CN102030642A - Synthesis method and application of intermediate of sulindac analogue - Google Patents
Synthesis method and application of intermediate of sulindac analogue Download PDFInfo
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Abstract
The invention discloses a synthesis method and application of intermediates of a sulindac analogue, relating to intermediates of a sulindac analogue. The intermediates are 5-fluoro-2-metyl-3-indene ethyl acetate (5a) and 5-fluoro-2-metyl-3-indene acetic acid (5b). The synthesis method comprises the following steps of: subjecting 4-fluorobenzaldehyde as an initial raw material, propionic anhydride as a solvent and propionic anhydride to a perkin reaction to obtain 4-fluoro-2-metyl-methylcinnamic acid; catalyzing the 4-fluoro-2-metyl-methylcinnamic acid with palladium carbon with the palladium content of 5-20 percent and reducing in the hydrogen gas atmosphere to obtain 3-(4-fluorine phenyl)-2-methyl propionate; subjecting the 3-(4-fluorine phenyl)-2-methyl propionate to the intramolecilar friedel-crafts acyl browning reaction under the action of polyphosphoric acid under the heating condition to form 6-fluoro-2-methyl indene ketone; and subjecting the 6-fluoro-2-methyl indene ketone and halogenated acetate to reformatsky reaction under the action of the activated zinc powder to obtain a crude product and eliminating the crude product in an acid solution to obtain 5-fluoro-2-metyl-3-indene acetate. The intermediates can be used for preparing novel sulindac analogues with anticancer activity.
Description
Technical field
The present invention relates to a kind of intermediate of sulindac analogue, especially the synthetic method that relates to a kind of sulindac intermediate 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) and 5-fluoro-2-methyl-3-indeneacetic acid (5b), and the application in synthesizing sulindac analogue 5-fluoro-2-methyl isophthalic acid-(4-methylbenzene methylene radical)-3-indeneacetic acid (K-80001 by name), 5-fluoro-2-methyl isophthalic acid-(4-ethylbenzene methylene radical)-3-indeneacetic acid (K-80002 by name) and 5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003 by name) with antitumour activity.
Background technology
About synthesizing of sulindac (Sulindac) intermediate 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) and 5-fluoro-2-methyl-3-indeneacetic acid (5b), both at home and abroad report is more is to be raw material (world patent WO9747295 with the 4-fluorobenzaldehyde, WO9747303, WO9603987, U.S. Pat 5902827, US5776962, European patent EP 508586).
The first step, under alkaline condition, 4-fluorobenzaldehyde (1) must be to fluoro-α-Jia Jirouguisuan (2) through condensation reaction with propionic anhydride;
Second step, must be to fluoro-Alpha-Methyl phenylpropionic acid (3) in ethanol to the fluoro-α-Jia Jirouguisuan with palladium carbon catalytic hydrogenation;
In the 3rd step, in the presence of a large amount of polyphosphoric acid,, get 6-fluoro-2-methyl indone (4) to fluoro-Alpha-Methyl phenylpropionic acid Cheng Huan;
In the 4th step, 6-fluoro-2-methyl indone and cyanoacetic acid condensation and hydrolysis in toluene solvant make 5-fluoro-2-methyl-3-indeneacetic acid (5b).Second step of this method is used solid catalyst---palladium carbon, can recycling, and consumption is little and can recycle and reuse; The 3rd step used polyphosphoric acid to finish Friedel-Crafts reaction, produced volatile sour gas in the time of can avoiding industrial production, reduced equipment corrosion and reduced topsoil, as long as carry out the minimizing environmental pollution that the water emission problem just can maximum; But the 4th step also comprised reagent such as acetate, ammonium acetate and toluene except raw material during reaction, and long reaction time, and resource consumption is more, the cost height.
In addition, wearing people such as expound one's ideas in writing (wears and expounds one's ideas in writing, message of congratulation, Wang Xiaozhong, Chen Yingqi, synthetic chemistry, 2008,76,614-616; High chemical engineering journal, 2009,23,673-678) on synthetic 5-fluoro-2-methyl-3-indeneacetic acid, make following method (to be starting raw material): the first step to fluorobenzyl chloride, in sodium methylate-methanol solution, compound and methyl-malonic ester condensation get corresponding diester; In second step, diester is hydrolysis in potassium hydroxide solution, gets 2-(4-luorobenzyl)-2-Methylpropanedioic acid; In the 3rd step, high temperature decarboxylation under solvent-free situation gets 3-(4-fluorophenyl)-2 Methylpropionic acid; In the 4th step, 3-(4-fluorophenyl)-2 Methylpropionic acid and excessive thionyl chloride carry out chloride, get 3-(4-fluorophenyl)-2-methyl-prop acyl chlorides, then get 6-fluoro-2-methyl indone by Catalyzed by Anhydrous Aluminium Chloride intramolecularly friedel-crafts acylation; In the 5th step, 6-fluoro-2-methyl indone and cyanoacetic acid condensation and hydrolysis in toluene solvant make 5-fluoro-2-methyl-3-indeneacetic acid.But this method uses thionyl chloride and aluminum chloride to finish Friedel-Crafts reaction, produces volatile sour gas during reaction, and inevitably etching apparatus and cause topsoil destroys environment.
2010, people such as Zhang Xiaokun have reported a series of sulindac similar and have had the newtype drug molecule of antitumour activity, and wherein the antitumous effect effect of compound 5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003 by name) is particularly evident.Experiment shows, when this molecularity in cancer cells during distinctive target molecule " tRXR α " albumen, not only can the anticancer growth, and can also activate in the body other cytokines and kill cancer cells.The very likely short PTS of giving birth to a kind of low toxicity pair and high curative effect of this project is for the cancer patients brings new hope.This achievement in research be distributed on " Cell " son periodical " Cancer Cell " go up (Cancer Cell2010,77,560-573).
Summary of the invention
The object of the present invention is to provide a kind of intermediate 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) of sulindac analogue and the synthetic method of 5-fluoro-2-methyl-3-indeneacetic acid (5b).
Another object of the present invention is to provide the intermediate 5-fluoro-2-methyl of described sulindac analog-3-indeneacetic acid ethyl ester (5a) and 5-fluoro-2-methyl-3-indeneacetic acid (5b) to have application in the sulindac analog 5-fluoro-2-methyl isophthalic acid of active anticancer-(4-methylbenzene methylene)-3-indeneacetic acid (K-80001 by name), 5-fluoro-2-methyl isophthalic acid-(4-ethylo benzene methylene)-3-indeneacetic acid (K-80002 by name) and 5-fluoro-2-methyl isophthalic acid-(4-cumene the methylene)-3-indeneacetic acid (being called K-80003) in preparation.
The intermediate 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) of sulindac analogue of the present invention and the chemical structural formula of 5-fluoro-2-methyl-3-indeneacetic acid (5b) are:
The intermediate 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) of sulindac analogue of the present invention and the synthetic route of 5-fluoro-2-methyl-3-indeneacetic acid (5b) are:
Wherein each compound is 4-fluorobenzaldehyde (1), 4-fluoro-2-tolyl acrylic acid (2), 3-(4-fluorophenyl)-2 Methylpropionic acid (3), 6-fluoro-2-methyl indone (4), 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a), 5-fluoro-2-methyl-3-indeneacetic acid (5b).
Its concrete steps are:
1) be starting raw material with the 4-fluorobenzaldehyde, propionic anhydride is a solvent, with propionic anhydride generation amber gold (Perkin) reaction, obtains 4-fluoro-2-tolyl acrylic acid under organic bases or inorganic salt effect;
In step 1), described organic bases can adopt Sodium Propionate or potassium propionate etc., and described inorganic salt can adopt salt of wormwood etc., preferred salt of wormwood; The molar feed ratio of described organic bases and 4-fluorobenzaldehyde can be (1～2): 1, and preferred feed ratio is (11～1.5): 1; The molar feed ratio of described inorganic salt and 4-fluorobenzaldehyde can be (1～2): 1, and preferred feed ratio is (11～1.5): 1; The temperature of described perkin's reaction can be 100～200 ℃, is preferably 135～165 ℃.The 4-fluorobenzaldehyde is 1 with the molecular volume ratio of propionic anhydride: (5～20) are preferably 1: 10.
2) the 4-fluoro-2-tolyl acrylic acid that step 1) is obtained is by palladium carbon (Pd/C) catalysis of 5%～20% palladium content, and reduction obtains 3-(4-fluorophenyl)-2 Methylpropionic acid in atmosphere of hydrogen;
In step 2) in, described atmosphere of hydrogen is preferably the atmosphere of hydrogen of 3～9 standard atmospheric pressures, can reclaim palladium carbon after filtration, continues to utilize; The palladium carbon of used 5%～20% palladium content is preferably the palladium carbon of 10% palladium content.
3) under polyphosphoric acid (PPA) effect, 3-(4-fluorophenyl)-2 Methylpropionic acid issues at heating condition and gives birth to intramolecular friedel-crafts acylation, forms 6-fluoro-2-methyl indone;
In step 3), the consumption of described polyphosphoric acid can be 5～30 times of 3-(4-fluorophenyl)-2 Methylpropionic acid by mass ratio, preferred 8～10 times; The temperature of described heating can be 55～120 ℃, preferred 75～95 ℃.
4) 6-fluoro-2-methyl indone and halogenated acetic acids ester be under the effect of activatory zinc powder, and reformatsky reaction takes place, in acidic solution, eliminate behind the crude product and obtain 5-fluoro-2-methyl-3-indeneacetic acid ester.
In step 4), described monobromo-acetic acid ester can be C
1～C
10Aliphatic alcohol ester or C
6～C
10Phenolic esters etc. are preferably methyl bromoacetate, ethyl bromoacetate and benzyl acetate bromide; Being used for the reagent of activated zinc powder can adopt I
2, CuCl, CuI, (CH
3)
3SiCl or glycol dibromide etc.; The molar feed ratio of described 6-fluoro-2-methyl indone and zinc powder, halogenated acetic acids ester can be 1: (1～3): (1～3), and preferred molar feed ratio is 1: (1.2～2): (1.1～1.5); Described reaction solvent for use can be tetrahydrofuran (THF), ethyl acetate, ether, toluene, benzene or N, dinethylformamide etc., and preferred solvent is tetrahydrofuran (THF), ether or toluene etc.; The temperature of described reaction can be room temperature～150 ℃, and preferable reaction temperature is 35～110 ℃, and the time of reaction can be 1～24h, and the preferred reaction time is 1～5h; The used acidic conditions of described elimination reaction is an acidic solution, as mineral acid (hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid), organic acid (formic acid, acetate, propionic acid, butyric acid and phenylformic acid) or mineral acid and organic acid mixing solutions, the mixing solutions (example hydrochloric acid/acetate mixed solution or sulfuric acid/acetate mixed solution) of preferred organic acid and mineral acid, the volume ratio of organic acid and mineral acid is (0.1～1): 1.
5-fluoro-2-methyl-3-indeneacetic acid ester can be hydrolyzed to 5-fluoro-2-methyl-3-indeneacetic acid (5b), wherein 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) partial hydrolysis, and 5-fluoro-2-methyl-3-indeneacetic acid methyl esters (5c) and 5-fluoro-2-methyl-3-indeneacetic acid benzyl ester (5d) complete hydrolysis.
The 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) and the 5-fluoro-2-methyl-3-indeneacetic acid (5b) that utilize aforesaid method to make can be used for preparing the active sulindac analogue of new type anticancer 5-fluoro-2-methyl isophthalic acid-(4-methylbenzene methylene radical)-3-indeneacetic acid (K-80001 by name), 5-fluoro-2-methyl isophthalic acid-(4-ethylbenzene methylene radical)-3-indeneacetic acid (K-80002 by name) or 5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003 by name), and its preparation route is as follows:
Its concrete steps are:
Make alkali with sodium alkoxide or potassium alcoholate, make solvent with corresponding alcohol, 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) or 5-fluoro-2-methyl-3-indeneacetic acid (5b) and 4-tolyl aldehyde (12a) condensation reaction get 5-fluoro-2-methyl isophthalic acid-(4-methylbenzene methylene radical)-3-indeneacetic acid (K-80001); With 4-ethylbenzene formaldehyde (12b) condensation reaction, 5-fluoro-2-methyl isophthalic acid-(4-ethylbenzene methylene radical)-3-indeneacetic acid (K-80002); With 4-isopropyl benzene formaldehyde (12c) condensation reaction, 5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003).
The used 4-substituted benzaldehyde of described condensation reaction is 4-tolyl aldehyde (12a), 4-ethylbenzene formaldehyde (12b) and 4-isopropyl benzene formaldehyde (12c).Used sodium alkoxide can be sodium methylate, sodium ethylate or sodium tert-butoxide, and used potassium alcoholate can be a potassium tert.-butoxide; The molar feed ratio of alkali and 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) or 5-fluoro-2-methyl-3-indeneacetic acid (5b), 4-substituted benzaldehyde (12a) is (1～5): 1: 1, preferred molar feed ratio was (1.5～2): 1: 1.The methanol solution of corresponding alcoholic solvent particular methanol sodium.Temperature of reaction is room temperature～100 ℃, 60 ℃ of preferable reaction temperature.Reaction times is 1～12h, preferred 3～5h.
Preparation flow of the present invention is brief, and is easy and simple to handle, protection environment, reaction conditions gentleness.Wherein the alkali in the step 1) substitutes Sodium Propionate with salt of wormwood, and is easy and simple to handle, shortens the reaction times, reduces cost; Step 2) catalyzer (the palladium carbon of 10% palladium content) consumption is little in, and environmental friendliness can be recycled; Use PPA in the step 3), produce volatile sour gas in the time of can avoiding industrial production, reduce equipment corrosion and reduce topsoil; Utilization thunder formal thatch base condensation reaction in the step 4), zincon is nontoxic, and speed of response is fast, and the end afterreaction just can finish feeding intake; The easy purifying of final product, the yield height, altogether five steps, overall yield is 35%～36%.
Embodiment
The present invention is further illustrated below by embodiment.
The preparation of embodiment 1:4-fluoro-2-tolyl acrylic acid (2)
In the 500mL three-necked bottle of prolong is housed, add the 4-fluorobenzaldehyde (1) of 52.0mL (480mmol), 72.8g (528mmol) Anhydrous potassium carbonate powder and 124.0mL propionic anhydride.After stirring, keep 12h after slowly being heated to 160 ℃.The cooling back adds 50mL water, adds about 10g yellow soda ash again, makes solution be alkalescence.The low-grade fever after-filtration, under the ice-water bath condition, with filtrate careful be acidified to pH=2～3 with concentrated hydrochloric acid.Wait to separate out crystal fully after, suction filtration, lurid crude product purified 4-fluoro-2-tolyl acrylic acid (2) 82.1g.
The preparation of embodiment 2:3-(4-fluorophenyl)-2 Methylpropionic acid (3)
4-fluoro-2-tolyl acrylic acid (2) 15.0g dissolve with methanol, low-grade fever adds the palladium carbon of 1.2g 10% palladium content to complete molten and add in the autoclave of 100mL, seal then and logical hydrogen in 0.8Mpa, stirring at room 10h.After the reaction end, filtration catalizer (reclaim and continue to use more than twice), filter cake is washed with small amount of methanol, removes under reduced pressure behind the merging filtrate and desolvates, and gets 3-(4-fluorophenyl)-2 Methylpropionic acid (3) 14.7g, two-step reaction yield 93%.
The preparation of embodiment 3:3-(4-fluorophenyl)-2 Methylpropionic acid (3)
The preparation manipulation process of 4-fluoro-2-tolyl acrylic acid (2) just substitutes alkali reaction times 16h with embodiment 1 with Sodium Propionate.Then catalytic hydrogenation gets 3-(4-fluorophenyl)-2 Methylpropionic acid (3), two-step reaction yield 87.0% with embodiment 2
The preparation of embodiment 4:6-fluoro-2-methyl indone (4)
The polyphosphoric acid of 100g in round-bottomed flask and oil bath after 80-85 ℃, drip 3-(4-fluorophenyl)-2 Methylpropionic acid (3) 9.60g (52.7mmol) gradually.React 4h under this temperature, pour into after the cooling in the trash ice, layering, water merges organic phase with ethyl acetate extraction 3 times (50mL * 3), uses saturated NaHCO
3Solution is washed (20mL * 2) twice, anhydrous sodium sulfate drying, concentrate 6-fluoro-2-methyl indone (4) 4.76g, productive rate 55%.
Above-mentioned saturated NaHCO
3When solution washing liquid is used concentrated hydrochloric acid acidifying pH=3, use ethyl acetate extraction again 3 times (30mL * 3), merge organic phase, anhydrous sodium sulfate drying concentrates and reclaims 3-(4-fluorophenyl)-2 Methylpropionic acid (3) 2.97g, and the rate of recovery is 31%.
The preparation of embodiment 5:5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) and 5-fluoro-2-methyl-3-indeneacetic acid (5b)
Under nitrogen protection, adding activatory zinc powder 5.0g (75.4mmol) in reflux condensing tube and the exsiccant three-necked bottle is housed to 250mL.Add 6-fluoro-2-methyl indone (4) 6.2g (37.7mmol) and exsiccant tetrahydrofuran (THF) 125mL, stir and be heated to 60 ℃ after, dropwise the mixing solutions of dripping bromine ethyl acetate 9.4g (56.5mmol) and tetrahydrofuran (THF) 25mL dripped off in half an hour.After the thin-layer chromatographic analysis reaction finishes, directly steam and remove tetrahydrofuran (THF) (recyclable utilization) to the ethyl acetate l00mL dilution of thick back, successively with 10% aqueous hydrochloric acid 25mL, water 25mL and saturated aqueous common salt 25mL washing, the organic phase anhydrous sodium sulfate drying, filter, remove under reduced pressure behind the solvent crude product.
The crude product mixed acid solution (sulfuric acid/acetate=1/10,30mL) after the dissolving, completely dissolve behind the stirring at room 5h.Reaction solution adds 20mL water dilution back dichloromethane extraction (30mL * 3), merging organic phase washes with saturated sodium bicarbonate solution, anhydrous sodium sulfate drying filters, and steams the mixture that gets 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) and 5-fluoro-2-methyl-3-indeneacetic acid (5b) after desolventizing.This mixture is carried out purifying, get 5-fluoro-2-methyl-3-indeneacetic acid ester (5a) 4.76g, productive rate 54%; 5-fluoro-2-methyl-3-indeneacetic acid (5b) 2.18g, proterties is a white solid, productive rate 28%.
5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a): IR (film) v
Max2981,2911,1736,1614,1590,1473,1368,1329,1308,1256,1154,1034cm
-1 1H NMR (400MHz, CDCl
3) δ 1.25 (t, J=7.1Hz, 3H), 2.12 (s, 3H), 3.29 (s, 2H), 3.48 (s, 2H), 4.14 (q, J=7.1Hz, 2H), 6.77-6.83 (m, 1H), 6.94-6.99, (m, 1H), 7.23-7.27 (m, 1H) ppm;
13C NMR (100MHz, CDCl
3) δ 14.1,14.3,31.5,42.1,60.9,105.8 (d, J
C-F=23.0Hz), 110.3 (d, J
C-F=23.0Hz), 123.7 (d, J
C-F=9.0Hz), 129.6 (d, J
C-F=3.0Hz), 137.2 (d, J
C-F=2.0Hz) 144.6,147.8 (d, J
C-F=9.0Hz), 162.2 (d, J
C-F=240.0Hz), 170.7ppm; MS (ESI) m/z 257 (M+Na
+, 100%).
5-fluoro-2-methyl-3-indeneacetic acid (5b): fusing point is 160-164 ℃.IR(film)v
max3425，1702，1636，1616，1471，1230，1169，918，854，799cm
-1；
1H?NMR(400MHz，CDCl
3)δ2.11(s，3H)，3.29(s，2H)，3.51(s，2H)，6.77-6.82(m，1H)，6.94-6.96，(m，1H)，7.23-7.27(m，1H)ppm；
13C?NMR(100MHz，CDCl
3)δ14.2，311，42.1，105.7(d，J
C-F＝23.5Hz)，110.5(d，J
C-F＝23.0Hz)，123.8(d，J
C-F＝9.2Hz)，128.9，137.1，145.2，147.5(d，J
C-F＝8.8Hz)，162.5(d，J
C-F＝241.5Hz)，176.6ppm；MS(ESI)m/z?207(M+H
+，80％)，229(M+Na
+，100％)。
The preparation of embodiment 6:5-fluoro-2-methyl-3-indeneacetic acid (5b)
With embodiment 5, ethyl bromoacetate is substituted with methyl bromoacetate, making product is 5-fluoro-2-methyl-3-indeneacetic acid (5b), proterties is a white solid, productive rate 80%.
The preparation of embodiment 7:5-fluoro-2-methyl-3-indeneacetic acid (5b)
With embodiment 5, ethyl bromoacetate is substituted with benzyl acetate bromide, making product is 5-fluoro-2-methyl-3-indeneacetic acid (5b), proterties is a white solid, productive rate 84%.
The preparation of embodiment 8:5-fluoro-2-methyl isophthalic acid-(4-methylbenzene methylene radical)-3-indeneacetic acid (K-80001)
Add 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) 650mg (3mmol) in the 25mL round-bottomed flask, use the 5mL dissolve with methanol, drip sodium methylate/methanol solution 3mL under the room temperature, stir and drip 4-tolyl aldehyde (12a) 0.35mL (3mmol) after 20 minutes again, keep 3h after reaction is warming up to 60 ℃.Reaction finishes, and removes methyl alcohol under reduced pressure, and remaining dope acetic acid ethyl dissolution is acidified to pH=3～4 with the 1N hydrochloric acid soln, with ethyl acetate extraction 3 times (15mL * 3), merges organic phase, and anhydrous sodium sulfate drying filters, and removes ethyl acetate under reduced pressure.Purified principal product (Z)-5-fluoro-2-methyl isophthalic acid-(4-methylbenzene methylene radical)-3-indeneacetic acid (K-80001) 804mg, the productive rate 87% of getting of crude product.Proterties is a yellow solid, and fusing point is 155-158 ℃; IR (film) v
Max3426,3022,2959,2915,1733,1717,1655,1599,1512,1470,1408,1381,1214,1172cm
-1 1H NMR (400MHz, CDCl
3) δ 2.19 (s, 3H), 2.41 (s, 3H), 3.58 (s, 2H), 6.53-6.59 (m, 1H), 6.85-6.89 (m, 1H), 7.16-7.44 (m, 6H) ppm;
13C NMR (100MHz, CDCl
3) δ 10.6,21.4,31.4,105.7 (d, J
C-F=23.0Hz), 110.6 (d, J
C-F=23.0Hz), 123.8 (d, J
C-F=9.0Hz), 129.2,129.3,129.8 (2C), 129.9 (d, J
C-F=3.0Hz), 131.0 (2C), 133.5,138.3,139.0,139.8,146.2 (d, J
C-F=9.0Hz), 162.7 (d, J
C-F=245.0Hz), 176.7ppm; MS (ESI) m/z 363 (M+Na
+, 100%) and .Anal.Calcd for C
20H
17FO
2: C, 77.90; H, 5.56.Found:C, 77.88; H, 5.99.
The preparation of embodiment 9:5-fluoro-2-methyl isophthalic acid-(4-ethylbenzene methylene radical)-3-indeneacetic acid (K-80002)
With embodiment 8,4-tolyl aldehyde (12a) is substituted with 4-ethylbenzene formaldehyde (12b), make (Z)-5-fluoro-2-methyl isophthalic acid-(4-ethylbenzene methylene radical)-3-indeneacetic acid (K-80002), productive rate 83%.Proterties is a yellow solid, and fusing point is 159-162 ℃ of .IR (film) v
Max3082,3024,2965,2923,1705,1604,1473,1465,1413,1312,1229,1168cm
-1 1H NMR (400MHz, CDCl
3) δ 1.29 (t, J=7.6Hz, 3H), 2.20 (s, 3H), 2.71 (q, J=7.6Hz, 2H), 3.59 (s, 2H), 6.54-6.60 (m, 1H), 6.86-6.90 (m, 1H), 7.19-7.44 (m, 6H) ppm;
13C NMR (100MHz, CDCl
3) δ 10.6,15.4,28.7,31.4,105.6 (d, J
C-F=23.0Hz), 110.6 (d, J
C-F=22.0Hz), 123.8 (d, J
C-F=8.0Hz), 128.0 (2C), 129.4 (2C), 129.7,129.9,131.0,133.7,138.9,139.7,144.6,146.1,162.6 (d, J
C-F=244.0Hz), 176.4ppm; MS (ESI) m/z 345 (M+Na
+, 100%) and .Anal.Calcd for C
21H
19FO
2: C, 78.24; H, 5.94.Found:C, 78.21; H, 5.55.
The preparation of embodiment 10:5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003)
With embodiment 8,4-tolyl aldehyde (12a) is substituted with 4-isopropyl benzene formaldehyde (12c), make (Z)-5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003), proterties is a yellow solid, productive rate 85%.Fusing point is 146-149 ℃; IR (KBr) v
Max3025,2958,2871,1701,1629,1603,1507,1464,1412,1315,1293,1171,1134cm
-1 1H NMR (400MHz, CDCl
3) δ 1.31 (d, J=6.9Hz, 6H), 2.20 (s, 3H), 2.97 (sept, J=6.9Hz, 1H), 3.59 (s, 2H), 6.55-6.61 (m, 1H), 6.85-6.90 (m, 1H), 7.19 (s, 1H), 7.25-7.45 (m, 5H);
13C NMR (100MHz, CDCl
3) δ 10.6,23.9,31.3,34.0,105.6 (d, J
C-F=24.7Hz), 110.6 (d, J
C-F=22.6Hz), 123.8 (d, J
C-F=9.2Hz), 126.5 (2C), 129.4 (2C), 129.7,129.8,131.0,133.7,139.0,139.6,146.2 (d, J
C-F=8.8Hz), 149.3,162.5 (d, J
C-F=245.6Hz), 176.1ppm; MS (ESI) m/z 359 (M+Na
+, 100%) and .Anal.Calcdfor C
22H
21FO
2: C, 78.55; H, 6.29.Found:C, 78.13; H, 6.02.
Embodiment 11:(Z)-preparation of 5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003)
With embodiment 8,5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) is substituted with 5-fluoro-2-methyl-3-indeneacetic acid (5b), 4-tolyl aldehyde (12a) is substituted with 4-isopropyl benzene formaldehyde (12c), make (Z)-5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003), productive rate 88%.
Embodiment 12:(Z)-preparation of 5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003)
With embodiment 8, with the mixture replacing of 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) with 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) and 5-fluoro-2-methyl-3-indeneacetic acid (5b), 4-tolyl aldehyde (12a) is substituted with 4-isopropyl benzene formaldehyde (12c), make (Z)-5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid (K-80003), productive rate 83%.
Claims (10)
1. the synthetic method of the intermediate of sulindac analogue is characterized in that the intermediate 5-fluoro-2-methyl-3-indeneacetic acid ethyl ester (5a) of described sulindac analogue and the chemical structural formula of 5-fluoro-2-methyl-3-indeneacetic acid (5b) are:
Its concrete steps are:
1) be starting raw material with the 4-fluorobenzaldehyde, propionic anhydride is a solvent, with propionic anhydride generation perkin's reaction, obtains 4-fluoro-2-tolyl acrylic acid under organic bases or inorganic salt effect;
2) the 4-fluoro-2-tolyl acrylic acid that step 1) is obtained is by the palladium carbon catalysis of 5%～20% palladium content, and reduction obtains 3-(4-fluorophenyl)-2 Methylpropionic acid in atmosphere of hydrogen;
3) under the polyphosphoric acid effect, 3-(4-fluorophenyl)-2 Methylpropionic acid issues at heating condition and gives birth to intramolecular friedel-crafts acylation, forms 6-fluoro-2-methyl indone;
4) 6-fluoro-2-methyl indone and halogenated acetic acids ester be under the effect of activatory zinc powder, and reformatsky reaction takes place, in acidic solution, eliminate behind the crude product and obtain 5-fluoro-2-methyl-3-indeneacetic acid ester.
2. the synthetic method of the intermediate of sulindac analogue as claimed in claim 1 is characterized in that in step 1), and described organic bases is Sodium Propionate or potassium propionate; Described inorganic salt are salt of wormwood.
3. the synthetic method of the intermediate of sulindac analogue as claimed in claim 1 is characterized in that in step 1), and the molar feed ratio of described organic bases and 4-fluorobenzaldehyde is 1～2: 1, and preferred feed ratio is 11～1.5: 1; The molar feed ratio of described inorganic salt and 4-fluorobenzaldehyde is 1～2: 1, and preferred feed ratio is 11～1.5: 1.
4. the synthetic method of the intermediate of sulindac analogue as claimed in claim 1 is characterized in that in step 1) the temperature of described perkin's reaction is 100～200 ℃, is preferably 135～165 ℃; The 4-fluorobenzaldehyde is 1: 5～20 with the molecular volume ratio of propionic anhydride, is preferably 1: 10.
5. the synthetic method of the intermediate of sulindac analogue as claimed in claim 1 is characterized in that in step 2) in, described atmosphere of hydrogen is the atmosphere of hydrogen of 3～9 standard atmospheric pressures; Described palladium carbon is the palladium carbon of 10% palladium content.
6. the synthetic method of the intermediate of sulindac analogue as claimed in claim 1 is characterized in that in step 3), and the consumption of described polyphosphoric acid is 5～30 times of 3-(4-fluorophenyl)-2 Methylpropionic acid by mass ratio, preferred 8～10 times.
7. the synthetic method of the intermediate of sulindac analogue as claimed in claim 1 is characterized in that in step 3), and the temperature of described heating is 55～120 ℃, preferred 75～95 ℃.
8. the synthetic method of the intermediate of sulindac analogue as claimed in claim 1 is characterized in that in step 4), and described monobromo-acetic acid ester is C
1～C
10Aliphatic alcohol ester or C
6～C
10Phenolic ester is preferably methyl bromoacetate, ethyl bromoacetate and benzyl acetate bromide; Being used for the reagent of activated zinc powder adopts I
2, CuCl, CuI, (CH
3)
3SiCl or glycol dibromide; The molar feed ratio of described 6-fluoro-2-methyl indone and zinc powder, halogenated acetic acids ester is 1: (1～3): (1～3), and preferred molar feed ratio is 1: (1.2～2): (1.1～1.5); Described reaction solvent for use is tetrahydrofuran (THF), ethyl acetate, ether, toluene, benzene or N, dinethylformamide, and preferred solvent is tetrahydrofuran (THF), ether or toluene; The temperature of described reaction is room temperature～150 ℃, and preferable reaction temperature is 35～110 ℃, and the time of reaction is 1～24h, and the preferred reaction time is 1～5h.
9. the synthetic method of the intermediate of sulindac analogue as claimed in claim 1, it is characterized in that in step 4), the used acidic conditions of described elimination reaction is an acidic solution, described acidic solution is selected from least a in mineral acid, the organic acid, and described mineral acid is selected from a kind of in hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, the phosphoric acid; Described organic acid is selected from a kind of in formic acid, acetate, propionic acid, butyric acid, the phenylformic acid, and the volume ratio of organic acid and mineral acid is 0.1～1: 1.
10. as the application of intermediate in preparation antitumour activity sulindac analogue 5-fluoro-2-methyl isophthalic acid-(4-methylbenzene methylene radical)-3-indeneacetic acid, 5-fluoro-2-methyl isophthalic acid-(4-ethylbenzene methylene radical)-3-indeneacetic acid or 5-fluoro-2-methyl isophthalic acid-(4-isopropyl benzene methylene radical)-3-indeneacetic acid of method synthetic sulindac analogue as described in any claim in the claim 1～9.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102701974A (en) * | 2012-05-25 | 2012-10-03 | 湖北远成药业有限公司 | Method for synthesizing cinnamate derivatives |
| WO2015100267A1 (en) * | 2013-12-23 | 2015-07-02 | Sanford-Burnham Medical Research Institute | Methods and compositions for treating cancer |
| US9611235B2 (en) | 2010-05-06 | 2017-04-04 | Sanford-Burnham Medical Research Institute | Methods and compositions related to a retinoid receptor-selective pathway |
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|---|---|---|---|---|
| US5902827A (en) * | 1998-04-17 | 1999-05-11 | Cell Pathways | Method for treating patients with psoriasis by administering substituted sulfonyl indenyl acetic acids, esters and alcohols |
| US6020379A (en) * | 1999-02-19 | 2000-02-01 | Cell Pathways, Inc. | Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5902827A (en) * | 1998-04-17 | 1999-05-11 | Cell Pathways | Method for treating patients with psoriasis by administering substituted sulfonyl indenyl acetic acids, esters and alcohols |
| US6020379A (en) * | 1999-02-19 | 2000-02-01 | Cell Pathways, Inc. | Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9611235B2 (en) | 2010-05-06 | 2017-04-04 | Sanford-Burnham Medical Research Institute | Methods and compositions related to a retinoid receptor-selective pathway |
| US10087156B2 (en) | 2010-05-06 | 2018-10-02 | Sanford Burnham Prebys Medical Discovery Institute | Methods and compositions related to retinoid receptor-selective pathway |
| CN102701974A (en) * | 2012-05-25 | 2012-10-03 | 湖北远成药业有限公司 | Method for synthesizing cinnamate derivatives |
| WO2015100267A1 (en) * | 2013-12-23 | 2015-07-02 | Sanford-Burnham Medical Research Institute | Methods and compositions for treating cancer |
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