CN104045592A - 5-fluoroindole-2-one preparation method - Google Patents

Abstract

The invention relates to a 5-fluoroindole-2-one preparation method. The method includes the steps of (1) reaction of 2, 4-difluornitrobenzene and dimethyl malonate to prepare 4-fluoro-2-(methyl malonate) nitrobenzene; and (2) reduction cyclization reaction of the 4-fluoro-2-(methyl malonate) nitrobenzene by iron powder to obtain target object 5-fluoroindole-2-one, or palladium/carbon reduction of the 4-fluoro-2-(methyl malonate) nitrobenzene to obtain target object 3-methoxycarbonyl-5-fluoroindole-2-one, and then hydrolysis reaction of the 3-methoxycarbonyl-5-fluoroindole-2-one to obtain the target object 5-fluoroindole-2-one. The method has the advantages of easily obtained raw materials, mild reaction conditions, high yield, less equipment investment, easy industrial production and the like.

Description

Process for preparing 5-fluoroindol-2-one

technical field

The invention relates to a preparation method of indole derivatives, in particular to a preparation method of 5-fluoroindol-2-one.

Background technique

5-fluoroindol-2-one is a very important pharmaceutical intermediate, widely used in the synthesis of analgesic and anti-inflammatory drugs. In recent years, it has also been used as a synthetic raw material for the synthesis of new multi-targeted oral drug Sunitinib and its derivatives for the treatment of tumors, which has gradually increased the market demand. At present, there is no supplier with mature production technology in China, so it is very necessary to synthesize and optimize it.

At present, 5-fluoroisatin, 2-methyl-4-fluoroaniline, 4-fluoroaniline, 3-fluoro-6-nitrophenylacetic acid and 2,4-difluoronitrobenzene are mainly used in its synthetic methods. as raw materials ([1] Shen Xuequan et al., Chemical Times, 2012, 26(4): 29-32; [2] Chen Xiuquan et al., Applied Chemical Industry, 2007, 36(9): 901-903; [3] Quallich G.J.et al.Synthsis1993,1993(1):51-53; [4]Harada,K.et al.WO0206228.2002-01-24;[5]Clark,R.D.et al.Synthesis,1991,1991(10):871 -878; [6] Kikugawa, Y.et al.J.Chem.Soc.1992,12:921-922.), synthesize 5-fluoroindol-2-one through one or more steps of reaction.

Based on the analysis of the above documents, most of the raw materials used in these documents have the disadvantages of expensive raw materials, harsh reaction conditions and unsatisfactory yields. The synthesis method using 2,4-difluoronitrobenzene as a raw material has some defects, and industrial production cannot be realized.

In view of this, it is a problem to be solved in the present invention to provide a method for preparing 5-fluoroindol-2-one from 2,4-difluoronitrobenzene (starting material) with simple steps.

Contents of the invention

The object of the present invention is to provide a method for preparing 5-fluoroindol-2-one from 2,4-difluoronitrobenzene (starting material), mild preparation conditions and low preparation cost, which overcomes the prior art problems in .

Method of the present invention comprises the steps:

(1) The step of preparing 4-fluoro-2-(dimethyl malonate) nitrobenzene by reacting 2,4-difluoronitrobenzene with dimethyl malonate;

or

First, 4-fluoro-2-(dimethylmalonate) nitrobenzene is reduced by palladium/carbon to obtain 3-methoxycarbonyl-5-fluoroindol-2-one, and then 3-methoxycarbonyl -5-fluoroindol-2-one undergoes a hydrolysis reaction to obtain the target product.

Known from the above-mentioned technology, the present invention takes 2,4-difluoronitrobenzene as starting raw material, through esterification with dimethyl malonate, iron powder reduction-cyclization or palladium carbon reduction-cyclization and hydrolysis to obtain 5 -Fluoroindol-2-one, and optimize the parameters in the method to increase the yield. The invention has the advantages of cheap and easy-to-obtain raw materials, simple operation of the synthesis method, high yield and the like, and is suitable for industrialized production.

Detailed ways

In a preferred technical scheme of the present invention, the reaction between 2,4-difluoronitrobenzene and dimethyl malonate is carried out in the presence of sodium methylate, and the reaction temperature is 5°C to 25°C (the more preferred reaction The temperature is 5°C to 10°C, and the optimum reaction temperature is 8°C).

In another preferred technical scheme of the present invention, the molar ratio of 2,4-difluoronitrobenzene, dimethyl malonate and sodium methylate is 1:(2～4):(2～4), 2, The optimal molar ratio of 4-difluoronitrobenzene, dimethyl malonate and sodium methoxide is 1:3:3.

In yet another preferred technical scheme of the present invention, 4-fluoro-2-(dimethylmalonate) nitrobenzene is reduced into a ring by iron powder in the presence of a mixture of acetic acid solution and hydrochloric acid solution Under conditions, in the mixture, the volume ratio of the acetic acid solution to the hydrochloric acid solution is (1-2):1, and the optimum volume ratio of the acetic acid solution to the hydrochloric acid solution is 2:1.

In yet another preferred technical solution of the present invention, the molar ratio of 4-fluoro-2-(dimethylmalonate) nitrobenzene to iron powder is 1:(2～5), 4-fluoro-2- The optimum molar ratio of (dimethyl malonate) nitrobenzene to iron powder is 1:4.

In yet another preferred technical scheme of the present invention, 3-methoxycarbonyl-5-fluoroindole-2 is obtained by palladium/carbon reduction of 4-fluoro-2-(dimethylmalonate) nitrobenzene -In the reaction of ketones, the molar weight of palladium is 0.5mol%～10mol% with the molar weight of 4-fluoro-2-(malonate dimethyl) nitrobenzene as calculation basis, the optimal palladium molar weight 1 mol%.

In yet another preferred technical scheme of the present invention, the target object (5-fluoroindol-2-one) is obtained through a hydrolysis reaction of 3-methoxycarbonyl-5-fluoroindol-2-one, and the hydrolysis reaction is It is carried out in the presence of 6M hydrochloric acid aqueous solution, the molar ratio of 3-methoxycarbonyl-5-fluoroindol-2-one to 6M hydrochloric acid aqueous solution is 1:(2~4), 3-methoxycarbonyl-5- The optimum molar ratio of fluoroindol-2-one to 6M hydrochloric acid aqueous solution is 1:3.

The invention has the advantages of easy-to-obtain raw materials, mild reaction, high yield, less equipment investment, easy industrial production and the like.

The present invention will be further elaborated below by the examples, and the examples given are all illustrative, not restrictive.

Example 1

(1) Preparation of 4-fluoro-2-(dimethylmalonate) nitrobenzene

Under the protective atmosphere of N ₂ , add 6.48g (120.0mmol) NaOCH ₃ and dried dimethyl sulfoxide (30mL) in the reaction flask, add 15.85g (120.0mmol) dimethyl malonate dropwise at room temperature (Dropping time is greater than 10min) and stirred, and then cooled to 8°C and slowly and uniformly added 6.36g (40.0mmol) of 2,4-difluoronitrobenzene (dropping time is greater than 40min). Continue to react, TLC tracks the reaction, after the completion of the reaction, add 14mL (80.0mmol) of 6M hydrochloric acid solution under constant stirring to quench, then add ethyl acetate and water to extract, combine the organic layers and wash 2 times with saturated brine, no Dried over sodium sulfate, spin-dried, and separated by column chromatography (eluted with ethyl acetate:petroleum ether=10:1) to obtain 4-fluoro-2-(dimethylmalonate)nitrobenzene, the yield was 88%.

(2) Preparation of 5-fluoroindol-2-one (target object)

Add 10.85g (40.0mmol) of raw material 10.85g (40.0mmol) 4-fluoro-2-(dimethylmalonate) nitrobenzene into the reaction flask, then add 40mL acetic acid and 80mL6M hydrochloric acid solution, reflux for 4h, then add 8.93g ( 160.0mmol) iron powder, continue to react, TLC tracking, after the completion of the reaction, stop heating, steam off the solvent, add ethyl acetate and stir, filter with diatomaceous earth and silica gel, wash the solid with ethyl acetate, and obtain the organic phase Washed twice with 1.0M hydrochloric acid solution, then washed with saturated brine and dried over anhydrous sodium sulfate, then concentrated, separated by column chromatography, and eluted with ethyl acetate:petroleum ether=3:1 (V/V) , to obtain solid 5-fluoroindol-2-one with a yield of 85%.

Example 2

(1) The preparation of 4-fluoro-2-(dimethylmalonate)nitrobenzene was the same as step (1) in Example 1.

(2) Preparation of 3-methoxycarbonyl-5-fluoroindol-2-one

Under _N2 atmosphere, add 2.71g (10.0mmol) 4-fluoro-2-(dimethylmalonyl)nitrobenzene and 0.24g (10% pd, 55% _H2O ) to the reaction flask Palladium carbon, after replacing the hydrogen, add 50mL of ethyl acetate, adjust the temperature to 20°C for reaction, TLC tracking, after the reaction is completed, add diatomaceous earth to filter, directly concentrate, column chromatography separation, use ethyl acetate: The compound 3-methoxycarbonyl-5-fluoroindol-2-one was eluted with petroleum ether=1:1 (V/V), and the yield was 92%.

(3) Preparation of 5-fluoroindol-2-one (target object)

Add 2.09g (10.0mmol) of 3-methoxycarbonyl-5-fluoroindol-2-one and 50mL of methanol in the reaction flask, add 5mL (30.0mmol) of 6M hydrochloric acid, and turn to reflux for reaction, TLC tracking After 2 hours of reaction, the solvent methanol was removed under reduced pressure, and ethyl acetate was added for extraction, then washed with saturated brine and dried with anhydrous sodium sulfate, then concentrated and separated by column chromatography, using ethyl acetate:petroleum ether=3: 1 (V/V) was eluted to give 5-fluoroindol-2-one as a white solid with a yield of 95%.

Example 3

(1) Preparation of 4-fluoro-2-(dimethylmalonate) nitrobenzene

Under the protective atmosphere of _N2 , 6.48g (120.0mmol) _NaOCH3 and dried dimethyl sulfoxide (30mL) were added to the reaction flask, and 13.21g (100.0mmol) dimethyl malonate was added dropwise at room temperature (Dropping time is greater than 10min) and stirred, and then cooled to 15°C and slowly and uniformly added 6.36g (40.0mmol) of 2,4-difluoronitrobenzene (dropping time is greater than 40min). Continue to react, TLC tracks the reaction, after the completion of the reaction, add 14mL (80.0mmol) of 6M hydrochloric acid solution under constant stirring to quench, then add ethyl acetate and water to extract, combine the organic layers and wash 2 times with saturated brine, no Dry over sodium sulfate, spin dry, and separate by column chromatography (eluted with ethyl acetate:petroleum ether=10:1 (V/V)) to obtain 4-fluoro-2-(dimethylmalonate) nitrate Base benzene, the yield is 80%.

(2) Preparation of 5-fluoroindol-2-one (target object)

Add 10.85g (40.0mmol) of raw material 10.85g (40.0mmol) 4-fluoro-2-(dimethylmalonate) nitrobenzene into the reaction flask, then add 40mL acetic acid and 80mL6M hydrochloric acid solution, reflux for 4h, then add 6.70g ( 120.0mmol) iron powder, continue to react, TLC tracking, after the completion of the reaction, stop heating, steam off the solvent, add ethyl acetate and stir, filter with diatomaceous earth and silica gel, wash the solid with ethyl acetate, and obtain the organic phase Washed twice with 1.0M hydrochloric acid solution, then washed with saturated brine and dried over anhydrous sodium sulfate, then concentrated, separated by column chromatography, and eluted with ethyl acetate:petroleum ether=3:1 (V/V) , to obtain solid 5-fluoroindol-2-one with a yield of 80%.

Example 4

(1) The preparation of 4-fluoro-2-(dimethylmalonate)nitrobenzene was the same as step (1) in Example 3.

(2) Preparation of 3-methoxycarbonyl-5-fluoroindol-2-one

Under _N2 atmosphere, add 2.71g (10.0mmol) 4-fluoro-2-(dimethylmalonyl)nitrobenzene and 0.24g (10% pd, 55% _H2O ) to the reaction flask Palladium carbon, after replacing the hydrogen, add 50mL of ethyl acetate, adjust the temperature to 30°C for reaction, TLC tracking, after the reaction is completed, add diatomaceous earth to filter, directly concentrate, column chromatography separation, use ethyl acetate: Petroleum ether=1:1 elution (v/v), the compound 3-methoxycarbonyl-5-fluoroindol-2-one was obtained with a yield of 85%.

(3) Preparation of 5-fluoroindol-2-one (target object)

Add 2.09g (10.0mmol) of 3-methoxycarbonyl-5-fluoroindol-2-one and 50mL of methanol in the reaction flask, add 3mL (18.0mmol) of 6M hydrochloric acid, and turn to reflux for reaction, TLC tracking After 2 hours of reaction, the solvent methanol was removed under reduced pressure, and ethyl acetate was added for extraction, then washed with saturated brine and dried with anhydrous sodium sulfate, then concentrated and separated by column chromatography, using ethyl acetate:petroleum ether=3: 1 (v/v) was eluted to give 5-fluoroindol-2-one as a white solid in a yield of 92%.

Claims (7)

1. prepared the method for 5-fluoro indole-2-ketone by 2,4-difluoro nitrobenzene for one kind, it is characterized in that, described method comprises the steps:

(1) reacted the step of the preparation fluoro-2-of 4-(dimethyl malonate base) oil of mirbane with dimethyl malonate by 2,4-difluoro nitrobenzene;

(2) by the fluoro-2-of 4-(dimethyl malonate base) oil of mirbane through iron powder reducing annulation, obtain the step of target compound (5-fluoro indole-2-ketone); Or

First reduced through palladium/carbon by the fluoro-2-of 4-(dimethyl malonate base) oil of mirbane, obtain 3-methoxycarbonyl-5-fluoro indole-2-ketone, then obtained the step of target compound by 3-methoxycarbonyl-5-fluoro indole-2-ketone through hydrolysis reaction.

2. the method for claim 1, is characterized in that, wherein 2, and 4-difluoro nitrobenzene reacts with dimethyl malonate under the condition that has sodium methylate to exist and carries out, and temperature of reaction is 5 DEG C～25 DEG C.

3. method as claimed in claim 2, is characterized in that, wherein, the mol ratio of 2,4-difluoro nitrobenzene, dimethyl malonate and sodium methylate is 1:(2～4): (2～4).

4. the method for claim 1, it is characterized in that, wherein, under the condition being existed at the mixture by being formed by acetum and hydrochloric acid soln through iron powder reducing annulation by the fluoro-2-of 4-(dimethyl malonate base) oil of mirbane, carry out, in described mixture, the volume ratio of acetum and hydrochloric acid soln is (1～2): 1.

5. method as claimed in claim 4, is characterized in that, wherein, the mol ratio of the fluoro-2-of 4-(dimethyl malonate base) oil of mirbane and iron powder is 1:(2～5).

6. the method for claim 1, it is characterized in that, wherein, reduced through palladium/carbon by the fluoro-2-of 4-(dimethyl malonate base) oil of mirbane, obtain in the reaction of 3-methoxycarbonyl-5-fluoro indole-2-ketone, taking the molar weight of the fluoro-2-of 4-(dimethyl malonate base) oil of mirbane as calculating benchmark, the molar weight of palladium is 0.5mol%～10mol%.

7. the method as described in claim 1 or 6, it is characterized in that, wherein, obtain target compound by 3-methoxycarbonyl-5-fluoro indole-2-ketone through hydrolysis reaction, described hydrolysis reaction is to carry out under 6M aqueous hydrochloric acid existence condition there being concentration, and the mol ratio of 3-methoxycarbonyl-5-fluoro indole-2-ketone and 6M aqueous hydrochloric acid is 1:(2～4).