• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid by reacting fluorobenzene with an acid halide, to form an indanone, reaction of the indanone with a methylthio (or methylsulfinyl) benzyl compound to form 5-fluoro-2-methyl-1-(p-methylthiobenzyl) or (p-methylsulfinylbenzyl)-indene and reacting said indene with a glyoxylic acid.
    公开号:SU886742A3
    申请号:SU742090754
    申请日:1974-12-19
    公开日:1981-11-30
    发明作者:Дж.Талл Роджер；Ф.Кзаджа Роберт；Ф.Шуман Ричард；Х.Пайнз Симан
    申请人:Мерк Энд Ко (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to an improved method for producing 5-fluoro-2-methyl-14 And-methylsulfinylbenzylidene) -inden-3-acetic acid or its salts exhibiting pharmacological g activity.
    A known method for producing 5-fluoro-2-methyl-1- (n-methylsulfinylbenzylidene inden-3-acetic acid or its salts, comprising 2-methyl-5-α-fluoro-1- (I-methylsulfinylbenzyl ) indene is reacted with N-bromosuccinimide in the presence of benzoyl peroxide in carbon tetrachloride, then dehydrobrominated in boiling pyridine and subjected to condensation with glycolic acid.
    A known method of producing 5-fluoro-2-methyl-1- (I-methylene sulfinylbenzylidene) indene-3-acetic acid or its 20 "salts, which consists in the fact that · 1 (fo-methylsulfiniphenylbenzyl) -2-methyl-3-bromo -5-fluoroindene is reacted with magnesium and the resulting mag-. the organic compound is treated with oxygen, then condensed with 1,1-dichloroethylene in dimethoxyethane. The condensation product is hydrolyzed with 90% sulfuric acid.
    A known method of obtaining the named compounds, which consists in the fact that 1- {I * methylthiobenzyl) - 2-methyl-5-. -fluorindene is reacted with pyridinium perbromide and the obtained 1- (y-methylsulfinylbeneyl) -2-methyl-3-bromo-5-fluorindene is treated with triphenylphosphonium carboxyethoxymethylide followed by alkaline hydrolysis of the resulting phosphonic salt.
    The disadvantage of these methods is the multi-stage synthesis of the target product.
    • Closest to the proposed is a method for producing 5-fluoro-2-methyl-14 I-methylsulfinylbeneylidea) -inden-3-acetic acid or its salts, which consists in the fact that 2-methyl-5 - fluoroindanone-1 is reacted with glycolic acid in pyridine in the presence of a strong base followed by oxidation of the obtained 2-methyl-5-φτορ-1H-methylthiobenzylidene) indene-3-acetic acid. The yield of the target product 23% P].
    The disadvantage of this method is the relatively low yield of the target product.
    The purpose of the invention is to increase the yield of the target product.
    The goal is achieved by the proposed method for producing 5-fluoro-2-methyl-1- (I-methylsulfinylbenzylidene) indene-3-acetic acid or its salts, which consists in the fact that 1Ci-methylthiobenzyl) -2-methyl-5-fluorindanone is reacted with glyoxylic acid or its ester in the presence of a strong base, and the resulting 1- (p-methylthiobenzylidene) -2-methyl-5-fluoroindenylideneacetic acid is oxidized and isomerized in any sequence, followed by isolation of the desired product in its free form or in the form of salt.
    Isomerization is preferably carried out in the presence of an acid or base.
    Distinctive features of the method are the interaction of I— (p-methylthiobenzyl) -2-methyl-5-fluorindanfna with glyoxylic acid or its ester, and also oxidation and isomerization in any sequence obtained with 1- (p-methylthiobenzylidene) -2 methyl 5-fluorindenylidene acetic acid. The yield of the target product is 60%.
    Alkalis are used as the base in the reaction with glyoxylic acid, especially in the presence of tetraalkylammonium halides, tetraalkylammonium hydroxides. The reaction is carried out without a solvent or in a solvent, for example, alcohol, aromatic hydrocarbons, pyridine, dioxane, acetonitrile, dimethylformamide, triglyme, dimethyl sulfoxide, water or a mixture thereof with an organic solvent.
    After condensation with glyoxylic acid, the reaction mixture can be directly subjected to isomerization under the influence of an existing base. For carrying out acid isomerization, alkyl sulfonic acids, arylsulfonic acids — .55 lots, acidic ion-exchange resins, arylcarboxylic acids, aliphatic carboxylic or mineral acids can be used. The isomerization is carried out without solvent or in a solvent, for example, halogenated hydrocarbons. The reaction temperature is from 0 to 15 ° C.
    As an oxidizing agent, hydrogen peroxide, basic periodates, hypohalogenites or organic peracids are used, as a solvent alkanoic acids, halogenated hydrocarbons, esters, alcohols or mixtures thereof are used.
    Example 1 5-Fluoro-2-methyl. -1 - (p-methylthiobenzyl) indene.
    g (1.04 mol) of magnesium chips is placed in a flask in an atmosphere with 400 ml of ether. Add 10 ml of 0.05 molar p-methylthiobenzylmagnesium chloride in ether and the mixture is heated to 30 ° C. About 2-3% 39.7 g (0.23 mol) of p-methylthiobenzyl ~ chloride in 75 ml of toluene are added. In 3-5 minutes
    Heating to 32-33 ° C with stirring indicates the beginning of the reaction. After standing for 5 minutes, the remaining benzyl chloride is added dropwise over 90 minutes. The mixture is left for 30 minutes with stirring. Then, 5-fluoro-2-methyl-1-indanone is added dropwise over 45 minutes. After 30 minutes, the milk mixture is decanted from magnesium. The flask and residual magnesium are rinsed with toluene. The reaction is quenched by the addition of 120 ml of 3 N. sulfuric acid. The bottom layer is discarded. To the organic layer add 80 ml of 1:10 sulfuric acid, acetic acid, mix thoroughly for 1 h and add water (100 ml). The top layer was discarded and the organic layer 1 was washed with 100 ml of water and 200 ml of 2 and.
    sodium hydroxide. After the final wash with water, the organic layer was concentrated to give 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indene. Also when using p-methylsulfinylbenzyl chloride instead of p-methylthiobenzylidene.
    Example 2. p-Methylthiobenzylgriphenylphosphonium chloride., 1 17.3 g of p-methylthiobenzyl chloride is added to 28 g of triphenylphosphine in 80 ml of benzene. The mixture is heated for 4 hours, cooled and collected by filtration, the obtained p-methylthiobenzyltriphenyl> phosphonium chloride. Yield 19 g, t 257258 ° С. L
    In a similar manner, but using p-metilsulfinilbenzilhlorida obtained p-metilsulfinilbenziltrife- nilfosfoniyhlorid r, t nA 258-262RS (with gas evolution).
    Example 3. 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) -inden. 5 _A. 5-Fluoro ~ 2-methyl ~ 1- (p-methylthiobenzylidene) -indane)
    169 mg (1.5 mm) of potassium tert-butoxide is dissolved in 2 ml of DMSO and treated with 651 mg (1.5 mm) of p-methylthioben-I® zyltriphenylphosphonium chloride dissolved in 1 ml of DO1C0. To this solution was added 270 mg (1.65 mm) of 5-fluoro-2-methyl-1-indanone in 2 ml of DMSO. The solution is heated at 75 ° C for - »5
    15.5 hours. Benzene and water are added, then the benzene layer is washed 5 times with water, dried with Na2S0 ^ and evaporated to dryness in -. Kuume. The yield is 915.6 mg. The substance is eluted through 8 g of silica gel 10 with benzene to remove triphenyl fomphin oxide. The eluate weighs 372 mg after evaporation of the solvent. The latter is subjected to rechromatography through 15 g of silica gel using hexane and semi-. And 95.9 mg of 5-fluoro-2-methyl-1- (p ~ methylthiobenzylidene) -indane, .67-70 ° С, is consumed.
    B. 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) -inden.
    mg of the benzylidene compound from eo Example A was mixed with 1 ml of acetic acid containing 100 mg of sulfuric acid, and the reaction mixture was stirred for 1 h at room temperature. Then the mixture was diluted with water and extracted with ether. The extract is concentrated in vacuo to obtain the desired substance.
    Using r-methylsulfinipbenzyltriphenylphosphonium chloride, the corresponding r-methylsulfinylbenzylidene derivative is obtained.
    Example 4. 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -inden.
    500 mg (1,755 mm) of 5-fluoro-2-methyl-I- (p-methylthiobenzyl) indene are dissolved in 5 ml of chloroform. To this solution was added 30% hydrogen peroxide (equivalent to 2.645 mm). The reaction mixture is left for an hour at room temperature, followed by the addition of 5 ml of glacial acetic acid and incubated for another hour. Then the reaction mixture was diluted with 25 ml of 1; 1 benzene-ether mixture and extracted with 6 x 25 ml of 3% aqueous sodium chloride. The solution was then dried with sodium sulfate and evaporated in vacuo to give an oil. Recrystallization from propanol gives 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indene.
    Example 5. 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) indenylidene-3-acetic acid.
    To 41.8 g (147 kmol) of indene (from Example 1) 150 ml of Triton B methanol solution (53.2 g of dry base, 317.5 mmol} are added and heated under nitrogen to 35 ° C. 14.63 g are added. glyoxylic acid (198 mmol), the mixture heated to 5 ° -55 ° C. is left for an hour at 50 ° C. Then it is diluted with 250 mp water and acidified with dilute sulfuric acid. The product is recrystallized in 90% yield to give a pure product, b PA
    185.5-188 ° C.
    If sodium hydroxide and tetramethylammonium chloride or tetramethylammonium hydroxide are used instead of Triton B in the above example, indenylidene-3-acetic acid is obtained.
    If 5-fluoro ~ 2-methyl-1- (r-methylsulfinylbenzene) -indene is used instead of the corresponding compound in the above example, 5-fluoro-2 ~ methyl-1- (p-methylsulfinylbenzyl) -indenylidone-3-acetic acid is obtained.
    If 5-fluoro-2-methyl-1- (p-methylsulfinylbenzene) -indene is used instead of the corresponding compound in the above example, 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -indenylidone-3-acetic acid is obtained.
    Example 6. 5-Fluoro ~ 2-methyl- ’-1- (p-methylthiobenzylidene) -inden-3-acetic acid.
    A suspension of 34.2 g of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -denylidene-3-acetic acid (from Example 5) in 342 ml of glacial acetic acid and 137 ml of concentrated HCl was stirred under nitrogen at 90 ° C for 10 hours. The mixture is cooled for 2-3 hours at room temperature and left for another 3 hours at 20-2 ^ 0. Then filtered, washed with a mixture of 70-30 acetic acid-water (about 100 ml), then washed with water to remove excess acid, 93% of the product is obtained, 180-183 ° C.
    If 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -indenylidene-3 “acetic acid 4g is used in the above example instead of the corresponding methyl * compound, 5-fluoro-2-methyl | . tyl-1 - (p-methylsulfinylbenzylidene) ^ -inden-3-acetic acid. The reaction can be carried out in an aprotic solvent, for example, 1,2-dichloroethane at an overpressure of 100 atm of HC1 gas at 50-100 l C.
    Example 7. 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) inden-3-acetic acid.
    g (50 mmol) of the product of example 6 is stirred in -94 ml of chloroform and 40 ml of acetic acid in a nitrogen atmosphere, the temperature is brought to 30 ° C. 5.3 ml of 9.6 N are added to the sludge. water mmol) for 1 min.
    The temperature is adjusted to 35 ^ 0. The mixture is left for 6 hours at a temperature of 35 ° C. Then 125 ml of water are added and the SSSC layer is concentrated to a small volume in 75 of which is then filtered 'and washed with 15 ml of cold (0-5 ° C) ethanol and dried in vacuum at 80 ° C. The product weighs 16.3 g (92%), 183-185 ° C.
    vacuum. The residue is crystallized with ml of ethanol 'and cooled to 0-5 ° C, left at 0-5 ° C. Product
    If sodium periodate or potassium hypochlorite is used instead of hydrogen peroxide in the above example, the desired substance is obtained.
    Example 8. 5-Fluoro-2-methyl-1 - (p-methylthiobenzylidene) * inden-3-acetic acid.
    A suspension of 34 g of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -indenylidene-3.-acetic acid in 150 ml of ethylene dichloride is heated to 70 ° C in an enamelled autoclave. Anhydrous carbon disulfide is introduced to increase the pressure to : 6 atm. The mixture was stirred under these conditions for 10 hours and then the gas was vented. The product is cooled to 0-5 ° C and after an hour it is filtered and washed with fresh ethylene chloride. Product yield 80%.
    Example 9. Add 147 mmol. (41.8 g) 5-fluoro-2-methyl-1- (I-methyl- (50 thiobenzyl indene to 75 ml of the drug solution. Triton-B (26.6 g, dry base, 1 -, - - ------- - —-..
    The mixture is stirred under nitrogen to 35 ° C. The mixture is diluted with 250 ml of water, acidified with dilute sulfuric acid, the gummy product is triturated with hexane. Get methyl ether
    1. Method for the preparation of 5-fluoro-2-methyl-1- (n-methylsulfinylbenzylidene) • indene-3-acetic acid or its salts based on 1- (i-methylthiobenzyl) ~ -2-methyl-5-fluorindanone using strong bases and oxidation reactions, characterized in that, in order to increase the yield of the target product, 1- (i-methylthiobenzyl) -2-methyl-5-fluorindanone is reacted with glyoxylic acid or its ester in the presence of _______ ~ ___, - - ______ 'PTS ii strong base and poluchen158,8 mmol) in methanol The heating hydrochloric wherein 1- (I-methylthiobenzylidene) -2-methyl-5-ftorindenilide acetic acid, in any order oxidized and isomerized followed. the selection of the target product in free form or in the form of sopi.
    5-fluoro-2-methyl-1- (I-methylthiobenzyl '-indenylidene-3-acetic acid, t pl'
    62.5-64 ° C.
    Suspended 34.2: g of methyl ester 5-fluoro-2 — methyl — 1- (I, methylthio-benzyl) ivdenylidene-5-acetic acid in 342 ml of glacial acetic acid and 137 ml of concentrated hydrochloric acid, stirred under nitrogen atmosphere at 90 ° С for 10 h, the reaction mixture is gradually cooled to room temperature (2-3 hours) and the reaction mixture is additionally kept at 20-25 ° С for 2 hours. Filtering off the resulting product, 5-fluoro-2-methyl-1- ( I-methylthiobenzylidene) -inden-3-acetic acid. washed with a mixture of 70:30 acetic acid-vodr (approximately 100 mp), then washed off the excess acid with water,% pA 180-183 C.
    Stirred 17 g (50 mmol) of 5-φτορ-2-methyl-1- (Y-methylthiobenzylidene) -indene-3-acetic acid with 94 ml of chlorofom and 40 ml of acetic acid in a nitrogen atmosphere at 30 ° C, and the reaction mixture is heated at 35 ° C for 6 h, add 125 ml of water, separate the slurry formed by chloroform and concentrate to a small volume in vacuo. The product contained in the residue is crystallized from 75 ml of ethanol, cooled to 0-5 ° C and the product is recovered by filtration, Ln 183-185 C.
    权利要求:
    Claims (2)
    [1]
    38 by the following compression of the obtained 2-methyl- .5-fluoro-1 - (I-methylthiobenzylidene) inden-3-acetic acid. The yield of the target product is 23% tO The disadvantage of this method is the relatively low yield of the target product. The purpose of the invention is to increase the yield of the target product. This goal is achieved by the proposed method for the preparation of 5-fluoro-2-methyl-1 Chi-methylsulfonylbenzylidene) inden-3-ycyclic acid or its salts, which means that 1-methyl-thiobenzyl) -2-methyl-5-fluoride-. non-reacted with glyoxylic acid or its ester in the presence of a strong base, and the resulting 1- (p-methylthiobenzylidene) -2-methyl-5-fluoridenylideneidene acetic acid is oxidized in any order and isometric, followed by separation of the target product in free form or in salt form. Isomerization is preferably carried out in the presence of an acid or base. Distinctive features of the method are the interaction of 1- (p-methylthiobenzyl) -2-methyl-5-fluorindane (@ with glyoxylic acid or its ester, as well as oxidation and isomerization in any sequence of the resulting 1- (p- methylthiobenzylidene) -2-methyl-5-fluoroindenylidene acetic acid. Target product 60%. Alkali is used as a base in the reaction with glyoxylic acid, especially in the presence of rajiore. tetraalkylammonium, tetraalkylammonium hydroxides. The reaction is carried out without solvent or in a solvent, on for example, alcohol, aromatic hydrocarbons, pyridine, dioxane, acetonitrile, dimethylformamide, triglyme, dimethyl sulfoxide, water or its mixture with an organic solvent.The reaction mixture after condensation with glyoxylic acid can be directly subjected to isomerization under the action of an already existing base. use alkylsulfuric acids, arylsulphonic acids, acidic ion exchange resins, aryl carboxylic acids, aliphatic carboxylic or mineral acids. Isomerization is carried out without a solvent or in a solvent, for example, galloid substituted hydrocarbons. The reaction temperature ranges from 0 to 150 ° C. Hydrogen peroxide, basic periodates, hypohalites or organic peracids are used as an oxidizing agent; alkanoic acids, halogen-substituted hydrocarbons, ethers, alcohols or mixtures thereof are used as solvents. Example 1 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) -inden. 25 g (1.04 mol) of magnesium chips are placed in a flask in No atmosphere with 400 ml of ether. 10 ml of 0.05 molar p-methylthiobenzyl magnesium chloride in ether is added and the mixture is heated to 30 ° C. Approximately 2-3% of 39.7 g (0.23 mol of p-methylthiobenzyl chloride in 75 ml of toluene is added. After 3-5 minutes. Warming up to 32-33 3 with stirring indicates the start of the reaction. After 5 minutes of addition the remaining benzyl chloride is added dropwise over 90 minutes, the mixture is left under stirring for 30 minutes, then 5-fluoro-2-methyl-1-indanone is added dropwise within 45 minutes after which the milky is decanted from magnesium. The flask and the residual magnesium are rinsed with toluene. The reaction is quenched by the addition of 120 ml of 3N sulfuric acid. The bottom layer is discarded. 80 ml of I: 10 sulfuric acid are added to the cooled layer, the acetic acid is displaced thoroughly for 1 hour and water (100 ml) is added. The upper layer is discarded and the organic layer is washed with 100 ml of water and 200 ml of 2N sodium hydroxide. washing with water, the organic layer is concentrated to obtain 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -inden. Also using p-methylsulfinylbenzyl chloride instead of p-methylthiobenzylidene. . Example 2. p-Methylthiobenzggryphenylphosphonium chloride., 17.3 g of p-methylthiobenzyl chloride was added to 28 g of triphenylphosphine in 80 ml of benzene. The mixture is heated for 4 hours, cooled, and the resulting p-methylthiobenzyltriphenylphosphonyl chloride is collected by filtration. Yield 19 g, t 257258 ° С. Similarly, but using p-methylsulfinylbenzyl chloride, p-methylsulfinylbenzyltriphenylphosphonium chloride, tj, 258-262PC (with evolution of gas) is obtained. Example 3. 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) -inden. A. 5-Fluoro-2-methyl- - (p-methylthiobansilidene) -indush 169 mg (1.5 mm) potassium tert-butoxy and dissolved in 2 ml of DMSO and treated with 651 mg (1.5 mm) p-methylthiobe zyltriphenylphosphonium chloride dissolved in 1 ml of DMSO. To this solution, 270 mg (1.65 mm) of 5-fluoro-2-methyl-1-indanone in 2 ml of DISO are added. The solution is heated at 15.5 hours. Benzene and water are added, then the layer of benzene is washed 5 times with water, dried with N0250, and evaporated to dryness in a va. cuome. The yield is 915.6 mg. The substance is eluted through 8 g of silica gel with benzene to remove triphenyl phosphine oxide. The eluate weighs 372 mg after evaporation of the solvent. The latter is subjected to rechromatography over 15 g of silica gel using hexane and 95.9 mg of 5-fluoro-2gmethyl-1- (p-metIlthiobenzylidene) -indane, -bt, is taken off. .67-70С. B, 5-Fluoro-2-methylg1- (p-methylthiobenzyl) -inden. 50 mg of the benzylidene compound and Example A are mixed with 1 ml of acetic acid containing 100 mg of sulfuric acid, and the reaction mixture is stirred for 1 hour at room temperature. The mixture is then diluted with water and extracted with ether. The extract is concentrated in vacuo to obtain the desired material. When using p-methylsulfinyl benzyltriphenylphosphonium chloride, the corresponding p-methylsulfinylbenzylidene derivative is obtained. PRIOR 4. 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -indi. 500 mg (1.755 mm) of 5-fluoro-2-me yl-1- (p-methylthiobenzyl) indene are dissolved in 5 ml of chloroform. OOH hydrogen peroxide (equivalent to 2.645 mm) is added to this solution. The reaction mixture is left for an hour at room temperature, followed by the addition of 5 ml of glacial acetic acid and allowed to stand for another hour. The reaction mixture is then diluted with 25 ml of a 1: 1 benzene-ether mixture and extracted with 6 x 25 ml of 3% aqueous sodium chloride. Then the solution is dried with sulfate, sodium and evaporated in vacuo to obtain an oil. Upon recrystallization from propanol, 5-fluoro-2-methyl-1- (p-methylsulfinnbexyl) -indene is obtained. Example 5. 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) -indenylidene-3-acetic acid. To 41.8 g (147 mmol) of indene (from example 1), 150 ml of a methanolic solution of Triton B (53.2 g of a dry base, 317.5 mmol) are added and heated under nitrogen to about 3 ° C. 14.63 g of glyoxylic acid (198 mmol) is added, the mixture heated to 50-55 ° is left for one hour at 50 ° C. It is then diluted with 250 ml of water and acidified with dilute sulfuric acid. The product is recrystallized in 90% yield to obtain the pure product, -fc 185.5-188Pc. If sodium hydroxide and tetramethylammonium chloride or tetramethylammonium hydroxide are used in place of Triton B in the above example, indenylidene-3-acetic acid is obtained. If 5-fluoro-2-methid-1- (p-methylsulfinylbenzene) -indene is used instead of the corresponding compound in the section. 5-fluoro-2-methyl-1-Cp-methylsulfinylbenzyl) -indenidine-3-acetic acid is obtained. If 5-fluoro-2-methyl-1- (p-metsh1sul-nilbenzene) -inden is used instead of the corresponding compound in the above example. 5-fluoro-2-methyl-1- (p-methylsulphinylbenzyl) -inspx-3-acetic is obtained. acid. Example 6. 5-Fluoro-2-methyl-1- (p-methylthiobenzylnden) -inden-3 acetic acid. Suspension of 34.2 g of 5-fluoro-2-methyl- (p-methylthiobenzyl) adenylidene-3-acetic the acids of example 5 in 342 ml of glacial acetic acid and 37 ml of concentrated HCl are stirred under nitrogen at 9 (YAS for 10 hours). The mixture is cooled for 2-3 hours at room temperature and left for an additional 3 hours at 20-2J C Then filtered, washed with a mixture of 70-30 acetic acid-water (about 100 ml), then washed with water to remove excess acid, 93% of the product is obtained, (d 180-183 ° C. If 5-fluoro-2-methyl-1- (p-methylsulfi nilbenzyl) -INDenilidene-3-acetic acid per acid is used in the above example, instead of the corresponding methylthio compound, 5-fluoro-2g-, methyl-1- (p-methylsulfinylbenzylidene) -inden-3-acetic acid is obtained. in an aprotic solvent, for example, 1,2-dichloroethane with an overpressure of 100 atm of HCl gas at SO-IOO C. Example 7. 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) inden-3-acetic acid. 17 g (50 mmol) of the product of example 6 are stirred in -94 ml of chloroform and 40 ml of acetic acid under nitrogen and the temperature is brought to 30 ° C. 5.3 ml of 9.6 n are added to the sludge. aqueous (51 mmol) for 1 min. The temperature is adjusted to. The mixture is left for 6 hours at the temperature and then 125 ml of water are added and the CHCla layer is concentrated to a small volume in vacuo. The residue is crystallized from 75 ml of ethanol and cooled to 0-5 ° C, read off at. The product is filtered and rinsed with 15 ml of cold. (0-5c) ethanol and dried in vacuo at 80 ° C. The product weighs 16.3 g (92%), 183-185 ° C. If sodium periodate or potassium hypochlorite is used instead of Persia hydrogen in the above Example, the target substance is obtained. Note: m 8. 5-Fluoro-2-methyl-1- (p-methylthiobenzylidene) inden-3-acetic acid. A suspension of 34 g of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -indenylidene-3. Acetic acid in 150 ml of ethylene dichloride is heated to 7 CgS in an enameled autoclave. Anhydrous carbon disulfide is injected until the pressure is increased to .6 atm. The mixture is stirred under these conditions for 10 hours and then the gas is vented. The product is cooled before and after an hour filtered and washed with fresh ethylene oxide. Product yield 80%. . , -. , Example 9. Add 147 mmol Ul) 8 g) 5-fluoro-2-methyl-1- {and methylthiobenzyl indidea to 75 ml of the solution of the preparation Triton-B (26.6 g, dry base , 158.8 mmol) in methanol, the mixture is heated under nitrogen to 35 ° C h. The mixture is diluted with 250 ml of water, acidified with dilute sulfuric acid, the resinous product is triturated with hexane. 5-fluoro-2-methyl-1- (I-methylthiobenzyl-α-indenylidene-3-acetic acid methyl ester is obtained, p 62, .. Suspended 34.2; g 5-fluoro 2-methyl-1- methyl ester ( And, -methylthio-benzyl) -indenylidene-5-acetic acid in 342 ml of glacial acetic acid and 137 ml of concentrated hydrochloric acid, stirred under nitrogen at 90 ° C 10 h, cooled gradually, the reaction mixture to room temperature {2-3 h) and additionally hold the reaction mixture at 20-25 ° C 2h. By filtering the resulting product, 5-fluoro-2-methyl-1- (y-methylthiobenzylidene) -inden-3-acetic acid. It is washed with 70:30 acetic acid-water (approximately 100 mp, then the excess acid is washed with water, knA 180-183 C. 17 g (50 mmol) of 5-fluoro-2-methyl- - (1-methylthiobenzylidene-inden-3 α-acetic acid with 94 ml of chlorofome and 40 ml of acetic acid under nitrogen at 30 ° C, the reaction mixture is heated at 35 ° C for 6 hours, 125% of water is added, the formed chloroform is separated and concentrated to a small volume in vacuo. the residue is crystallized from 75 ml of ethanol, cooled to 0-5 s and the product is removed by filtration, LP 183-185 C. The formula from Shaving 1. A method for preparing 5-fluoro-2-methyl-1- (and methylsulfinylbenzylidene) indene-3-acetic acid or its salts based on 1- (c-methythiobenzyl) -2-methyl-5-fluoro-indanone using -; a strong base and an oxidation reaction, characterized in that, in order to increase the yield of the target product, 1- (Y) -methylthiobenzyl) -2-methyl-5-fluoro-indanone is reacted with glyoxylic acid or its ester in the presence of a strong base and the resulting 1-C-methylthiobenzylidene-2-methyl-5-fluoridenylideneacetic acid in any subsequent atelnosti oxidized and isomerized followed vzdeleniem title product in free form or in salt form.
    988674210
    [2]
    2. The method according to p. 1, distinguish-Sources of information,.
    w and so that isomerization is taken into account in the examination of water in the presence of acid or base 1. US Patent No. 3732292,
    vani .kl.S 07C 147/00, published 1973 | prototype
    类似技术:
    公开号 | 公开日 | 专利标题
    SU886742A3|1981-11-30|Method of preparing 5-fluoro-2-methyl-1-| indene-3-acetic acid or its salts
    US4658055A|1987-04-14|Method for manufacture of 7-|heptanoic acid derivative
    JPH09208516A|1997-08-12|Production of alpha, beta-unsaturated organic carboxylic acid
    US20050261513A1|2005-11-24|Process for producing indenol esters or ethers
    KR870001537B1|1987-09-02|Process for preparing new derivative of phenyl aliphatic carboxylic acids
    EP0226161B1|1989-11-08|Improved process for preparing 5-|-2,2-dimethylpentanoic acid
    SU824893A3|1981-04-23|Method of preparing 5-fluoro-2-methyl-1-| indene-3-acetic acid
    US4849535A|1989-07-18|Production of cyclopentenylheptanoic acid derivatives
    GB2165841A|1986-04-23|Chalcone derivatives
    US4024182A|1977-05-17|Preparation of aryl-butadienoic acids
    US4320143A|1982-03-16|Fluoro-prostaglandins and process for their preparation
    EP0037588B1|1984-09-05|Method of preparing furfuryl alcohols
    HU176293B|1981-01-28|Process for preparing salicylic acid derivatives
    US4016196A|1977-04-05|Butenoic and pyruvic acid derivatives
    US4933461A|1990-06-12|Preparation of a piperidinylcyclopentylheptenoic acid derivative
    US4761508A|1988-08-02|1,1-|phenylethylene and method for preparing it
    JP3051567B2|2000-06-12|Novel derivatives of cyclic lactones, process for preparing the same, and processes for preparing 15-pentadecanolide and its homologues
    US3703597A|1972-11-21|Preparation of benzilic acid compounds
    JP3838682B2|2006-10-25|Process for producing 2-methyl-4-oxo-2-cyclohexenecarboxylic acid ester and novel intermediate thereof
    EP0142979B1|1989-02-01|Improvements in the production of halocyclopropyl-substituted phenoxyalkanoic acids and esters
    JP4304758B2|2009-07-29|Method for producing para-acetoxystyrene
    EP0296463B1|1992-06-10|Thiophen compounds and their preparation
    JP2755368B2|1998-05-20|Method for producing pyrimidine derivative and thiamine
    EP0101003B1|1986-07-09|Process for preparing 4-oxo-4,5,6,7-tetrahydrobenzofuran derivative
    SU963462A3|1982-09-30|Process for producing 2-acrylpropionic acid
    同族专利:
    公开号 | 公开日
    US3970693A|1976-07-20|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3870753A|1973-12-20|1975-03-11|Merck & Co Inc|Process for preparing indenyl acetic acids|EP0567953B1|1992-04-28|1996-03-13|Hoechst Aktiengesellschaft|Process for the preparation of substituted indanones|
    US5998477A|1996-06-13|1999-12-07|Cell Pathways Inc.|Substituted methoxy benzylidene indenyl-acetic and propionic acids for treating patients with precancerous lesions|
    US5965619A|1996-06-13|1999-10-12|Cell Pathways Inc.|Method for treating patients having precancerous lesions with substituted indene derivatives|
    US6063818A|1996-06-13|2000-05-16|Cell Pathways Inc.|Substituted benzylidene indenyl formamides, acetamides and propionamides|
    US6121321A|1996-06-13|2000-09-19|Cell Pathways, Inc.|Substituted methoxy benzylidene indenyl acetic and propionic acids for treating patients with precancerous lesions|
    US5948779A|1997-12-12|1999-09-07|Cell Pathways, Inc.|Substituted condensation products of n-benzyl-3-indenyl acetamides with heterocyclic aldehydes|
    US6028116A|1998-04-03|2000-02-22|Cell Pathways, Inc.|Substituted condensation products of 1H-indenyl-hydroxyalkanes with aldehydes for neoplasia|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/486,031|US3970693A|1974-07-05|1974-07-05|Process for preparing indene acetic acids|
    [返回顶部]