JP4254093B2 - Method for producing 5-halogenoindole - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for producing 5-halogenoindoles. 5-halogenoindole is a compound useful as an intermediate raw material for pharmaceuticals, agricultural chemicals and the like, and in particular, 5-fluoroindole is a compound that can be a synthetic intermediate for pharmaceuticals such as antibiotics.
[0002]
[Prior art]
Conventionally, the following documents have been disclosed as a method for producing 5-halogenoindole.
(1) Heterocycles, 22 , 195 (1984); 5-halogeno-2-nitrotoluene in N, N-dimethylformamide was reacted with N, N-dimethylformamide dimethylacetal to give 5-halogeno-β-dimethylamino-2 A method for producing 5-halogenoindole by producing nitrostyrene and then reducing and cyclizing with Raney nickel in a hydrogen atmosphere is disclosed. However, this method has a problem that the yield of the desired product from 5-halogeno-2-nitrotoluene is low (46.9% for 5-fluoroindole and 68.6% for 5-chloroindole).
(2) J. Chem. Soc., 1959 , 1913; 5-fluoro-2-nitrotoluene is reacted with diethyl oxalate in a mixed solvent of diethyl ether and ethanol in the presence of potassium to give 5-fluoro-2- After producing potassium nitrophenylpyruvate, this was then reacted with aqueous ammonia and iron sulfate, and the resulting solid was heated under acidic conditions to produce 5-fluoroindole. It is disclosed. However, this method has a problem that the yield of the 5-fluoro-2-nitrotoluene target product is as low as 15%.
(3) J. Heterocycl. Chem., 2 , 298 (1965); In a tetrachloromethane solvent, m-fluorotoluene is reacted with N-bromosuccinimide to form m-fluorobenzyl bromide. In a mixed solvent of ethanol and ethanol, potassium cyanide is reacted to form m-fluorobenzyl cyanide, which is then nitrated with nitric acid or the like to form 2-nitro-5-fluorobenzyl cyanide. A method for producing 5-halogenoindole by reduction and cyclization with palladium / carbon in a hydrogen atmosphere is disclosed. However, this method has a problem that the yield of the target product from m-fluorotoluene is as low as 21%.
All of the production methods have various problems such as a complicated reaction system and a low yield, which is disadvantageous as an industrial production method.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to solve the above-mentioned problems and to increase 5-halogenoindole from 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate which is easily available by a simple method. An industrially suitable process for producing 5-halogenoindole obtained in a yield is provided.
[0004]
[Means for Solving the Problems]
The subject of the present invention is
(A) General formula (1)
[0005]
[Formula 4]
[0006]
(In the formula, R represents a hydrocarbon group, and X represents a halogen atom.)
2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate represented by the general formula (2)
[0007]
[Chemical formula 5]
[0008]
(Wherein X is as defined above.)
A first step of 5-halogeno-2-nitrobenzyl cyanide represented by
(B) a second step of cyclizing 5-halogeno-2-nitrobenzyl cyanide under reducing conditions;
General formula (3), characterized by comprising
[0009]
[Chemical 6]
[0010]
(Wherein X is as defined above.)
A process for producing 5-halogenoindole represented by
DETAILED DESCRIPTION OF THE INVENTION
The present invention
(A) 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate represented by the general formula (1) is decarboxylated to give a 5-halogeno-2-nitro represented by the general formula (2) The first step of benzylcyanide,
(B) a second step of cyclizing 5-halogeno-2-nitrobenzyl cyanide under reducing conditions;
2-halogenoindole is obtained as a reaction product by two steps comprising:
[0011]
Subsequently, the two steps will be sequentially described.
(A) First Step In the first step of the present invention, 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate represented by the general formula (1) is decarboxylated to give a general formula (2 Is a step of obtaining 5-halogeno-2-nitrobenzyl cyanide represented by
[0012]
The 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetic acid ester used in the first step of the present invention is represented by the above general formula (1). In the general formula (1), R is a hydrocarbon group, specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group. Alkyl groups such as decyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group; aralkyl groups such as benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group; phenyl group , Phenyl groups such as tolyl group, naphthyl group and anthranyl group. These groups include various isomers.
[0013]
Although the 1st process of this invention will not be specifically limited if it is the decarboxylation method generally performed, It is preferable to carry out in presence of an acid.
[0014]
Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as methanesulfonic acid and acetic acid, but inorganic acids are preferable, and hydrochloric acid is more preferable. In addition, you may use these acids individually or in mixture of 2 or more types.
[0015]
The amount of the acid used is preferably 1 to 20 mol, more preferably 5 to 10 mol, relative to 1 mol of 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetic acid ester.
[0016]
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. For example, water; methanol, ethanol, isopropyl alcohol, n -Alcohols such as butyl alcohol and t-butyl alcohol; ethers such as tetrahydrofuran and dioxane may be mentioned, but water, alcohols, and more preferably water, methanol, and ethanol are used. In addition, you may use these solvents individually or in mixture of 2 or more types.
[0017]
The amount of the solvent used is appropriately adjusted depending on the uniformity and agitation of the solution, but is preferably 2 to 100 g, based on 1 g of 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate, Preferably it is 4-50g.
[0018]
The first step of the present invention is performed, for example, by a method such as mixing 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetic acid ester, acid and solvent and stirring. The reaction temperature at that time is preferably 5 to 110 ° C., more preferably 20 to 100 ° C., and the reaction pressure is not particularly limited.
[0019]
According to the first step of the present invention, 5-halogeno-2-nitrobenzylcyanide is obtained, which is once isolated by a general method such as recrystallization, distillation, column chromatography after the completion of the reaction. Although it may be purified and used in the second step, it may be used in the second step without isolation and purification.
[0020]
(B) Second step The second step of the present invention is a step in which 5-halogeno-2-nitrobenzyl cyanide obtained in the first step is cyclized under reducing conditions to obtain 5-halogenoindole. .
[0021]
The second step of the present invention is not particularly limited as long as it is a reduction method generally performed, but it is preferably performed in a hydrogen atmosphere in the presence of a catalyst.
[0022]
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 and the like are mentioned, and palladium / carbon and Raney nickel are preferably used. In addition, you may use these catalysts individually or in mixture of 2 or more types.
[0023]
The amount of the catalyst used is preferably 0.01 to 10% by mass, more preferably 0.05 to 1% by mass, in terms of metal atom, based on 5-halogeno-2-nitrobenzyl cyanide.
[0024]
The second step of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, t-butyl Alcohols such as alcohols; Carboxylic acid esters such as methyl acetate and ethyl acetate; Aromatic hydrocarbons such as benzene and toluene; Ethers such as tetrahydrofuran and dioxane are preferable, but alcohols and carboxylic acid esters are preferable. More preferably, methanol, ethanol or ethyl acetate is used. In addition, you may use these solvents individually or in mixture of 2 or more types.
[0025]
The amount of the solvent used is appropriately adjusted depending on the homogeneity and agitation of the solution, but is preferably 1 to 50 g, more preferably 3 to 30 g, relative to 1 g of 5-halogeno-2-nitrobenzyl cyanide.
[0026]
In the second step of the present invention, for example, in a hydrogen atmosphere (which may be diluted with an inert gas), 5-halogeno-2-nitrobenzyl cyanide, a catalyst and a solvent are mixed and stirred. Done by the method. The reaction temperature at that time is preferably 0 to 120 ° C., more preferably 20 to 60 ° C., and the reaction pressure is preferably 0.1 to 5 MPa, more preferably 0.1 to 2 MPa.
[0027]
Further, if necessary, an acid or activated carbon may be added to increase the reactivity. Specific examples of the acid include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid; formic acid, acetic acid, Although organic acids, such as propionic acid, are mentioned, Preferably an organic acid is used, More preferably, an acetic acid is used. In addition, these acids may be used alone or in combination of two or more, or the acid and activated carbon may be used simultaneously.
[0028]
The amount of the acid used is preferably 0.01 to 20 mol, more preferably 0.1 to 5.0 mol, with respect to 1 mol of 5-halogeno-2-nitrobenzyl cyanide.
[0029]
The amount of the activated carbon used is preferably 0.01 to 10 g, more preferably 0.1 to 5.0 g, with respect to 1 g of 5-halogeno-2-nitrobenzyl cyanide.
[0030]
5-halogenoindole is obtained by the second step of the present invention, and this is isolated and purified by a general method such as recrystallization, distillation, column chromatography, etc. after the reaction is completed.
[0031]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
[0032]
Reference Example 1 (Synthesis of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel, 4.62 g (83.8 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide and 20 ml of dimethyl sulfoxide were added under an argon atmosphere. % Methyl cyanoacetate 8.37 g (83.8 mmol) was slowly added dropwise over 10 minutes. While maintaining the temperature of the reaction solution at 20 to 30 ° C., 6.76 g (41.6 mmol) of 98% pure 2,4-difluoronitrobenzene was slowly added dropwise over 1 hour, followed by reaction at the same temperature for 6 hours. After completion of the reaction, 10 ml of toluene was added while keeping the temperature of the reaction solution at 10 ° C. or lower in an ice bath, and 41.9 ml (41.19 mmol) of 1 mol / l hydrochloric acid was slowly added dropwise. Then, the organic layer was separated, washed with 50 ml of water and 50 ml of saturated brine in this order, and the organic layer was concentrated under reduced pressure. The obtained concentrated liquid was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene) to obtain white crystals, purity 99.4% (area percentage by high performance liquid chromatography) Of 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate (isolated yield based on 2,4-difluoronitrobenzene: 80.0%).
The physical properties of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate were as follows.
[0033]
Melting point: 43-44 ° C
EI-MS (m / e); 192 (M-NO ₂ ), CI-MS (m / e); 239 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 3.88 (3H, s), 5.71 (1H, s), 7.3 to 7.4 (1H, m), 7.45 to 7.55 (1H, m), 8.3 to 8.4 ( 1H, m)
[0034]
Example 1 (Synthesis of 5-fluoro-2-nitrobenzyl cyanide)
Methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate with a purity of 99.4% synthesized in Reference Example 1 under an argon atmosphere was placed in a 200-ml glass flask equipped with a stirrer and a thermometer. g (33.3 mmol), 33 ml of 6 mol / l hydrochloric acid and 33 ml of methanol were added, and the mixture was heated to 85 ° C. and reacted for 9 hours. After completion of the reaction, the reaction solution was cooled to 0 to 0 ° C. with an ice bath and stirred for 30 minutes to precipitate crystals. After filtering the precipitated crystals, it was added to 67 ml of a methanol / water mixed solvent (= 2/1 (volume ratio)), and the liquid temperature was raised to 70 ° C. to completely dissolve the crystals. The reaction solution was cooled again to 0 to 0 ° C. with an ice bath and stirred for 30 minutes to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain 4.85 g of 5-fluoro-2-nitrobenzyl cyanide having a purity of 99.0% (quantitative value by high performance liquid chromatography) as white crystals (2 -(5-Fluoro-2-nitrophenyl) -2-cyanoacetic acid based on isolated yield: 80.1%).
The physical properties of 5-fluoro-2-nitrobenzyl cyanide were as follows.
[0035]
Melting point: 65-66 ° C
EI-MS (m / e); 180 (M +), CI-MS (m / e); 181 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 4.21 (2H, s), 7.23-7.28 (1H, m), 7.46-7.49 (1H, m), 8.26-8.31 (1H, m)
[0036]
Example 2 (Synthesis of 5-fluoroindole)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a reflux condenser, and a gas introduction tube, 98.5% purity of 5-fluoro-2-nitrobenzyl cyanide 4.85 synthesized in Example 1 was added under an argon atmosphere. g (26.7 mmol) and 60 ml of methanol were added. Next, the temperature of the reaction solution was raised to 40 to 45 ° C., 0.5 g of 5 mass% palladium / carbon (49% water-containing product) was added with stirring, and hydrogen was supplied at normal pressure with a flow rate of 15.0 ml / min. The reaction was carried out at the same temperature for 3 hours while blowing. Then, once the atmosphere in the reaction system was changed to an argon atmosphere, 0.5 g of 5% by mass palladium / carbon (49% water-containing product) was added again, and hydrogen was blown at a normal flow rate at a flow rate of 15.0 ml / min. The reaction was allowed to proceed for an additional 3 hours at temperature. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated solution was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene), and white crystals, purity 99.5% (quantitative value by high performance liquid chromatography) ) Was obtained (isolated yield based on 5-fluoro-2-nitrobenzyl cyanide: 79.8%).
The physical property values of 5-fluoroindole were as follows.
[0037]
Melting point: 47-48 ° C
EI-MS (m / e); 135 (M +), CI-MS (m / e); 136 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 6.50 (1H, s), 6.91 to 6.98 (1H, m), 7.23 to 7.32 (3H, m), 8.23 (1H, brs)
[0038]
Reference Example 2 (Synthesis of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel, 5.08 g (92.2 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide were added under an argon atmosphere, followed by stirring at room temperature with a purity of 99. % 9.21 g (92.2 mmol) of methyl cyanoacetate was slowly added dropwise over 10 minutes. While maintaining the temperature of the reaction solution at -15 to -10 ° C, 6.80 g (41.9 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was dropped slowly over 1 hour, and then reacted at the same temperature for 2 hours. . After completion of the reaction, 50 ml of ethyl acetate was added while keeping the temperature of the reaction solution at 10 ° C. or lower in an ice bath, and 50.3 ml (50.3 mmol) of 1 mol / l hydrochloric acid was slowly added dropwise. Then, the organic layer was separated and washed with 50 ml of water and 50 ml of saturated brine in this order, and the organic layer was concentrated under reduced pressure to give 2- (5-fluoro-2-nitro with a purity of 69.8% as an oily yellow liquid. 13.55 g of methyl phenyl) -2-cyanoacetate was obtained (isolated yield based on 2,4-difluoronitrobenzene: 94.7%).
[0039]
Example 3 (Synthesis of 5-fluoro-2-nitrobenzyl cyanide)
Methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate with a purity of 69.8% synthesized in Reference Example 2 under an argon atmosphere was placed in a 200-ml glass flask equipped with a stirrer and a thermometer. g (39.7 mmol), 3 mol / l hydrochloric acid 79 ml and methanol 39 ml were added, and the mixture was heated to 85 ° C. and reacted for 9 hours. After completion of the reaction, the reaction solution was cooled to 0 to 0 ° C. with an ice bath and stirred for 30 minutes to precipitate crystals. After filtering the precipitated crystals, it was added to 27 ml of a methanol / water mixed solvent (= 2/1 (volume ratio)), and the liquid temperature was raised to 70 ° C. to completely dissolve the crystals. The reaction solution was cooled again to 0 to 0 ° C. with an ice bath and stirred for 30 minutes to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain 6.27 g of 5-fluoro-2-nitrobenzyl cyanide having a purity of 99.2% (area percentage by high performance liquid chromatography) as white crystals (2 -(5-Fluoro-2-nitrophenyl) -2-cyanoacetic acid based on isolated yield: 87.0%).
[0040]
Example 4 (Synthesis of 5-fluoroindole)
A 99.2% pure 5-fluoro-2-nitrobenzyl cyanide synthesized in Example 3 was placed in a 200 mL glass flask equipped with a stirrer, thermometer, reflux condenser and gas inlet tube under an argon atmosphere. g (34.5 mmol) and 40 ml of methanol were added. Next, the temperature of the reaction solution is raised to 40 to 45 ° C., 0.6 g of 5 mass% palladium / carbon (49% water-containing product) is added with stirring, and hydrogen is supplied at normal pressure with a flow rate of 20.0 ml / min. The reaction was carried out at the same temperature for 3 hours while blowing. Then, once the inside of the reaction system was put into an argon atmosphere, 0.6 g of 5% by mass palladium / carbon (49% water-containing product) was added again, and hydrogen was blown in at normal pressure at a flow rate of 20.0 ml / min. The reaction was allowed to proceed for an additional 3 hours at temperature. After completion of the reaction, 0.5 g of activated carbon was added to the reaction solution, and the mixture was heated to 70 ° C. and stirred. The reaction was then filtered and the filtrate was concentrated under reduced pressure. The obtained concentrated solution was dissolved in 6 ml of methanol and slowly added to 33 ml of cold water at 0 to 0 ° C. to precipitate crystals. The crystals were filtered and dried under reduced pressure to obtain 4.20 g of 5-fluoroindole having a purity of 99.5% (quantitative value by high performance liquid chromatography) as white crystals (based on 5-fluoro-2-nitrobenzyl cyanide standard). Isolated yield: 89.8%).
[0041]
Example 5 (Synthesis of 5-fluoroindole)
A 99.0% pure 5-fluoro-2-nitro synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a reflux condenser and a gas introduction tube. 4.85 g (26.7 mmol) of benzylcyanide, 60 ml of methanol and 0.45 ml (26.6 mmol) of acetic acid were added. Next, the temperature of the reaction solution was raised to 40 to 45 ° C., 0.5 g of 5 mass% palladium / carbon (49% water-containing product) was added with stirring, and hydrogen was supplied at normal pressure with a flow rate of 15.0 ml / min. The reaction was carried out at the same temperature for 10 hours while blowing. After completion of the reaction, the reaction solution was filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 3.49 g of 5-fluoroindole was formed (based on 5-fluoro-2-nitrobenzyl cyanide standard). Reaction yield: 95.0%).
[0042]
Example 6 (Synthesis of 5-fluoroindole)
A 99.0% pure 5-fluoro-2-nitro synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a reflux condenser and a gas introduction tube. 5.00 g (27.5 mmol) of benzylcyanide, 30 ml of methanol and 3.0 g of activated carbon (manufactured by Takeda Pharmaceutical Co., Ltd .: Shirasagi A) were added. Next, the temperature of the reaction solution was raised to 40 to 45 ° C., 0.5 g of 5 mass% palladium / carbon (49% water-containing product) was added with stirring, and hydrogen was supplied at normal pressure with a flow rate of 15.0 ml / min. The reaction was carried out at the same temperature for 10 hours while blowing. After completion of the reaction, the reaction solution was filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 3.49 g of 5-fluoroindole was formed (based on 5-fluoro-2-nitrobenzyl cyanide standard). Reaction yield: 94.0%).
[0043]
Example 7 (Synthesis of 5-fluoroindole)
In a pressure-resistant container having an internal volume of 100 ml equipped with a stirrer, a thermometer and a gas introduction tube, 5.00 g of 5-fluoro-2-nitrobenzyl cyanide having a purity of 99.0% synthesized in the same manner as in Example 1 under an argon atmosphere (27.5 mmol), 30 ml of methanol and 0.5 g of 5% by mass palladium / carbon (49% water-containing product) were added. Next, after the inside of the reaction system was replaced with hydrogen, the temperature of the reaction solution was raised to 55 to 60 ° C., and the hydrogen pressure was set to 0.9 MPa (gauge pressure), and the reaction was performed at the same temperature for 10 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 3.42 g of 5-fluoroindole was formed (based on 5-fluoro-2-nitrobenzyl cyanide standard). Reaction yield: 92.0%).
[0044]
【The invention's effect】
According to the present invention, industrially suitable 5 is obtained in a simple manner by obtaining 5-halogenindole in a high yield from 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate which is easily available. -We can provide a method for producing halogenoindole.

Claims (7)

(A) General formula (1)
(Wherein R represents a hydrocarbon group, and X represents a halogen atom) 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetic acid ester represented by Formula (2)
(Wherein X has the same meaning as described above) 5-halogeno-2-nitrobenzyl cyanide shown in (B), then 5-halogeno-2-nitrobenzyl cyanide, palladium, a catalyst containing at least one metal atom selected from the group consisting of platinum and nickel with respect to 5-halogeno-2-nitrobenzyl cyanide is present in 0.01 to 10 mass% in terms of metal atom, 5 - adding 0.01~10g of activated carbon with respect halogeno-2-nitrobenzyl cyanide 1g, characterized in that it comprises a second step, the cyclization while introducing hydrogen, the formula (3)
(Wherein, X is as defined above), a method for producing 5-halogenoindole. The second step is performed by adding 0.1 to 5.0 g of activated carbon. Five- How to make halogenoindole. The second step is performed at normal pressure. Five- How to make halogenoindole. The method for producing 5-halogenoindole according to any one of claims 1 to 3 , wherein the second step is performed by adding an acid. The method for producing 5-halogenoindole according to any one of claims 1 to 4 , wherein the first step is performed in the presence of an acid. The 5-halogeno of any one of Claims 1-5 whose usage-amount of a catalyst is 0.05-1 mass% in conversion of a metal atom with respect to 5-halogeno-2-nitrobenzyl cyanide. Indole manufacturing method. X is a fluorine atom, The manufacturing method of 5-halogeno indole of any one of Claims 1-6 .