 | 详情 | |
| (II) | 62891 | 1,4-dichloro-2-methyl-5-nitrobenzene | C7H5Cl2NO2 | 详情 | 详情 | |
| (III) | 21487 | N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine | C9H22N2O | 详情 | 详情 | |
| (IV) | 62892 | (E)-2-(2,5-dichloro-4-nitrophenyl)-N,N-dimethyl-1-ethenamine; N-[(E)-2-(2,5-dichloro-4-nitrophenyl)ethenyl]-N,N-dimethylamine | C10H10Cl2N2O2 | 详情 | 详情 | |
| (V) | 16280 | 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) | 87691-87-0 | C11H13N3S | 详情 | 详情 |
| (VI) | 62893 | 3-{4-[(E)-2-(2,5-dichloro-4-nitrophenyl)ethenyl]-1-piperazinyl}-1,2-benzisothiazole | C19H16Cl2N4O2S | 详情 | 详情 | |
| (VII) | 62894 | 3-[4-(2,5-dichloro-4-nitrophenethyl)-1-piperazinyl]-1,2-benzisothiazole | C19H18Cl2N4O2S | 详情 | 详情 | |
| (VIII) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (IX) | 62895 | dimethyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)malonate | C24H25ClN4O6S | 详情 | 详情 | |
| (X) | 62896 | 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)acetic acid | C21H21ClN4O4S | 详情 | 详情 | |
| (XI) | 62897 | methyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)acetate | C22H23ClN4O4S | 详情 | 详情 | |
| (XII) | 34458 | Cyanoacetic acid methyl ester; methyl 2-cyanoacetate | 105-34-0 | C4H5NO2 | 详情 | 详情 |
| (XIII) | 62898 | methyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)-2-cyanoacetate | C23H22ClN5O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXVIII)A different strategy was based on the Knoevenagel condensation of ketone (XIV) with methyl cyanoacetate (XXXVIII) to produce the alkylidene cyanoacetate (XXXIX). Double-bond epoxidation by means of H2O2 led to (XL), which was further rearranged to keto amide (XLI). Decarboxylation of (XLI) under Hofmann rearrangement conditions furnished the arylpropionic acid (IX)
| 【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 . |
| 【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 62687 | 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid | C14H14O2S | 详情 | 详情 | |
| (XIV) | 62689 | 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone | C13H12OS | 详情 | 详情 | |
| (XXXVIII) | 34458 | Cyanoacetic acid methyl ester; methyl 2-cyanoacetate | 105-34-0 | C4H5NO2 | 详情 | 详情 |
| (XXXIX) | 62709 | methyl (E)-2-cyano-3-[4-(3-methyl-2-thienyl)phenyl]-2-butenoate | C17H15NO2S | 详情 | 详情 | |
| (XL) | 62710 | methyl 2-(aminocarbonyl)-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate | C17H17NO4S | 详情 | 详情 | |
| (XLI) | 62711 | 3-[4-(3-methyl-2-thienyl)phenyl]-2-oxobutanamide | C15H15NO2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Reaction of methyl cyanoacetate (I) with benzylamine (II) at 100 C gives N-benzyl cyanoacetamide (III). Subsequent condensation of (III) with 3,4-dihydroxybenzaldehyde (IV) in the presence of NaH provides the title compound.
| 【1】 Gazit, A.; et al.; Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J Med Chem 1991, 34, 6, 1896. |
合成路线5
该中间体在本合成路线中的序号：(VI)Salicylaldehyde (I) was alkylated with 1,3-dibromopropane (II) to provide bromopropyl ether (III). Furter displacement of the bromine of (III) with the potassium salt of 2-mercaptoimidazole (IV) gave thioether (V). Condensation of methyl cyanoacetate (VI) with 3-chlorobenzylamine (VII) at 120 C afforded cyanoacetamide (VIII). Finally, Knoevenagel reaction of (VIII) with benzaldehyde (V) in the presence of beta-alanine furnished the title compound.
| 【1】 Gazit, A.; Levitzki, A.; Reuveni, H.; Poradosu, E.; alpha-Cyanocinnamide derivatives: A new family of non-peptide, non-sulfhydryl inhibitors of Ras farnesylation. Bioorg Med Chem 1999, 7, 8, 1727. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17022 | beta-Alanine; 3-aminopropionic acid | 107-95-9 | C3H7NO2 | 详情 | 详情 | |
| (I) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (II) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (III) | 34455 | 2-(3-bromopropoxy)benzaldehyde | C10H11BrO2 | 详情 | 详情 | |
| (IV) | 34456 | 1H-imidazole-2-thiol; 1H-imidazol-2-ylhydrosulfide | 872-35-5 | C3H4N2S | 详情 | 详情 |
| (V) | 34457 | 2-[3-(1H-imidazol-2-ylsulfanyl)propoxy]benzaldehyde | C13H14N2O2S | 详情 | 详情 | |
| (VI) | 34458 | Cyanoacetic acid methyl ester; methyl 2-cyanoacetate | 105-34-0 | C4H5NO2 | 详情 | 详情 |
| (VII) | 34459 | (3-chlorophenyl)methanamine; 3-chlorobenzylamine | 4152-90-3 | C7H8ClN | 详情 | 详情 |
| (VIII) | 34460 | N-(3-chlorobenzyl)-2-cyanoacetamide | C10H9ClN2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)Enamino ketone (II) was synthesized by treatment of benzothiophenone (I) with dimethylformamide dimethylacetal. Condensation of (II) with methyl cyanoacetate (III) led to the pyridone-fused tricyclic system (IV), which was further aromatized to (V) using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Ester group hydrolysis in (V) under acidic conditions afforded acid (VI). This was finally decarboxylated in refluxing quinoline in the presence of copper powder.
| 【1】 Fossa, P.; et al.; Novel angular furo and thieno-quinolinones: Synthesis and preliminary photobiological studies. Bioorg Med Chem 2002, 10, 3, 743. |
| 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) | 11045 | 6,7-Dihydro-1-benzothiophen-4(5H)-one; 4-Keto-4,5,6,7-tetrahydrothianaphthene; Tetrahydrobenzo(b)thiophene-4-one | 13414-95-4 | C8H8OS | 详情 | 详情 |
| (II) | 56091 | 5-[(E)-(dimethylamino)methylidene]-6,7-dihydro-1-benzothiophen-4(5H)-one | C11H13NOS | 详情 | 详情 | |
| (III) | 34458 | Cyanoacetic acid methyl ester; methyl 2-cyanoacetate | 105-34-0 | C4H5NO2 | 详情 | 详情 |
| (IV) | 56092 | methyl 2-oxo-1,2,5,6-tetrahydrothieno[2,3-h]quinoline-3-carboxylate | C13H11NO3S | 详情 | 详情 | |
| (V) | 56093 | methyl 2-oxo-1,2-dihydrothieno[2,3-h]quinoline-3-carboxylate | C13H9NO3S | 详情 | 详情 | |
| (VI) | 56094 | 2-oxo-1,2-dihydrothieno[2,3-h]quinoline-3-carboxylic acid | C12H7NO3S | 详情 | 详情 |