KR20030095677A - Process for preparing 3-chloro-2-(4-chloro-2-fluoro- 5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole - Google Patents

Abstract

PURPOSE: A process for preparing 3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl)- 4,5,6,7-tetrahydro-2H-indazole is provided, thereby improving its preparation yield and converting by-products of the preparation into starting material. CONSTITUTION: A process for preparing 3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl)- 4,5,6,7-tetrahydro-2H-indazole of the formula 1 comprises the steps of: reacting 2- (2-fluoro-4-chloro-5-hydroxyphenyl)- 2,3a,4,5,6,7- hexahydroindazole-3-one of the formula 2 with phosgene; concentrating the phosgene reaction mixture under reduced pressure; dissolving the concentrate in an organic solvent; adding ammonia water or hydroxide solution to the organic solvent and filtering solids; and distilling the filtrated solution, wherein the organic solvent is ethylacetate; the addition of ammonia water or hydroxide solution is carried out at room temperature; the solids are mainly constituted of a compound of the formula 2, and the by-products of the reaction include a dimer represented by the formula 3a, 3b or 3c.

Description

Process for preparing 3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole -(4-chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole}

The present invention is a method for preparing 3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole represented by the following formula (1) In more detail, in the following method of preparing a compound of Chemical Formula 1 by reacting in the presence of phosgene by using the compound of Chemical Formula 2 as a starting material, the reaction product mixture produced as a result of the phosgene reaction 3-chloro-2- (4-chloro-2-fluoro-5-) represented by Chemical Formula 1, characterized in that the solid material produced by adding aqueous ammonia or hydroxide solution to the filtrate was filtered and recovered. Hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole.

3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole represented by Chemical Formula 1 is useful in various industrial fields. It is particularly useful as an intermediate of pesticides, medicines and herbicides.

As a related art related to the preparation method of the present invention, British Patent Publication No. 2,127,410 describes a method for preparing a compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 2 with phosgene. However, according to the above-mentioned known production method, the reaction yield is very low as 26%, a large amount of side products are generated, and it is difficult to separate the target of high purity and have very low reproducibility. In addition, in the known method, silica gel column chromatography, which is very expensive and difficult to separate in large quantities, has to be performed for separation of a production target, and thus there is much room for improvement in industrial application.

The present inventors have made efforts to increase the production yield of the compound represented by Chemical Formula 1, which is industrially useful, and in particular, intensively studied a method for easily separating and purifying a target product into a reaction mixture. As a result, if the compound represented by the formula (2) is reacted in the presence of phosgene, and further treated with an aqueous solution of ammonia water or hydroxide, it is possible to effectively remove the side products generated together economically and industrially The present invention was completed by finding that the compound represented by Chemical Formula 1 can be easily obtained with high purity.

The present invention has an object to provide a method for producing a compound represented by the formula (1) economically and industrially easy.

The present invention provides phosgene to 2- (2-fluoro-4-chloro-5-hydroxyphenyl) -2,3a, 4,5,6,7-hexahydroindazol-3-one represented by the following formula (2): To 3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole represented by the following Chemical Formula 1 In the manufacturing method,

The phosgene reaction mixture is concentrated under reduced pressure, and then dissolved in an organic solvent. The resulting solid is filtered by addition of aqueous ammonia or hydroxide solution, and the filtrate is distilled off.

Referring to the present invention in more detail as follows.

The present invention is carried out in the production method for reacting the compound represented by the formula (2) in the presence of phosgene to obtain the compound represented by the formula (1) as a target, in the reaction product mixture resulting from the phosgene reaction as a side product Since the presence of a large amount is not difficult to separate the target with high purity, in the present invention, by adding aqueous ammonia or hydroxide solution to the phosgene reaction mixture, the secondary product is simply filtered and converted into a solid starting material and a liquid target. Distillation purification relates to a method for obtaining the desired compound represented by the formula (1).

The inventors separated the structure by silica gel chromatography in order to find out the components of the minor product contained in the reaction mixture generated as a result of the phosgene reaction described above, and as the secondary product as the following formula (3a), (3b) and (3c) It was confirmed that the dimer compound represented was included.

In the present invention, instead of separating and removing the dimer compound, a method for converting the compound represented by Chemical Formula 1 was developed. As a result, it is easy to purify by increasing the yield of the target product as well as reducing the content of the secondary product. However, the present invention is excellent.

The dimers represented by Chemical Formulas 3a, 3b, and 3c are compounds having a property of being decomposed by a base, and can be easily decomposed by ammonia or hydroxide to be converted into reactants and targets. Thus, as a result of stirring and adding aqueous solution of ammonia or hydroxide to the phosgene reaction mixture, the dimers represented by Chemical Formulas 3a, 3b, and 3c are decomposed to a target material represented by Chemical Formula 1 and a starting material represented by Chemical Formula 2. It was confirmed to be separated.

Ammonia water is suitable for decomposition of the dimer _, but the same effect can be obtained by using a hydroxide containing LiOH, NaOH, Ca (OH) _2, KOH, alkyl ammonium hydroxy and the like. Ethyl acetate may be used as the solvent, but other organic solvents such as methylene chloride, chloroform, dichloroethane, toluene, THF, and water may be used, and a mixed solvent may be used. The reaction temperature is appropriate at room temperature, but may be reacted by lowering the temperature with ice water or heating it slightly.

When the reaction mixture is treated under the above conditions, the starting material represented by Chemical Formula 2 is obtained as a solid having low solubility in water and an organic solvent such as ethyl acetate, and the target compound represented by Chemical Formula 1 is ethyl Since it has good solubility in organic solvents such as acetate and is dissolved in the reaction solution, it can be easily obtained by distilling under reduced pressure after distilling off the organic layer after filtering the solid.

Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1:

1.5 M phosgene solution dissolved in toluene in 150 g of 2- (2-fluoro-4-chloro-5-hydroxyphenyl) -2,3a, 4,5,6,7-hexahydroindazol-3-one 1.4 L was added, and the mixture was refluxed for 7 hours and then distilled under reduced pressure.

The phosgene reaction mixture was added to 500 mL of ethyl acetate and stirred, and slowly added 300 mL of 28% aqueous ammonia, followed by stirring at room temperature for 3 hours. The solid was filtered after neutralizing with hydrochloric acid. The filtered solid was washed with water and dried, and this solid material was 2- (2-fluoro-4-chloro-5-hydroxyphenyl) -2,3a, 4,5,6,7- used as starting material. 96 g (yield 64%) was recovered as hexahydroindazol-3-one.

On the other hand, the organic layer of the filtrate is separated and washed sequentially with water and brine, and then the solvent is distilled under reduced pressure to the desired 3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl) -4, 52 g (yield 33%) of 5,6,7-tetrahydro-2H-indazole were obtained.

In addition, the starting material recovered as a solid is reacted in the presence of phosgene by the above-described method, and then the reaction is carried out 8 times by adding ammonia water to the reaction product mixture to give the desired 3-chloro-2- (4 137 g (91% yield) of -chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole were obtained.

¹ H NMR (CDCl ₃ , ppm) δ 9.20 (brs, 1H), 7.18 (d, J = 9.2 Hz, 1H), 7.07 (d, J = 6.7 Hz, 1H), 2.80-2.42 (m, 4H) , 1.89-1.68 (m, 4H); MS (20 eV) m / z (real intensity) 300 (M ⁺ , 92).

Example 2:

In the same manner as in the above-described method, a hydroxide was used in place of ammonia water.

1.5 M phosgene solution dissolved in toluene in 150 g of 2- (2-fluoro-4-chloro-5-hydroxyphenyl) -2,3a, 4,5,6,7-hexahydroindazol-3-one 1.4 L was added and refluxed for 7 hours, followed by distillation under reduced pressure. 500 mL of methyl alcohol was added to the phosgene reaction mixture, and the resultant mixture was slowly added with a saturated aqueous solution of NaOH, followed by stirring at room temperature for 3 hours. Methyl alcohol was distilled under reduced pressure, excess ethyl acetate was added, neutralized with hydrochloric acid, and the solid was filtered. The filtered solid was washed with water and dried, and this solid material was 2- (2-fluoro-4-chloro-5-hydroxyphenyl) -2,3a, 4,5,6,7- used as starting material. 94 g (yield 63%) was recovered as hexahydroindazol-3-one.

On the other hand, the organic layer of the filtrate is separated and washed sequentially with water and brine, and then the solvent is removed under reduced pressure to give the desired 3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl) -4 51 g (yield 33%) of, 5,6,7-tetrahydro-2H-indazole were obtained.

In addition, the starting material recovered as a solid is reacted in the presence of phosgene by the above-described method, and then the reaction is carried out eight times by adding a saturated aqueous NaOH solution to the reaction mixture. 135 g (yield 90%) of (4-chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole were obtained.

Reference Example:

3-chloro-2- (4-chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole and 2- (2-fluoro-4-chloro Preparation and Separation of -5-hydroxyphenyl) -2,3a, 4,5,6,7-hexahydroindazol-3-one dimers (Compounds 3a, 3b, 3c)

1.5 M phosgene dissolved in toluene in 2- (2-fluoro-4-chloro-5-hydroxyphenyl) -2,3a, 4,5,6,7-hexahydroindazol-3-one (1.5 g) 30 mL of the solution was added and refluxed for 12 hours, followed by distillation under reduced pressure. Dimer compounds 3a (0.15 g), 3b (0.31 g), and 3c (0.66 g) were separated from the reaction mixture using a silica gel column (developing solvent: n-hexane / ethyl acetate = 3/1).

Dimer Compound 3a . ¹ H NMR (CDCl ₃ , ppm) δ 7.31 (d, J = 6.7 Hz, 2H), 7.27 (d, J = 9.2 Hz, 2H), 2.59 (m, 4H), 2.40 (m, 4H), 1.81 -1.59 (m, 8H); MS (20 eV) m / z (rel intensity) 628 (M ⁺ , 47).

Dimer compound 3b . ¹ H NMR (CDCl ₃ , ppm) δ 8.29 (brs, 1H), 7.32 (d, J = 6.7 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.03 (d, J = 9.2 Hz , 1H), 6.94 (d, J = 6.7 Hz, 1H), 2.96-2.12 (m, 8H), 1.86-1.61 (m, 8H); MS (20 eV) m / z (rel intensity) 609 (M ⁺ , 30).

Dimer compound 3c . ¹ H NMR (CDCl ₃ , ppm) δ 8.25 (brs, 2H), 7.38 to 6.92 (m, 4H), 2.98 to 2.25 (m, 8H), 1.88 to 1.64 (m, 8H); MS (20 eV) m / z (rel intensity) 591 (M ⁺ , 12).

As described above, the manufacturing method of the present invention has the advantage that the yield is high and the separation process is simple compared to the existing method. In addition, it is an industrially excellent manufacturing method in that it is an invention that has developed a process for converting side products into starting materials and targets without waste disposal.

Claims (6)

2- (2-fluoro-4-chloro-5-hydroxyphenyl) -2,3a, 4,5,6,7-hexahydroindazol-3-one represented by the following formula (2) in the presence of phosgene The resulting phosgene reaction mixture was concentrated under reduced pressure, dissolved in an organic solvent, and the solid material produced by adding aqueous ammonia or hydroxide solution was filtered, and the filtrate was distilled to obtain 3-chloro-2- represented by the following formula (1). A process for recovering (4-chloro-2-fluoro-5-hydroxyphenyl) -4,5,6,7-tetrahydro-2H-indazole. The method according to claim 1, wherein the organic solvent is ethyl acetate. The method according to claim 1, wherein the aqueous ammonia or hydroxide solution is added at room temperature. The method of claim 1, wherein the main component of the solid material to be filtered is a compound represented by the formula (2). The method of claim 1, wherein the phosgene reaction mixture is a side product, and a dimer represented by the following Chemical Formula 3a, 3b, or 3c is included. The method of claim 1, wherein the reaction with the phosgene is carried out at room temperature.