JP2009040790A - Process for preparing 5-fluorooxyindole - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially suitable process for preparing 5-fluorooxyindole which obtains 5-fluorooxyindole from an easily available 2-(5-fluoro-2-nitrophenyl) malonic acid diester in a high yield by a simple method. <P>SOLUTION: The process for preparing 5-fluorooxyindole comprises (A) a first step of cyclizing 2-(5-fluoro-2-nitrophenyl)malonic acid diester under reducing conditions to form a 5-fluorooxyindole-3-carboxylic acid ester and then (B) a second step of decarboxylating the 5-fluorooxyindole-3-carboxylic acid ester. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a process for producing 5-fluorooxindole from 2- (5-fluoro-2-nitrophenyl) malonic acid diester. 5-fluorooxindole is a useful compound as a synthetic intermediate for pharmaceuticals such as anticancer agents and anti-inflammatory analgesics.

Conventionally, as a method for producing 5-fluoro oxindole from 2- (5-fluoro-2-nitrophenyl) malonic acid diester, in Synthesis, 1993, 51, in a mixed solvent of water and dimethyl sulfoxide, 2- ( Lithium chloride is allowed to act on dimethyl 5-fluoro-2-nitrophenyl) malonate to form methyl 5-fluoro-2-nitrophenylacetate, and then decarboxylated in acetic acid in the presence of iron. Describes a process for producing 5-fluorooxindole. However, this method has a problem that the reaction system is complicated and the total yield of the target product is as low as 49%.

  The object of the present invention is to solve the above-mentioned problems and to produce 5-fluorooxindole in high yield from 2- (5-fluoro-2-nitrophenyl) malonic acid diester which is easily available by a simple method. An industrially suitable process for producing 5-fluorooxindole obtained in (1) is provided.

  The subject of this invention is (A) General formula (1).

(In the formula, R ¹ and R ² may be the same or different and each represents a group not involved in the reaction.)
2- (5-Fluoro-2-nitrophenyl) malonic acid diester represented by the general formula (2)

(In the formula, R ¹ has the same meaning as described above.)
A first step of producing a 5-fluorooxyindole-3-carboxylic acid ester represented by formula (B), and then a second step of decarboxylating the 5-fluorooxyindole-3-carboxylic acid ester. (3), characterized by

It is solved by the process for producing 5-fluorooxindole represented by

  According to the present invention, industrially suitable 5-fluorooxindole is obtained in a high yield from 2- (5-fluoro-2-nitrophenyl) malonic acid diester which is easily available by a simple method. A method for producing oxindole can be provided.

  In the present invention, (A) 2- (5-fluoro-2-nitrophenyl) malonic acid diester represented by the general formula (1) is cyclized under reducing conditions to give a 5- 5-step by two steps comprising a first step of producing a fluorooxyindole-3-carboxylic acid ester, (B) and then a second step of decarboxylating the 5-fluorooxyindole-3-carboxylic acid ester. Fluorooxindole is obtained as a reaction product.

Subsequently, the two steps will be sequentially described.
(A) First Step In the first step of the present invention, 2- (5-fluoro-2-nitrophenyl) malonic acid diester represented by the general formula (1) is cyclized under reducing conditions to give a general formula ( In this step, a 5-fluorooxyindole-3-carboxylic acid ester represented by 2) is obtained.

The 2- (5-fluoro-2-nitrophenyl) malonic acid diester used in the first step of the present invention is represented by the general formula (1). In the general formula (1), R ¹ and R ² may be the same or different and are groups not involved in the reaction. Specifically, for example, an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group Show.

  As the alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferable, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. Is mentioned. These groups include various isomers.

  The cycloalkyl group is particularly preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. These groups include various isomers.

  The aralkyl group is particularly preferably an aralkyl group having 7 to 10 carbon atoms, and examples thereof include a benzyl group, a phenethyl group, a phenylpropyl group, and a phenylbutyl group. These groups include various isomers.

  As the aryl group, an aryl group having 6 to 14 carbon atoms is particularly preferable, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, and an anthranyl group. These groups include various isomers.

  Although the 1st process of this invention will not be specifically limited if it is the reduction method generally performed, It is preferable to perform in the hydrogen atmosphere in presence of a catalyst.

  The catalyst contains at least one metal atom selected from the group consisting of palladium, platinum, and nickel. Specifically, for example, palladium / carbon, palladium / barium sulfate, palladium hydroxide / carbon, platinum / Carbon, palladium-platinum / carbon, platinum oxide, Raney-nickel, etc. are mentioned, but palladium / carbon is preferably used.

  The amount of the catalyst used is preferably 0.01 to 1.0% by weight, more preferably 0.05 to 0.5% by weight, in terms of metal atom, based on 2- (5-fluoro-2-nitrophenyl) malonic acid diester. In addition, you may use these catalysts individually or in mixture of 2 or more types.

  The first step of the present invention is preferably carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction, water; alcohols such as methanol and ethanol; methyl acetate; Esters such as ethyl acetate; aromatic short or hydrogen compounds such as benzene and toluene; ethers such as tetrahydrofuran and dioxane are preferable, but water, alcohols, esters, more preferably water, methanol, ethanol, Ethyl acetate is used.

  The amount of the solvent used is appropriately adjusted depending on the uniformity and agitation of the solution, but is preferably 3 to 50 times by weight, more preferably 2 to 5- (5-fluoro-2-nitrophenyl) malonic acid diester. 5 to 30 times by weight. In addition, you may use these solvents individually or in mixture of 2 or more types.

  The first step of the present invention is performed by, for example, a method of mixing 2- (5-fluoro-2-nitrophenyl) malonic acid diester, catalyst and solvent in a hydrogen atmosphere and stirring. The reaction pressure at that time is preferably 0.1 to 5 MPa, more preferably 0.1 to 2 MPa, and the reaction temperature is preferably 20 to 80 ° C., more preferably 30 to 60 ° C.

  In the first step of the present invention, a solution containing 5-fluorooxindole-3-carboxylic acid ester as a main product is obtained. In the present invention, however, the solution is usually separated after separation of the catalyst if necessary. The next step is carried out as is or after concentration. However, in some cases, the produced 5-fluorooxyindole-3-carboxylic acid ester is once isolated by a general method such as recrystallization, distillation, column chromatography, etc., and then the next step is performed. Also good.

  Further, the general formula (2) obtained in the first step of the present invention.

(Wherein R ¹ has the same meaning as described above), 5-fluorooxyindole-3-carboxylic acid ester (keto type) is a novel compound useful as an intermediate of 5-fluorooxyindole. . In the solution, the general formula (4)

(Wherein, R ¹ has the same meaning as described above), and may be in equilibrium with the enol type.

(B) Second Step In the second step of the present invention, 5-fluorooxyindole-3-carboxylic acid ester represented by the general formula (2) obtained in the first step is decarboxylated to give 5-fluorooxy This is a process for obtaining indole.

  The second step of the present invention is not particularly limited as long as it is a general decarboxylation method, but it is preferably performed in the presence of an acid.

  Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, acetic acid, and the like. Preferably, hydrochloric acid and sulfuric acid are used.

  The amount of the acid used is preferably 1 to 10 times mol, more preferably 2 to 5 times mol, with respect to the 5-fluorooxyindole-3-carboxylic acid ester. In addition, you may use these acids individually or in mixture of 2 or more types.

  In the second step of the present invention, the reaction is preferably carried out in the presence of a solvent, and the solvent to be used is not particularly limited as long as it does not inhibit the reaction. Water; methanol, ethanol, n-butyl alcohol, t- Examples include alcohols such as butyl alcohol, ethers such as tetrahydrofuran and dioxane; hydrocarbons such as cyclohexane and toluene, preferably water, alcohols and ethers, more preferably water, methanol and ethanol. .

  The amount of the solvent used is appropriately adjusted depending on the uniformity and agitation of the solution, but is preferably 2 to 20 times by weight, more preferably 4 to 10% by weight with respect to the 5-fluorooxyindole-3-carboxylic acid ester. Is double. In addition, you may use these solvents individually or in mixture of 2 or more types.

  In the second step of the present invention, for example, in an inert gas atmosphere, the 5-fluorooxindole-3-carboxylic acid ester obtained in the first step or a reaction solution containing this, an acid and a solvent are mixed, It is performed by a method such as stirring. The reaction temperature at that time is preferably 20 to 110 ° C., more preferably 50 to 90 ° C., and the reaction pressure is not particularly limited.

  The 5-fluorooxindole obtained in the second step of the present invention is separated and purified by a general method such as recrystallization, distillation, column chromatography or the like.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Reference example 1
(Synthesis of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate)
Under an argon atmosphere, 3.40 g (62.9 mmol) of sodium methoxide and 30 ml of dimethyl sulfoxide were added to a glass flask having an internal volume of 200 ml equipped with a stirrer, thermometer, distillation apparatus and dropping funnel, and then stirred at room temperature. Then, 8.48 g (62.9 mmol) of dimethyl malonate having a purity of 98% was slowly added dropwise over 5 minutes. Furthermore, 10 ml of cyclohexane was added, and after raising the temperature to 100 to 105 ° C., the produced methanol was azeotropically distilled (evaporated) together with cyclohexane. After repeating this operation (distilling off methanol) twice, the mixture was cooled to 70 ° C., and 5.10 g (31.4 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was slowly added dropwise over 10 minutes. The reaction was carried out at 1 ° C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of toluene was added, and 5.25 ml (31.4 mmol) of 6 mol / l hydrochloric acid was slowly added dropwise with stirring. Next, the organic layer was separated, washed with water (50 ml) and saturated brine (50 ml) in that order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, developing solvent: hexane: ethyl acetate = 9: 1 (volume ratio)) to give white crystals, 5.60 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate with a purity of 98% (area percentage of high performance liquid chromatography) was obtained (isolation yield 64%). The physical properties of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate were as follows.

EI-MS (m / e); 225 (M-NO ₂ ), CI-MS (m / e); 272 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 3.82 (6H, s), 5.40 (1H, s), 7.20 to 7.35 (2H, m), 8.1 to 8.2 (1H, m)

Example 1
98% pure 2- (5-fluoro-2-nitrophenyl) malon synthesized according to Reference Example 1 in a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer and a gas introduction tube under an argon atmosphere 3.93 g (14.2 mmol) of dimethyl acid, 0.5 g of 5 wt% palladium / carbon (49% water-containing product) (0.12 mmol as palladium atom) and 50 ml of ethyl acetate were added. Subsequently, the inside of the system was replaced with hydrogen and reacted at 20 ° C. for 2 hours under a hydrogen pressure of 0.15 MPa. After completion of the reaction, the reaction solution was filtered to remove the catalyst, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, developing solvent: chloroform), As white crystals, 2.76 g of 5-fluoro-3-methoxycarbonyloxyindole having a purity of 99% (area percentage by high performance liquid chromatography) was obtained (isolation yield: 92%). 5-Fluoro-3-methoxycarbonyloxyindole is a novel compound having the following physical properties. From the integral value of ¹ H-NMR, keto type and enol type were present at a ratio of 1: 2.2 in deuterated chloroform.

Melting point: 142-143 ° C
EI-MS (m / e); 209 (M +), CI-MS (m / e); 210 (M + 1)
FT-IR (KBr method, cm ⁻¹ ); 3300-2600, 1647, 1569, 1481, 1204, 1160, 1108
¹ H-NMR (CDCl ₃ , δ (ppm));
Keto type: 3.82 (3H, s), 4.48 (1H, s), 6.81 to 6.88 (1H, m), 6.99 (1H, ddd, J = 2.7, 8.5, 8.5Hz), 7.08 to 7.13 (1H, m) 8.18 (1H, s)
Enol type: 3.97 (3H, s), 6.81 to 6.88 (1H, m), 6.96 to 7.02 (1H, m), 7.39 (1H, dd, J = 2.3, 9.4Hz), 8.24 (1H, s)

Example 2
A 98% pure 2- (5-fluoro-2-2) compound synthesized according to Reference Example 1 under an argon atmosphere in a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer, a reflux condenser and a gas introduction tube. 60.0 g (0.22 mol) of dimethyl nitrophenyl) malonate and 228 g of methanol were added. While stirring, while maintaining the liquid temperature at 40 to 45 ° C., 3.0 g of 5 wt% palladium / carbon (49% water-containing product) (0.72 mmol as palladium atom) was added. Subsequently, the reaction was carried out at the same temperature for 3 hours while blowing hydrogen at a flow rate of 123 ml / min at normal pressure. After completion of the reaction, the reaction solution was filtered to remove the catalyst, and then the filtrate was concentrated under reduced pressure. To the resulting concentrate, 80 ml of methanol and 240 ml of water were added and cooled to 10 ° C. Next, the precipitated crystals were filtered and dried to obtain 54.5 g of 5-fluoro-3-methoxycarbonyloxyindole having a purity of 80% (analyzed by high performance liquid chromatography) as white crude crystals (isolated product). 94%).

Example 3
5-Fluoro-3-methoxy with a purity of 80% (analyzed by high performance liquid chromatography) synthesized in Example 2 was placed in a glass flask having an internal volume of 500 ml equipped with a stirrer, thermometer, dropping funnel and reflux condenser. Crude crystals of carbonyloxyindole (26.5 g, 0.10 mol), methanol (66.9 g), and 6 mol / l hydrochloric acid (52.0 ml, 0.31 mol) were added and reacted at 70-80 ° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 55.0 ml (0.44 mol) of 8 mol / l sodium hydroxide aqueous solution was added, and the mixture was stirred at 40 ° C. for 30 minutes. Then 8.3 ml (0.10 mol) of 12 mol / l hydrochloric acid was added. After distilling off methanol under reduced pressure, the reaction solution was cooled to 0 to 5 ° C., and a solid was precipitated. The obtained solid was recrystallized from isopropyl alcohol / water to obtain 12.6 g of 5-fluorooxindole having a purity of 99% (area percentage by high performance liquid chromatography) as white crystals (isolation yield 80%). The physical property values of 5-fluorooxindole were as follows.

Melting point: 141-142 ° C
EI-MS (m / e); 151 (M +), CI-MS (m / e); 152 (M + 1)
Elemental analysis: carbon 63.56%, hydrogen 4.02%, nitrogen 9.29%
(Theoretical value (C ₈ H ₆ NOF); carbon 63.57%, hydrogen 4.00%, nitrogen 9.27%)
FT-IR (KBr method, cm ⁻¹ ); 3400-2500, 1700, 1633, 1485, 1317, 1195, 745, 673, 591
¹ H-NMR (CDCl ₃ , δ (ppm)); 3.56 (2H, s), 6.75 to 6.85 (1H, m), 6.85 to 7.00 (2H, m), 9.03 (1H, brs)

Claims (5)

(A) General formula (1)

(Wherein R ¹ and R ² may be the same or different and each represents a group not involved in the reaction). The 2- (5-fluoro-2-nitrophenyl) malonic acid diester represented by And cyclized with general formula (2)

(In the formula, R ¹ has the same meaning as described above.) (B) Next, 5-fluorooxyindole-3-carboxylic acid ester is produced. A second step of decarboxylating the acid ester, comprising formula (3)

The manufacturing method of 5-fluoro oxindole shown by these.   The process for producing 5-fluorooxindole according to claim 1, wherein the cyclization under reducing conditions in the first step is carried out in a hydrogen atmosphere in the presence of a catalyst.   The process for producing 5-fluorooxindole according to claim 2, wherein the catalyst contains at least one metal atom selected from the group consisting of palladium, platinum and nickel.   The method for producing 5-fluorooxindole according to claim 1, wherein the decarboxylation in the second step is carried out in the presence of an acid. General formula (2)

(Wherein R ¹ has the same meaning as described above), 5-fluorooxyindole-3-carboxylic acid ester.