WO2020125581A1 - Amide derivatives and preparation method for intermediates thereof - Google Patents

Abstract

Provided are a compound as represented by formula VI and a preparation method for an intermediate thereof. By using the method, the compound as represented by formula VI can be prepared and obtained efficiently, conveniently, and safely, and the purity of the compound as represented by final product formula VI is significantly improved. <img file="dest_path_image001.jpg" he="98.16" img-content="drawing" img-format="jpg" inline="yes" orientation="portrait" wi="90.75"/>

Description

Preparation method of amide derivatives and intermediates Technical field

The invention relates to a preparation method of amide-like derivatives and intermediates thereof.

Background technique

Schizophrenia is the most serious and most harmful disease of all mental diseases, with a global incidence rate of about 1-2%. The lifetime prevalence of patients with schizophrenia is 0.7 to 0.8%, and there is no obvious correlation with gender, race, or social boundaries, and the mortality rate is 2 to 3 times higher than that of the general population. The latest research shows that the social burden of mental illness ranks first in China's disease, surpassing cardiovascular and cerebrovascular diseases, respiratory system and malignant tumors.

Patent WO2017084627A discloses a compound that acts on dopamine D ₂ , 5-HT _1A and 5-HT _2A receptors and its preparation method, and has good anti-neurological activity. The compound structure is as follows:

However, the preparation method disclosed in this patent has many defects such as high toxicity of reaction materials, long reaction time, high impurity content, low purity, difficulty in industrial scale production, serious environmental pollution and so on. Therefore, the present invention provides a new Synthetic ideas and routes, the entire process greatly reduces the reaction time, avoids harsh reaction conditions, and the process is strong in operability, which is beneficial to industrial production needs and reduces environmental protection pressure; in addition, due to changes in reaction conditions, it can reduce the generation of impurities and reduce the final product. Purification difficulty and cost.

Summary of the invention

The invention provides a method for preparing the compound represented by formula VI and its key intermediates (compounds represented by formula III, formula IV and formula V),

Wherein X _{1 is} selected from fluorine or chlorine, and n is selected from any integer between 1 and 3.

The present invention provides a method for preparing a compound represented by formula V, which includes the following steps: in the presence of a catalyst, a basic substance, and an organic solvent, a compound represented by formula IV reacts with a compound represented by formula (1) to obtain the formula Ⅴ The compound,

Where n is selected from any integer between 1 and 3; the catalyst is selected from onium salt phase transfer catalysts; and the basic substance is selected from carbonate.

In an embodiment of the present invention, n is 1 or 2.

In an embodiment of the present invention, the onium salt phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (TEBA), trioctylammonium chloride (TCMAC ) Or cetyltrimethylammonium bromide (CTMAB), preferably TEBA.

In an embodiment of the present invention, the carbonate is selected from sodium carbonate or potassium carbonate, preferably potassium carbonate.

In an embodiment of the present invention, the organic solvent is selected from nitriles or ketones. In an embodiment of the present invention, the nitrile is preferably acetonitrile, and the ketone is selected from acetone, 2-butanone, pent-2-one, pent-3-one, hex-2-one, or hex-3 -Ketone, preferably acetone.

In an embodiment of the present invention, in order to achieve the purpose of full reaction and a good yield, the molar ratio of the compound represented by formula IV to the compound represented by formula (2) may be 1:1 to 1:4, preferably 1:2 or 1:3; the molar ratio of the compound of formula IV to potassium carbonate is selected from 1:1 to 1:5, preferably 1:2 or 1:3; the formula IV The molar ratio of the compound to the catalyst is selected from 50:1 to 20:1, preferably 35:1 to 25:1. Further, the catalyst is selected from TEBA.

In an embodiment of the present invention, in order to allow the reaction to proceed thoroughly, the reaction time for preparing the compound represented by formula V from the compound represented by formula IV and the compound represented by formula (1) is selected from 4 to 7 hours, It is preferably 6 hours; the reaction temperature is selected from 50 to 80°C, preferably 50 to 70°C.

In an embodiment of the present invention, the compound represented by formula (1) is preferably:

When the compound represented by formula (1) of the present invention is 1-bromo-3-chloropropane, it was surprisingly found that the content of impurities in the final product can be significantly reduced, and the purity of the final product is significantly improved.

The present invention further provides a method for preparing a compound represented by formula VI, comprising the steps of: reacting a compound represented by formula V with a compound represented by formula (2) in the presence of a catalyst, a carbonate, and an organic solvent, The compound of formula VI is thus prepared;

Wherein X _{1 is} selected from fluorine or chlorine, preferably fluorine; n is 1 or 2, preferably 1, and the compound represented by formula (2) may also be selected from salts formed with acids, such as hydrochloride.

In an embodiment of the present invention, the catalyst is selected from elemental iodine, potassium iodide or sodium iodide, preferably sodium iodide; the carbonate is selected from sodium carbonate or potassium carbonate.

In an embodiment of the present invention, the organic solvent is selected from nitriles or ketones. In an embodiment of the present invention, the nitrile is preferably acetonitrile, and the ketone is selected from acetone, 2-butanone, pent-2-one, pent-3-one, hex-2-one or hex- 3-ketone, preferably acetone.

In an embodiment of the present invention, in order to achieve the purpose of full reaction and a good yield, the molar ratio of the compound represented by Formula V to the compound represented by Formula (2) may be 1:1 to 1:2, preferably 1:1; the molar ratio of the compound represented by formula V to potassium carbonate is selected from 1:1 to 1:5, preferably 1:2 or 1:3; the compound represented by formula IV and the catalyst The molar ratio is selected from 60:1 to 30:1, preferably 50:1 to 30:1. Further, the catalyst is selected from NaI or KI.

In an embodiment of the present invention, the compound represented by formula VI is preferably the following compound:

The present invention further provides a method for preparing the compound represented by formula IV, which includes the following steps: the compound represented by formula III is prepared in the presence of a Lewis acid and an organic solvent to obtain the compound represented by formula III.

In an embodiment of the present invention, the Lewis acid is selected from molecular Lewis acids; the molecular Lewis acid is selected from boron trifluoride, ferric chloride, aluminum trichloride, and trioxide Sulfur, dichlorocarbene or niobium pentachloride, preferably aluminum trichloride or ferric chloride.

In an embodiment of the present invention, the organic solvent is selected from tetrahydrofuran (THF), hexanol, methanol, toluene, N,N-dimethylformamide (DMF), preferably toluene.

In an embodiment of the present invention, in order to achieve the purpose of full reaction and good yield, the molar ratio of the compound represented by Formula III to Lewis acid may be 1:1 to 1:4, preferably 1:2 or 1:3.

In an embodiment of the present invention, in order to allow the reaction to proceed thoroughly, the reaction time of the compound of formula IV prepared from the compound of formula III and the Lewis acid may be 3 to 6 hours, preferably 4 hours; The reaction temperature is selected from 100 to 130°C, preferably 110 to 120°C.

The present invention further provides a method for preparing a compound represented by formula III, which includes the following steps:

Step 1: react in the presence of an acid-binding agent and an organic solvent to prepare a compound of formula I;

Step 2: react in the presence of P ₂ O ₅ and methanesulfonic acid to prepare the compound of formula II;

Step 3: react with methyl iodide in the presence of a strong base and an organic solvent to prepare the compound of formula III;

Wherein the acid binding agent is selected from pyridine or triethylamine, preferably triethylamine; the strong base is selected from NaH or KH, preferably NaH; the organic solvent in step 1 is selected from dichloromethane; step 3 The organic solvent in is selected from 4-dimethylaminopyridine (DMAP) or N,N-dimethylformamide (DMF).

In an embodiment of the present invention, in step 1, in order to achieve the purpose of full reaction and a good yield, the molar ratio of the 4-methoxyphenethylamine to the acid binding agent may be 1:1 ~1:2, preferably 1:1.5; the molar ratio of the 4-methoxyphenethylamine to ethyl chloroformate is selected from 1:1 to 1:3, preferably 1:1 to 1:1.5.

In an embodiment of the present invention, in step 2, in order to achieve a sufficient reaction and achieve a good yield, the molar ratio of the compound represented by formula I to P ₂ O ₅ may be 1:1 to 2 :1, preferably 1:1 to 1.5:1.

In an embodiment of the present invention, in step 3, in order to achieve the purpose of full reaction and a good yield, the molar ratio of the compound represented by formula II to a strong base may be 1:1 to 1:2 , Preferably 1:1 to 1:1.5; the molar ratio of the compound represented by formula II to methyl iodide may be 1:1 to 1:2, preferably 1:1 to 1:1.5.

The present invention further provides a method for synthesizing the compound represented by formula VI, which is as follows:

Wherein X ₁ is fluorine; n is 1 or 2, preferably 1.

The present invention further uses the compound represented by formula III, formula IV or formula V for preparing the compound represented by formula VI,

Where n is 1 or 2, preferably 1; X ₁ is fluorine or chlorine, preferably fluorine.

The present invention further provides the use of the compound represented by formula V in the preparation of the compound represented by formula VI, the purity of the compound represented by formula VI obtained by the preparation is above 99%,

Where n is 1 or 2, preferably 1; X ₁ is fluorine or chlorine, preferably fluorine.

The present invention further provides a method for purifying and purifying the compound represented by formula VI, which includes the following steps:

① Dissolve the crude product of formula VI in an organic solution;

②, add activated carbon to stir and filter;

③ Cooling and stirring at room temperature, and suction filtration to obtain a solid;

(4) Wash the solid with an organic solvent and dry it for 5 to 10 hours to obtain the compound represented by Formula V as a white powdery solid.

In an embodiment of the present invention, the organic solvent is selected from one or more of ketones and C _1-3 alcohols. In an embodiment of the present invention, the ketones are selected from acetone or methyl ethyl ketone; the C _1-3 alcohols are selected from methanol, ethanol, n-propanol, or isopropanol.

In an embodiment of the present invention, the organic solvent is selected from a mixed solvent of acetone and methanol, and the volume ratio of acetone to methanol may be 5:1 to 10:1, preferably 10:1.

In an embodiment of the present invention, step ① further includes a heating process, and the heating temperature may be 60-70°C.

In an embodiment of the present invention, the stirring time in step ③ may be 5-10 hours, preferably 5-7 hours.

In an embodiment of the present invention, the drying temperature in step ④ may be 50-70°C, preferably 50-60°C.

Beneficial effects of invention

The preparation method of the novel compound represented by formula VI and its key intermediates (compounds represented by formula III, formula IV and formula V) provided by the present invention can significantly improve the final preparation compared with the preparation method disclosed in the prior art The purity of the product is more than 99.8% compared with the existing technology, which meets the standards of pharmaceutical grade raw materials for human use. In addition, the new preparation method uses AlCl ₃ demethylation to prepare the intermediate formula IV compound, labor protection requirements Low, strong operability, more suitable for industrial production.

detailed description

The present invention will be explained in more detail in conjunction with the following embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and do not limit the essence and scope of the present invention.

Test conditions of the instruments used in the experiment:

1. High Performance Liquid Chromatography (High Performance Liquid Chromatograph, HPLC)

Instrument model: Agilent 1260 (DAD) binary pump liquid chromatography

Column: SHIMADZU VP-ODS C18 column (4.6×250mm, 5μm)

Mobile phase:

A: 0.01mol/L potassium dihydrogen phosphate, 0.1% triethylamine (pH adjusted to 2.5 with phosphoric acid)-methanol (90:10)

B: 0.01mol/L potassium dihydrogen phosphate, 0.1% triethylamine (pH adjusted to 2.5 with phosphoric acid)-methanol (20:80)

Flow rate: 1.0ml/min Column temperature: 35℃

Wavelength: 210nm Injection volume: 15μL

Gradient conditions (volume ratio):

Example 1: Preparation of ethyl (4-methoxyphenethyl) carbamate (intermediate I)

Add 275.0g (2.55mol) ethyl chloroformate (industrially pure, purchased from Shanghai Beihe Chemical Co., Ltd.) and 2500mL of dichloromethane to a 5L reaction flask, stir, and cool to 0°C in an ice-salt bath, slowly add dropwise 350g (2.32mol) 4-methoxyphenethylamine dissolved in 1000mL of dichloromethane (industrial pure, purchased from Shanghai Merrill Chemical Technology Co., Ltd.), control the system temperature 0 ~ 5 ℃; after the dropwise addition, slowly add 351g (3.48mol) triethylamine, control the temperature of the system 5 ~ 10 ℃; after the dropwise addition, stirring at room temperature (25 ± 5 ℃) for 1 hour.

After the reaction was completed, 1000 mL of water was added to the reaction solution to quench the reaction, and the mixture was stirred for 5 minutes. The liquid was left to stand to obtain an organic layer, and the organic phase was washed with 600 mL of 1 mol/L hydrochloric acid solution; the organic phase was washed with 600 mL of saturated sodium chloride solution, 150g of anhydrous sodium sulfate was dried for 1 hour and filtered; the filtrate was concentrated to dryness to obtain a light yellow oil, which was cooled at room temperature for 1h to obtain a light yellow solid 508g, yield 98.3%, MS (ESI) m/z 223.3 ([M +H] ⁺ ).

Example 2: Preparation of 7-methoxy-3,4-dihydroisoquinoline-1(2H)-one (intermediate II)

Add 510.0g (1.80mol) of phosphorus pentoxide and 2000mL of methanesulfonic acid to the 5L reaction flask, stir, and heat the oil bath at 125～130℃ until the phosphorus pentoxide completely dissolves; place at room temperature and stir to cool down to the system The temperature was lowered to 70°C, and 1000 g (2.24 mol) of intermediate I was added. The oil bath was heated at 125°C and reacted for 2 hours.

After the reaction was completed, the temperature was lowered, 500 g of ice was added to quench the reaction, 5000 mL of water was added to the system, and extracted with dichloromethane 6 times (1200 mL/time), the organic phases were combined, 500 g of anhydrous potassium carbonate was added and stirred for 0.5 hours, and suction filtered. The solution was dried with 500g of anhydrous sodium sulfate for 1 hour, filtered with suction, and the filtrate was concentrated to dryness to obtain a brown oil, which was cooled at 0°C for 5 hours, filtered with suction, and the filter cake was washed with 300mL of ethyl acetate at 50±5°C After drying for 8 hours, 436.5 g of off-white solid was obtained with a yield of 55.1% and MS (ESI) m/z 177.1 ([M+H] ⁺ ).

Example 3: Preparation of 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (intermediate III)

Add 54.2g (1.36mol) of 60% sodium hydride and 1000ml of N,N-dimethylformamide to the 3L reaction flask, stir, and cool to 0-5°C in an ice-salt bath. Slowly add 500mL of N,N- 200g (1.13mol) of intermediate II dissolved in dimethylformamide, control the temperature of the system 5～10℃; after the dropwise addition, slowly add 176.5g (1.24mol) methyl iodide, control the temperature of the system 10～15℃; dropwise After completion, stir at room temperature (25±5°C) for 1 hour.

Add 500 mL of water drops to the reaction solution to quench the reaction; then add 4 L of water to mix with the reaction solution, add 1630 g of sodium chloride to saturation, extract 6 times with ethyl acetate (800 mL/time), combine organic phases, use saturated sodium chloride The solution was washed 3 times (500 mL/time), dried with 300 g of anhydrous sodium sulfate for 1 hour; filtered, and the filtrate was concentrated to dryness to obtain a tan oil 258 g, with a yield of over 100%, MS (ESI) m/z 191.1 ([M +H] ⁺ ).

Example 4: Preparation of 7-hydroxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (intermediate IV)

Add 257.6g (1.94mol) anhydrous aluminum chloride and 1500mL toluene to the 3L reaction flask, stir at room temperature (25±5°C), and slowly add 185.0g (0.97mol) intermediate III dissolved in 300mL toluene; After the addition is complete, the oil bath is heated to reflux (approximately 114-115°C), protected by nitrogen, and the reaction is timed for 4 hours.

After the reaction was completed, cool to 70°C at room temperature, pour out the toluene solution, pour 2000mL of 4mol/L hydrochloric acid solution into the bottle, add ice to cool down, stir at room temperature for 1 hour, filter, and wash the filter cake with 500mL of water until neutral; use 1000mL Dissolve the filter cake with 2mol/L sodium hydroxide solution, wash with 500mL toluene and 500mL dichloromethane in sequence; adjust the pH of the water layer to 3~4 with 36% hydrochloric acid solution, cool in an ice bath, stir for 0.5 hours, filter, filter cake It was washed with 500 mL of water until neutral, and the filter cake was dried at 50±5° C. for 12 hours to obtain 162.1 g of off-white solid with a yield of 94.7%. MS (ESI) m/z 177.2 ([M+H] ⁺ ).

Example 5: 7-(3-chloropropoxy)-2-methyl-3,4-dihydroisoquinoline-1(2H)-one (intermediate V)

156.0 g (0.88 mol) of intermediate IV, 277.6 g (1.76 mol) of the compound represented by formula (1), 364.9 g (2.64 mol) of anhydrous potassium carbonate, 6.0 g (0.03 mol) of benzyl triethylammonium chloride Add 1600mL of acetone to a 3L reaction flask, heat the oil bath to reflux (about 60 ~ 65 ℃), and stir for 6 hours.

After the reaction was completed, the filtrate was filtered, and the filtrate was concentrated to dry solvent under reduced pressure to obtain a yellow oil; 500mL of acetone was added to dissolve, stirred at room temperature, 3000mL of n-hexane was added, cooled and stirred in an ice bath for 1 hour, filtered, and the filter cake was dried at 50±5℃ for 6 hours. 213.2 g of off-white solid was obtained, yield 95.8%, MS (ESI) m/z 254.1 ([M+H] ⁺ ).

Example 6: 7-(3-(4-(6-fluorobenzo[d]isoxazolin-3-yl)piperidin-1-yl)propoxy)-2-methyl-3, 4-dihydroisoquinoline-1(2H)-one (compound of formula VI, crude product)

210.0 g (0.83 mol) of intermediate V, 223.6 g (0.87 mol) of the hydrochloride of the compound represented by formula (2), 344.3 g (2.64 mol) of anhydrous potassium carbonate, 3.7 g (0.02 mol) of sodium iodide and 2100mL of acetonitrile was added to the 5L reaction flask, the oil bath was heated to reflux (about 80 ~ 85 ℃), and stirred for 24 hours.

After the reaction was completed, it was filtered, the filtrate was placed in an ice bath and stirred for 3 hours, filtered, and the filter cake was dried at 50±5°C for 3 hours to obtain 264.6 g of a yellow solid, that is, the crude compound of formula VI, with a yield of 82.6%.

Example 7: 7-(3-(4-(6-fluorobenzo[d]isoxazolin-3-yl)piperidin-1-yl)propoxy)-2-methyl-3, 4-dihydroisoquinoline-1(2H)-one (compound of formula VI, purified and purified)

Add 260.0g of crude compound of formula VI, 800mL of acetone and 80ml of methanol to a 2000mL reaction flask, heat the water bath to reflux (about 60 ~ 65 ℃), stir until completely dissolved, add 8.0g of activated carbon, stir for 10 minutes, while hot After filtration, the filtrate was transferred to a 2000mL reaction flask, placed at room temperature (25±5°C), cooled and stirred for 4 hours; suction filtered, washed with 200mL acetone, and the filter cake was dried at 50±5°C for 6 hours to obtain an off-white powder of 180.3 g, the finished product of CY150112, the yield is 79.3%.

¹ H-NMR (600 MHz, CDCl3) δ 2.02-2.19 (m, 8H), 2.60 (t, 2H, J = 12 Hz), 2.96 (t, 2H, J = 12 Hz), 3.09-3.11 (m, 3H) , 3.18 (s, 3H), 3.56 (t, 2H, J = 12 Hz), 4.11 (t, 2H, J = 6 Hz), 6.98-7.00 (m, 1H), 7.06-7.10 (m, 2H), 7.24 7.26 (m, 1H), 7.64 (d, 1H, J = 6 Hz), 7.74-7.76 (m, 1H). MS (ESI) m/z 438.2 ([M+H] ⁺ ).

Example 8: Purity comparison of the compound (final product) represented by formula VI obtained by different preparation methods

Comparative samples

synthetic route:

Preparation method: Refer to WO2017084627A Example 1 and Example 5 for preparation.

Purification method: Refer to the method described in Example 7 of the present invention for purification and purification.

Test sample

Synthetic route: Prepared according to the route described in Examples 1-6.

Preparation method: Prepared according to the method described in Examples 1-6.

Purification method: Refer to the method described in Example 7 for purification and purification.

The comparison sample and the test sample were determined by HPLC, and the mass percentage of the compound represented by formula VI in the comparison sample and the test sample was calculated according to the area normalization method. The specific test results are shown in Table 1.

Table 1 HPLC purity of comparative samples and test samples

sample name	Retention time (min)	height	area	HPLC content (%)
Comparative samples	31.820	90921937	2717110	92.38
Test sample	31.219	98195298	2934467	99.77

Test results: In the new preparation process described in the present invention, especially when step 4 uses AlCl ₃ instead of HBr and step 5 uses 1-bromo 3-chloropropane instead of 1,3-dibromopropane, it can be significantly improved The purity of the compound (final product) shown in formula VI can reach more than 99%. The quality of the API is qualified and meets the grade of human API. At the same time, there are fewer impurities, which greatly reduces the subsequent impurity identification work. The LC purity of the preparation process of the comparative sample is only 92.38%, which contains many unknown impurities, and the quality of the raw material is unqualified, which is not up to the level of human raw material.

Claims (10)

1. A method for preparing a compound represented by formula V includes the steps of: reacting a compound represented by formula IV with a compound represented by formula (1) in the presence of a catalyst, a basic substance, and an organic solvent, thereby preparing Compounds of formula V;

   

   Where n is selected from any integer between 1 and 3; the catalyst is selected from onium salt phase transfer catalysts; and the basic substance is selected from carbonate.
2. The preparation method according to claim 1, wherein n is 1 or 2; the onium salt phase transfer catalyst is selected from tetrabutylammonium bromide, benzyltriethylammonium chloride, trioctylammonium chloride or Cetyltrimethylammonium bromide; the carbonate is selected from sodium carbonate or potassium carbonate.
3. The preparation method according to claim 1, wherein the compound represented by formula VI includes the following preparation: in the presence of a catalyst, a carbonate and an organic solvent, the compound represented by formula V and formula (2) Showing compound reaction;

   

   Wherein X _{1 is} selected from fluorine or chlorine; n is 1 or 2; the catalyst is selected from iodine element, potassium iodide or sodium iodide; the carbonate is selected from sodium carbonate or potassium carbonate.
4. The preparation method according to claim 3, wherein the compound represented by formula VI is:

   
5. The preparation method according to any one of claims 1 to 4, wherein the organic solvent is selected from nitriles and ketones; the nitrile is selected from acetonitrile, and the ketone is selected from acetone, 2-butanone, and pentane -2-one, pent-3-one, hex-2-one or hex-3-one.
6. The preparation method according to claim 1, wherein the compound represented by formula IV is prepared by the compound represented by formula III in the presence of a Lewis acid and an organic solvent:

   

   Wherein said Lewis acid is selected from boron trifluoride, ferric chloride, aluminum trichloride, sulfur trioxide, dichlorocarbene or niobium pentachloride, preferably aluminum trichloride.
7. The production method according to claim 6, wherein the organic solvent is selected from tetrahydrofuran, hexanol, methanol, toluene, N,N-dimethylformamide, preferably toluene.
8. The preparation method according to any one of claims 6-7, wherein the compound of formula III is prepared by the following steps:

   

   Step 1: react in the presence of an acid-binding agent and an organic solvent to prepare a compound of formula I;

   Step 2: react in the presence of P ₂ O ₅ and methanesulfonic acid to prepare the compound of formula II;

   Step 3: react with methyl iodide in the presence of a strong base and an organic solvent to prepare the compound of formula III;

   Wherein the acid binding agent is selected from pyridine or triethylamine; the strong base is selected from NaH or KH; the organic solvent in step 1 is selected from dichloromethane; the organic solvent in step 3 is selected from 4- Dimethylaminopyridine or N,N-dimethylformamide.
9. The preparation method according to any one of claims 3-4, wherein the compound represented by formula VI is purified by a method including the following steps:

   ① Dissolve the crude product of formula VI in an organic solution;

   ②, add activated carbon to stir and filter;

   ③ Stir at room temperature with cooling and suction to obtain a solid;

   ④. Wash the solid with an organic solvent and dry for 5 to 10 hours to obtain a purified compound represented by formula VI;

   Wherein the organic solvent is selected from one or more of ketones and C _1-3 alcohols; the ketones are selected from acetone or methyl ethyl ketone; the C _1-3 alcohols are selected from methanol, ethanol, N-Propanol or isopropanol.
10. The use of the compound represented by formula V in the preparation of the compound represented by formula VI, wherein the purity of the compound represented by formula VI obtained is more than 99%,

    

    Where n is 1 or 2, preferably 1; X ₁ is fluorine or chlorine, preferably fluorine.