• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    Process for preparing 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl acetic acid by reacting 5-fluoro-2-methyl-1-(p-methylthiobenzyl) or (p-methylsulfinylbenzyl)-indene with a glyoxylic acid.
    公开号:SU971096A3
    申请号:SU802870003
    申请日:1980-01-22
    公开日:1982-10-30
    发明作者:Дж.Талл Роджер；Ф.Кзаджа Роберт；Ф.Шуман Ричард；Х.Пайнз Симан
    申请人:Мерк Энд Ко,Инк(Фирма)；
    IPC主号:
    专利说明:

    The purpose of the invention is to increase the yield of the product. Postaapena goal is achieved by the fact that according to the method of obtaining Z-f br-2-methyl-1- (p-methylsula) ynylbenzyl "iden) -inden 3-acetic acid or its salts, which is that 5- -fluoro 2- -methylindanone is reacted with a Wittig reagent containing p-methylthiobenzyl or p -methylsulfinylbenzyl groups, and the 5-fluoro-2-methyl-1 "(g - R benzylidene) indan obtained in this case, where R is methylthio or methylsulfinyl, is isomerized into 5-fluoro-2-methyl-1- (p - R-benzyl) indene, where R has the same meaning, which condenses with glyoxylic acid its salt or ester and the resulting 5-fluoro-2-methyl-1- (p-R-benzyl) indenylidene-3-acetic acid, if R is methylsulfinyl, is labeled or, if R is methylthio, in any sequence is oxidized or isomerized. I The condensation reaction between 5-fluoro-2-methyl-1- (p-methylthio - or methylsulfinylbenzyl) indene and glyoxylic acid takes place in the presence of a strong base, for example shelrna and alkaline earth hydroxides (N aOH, KOH), especially in the presence of a halide salt than a vertical ammonium as a catalyst (for example, -alkylbenzylammonium halo-alkamylammonium halide; 0.1-1, O mmol of the halide per hydroxide), alkaline or alkaline earth Cj.g-alkoxide (N aCCHi, K-tri-butoxide), tetra - C-alkylammonium hydroxide or benzyltri C g - alkylammon Hydroxides (benzyltrimethylammonium hydroxide) {Triton c). It is preferable to use a trialkylbenzylammonium hydroxide or hydroxide as a strong base. tetraalkylammo ™ neither. The reaction can proceed without a solvent, it is undesirable to use such a solvent that can be introduced into the reaction mixture or used in combination with a strong base. C. can be used. C. - alkanols (methanol, butanol), aromatic solvents, for example, benzene, pyridine or toluene or dioxane, acetonitrile, dimethylformamide, triglyme, dimethyl sulfoxide, water, or mixtures of water and organic solvents. In fact, any solvent can be used in which indene and glyoxylic acid are sufficiently soluble. The preferred solvent is a C.-alkanol, especially methanol. The molar ratio of base to glyoxy acid may be at least slightly more than one mole to one, preferably about 1.1 to 4.0 moles of base to glyoxylic acid, and especially 1, 2j to 2.5. The molar ratio of glyoxylic acid and indene is not critical and can be approximately 1-3.0 mol to 1 and preferably 1.5: 1.0 mol of indene. Alternatively, alkali or alkaline earth salts, aryl or alkyl esters can be used, especially C-j-alkyl, instead of glyoxylic free acid or any acid salt of a strong base B as the starting material. Under these conditions, the amount of strong base used in the reaction with the glyoxylic acid salt or ether should not exceed the catalytic amount, although the above ratio can be applied. The order of addition of the reagents is not critical, but it is desirable to add glyoxylate acid compound to the indene and base reaction mixture. It is preferable to carry out the reaction for 15 minutes to 5 hours, in particular, 1 / 2-3 hours. The reaction can proceed at 0 ° C-150 ° C, preferably at 10 ° C-80 ° C and especially at 35 ° C - 60 ° s After completion of the condensation reaction, isomerization of the resulting 5-fluoro-2-methyl-1- (p-methylthio) - or (methylsulfinyl benzyl) indenylidene-3-acetic acid is carried out in the form of its acid additive or ester and without isolation. This is especially important if isomerization is required under basic conditions, i.e. the reaction mixture from the previous step is already basic and the usual further reaction will result in isomerization of the product. Other strong isomerization bases used in the previous step can also be used. However, it is advisable to carry out isomerization using an acid and it is preferable to isolate the reaction product. Various organic and / or inorganic acids can be used, for example, alkylsulfonic (methanesulfonic), arylsulfonic (toluenesulfonic), acidic ion-exchange resins (e.g. Dovex 50), ari carboxylic (p-nitrobenzoic acid), aliphatic (alkanoic acids, for example , acetic acid, propionic acid, trichloroacetic acid and
    trifluorotssusna), mineral acids (phosphoric, hydrochloric, hydrobromic and sulfuric), but mineral acids or mixtures of mineral and organic acids are preferred, preferably
    C.-alkanoic acids (for example, hydrochloric and acetic acid, hydrobromic and propionic acid). The ratio of acid and indenylidene is not critical and therefore suitable catalytic amounts of acid can be used.
    However, it is preferable to use 0.1-5 O mol of acid to indenylidene and especially 1.0: 20. The reaction can be with or without a solvent, and if solvents are used, they are used, as indicated above, for the reaction of glyoxylic acid, i.e., inert, as well as halo-substituted hydrocarbons, such as aliphatic halides (ethylene dichloride) or halobenzenes. Preferably, the reaction is carried out using an acid or a halogen-substituted hydrocarbon as solvent. If a weak acid is used as a solvent, it is better to use strong acids (aryl sulfonic or mineral acids). For example, unsubstituted alkanoic acids (acetic) can be used as a solvent, arylsulfonic (toluenesulfonic acids) and especially mineral acids (hydrochloric). When using halogen-substituted hydrocarbons as solvents, it is preferable to use mineral acids as catalysts, and especially anhydrous mineral acids, for example, hydrogen chloride. The time and temperature of the reaction are not critical parameters, but the higher the temperature, the shorter the reaction time for its completion, therefore, the reaction can proceed at a temperature of about 0 ° -150 ° C and preferably at 5 °.
    When using the p-methylthiocompound as the starting substance, the oxidation of the methylthio group to the methylsulfinyl group can occur at any phase of the reaction process, for example, immediately after reacting with glyoxylic acid or after isomerization, but preferably after the latter. Oxidation can occur when using periodate or hypogalite, preferably alkali or alkaline earth metals, or organic peracids, for example, peracetic and mononadphthalic
    acids. However, the preservative of the gm-agent oxidation is. The reaction preferably proceeds in the presence of a solvent. To do this, you can use C.j-alkanoic acids (acetic acid), glodo-substituted hydrocarbons (chloroform), ethers (dioxane), Cj, alkanols (isopropanol), or mixtures thereof.
    The molar ratio of oxidant to indane is 5:10, but preferably .8: 1.5. Preferably, the reaction time is 1-18 hours and especially 2-6 hours at and especially at 25-5b ° C.
    If it is desired to use glyoxylic acid ester, the final compound of the free acid is obtained in the isomerization process, especially with some water, when the isomerization proceeds at elevated temperatures. Accordingly, aliphatic, aromatic or heterocyclic esters can be used.
    In the Wittig reaction, for example, trif-nilphosphine or substituted triphenylphosphine is treated with the corresponding benzyl halide (p-methylthio- or p-h methylphenyl benzyl halide) in the melt or in the presence of suitable solvents to form the phosphonium salt. Various solvents can be used: benzene, nitrobenzene, xylene, ether, or acetonitrile. dimethylformavd, nitrophene) formic acid, acetic acid and ethyl acetate. The production of phosphonium salt occurs at tempergate intervals from 0 to 2 ° C, in particular from 25 to 75 ° C. The molar concentration of triphenylphosphine to the benzyl halide can vary from 2 to 1 mol, and preferably 1.2: 1 mol. The phosphonium salt must be separated and then converted to a Wittig reagent using organic metals or alcohols. In the first case, phenyl lithium or P-butyl lithium is a common proton acceptor and ether or tetrahydrofuran is used as a solvent. In the second case, it is possible to use a metal alkoxide and the corresponding alcohols as a proton acceptor as a solvent.
    权利要求:
    Claims (1)
    [1]
    The Wittig reagent is usually not separated and the reaction is carried out in the same reaction vessel. Base reaction with the phosphine salt usually occurs at an equimolar ratio, although an excess of base can be used, which is more expedient. The reaction can proceed at a temperature of from 0 ° C to the boiling point of the solvent, and preferably at 25-5 ° C. After the base has been added, indanone is added, about a B equimolar amount with a Wittig reagent, although the possibility of using a larger or smaller amount is not excluded. The reaction proceeds at a temperature from to the boiling point of the dissolved solids, but it is preferable to 25SO C until the reaction is complete. The intermediate indene can then be separated by standard methods. In cases where the Wittig reagent is first separated, the reaction with indane can easily proceed in various inert solvents. Solvents such as ether, benzene,; ethyl acetate, hexane, or petroleum ether may be used. . Example 1. 5-Flu1) -2-methyl-1- (p-methylthiobenzyl) indene. A.5-fluoro-2-methyl-1- (p-methylthiobene zilidene) indan. 169 mg (1.5 mm) of potassium tert-butoxide are dissolved in 2 ml of DMSO and treated with 651 mg (1.5 mm) of p-methylthiobenzyl triphenylphosphonium chloride dissolved in 1 ml of DMSO. 270 mg (1.65 mm) of 5- -4) torus-2-methyl-1-indanone in 2 ml of DMSO are added to this solution. The solution is heated at 75 ° C for 15.5 hours. Benzene: and water are added. - then the benzene layer is washed 5 times with water. The benzene layer is dried N and evaporated to dryness in vacuo. The yield is 915.6 mg. The substance is eluted through 8 g of silica gel with benzene to remove the triphenylphosphine oxide. The eluate weighs 372 mg after removal of the solvent. The latter is subjected to rechromatography on 15 g of silica gel using hexane and 95.9 mg of 5-fluoro-2-methyl-1- (p-methylthiobenzyl-yenium) incan are separated, mp. 57-70 ° C B.5-fluoro-2- methyl 1- (p-methylthiobenzyl) indene. 5O mg of the obtained compound is mixed with 1 ml of acetic acid containing 100 mg of sulfuric acid, and the reaction mixture is stirred for 1 h at a constant temperature. The mixture is then diluted by boiling and extracted with ether. The ether extract is concentrated in vacuo to give the desired substance. Also, when using p-methylsulphinylbenzyltriphenylphosphonium chloride, the corresponding substance p-methylsulfinylbenzylinden is obtained. Example 2. 5-4 | TOP-2-met1sh-1 - (p -methylsu.sh-finibenzshOinpen. 9 96.8 500 mg (1.755 mm) 5-fluoro-2-methyl-1- (p-methylthiobenzyl) - the indene is dissolved in 5 ml of chloroform. 30% hydrogen peroxide (equivalent to 2.645 mm) is added to this solution. The reaction mixture is stored for 1 hour at room temperature, followed by the addition of 5 mm of glacial acetic acid. After 1 hour the reaction mixture is diluted with 25 ml of a mixture of benzene: ether 1: 1 and extracted with 6 of 25 ml of 3% aqueous sodium chloride. The solution is then dried with sodium sulfate and evaporated in vacuo to give an oil. 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indene is obtained from talization from propanol. Example 3. 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indenylidene-3-acetic acid. g (147 mmol) 5-fluoro-2-methyl-1- (p-methylthiobenzyl) is added 150 ml of a solution of Triton B in methanol (53.2 g, dry base 317.7 mmol) and the mixture is heated under nitrogen at 35 ° C. 14.63 g of glyoxylic acid 1 (198 mmol) are added and the mixture is heated; Tu to 50-55 ° C, left for 1 h at 50 ° C. It is then diluted with 250 ml of water and acidified with dilute sulfuric acid. The product is recrystallized with a yield of 9O% to obtain a pure product, so pl. 185-188 ° C. If sodium hydroxide and tetramethylammonium chloride or tetramethylammonium hydroxide are used instead of Triton B. in the above example, indidylidene-3-acetic acid is obtained. Also, if 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indene is used in place of the corresponding compound in step 7; in the azan example, 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indenylidene-3-acetic is obtained acid. Example 4. 5 torus-2-methyl-1- (p-methylthiobenzylidene) inden-3-acetic acid. A suspension of 34.2 g of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indenylidene-3-acetic acid (from example 3) in 342 ml of glacial acetic acid and 137 ml of concentrated HCE is stirred under a nitrogen atmosphere at for 10 hours. The mixture is cooled for 2-3 hours at room temperature and left for another 3 hours at 200 ° C. It is then filtered, washed with acetic acid: water 7O: 30 (about 100 ml), then washed with water to remove excess acid. Get 93% of the product, so pl. 18 ° -183 ° C. Also, if 5-fluoro-2-methyl-1- (p-methylsulfenylbenzyl) indenylidene-3-acetic acid is used in the above example instead of the corresponding methylthio compound, 5-fluoro-2-megyl-1- (p- methylsulfinylbenzylcene) inden-3-acetic acid. The reaction can be carried out with an aprotic solvent, for example, 1,2-dichloroethane at an overpressure of 1OO atm of NSV gas at a C-OO C. Example 5. 5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) inden-3-acetic acid acid. 17 g (5.0 mmol) of the obtained substance are stirred in 94 ml of chloroform and 4 O ml of acetic acid in a nitrogen atmosphere, the temperature is brought to 30 ° C, 5.3 ml of 9.6 n is added. aqueous solution (51 mmol) for 1 min. The temperature is brought to 35 ° C and kept at this temperature for 6 hours. Then 125 ml of water and CHSW | concentrated to a small volume in a vacuum. The residue is crystallized from 75 ml of ethanol and cooled to 0-5 ° C. After aging at 0-5 ° C, the product is filtered and washed with 15 ml of cold (05 ° C) ethanol and dried under vacuum. Vyhots16.3g (929), pl. 183-185 ° C. Also, if sodium periodate or potassium hyperchlorite is used instead of hydrogen peroxide in the above example, the desired product is obtained. Example 6. 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 enameled autoclave. Anhydrous carbon disulfide is injected until the pressure increases to 6 atm. The mixture is stirred under these conditions for 1 oh and the aegeum is evacuated. The product is cooled at -5 ° C, filtered after an hour and washed with fresh ethylene dichloride. The product yield of 8O%. Example 7. 147 mol (41.8 g) of 5-fluoro-2-methyl-1- (par-methyl thiobenzyl) indene are added to 75 ml of Triton B methanol solution (26.6 g; 158.8 mmol) and the mixture is heated in nitrogen atmosphere to 35 ° C. Add 17.1 methyl glyoxalic ester (194 mmol) and heat the resulting mixture to 5O-55 ° C for 1 h. Dilute the mixture in 25 O ml of water and oxidize with help. diluted sulfuric acid. Triturate the resulting rubber-like product with hexane to give methyl ester of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indenylidene-3-acetic acid), mp. 62.5-64 C. 34.2 g of methyl 5-fluoro-2-methyl-1- (g-methylthiobenzyl) indenyl 1 -chenyl-3-acetic acid in 342 ml of glacial acetic acid are suspended in 342 ml of glacial acetic acid hydrochloric acid in a nitrogen atmosphere at 90 ° C for 10 hours. Slowly cool the reaction mixture to room temperature (2-3 hours) and keep the reaction mixture at 2025 ° C for 3 hours. Filter the resulting 5-flu-2-2-methyl-1 - (p-methylthiobenzylidene) inden-3-acetic acid and washed with a mixture of acetic acid and water in a ratio of 70: 30 (approximately 100 ml), then washed with water to remove excess acid; the resulting product has m. pl. 18 ° -183 ° C. 17 g (5O mmol) of 5-4 | tor-2-methyl-1- (para-methylthiobenzylidene) inden-3-acetic acid, 94 ml of chloroform and 40 ml of acetic acid are mixed under nitrogen at 30 ° C. 5.4 ml of 9.6 n is added to this mixture. (51 mmol) for 1 min. Heat the reaction mixture to 35 ° C for 6 hours. 127 ml of water are added, the chloroform layer is separated and concentrated in vacuo. The residue is crystallized from 75 ml of ethanol. Cool the resulting product to 0-5 With and filtered, so pl. 183-185 ° C., Claim of the invention. A method of producing 5-fluoro-2-methyl-1-, (p-methylsulfinylbenzylidene) inden-3-acetic acid or its salts, including the conversion of 5-fluoro-2-methylinanone to 5 fluor-2-methyl-1- (p-methyliobenzyl) indene, its subsequent condensation with a carboxylic acid or its derivative in the presence of a base, and an oxidation stage, which is also different with heme, in order to increase the yield of the target product, 5- the fluoro- (1 2-methyl indannn is subjected to interaction with the Wittig reagent, the иш -methylthiobenzyl and p-methylsulfinyl-ensyl groups, and 5-fluoro-2-methyl-1- (p-R-benzylidene) ndan, where R is methylthio or methylsupinyl, is measured in 5-fluoro-2-methyl-1- (p-R-benzyl) indene, where R has the above meaning, which is condensed with glyoxylic acid, its salt or ether, and the resulting 5-fluoro-2-
    1197109612
    -methyl-1- (p - I-benayl) inenylidene-3-. Sources of information,
    - acetic acid, if R - is methyl-taken into account during examination
    finish, isomerized or, if P is 1-methyl-1. US patent Mb 3732292,
    thio group, in any sequence C O7 C 147 / OO, published. 1973
    are oxidized or isomerized.5 (prototype).
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    US3870753A|1975-03-11|
    ZA748081B|1976-08-25|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3732292A|1970-05-01|1973-05-08|Merck & Co Inc|Indenyl compounds|US3970693A|1974-07-05|1976-07-20|Merck & Co., Inc.|Process for preparing indene acetic acids|
    US3998875A|1974-10-02|1976-12-21|Merck & Co., Inc.|Process of preparing 5-fluoro-2-methyl-1--indenyl-3-acetic acid|
    US4465855A|1978-05-23|1984-08-14|Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt|Process for the preparation of arylacetic acid derivatives|
    US5998477A|1996-06-13|1999-12-07|Cell Pathways Inc.|Substituted methoxy benzylidene indenyl-acetic and propionic acids for treating patients with precancerous lesions|
    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|
    US5965619A|1996-06-13|1999-10-12|Cell Pathways Inc.|Method for treating patients having precancerous lesions with substituted indene derivatives|
    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
    US426864A|US3870753A|1973-12-20|1973-12-20|Process for preparing indenyl acetic acids|
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