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【结 构 式】 
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【分子编号】28858 【品名】diethyl ethoxymagnesiummalonate 【CA登记号】 |
【 分 子 式 】C9H16MgO5 【 分 子 量 】228.52804 【元素组成】C 47.3% H 7.06% Mg 10.64% O 35.01% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of 2-chloro-3,5-dinitrobenzoic acid (I) with thionil chloride, followed by treatment with diethyl ethoxymagnesium malonate gives diethyl 2-chloro-3,5-dinitrobenzoylmalonate (II), which is hydrolyzed and decarboxylated in hot sulfuric acid/propionic acid yielding 2-chloro-3,5-dinitroacetophenone (III). Reaction of (III) with thioglycolic acid by means of NaHCO3 in refluxing isopropanol gives the thioacetic acid compound (IV), which is cyclized in refluxing propionic acid yielding 3-methyl-5,7-dinitrobenzothiophene (V). Partial selective reduction of one of the nitro groups in (V) by means of ammonium sulfide in ethanol leads to 7-amino-3-methyl-5-nitrobenzothiophene (VI), which is diazotied by treatment with NaNO2 in hydrochloric acid. The following reaction with diethylamine in alkaline solution gives the triazene derivative (VII), which is finally fluorinated by reaction with anhydrous HF yielding 7-fluoro-3-methyl-5-nitrobenzothiophene (VIII). Catalytical reduction of (VIII) yields 5-amino-7-fluoro-3-methylbenzothiophene (IX), which is converted to 5-hydrazino-7-fluoro-3-methylbenzothiophene (X) by diazotation and subsequent reduction by means of stannous chloride in hydrochloric acid. The reaction of (X) with N-ethyl-4-piperidone (XI) in refluxing isopropanol gives the corresponding hydrazone, which is cyclized in refluxing isopropanol/HCl yiellding tiflucarbine base. Finally, this compound is converted to the lactate by means of lactic acid in acetone.
| 【1】 Urda, E.; Sahi, J.; Wen, Y.-H.; et al.; IXth Intl Symp Med Chem (September 14-18, Berlin) 1986, 30, 9, 977. |
| 【2】 Schollnhammer, G.; Seidel, P.-R. (Troponwerke GmbH & Co KG); 7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, a process for their preparation and medicaments containing them. EP 0120439; US 4816461 . |
| 【3】 Glaser, T.; Seidel, P.-R.; Tiflucarbine. Drugs Fut 1987, 12, 6, 562. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 18524 | 2-sulfanylacetic acid | 68-11-1 | C2H4O2S | 详情 | 详情 |
| (A) | 28858 | diethyl ethoxymagnesiummalonate | C9H16MgO5 | 详情 | 详情 | |
| (I) | 28857 | 2-chloro-3,5-dinitrobenzoic acid | 2497-91-8 | C7H3ClN2O6 | 详情 | 详情 |
| (II) | 28859 | diethyl 2-(2-chloro-3,5-dinitrobenzoyl)malonate | C14H13ClN2O9 | 详情 | 详情 | |
| (III) | 28860 | 1-(2-chloro-3,5-dinitrophenyl)-1-ethanone | C8H5ClN2O5 | 详情 | 详情 | |
| (IV) | 28861 | 2-[(2-acetyl-4,6-dinitro-2,4-cyclohexadien-1-yl)sulfanyl]acetic acid | C10H10N2O7S | 详情 | 详情 | |
| (V) | 28862 | 3-methyl-5,7-dinitro-1-benzothiophene | C9H6N2O4S | 详情 | 详情 | |
| (VI) | 28863 | 3-methyl-5-nitro-1-benzothiophen-7-ylamine | C9H8N2O2S | 详情 | 详情 | |
| (VII) | 28864 | (E)-3,3-dimethyl-1-(3-methyl-5-nitro-1-benzothiophen-7-yl)-1-triazene | C11H12N4O2S | 详情 | 详情 | |
| (VIII) | 28865 | 7-fluoro-3-methyl-5-nitro-1-benzothiophene | C9H6FNO2S | 详情 | 详情 | |
| (IX) | 28866 | 7-fluoro-3-methyl-1-benzothiophen-5-amine | C9H8FNS | 详情 | 详情 | |
| (X) | 28867 | 1-(7-fluoro-3-methyl-1-benzothiophen-5-yl)hydrazine | C9H9FN2S | 详情 | 详情 | |
| (XI) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (XII) | 28869 | 2-hydroxypropionic acid; Lactic acid | 50-21-5 | C3H6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Methyl 4-amino-2,5-difluoro-3-methylbenzoate (I) was oxidized to the corresponding nitro derivative (II) with sodium perborate in TFA-AcOH. Acid hydrolysis of the methyl ester afforded carboxylic acid (III), which was converted into acid chloride (IV) employing oxalyl chloride and a catalytic amount of DMF. Condensation of (IV) with the magnesium salt of diethyl malonate, followed by acid-catalyzed decarbethoxylation gave rise to keto ester (V). Subsequent condensation of (V) with triethyl orthoformate in the presence of acetic anhydride yielded the ethoxymethylene derivative (VI). Reaction of (VI) with aniline (VII) followed by cyclization of the intermediate enamine in the presence of K2CO3 afforded quinolone (VIII). The nitro group of (VIII) was then reduced to aniline (IX) by means of iron and AcOH. Finally, acid deprotection of the Boc group of (IX) gave the title compound.
| 【1】 Sakae, N.; Yazaki, A.; Kuramoto, Y.; Yoshida, J.; Niino, Y.; Oshita, Y.; Hirao, Y.; Hayashi, N.; Amano, H. (Wakunaga Pharmaceutical Co., Ltd.); Novel pyridonecarboxylic acid derivs. or salts thereof and drugs containing the same as the active ingredient. EP 0945435; WO 9823592 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28858 | diethyl ethoxymagnesiummalonate | C9H16MgO5 | 详情 | 详情 | ||
| (I) | 38173 | methyl 4-amino-2,5-difluoro-3-methylbenzoate | C9H9F2NO2 | 详情 | 详情 | |
| (II) | 38174 | methyl 2,5-difluoro-3-methyl-4-nitrobenzoate | C9H7F2NO4 | 详情 | 详情 | |
| (III) | 38175 | 2,5-difluoro-3-methyl-4-nitrobenzoic acid | C8H5F2NO4 | 详情 | 详情 | |
| (IV) | 38176 | 2,5-difluoro-3-methyl-4-nitrobenzoyl chloride | C8H4ClF2NO3 | 详情 | 详情 | |
| (V) | 38177 | ethyl 3-(2,5-difluoro-3-methyl-4-nitrophenyl)-3-oxopropanoate | C12H11F2NO5 | 详情 | 详情 | |
| (VI) | 38178 | ethyl (Z)-2-(2,5-difluoro-3-methyl-4-nitrobenzoyl)-3-ethoxy-2-propenoate | C15H15F2NO6 | 详情 | 详情 | |
| (VII) | 38179 | tert-butyl 5-amino-2,4-difluorophenylcarbamate | C11H14F2N2O2 | 详情 | 详情 | |
| (VIII) | 38180 | ethyl 1-[5-[(tert-butoxycarbonyl)amino]-2,4-difluorophenyl]-6-fluoro-8-methyl-7-nitro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C24H22F3N3O7 | 详情 | 详情 | |
| (IX) | 38181 | ethyl 7-amino-1-[5-[(tert-butoxycarbonyl)amino]-2,4-difluorophenyl]-6-fluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C24H24F3N3O5 | 详情 | 详情 |