CN115124440B - Preparation method of prothioconazole intermediate - Google Patents

Preparation method of prothioconazole intermediate Download PDF

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CN115124440B
CN115124440B CN202210735493.8A CN202210735493A CN115124440B CN 115124440 B CN115124440 B CN 115124440B CN 202210735493 A CN202210735493 A CN 202210735493A CN 115124440 B CN115124440 B CN 115124440B
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prothioconazole
inorganic base
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CN115124440A (en
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徐武双
刘鹏飞
刘玉超
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Jiangsu Qizhou Green Technology Research Institute Co ltd
Jiangsu Sevencontinent Green Chemical Co Ltd
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Jiangsu Sevencontinent Green Chemical Co Ltd
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C241/00Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C241/02Preparation of hydrazines
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/101,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12Oxygen or sulfur atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/02Systems containing only non-condensed rings with a three-membered ring
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a preparation method of a prothioconazole intermediate, which comprises the following steps: (1) Subjecting o-chloroacetic acid to an acyl chlorination reaction to produce a compound I, wherein X is selected from fluorine, chlorine, bromine or iodine; (2) Reacting dimethyl malonate with an inorganic base to form a compound ii; (3) Reacting the compound I with the compound II to generate a compound III; (4) The compound III is subjected to cyclopropanation reaction to generate a compound IV, and then is subjected to hydrolysis decarboxylation reaction to generate a compound V; (5) And (3) performing chlorination reaction on the compound V to generate the prothioconazole intermediate. The preparation method avoids the use of Grignard reagent, does not need to be carried out under the harsh anhydrous and anaerobic condition, and reduces the potential safety hazard of production; the preparation method provided by the invention has the advantages that the raw materials used are low in price, the preparation cost of the prothioconazole intermediate is reduced, and the preparation method is suitable for industrial production.

Description

Preparation method of prothioconazole intermediate
Technical Field
The invention particularly relates to a preparation method of a prothioconazole intermediate.
Background
The prothioconazole (prothioconazole) is a novel efficient spectral triazole fungicide developed by German Bayer company 1995, is mainly applied to cereal crops such as wheat and rice, and rape, peanut and beans, and has good control effects on powdery mildew, leaf rust, stripe rust, banded sclerotial blight, leaf spot, sclerotial blight and leaf streak. The synthesis of prothioconazole cannot bypass an important intermediate, and the chemical structural formula is as follows:
at present, three main methods for synthesizing prothioconazole intermediates are as follows:
One of them is disclosed in chinese patent CN110590499 a: in methyl tetrahydrofuran solution, 1 o-chlorochlorobenzene and magnesium generate Grignard reagent, and then nucleophilic reaction is carried out with 2-chloro-1-chlorocyclopropylethanone, thus obtaining an important intermediate of prothioconazole. The preparation method mainly has the following defects: (1) The Grignard reagent is needed for reaction, and is easy to be decomposed and exploded violently when meeting water and oxygen, and the reaction is more harsh under anhydrous and anaerobic conditions, thus being not beneficial to amplification experiments and safe production; (2) The method has high requirements on equipment, and certain potential safety hazards exist in the generation and storage of the Grignard reagent.
Second, as disclosed in patent US5146001 a: 1-chloro-2-chloromethylbenzene is used as a starting material to generate an organic zinc reagent (Grignard reagent) and then reacts with 1-chlorocyclopropane formyl chloride in a nucleophilic way to obtain the prothioconazole intermediate. The preparation method mainly has the following defects: (1) the method has the advantages of overlong steps and lower overall yield after being folded; (2) The Grignard reagent is needed in the reaction, the anhydrous and anaerobic condition is needed in the reaction, the reaction is more severe, and the amplification experiment and the safe production are not facilitated; (3) The method has high requirements on equipment, and certain potential safety hazards exist in the generation and storage of the Grignard reagent.
And thirdly, taking o-chlorobenzonitrile as a starting material, condensing with methyl cyclopropanecarboxylate to obtain an intermediate, hydrolyzing and decarboxylating, and finally introducing chlorine gas to obtain an important intermediate of prothioconazole. The preparation method mainly has the following defects: (1) The overall yield of the reaction is low (less than 50 percent), and the method is not suitable for industrial production; and (2) the raw materials are expensive and the production cost is high.
Disclosure of Invention
The invention aims to provide a preparation method of prothioconazole intermediate, which has low raw material price, does not need to use Grignard reagent and is suitable for industrial production.
In order to achieve the above purpose, the invention adopts the following technical scheme:
A method for preparing a prothioconazole intermediate, comprising the following steps: (1) The O-chloroacetic acid is subjected to acyl chlorination reaction to generate a compound I, wherein the structural formula of the compound I is The X is selected from fluorine, chlorine, bromine or iodine; (2) Reacting dimethyl malonate with an inorganic base to form a compound II of formula/>Wherein A is selected from sodium or potassium; (3) Reacting the compound I and the compound II to form a compound III, wherein the structural formula of the compound III is/>(4) The compound III is subjected to cyclopropanation reaction to generate a compound IV, and then is subjected to hydrolysis decarboxylation reaction to generate a compound V, wherein the structural formula of the compound IV is/>The structural formula of the compound V is/>(5) The compound V is subjected to chlorination reaction to generate the prothioconazole intermediate, and the structural formula of the prothioconazole intermediate is/>
Preferably, the step of reacting the compound I with the compound ii to form the compound iii comprises: reacting the compound II, alkali and magnesium chloride in the presence of an organic solvent, then adding the compound I into a reaction system for reaction, and then adding hydrochloric acid for reaction.
Further preferably, the specific step of reacting the compound I with the compound ii to form the compound iii comprises: and respectively adding the compound II, the organic solvent, the alkali and the magnesium chloride into a reactor, carrying out heat preservation reaction for 2-3 h at 15-25 ℃, then cooling to 0-10 ℃, adding the compound I in a dropwise manner, heating to 20-25 ℃ after the dropwise addition, carrying out heat preservation reaction for 16-17 h, then adding the hydrochloric acid, and heating to 40-50 ℃ for reaction for 1.5-2.5 h.
Still more preferably, the base is selected from triethylamine.
Still more preferably, the organic solvent in the step (3) includes one or more of acetonitrile, DMF (N, N-dimethylformamide), and methanol.
According to some preferred embodiments, the ratio of the mass of the compound II to the mass of the compound I is 1 (1.0-1.3), such as 1:1.0, 1:1.1, 1:1.2, 1:1.3, etc.
Further preferably, the feeding mass ratio of the compound II to the alkali to the magnesium chloride is 1.0: (0.9-1.7): (0.5 to 1.2), and further 1: (0.9-1.2): (0.5-0.7), for example 1:0.9:0.5, 1:1.0:0.5, 1:1.1:0.5, 1:1.2:0.5, 1:0.9:0.6, 1:1.0:0.6, 1:1.1:0.6, 1:0.9:0.7, 1:1.0:0.7, 1:1.1:0.7, etc.
Preferably, the step of cyclopropanation of said compound iii to compound iv comprises: reacting the compound III, dihaloethane including one or more of dichloroethane, difluoroethane, dibromoethane, and an inorganic base including potassium carbonate and/or sodium carbonate in the presence of an organic solvent.
Further preferably, in the step (4), the feeding mass ratio of the compound iii to the dihaloethane is 1: (0.5-1.5), e.g., 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:1, etc.
Further preferably, in the step (4), the feeding mass ratio of the compound iii to the inorganic base is 1: (0.4 to 1.1), for example, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, etc.
Preferably, the cyclopropanation reaction is carried out at a temperature of 65-75 ℃ for a time of 6-7 hours.
Preferably, the organic solvent used in the cyclopropanation reaction comprises one or more of acetonitrile, DMF, methanol.
Preferably, the specific steps of the hydrolytic decarboxylation reaction include: after the cyclopropanation reaction is finished, removing the organic solvent, then adding methanol, water and sodium hydroxide, reacting for 2-3 hours at 35-45 ℃, and after the reaction is finished, adding hydrochloric acid, heating to 40-50 ℃ and reacting for 1.5-2.5 hours.
Further preferably, the mass ratio of the compound III to the sodium hydroxide is 1: (0.2 to 0.5), for example, 1:0.2, 1:0.3, 1:0.4, 1:0.5, etc.
Preferably, the specific step of subjecting the o-chloroacetic acid to an acyl chlorination reaction to produce the compound I comprises: adding the o-chloroacetic acid and the phosphorus trichloride into a reactor, stirring, preserving the temperature at 25-35 ℃, and introducing a halogenating reagent to react for 3-4 hours; wherein the halogenating reagent is chlorine, and the feeding mass ratio of the o-chloroacetic acid to the phosphorus trichloride is 1: (0.5-1.2), e.g., 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, etc.
Preferably, the specific step of reacting said dimethyl malonate with said inorganic base to form said compound ii comprises: and respectively adding dimethyl malonate and an alcohol solvent into a reactor, preserving heat at 15-25 ℃, dropwise adding a mixed solution of the alcohol solvent and inorganic base, heating to 70-80 ℃ after the addition, carrying out reflux reaction, filtering while the mixture is hot, cooling the filtrate to 0-10 ℃, and separating out the compound II.
Further preferably, the alcohol solvent is one or more of methanol, ethanol, propanol.
Further preferably, in the step, the inorganic base is potassium hydroxide and/or sodium hydroxide, and the feeding mass ratio of the dimethyl malonate to the inorganic base is 1: (0.2 to 1.1), for example, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, etc.
Preferably, the specific step of subjecting said compound v to a chlorination reaction to produce said prothioconazole intermediate comprises: respectively adding the compound V and a chlorinating reagent into a reactor, and reacting for 6-7 h at 65-75 ℃ in a heat preservation way; wherein the chlorinating reagent is dichloroethane and/or chlorine gas, and the feeding mass ratio of the compound V to the chlorinating reagent is 1: (0.5 to 1.5), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, etc.
Preferably, the prothioconazole intermediate is prepared under the protection of nitrogen.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
The preparation method avoids the use of Grignard reagent, does not need to be carried out under the harsh anhydrous and anaerobic condition, and reduces the potential safety hazard of production;
The preparation method provided by the invention has the advantages that the raw materials used are low in price, the preparation cost of the prothioconazole intermediate is reduced, and the preparation method is suitable for industrial production.
Detailed Description
According to the application, o-chloroacetic acid and dimethyl malonate are used as starting materials, and the prothioconazole intermediate is prepared through the reactions of acyl chlorination, condensation, decarboxylation, cyclopropanation, chlorination and the like. The scheme of the application is further discussed below.
According to some preferred embodiments, a method for preparing a prothioconazole intermediate, the method comprising the steps of:
(1) Under the protection of N 2, o-chloroacetic acid and phosphorus trichloride are added into a reactor, stirred, kept at 25-35 ℃ and introduced with a halogenating reagent for reaction for 3-4 hours, and a compound I is generated, wherein the structural formula of the compound I is X is selected from fluorine, chlorine, bromine or iodine;
(2) Under the protection of N 2, dimethyl malonate and an alcohol solvent are respectively added into a reactor, the temperature is kept at 15-25 ℃, a mixed solution of the alcohol solvent and inorganic alkali is dripped, after the addition is finished, the temperature is raised to 70-80 ℃, the reflux reaction is carried out while the mixture is hot, the filtrate is cooled to 0-10 ℃, a compound II is separated out, and the structural formula of the compound II is that Wherein A is selected from sodium or potassium;
(3) Under the protection of N 2, respectively adding a compound II, an organic solvent, alkali and magnesium chloride into a reactor, carrying out heat preservation reaction for 2-3 h at 15-25 ℃, then cooling to 0-10 ℃, adding a compound I in a dropwise manner, heating to 20-25 ℃ after the dropwise addition is finished, carrying out heat preservation reaction for 16-17 h, then adding hydrochloric acid, heating to 40-50 ℃ and carrying out reaction for 1.5-2.5 h, thereby generating a compound III, wherein the structural formula of the compound III is that
(4) Under the protection of N 2, the compound III, dihaloethane and inorganic base are reacted in the presence of organic solvent, the temperature is kept between 65 ℃ and 75 ℃, stirring reaction is carried out for 6 to 7 hours, after the reaction is finished, the organic solvent is removed, methanol, water and sodium hydroxide are added, stirring reaction is carried out for 2 to 3 hours at 35 ℃ to 45 ℃, hydrochloric acid is added after the reaction is finished, the temperature is increased to 40 ℃ to 50 ℃ for reaction for 1.5 to 2.5 hours, and the compound V is produced, wherein the structural formula of the compound V is
(5) Under the protection of N 2, respectively adding a compound V and a chlorinating reagent into a reactor, and carrying out heat preservation reaction for 6-7 h at 65-75 ℃ to obtain a prothioconazole intermediate, wherein the structural formula of the prothioconazole intermediate is
According to some specific and preferred embodiments, a reaction equation for a prothioconazole intermediate is as follows:
the scheme of the invention has at least the following specific advantages:
(1) The invention avoids the use of Grignard reagent (organic metal reagent), the reaction is not required to be carried out under the harsh conditions of no water and no oxygen, and the reaction condition is milder; compared with the high requirements of Grignard reagent on the reactor, the method has low requirements on the reactor; compared with the Grignard reagent which is easy to explode, the preparation method has high safety coefficient.
(2) The invention has low price and is easy to obtain, and the production cost of the prothioconazole intermediate is reduced.
(3) The preparation method of the prothioconazole intermediate has fewer steps and improves the yield compared with the prior art.
(4) The preparation method of the invention also has the advantages of less three wastes, short time and the like, and is especially suitable for industrial production.
The invention is further described below with reference to examples. The present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions which are not noted are conventional conditions in the industry. The technical features of the various embodiments of the present invention may be combined with each other as long as they do not collide with each other.
Unless otherwise specified, the yields in the examples below refer to molar yields.
Example 1
Under the protection of N 2, 17.0g of o-chloroacetic acid and 13.7g of phosphorus trichloride are sequentially added into a reaction bottle, stirred, kept at 25-35 ℃, slowly introduced with chlorine, after 3-4 hours, after the introduction reaction is finished, the solvent (phosphorus trichloride) is removed after the reaction is detected to be complete by GC (gas chromatography), and the reaction is directly carried out without purification.
HPLC (high performance liquid chromatography) showed compound I to be 95% pure with 97.3% yield.
Example 2
Under the protection of N 2, 13.2g of dimethyl malonate and 20g of methanol are sequentially added into a reaction bottle, the mixture solution of 20g of methanol and 5.6g of potassium hydroxide is slowly dripped at 15-25 ℃ under the heat preservation, the temperature is raised to 70-80 ℃ after the addition is completed for about 1.5-2 hours, the reflux reaction is carried out, the reaction byproduct dipotassium salt (filter residue) is filtered and removed while the reaction product is hot, the filtrate is cooled to 0-10 ℃, and the solid (compound II) is separated out, wherein the yield is 87.3%.
Example 3
Under the protection of N 2, 15.6g of potassium methyl malonate (compound II), 20g of acetonitrile, 16.2g of triethylamine and 9.5g of magnesium chloride are sequentially added into a reaction bottle, the temperature is kept at 15-25 ℃, stirring is carried out for 2-3 h, the temperature is reduced to 0-10 ℃, 18.8g of o-chlorobenzoyl acetyl chloride (compound I) is slowly added dropwise, the charging is completed after about 0.5-1 h, the temperature is raised to 20-25 ℃, the temperature is kept for 16-17 h, hydrochloric acid is added, the temperature is raised to 40-50 ℃ for 2h, water and ethyl acetate are added for extraction, the solvent is removed, and the direct reaction is carried out without purification.
HPLC showed 92% purity of compound iii with a total yield of 82.3%.
MS-EI(m/z,%):227(M++H+);265(M++K+)。
Example 4
Under the protection of N 2, 22.6g of 4- (2-chlorophenyl) -3-oxo-methyl butyrate (compound III), 14.5g of potassium carbonate, 20g of dichloroethane and 10g of acetonitrile are sequentially added into a reaction bottle, the temperature is kept at 65-75 ℃, stirring is carried out for 6-7 h, after the reaction is finished, the solvent is removed, 10g of methanol, 15g of water and 8.4g of sodium hydroxide are added, stirring is carried out for 2-3 h at 35-45 ℃, after the reaction is finished, 18g of concentrated hydrochloric acid is added, the temperature is raised to 40-50 ℃ for 2h, finally ethyl acetate is added for extraction, the solvent is removed, and the direct casting reaction is carried out without purification.
HPLC showed 93% purity of compound v with 85.1% yield.
MS-EI(m/z,%):195(M++H+);233(M++K+)。
Example 5
Under the protection of N 2, 19.4g of 2-chlorophenyl-1-cyclopropyl ethanone (compound V) and 20g of dichloroethane are sequentially added into a reaction bottle, chlorine is introduced, the reaction is carried out at 65-75 ℃ under stirring for 6-7 h, and after the reaction is finished, the solvent (dichloroethane) is removed, so that the target product (compound VI) is obtained.
HPLC showed compound VI to be 93% pure with a yield of 81.2%.
MS-EI(m/z,%):229(M++H+);227(M+-H+)。
The present invention has been described in detail with the purpose of enabling those skilled in the art to understand the contents of the present invention and to implement the same, but not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.

Claims (8)

1. A method for preparing a prothioconazole intermediate, which is characterized by comprising the following steps:
(1) The O-chloroacetic acid is subjected to acyl chlorination reaction to generate a compound I, wherein the structural formula of the compound I is The X is selected from chlorine;
(2) Reacting dimethyl malonate with an inorganic base to form a compound II of the formula Wherein A is selected from sodium or potassium;
(3) Reacting the compound II, alkali and magnesium chloride in the presence of an organic solvent at 15-25 ℃ for 2-3 hours, then cooling to 0-10 ℃, adding the compound I into a reaction system, heating to 20-25 ℃, reacting for 16-17 hours at a temperature of 16-17 hours, then adding hydrochloric acid, and reacting for 1.5-2.5 hours at a temperature of 40-50 ℃ to obtain a compound III, wherein the structural formula of the compound III is that
(4) Reacting the compound III, dihaloethane and inorganic base for 6-7 h at 65-75 ℃ in the presence of an organic solvent to generate a compound IV, removing the organic solvent after the reaction is finished, adding methanol, water and sodium hydroxide, reacting for 2-3 h at 35-45 ℃, adding hydrochloric acid after the reaction is finished, heating to 40-50 ℃ and reacting for 1.5-2.5 h to generate a compound V, wherein the structural formula of the compound IV is thatThe structural formula of the compound V is/>
(5) Respectively adding the compound V and a chlorinating reagent into a reactor, and carrying out heat preservation reaction for 6-7 hours at 65-75 ℃ to generate the prothioconazole intermediate, wherein the structural formula of the prothioconazole intermediate is as followsThe chlorinating agent is dichloroethane and/or chlorine gas.
2. The method for preparing the prothioconazole intermediate according to claim 1, wherein said compound I is added dropwise; and/or the number of the groups of groups,
The base is selected from triethylamine, and the organic solvent in the step (3) comprises one or more of acetonitrile, methanol and DMF; and/or the number of the groups of groups,
The feeding mass ratio of the compound II to the compound I is 1 (1.0-1.3), and the feeding mass ratio of the compound II to the alkali to the magnesium chloride is 1.0: (0.9 to 1.7): (0.5 to 1.2).
3. The method for producing prothioconazole intermediate according to claim 1, wherein said dihaloethane comprises one or more of dichloroethane, difluoroethane and dibromoethane, and said inorganic base in step (4) comprises potassium carbonate and/or sodium carbonate.
4. The method for preparing prothioconazole intermediate according to claim 1, wherein in said step (4), the feed mass ratio of said compound iii to said dihaloethane is 1: (0.5-1.5), wherein the feeding mass ratio of the compound III to the inorganic base is 1: (0.4-1.1); and/or the number of the groups of groups,
The organic solvent used in the step (4) comprises one or more of acetonitrile, DMF and methanol.
5. The method for preparing prothioconazole intermediate according to claim 1, wherein said specific step of subjecting said o-chloroacetic acid to an acyl chlorination reaction to produce said compound I comprises: adding the o-chloroacetic acid and the phosphorus trichloride into a reactor, stirring, preserving the temperature at 25-35 ℃, and introducing a halogenating reagent to react for 3-4 hours; wherein the halogenating reagent is chlorine, and the feeding mass ratio of the o-chloroacetic acid to the phosphorus trichloride is 1: (0.5 to 1.2).
6. The method for preparing prothioconazole intermediate according to claim 1, wherein said specific step of reacting dimethyl malonate with said inorganic base to form said compound ii comprises: respectively adding dimethyl malonate and an alcohol solvent into a reactor, preserving heat at 15-25 ℃, dropwise adding a mixed solution of the alcohol solvent and inorganic base, heating to 70-80 ℃ after the addition, carrying out reflux reaction, filtering while the mixture is hot, cooling the filtrate to 0-10 ℃, and separating out the compound II;
the alcohol solvent is one or more of methanol, ethanol and propanol;
The inorganic base is potassium hydroxide and/or sodium hydroxide, and the feeding mass ratio of the dimethyl malonate to the inorganic base is 1: (0.2 to 1.1).
7. The preparation method of the prothioconazole intermediate according to claim 1, wherein the feeding mass ratio of said compound v to said chlorinating agent is 1: (0.5 to 1.5).
8. The process for the preparation of prothioconazole intermediate according to any one of claims 1 to 7, wherein said prothioconazole intermediate is prepared under the protection of nitrogen.
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