CN112194628A

CN112194628A - Preparation method of nyconazole hydrochloride

Info

Publication number: CN112194628A
Application number: CN202010469917.1A
Authority: CN
Inventors: 任亚东; 夏春森; 郭海伟; 汪刘恒; 刘志强; 袁海成
Original assignee: Yangtze River Pharmaceutical Group Guangzhou Hairui Pharmaceutical Co ltd; Yangtze River Pharmaceutical Group Co Ltd
Current assignee: Yangtze River Pharmaceutical Group Guangzhou Hairui Pharmaceutical Co ltd; Yangtze River Pharmaceutical Group Co Ltd
Priority date: 2020-05-28
Filing date: 2020-05-28
Publication date: 2021-01-08

Abstract

The invention discloses a preparation method of naphthoconazole hydrochloride. The preparation method comprises the following steps: (1) taking a compound shown in the formula III and bromopentane as reaction raw materials, reacting under an alkaline condition, and extracting a product obtained by the reaction; reacting the extracted and separated organic product with hydrogen chloride to form salt, and obtaining the nyconazole hydrochloride;

optionally, further comprising step (2): and refining the obtained naphthoconazole hydrochloride. According to the method, the reaction conditions for preparing each intermediate, the intermediate post-treatment process and the nyconazole hydrochloride refining process are strictly controlled, so that the prepared nyconazole hydrochloride has high purity, and the residual solvent and impurity content is very low. The obtained nyconazole hydrochloride also has excellent stability.

Description

Preparation method of nyconazole hydrochloride

Technical Field

The invention belongs to the field of compound preparation, and particularly relates to a preparation method of naphthoconazole hydrochloride.

Background

Nalconazole hydrochloride (molecular formula C)₁₇H₂₂N₂OS. HCl, CAS No.130773-02-3), having the chemical name: (E) -1- [ 2-methylsulfanyl-1- [2- (pentyloxy) phenyl]Vinyl radical]-1H-imidazole hydrochloride having the structure shown below:

the neconazole hydrochloride is a novel imidazole antifungal drug and has double effects of antibiosis and sterilization. It has broad antibacterial spectrum, and has broad-spectrum antibacterial effect on yeast-like fungus, dermatophyte, tinea versicolor fungus, coloring fungus and other filamentous fungi.

At present, the preparation method capable of effectively reducing the content of related substances in the nyconazole hydrochloride, reducing the solvent residue in the preparation process and effectively improving the stability of the nyconazole hydrochloride is still widely concerned by pharmaceutical researchers, and needs to be studied in depth.

Disclosure of Invention

The invention provides a preparation method of naphthoconazole hydrochloride, which comprises the following steps:

(1) taking a compound shown in the formula III and bromopentane as reaction raw materials, reacting under an alkaline condition, and extracting a product obtained by the reaction; reacting the extracted and separated organic product with hydrogen chloride to form salt, and obtaining the nyconazole hydrochloride;

optionally, the method further comprises the step (2) of refining the nyconazole hydrochloride obtained in the step.

According to the invention, in step (1), the mass ratio of the compound of formula III to bromopentane is 1 (0.5-1.0), for example 1 (0.6-0.9), exemplarily 1: 0.79.

According to the present invention, in step (1), the compound of formula III can be obtained by purifying and refining the crude compound of formula III in an alcoholic solvent (e.g. methanol, ethanol) and water. Wherein the mass ratio of the crude compound of the formula III to the alcohol solvent is 1 (20-30), such as 1 (22-28), and exemplary is 1: 25. Wherein the mass ratio of the crude compound of formula III to water is 1 (15-25), such as 1 (17-23), exemplarily 1: 20. Wherein, the purification and refining process comprises the following steps: the crude compound of formula III is first dispersed in an alcoholic solvent (e.g. methanol, ethanol), heated (e.g. at a temperature of 60-70 ℃) for a period of time (e.g. 0.5-2h), cooled to 45-55 ℃, then water is slowly added thereto, heated (e.g. at a temperature of 55-65 ℃) for a period of time (e.g. 1-3h), cooled (e.g. to 10-20 ℃) and the product is then worked up. Further, the post-treatment includes filtration, washing and drying (e.g., drying to a weight loss of 1.0%); for example, washing with chloroform, for example, by vacuum drying (vacuum drying temperature 45-55 ℃ C., vacuum drying time 3-6 hours).

Wherein, the crude compound of formula III can be prepared by step S1: taking a compound of a formula II, imidazole and thionyl chloride as reaction raw materials, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a crude product of the compound of the formula III;

wherein, in step S1, the mass ratio of the compound of formula II, imidazole and thionyl chloride is 1 (2-3) to (0.8-1.6), such as 1 (2.2-2.8) to (1.0-1.4), exemplarily 1:2.65: 1.15.

The reaction may be performed in a solvent, for example, the solvent is at least one of dichloromethane and chloroform, preferably dichloromethane. Further, the mass ratio of the solvent to the compound of formula II is (40-80):1, e.g., (45-60): 1.

In step S1, the order of adding imidazole and thionyl chloride is: imidazole is added into solvent, evenly stirred, cooled to 0-10 ℃, and then thionyl chloride is added. Wherein the thionyl chloride needs to be added slowly, and the temperature of the reaction system is preferably controlled not to exceed 25 ℃ during the addition of the thionyl chloride. Further, after the thionyl chloride is added, the reaction is carried out at 15-25 ℃ for 10-30min, for example, at 18-22 ℃ for 20 min.

Wherein, in step S1, the compound of formula II is added in the form of a solution, for example, a dichloromethane solution of the compound of formula II. Wherein the dichloromethane solution of the compound of the formula II needs to be slowly added, and the temperature of the reaction system is preferably controlled not to exceed 25 ℃ during the addition of the dichloromethane solution of the compound of the formula II. Further, after the dichloromethane solution of the compound of formula II is added, the reaction is carried out for 2-6h at 20-30 ℃, for example, for 3-5h at 22-28 ℃.

In step S1, the reaction process is performed under an inert atmosphere, for example, nitrogen, helium or argon, preferably nitrogen.

Wherein, in step S1, when the content of the compound of formula II in the reaction system is less than 5%, the reaction is considered to be completed.

Wherein, in step S1, the post-processing includes adding water for quenching: removing the inert atmosphere, cooling the system (for example, to below 10 ℃), adding water into the system, and quenching the reaction. Further, the mass ratio of the mass of water to the compound of formula II is (5-10):1, e.g., (6-9):1, illustratively 7: 1. Further, the water is added slowly, and the temperature of the system is preferably controlled not to exceed 25 ℃ during the water addition.

Further, the post-treatment also includes extraction: after the water is added, stirring, standing for layering, separating liquid, and collecting an organic phase. Further, the post-treatment also comprises reduced pressure concentration, and the collected organic phase is subjected to reduced pressure concentration under the conditions that the temperature is not higher than 40 ℃ and the light is avoided until no condensate flows out basically.

Further, the post-treatment further comprises heating and refluxing: adding chloroform into the product obtained by vacuum concentration, heating to reflux (such as 60-70 deg.C, reflux time 2-6 hr, such as 63-77 deg.C, reflux time 3-5 hr), cooling after reflux (such as 30-40 deg.C, such as 33-37 deg.C), stirring for a certain period of time (such as 3-8 hr, such as 4-6 hr), and filtering.

Further, the post-treatment also comprises pulping: pulping the solid obtained by filtering with trichloromethane until no liquid flows out basically, and collecting a solid product; wherein, the beating times are at least one, such as two times, three times, preferably two times; wherein the mass ratio of chloroform to the compound of formula II used per break is (1.5-5):1, e.g. (2-4):1, exemplary 2.5:1, 2.92:1, 3.2: 1.

Further, the post-treatment further comprises drying: the solid product is dried, for example, under vacuum, to a loss on drying of 1.0% or less. Wherein the temperature of the vacuum drying is 45-55 ℃, such as 47-52 ℃; the vacuum drying time is 2-6, for example 3-5 h.

According to the present invention, the compound of formula II may be prepared by step S2: taking a compound shown in a formula I and sodium methyl mercaptide as reaction raw materials, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a compound shown in a formula II;

in step S2, the mass ratio of the compound of formula I to sodium thiomethoxide is 1 (1.8-3.0), such as 1 (1.9-2.5), and exemplary is 1:2.34, 1: 2.4.

In step S2, the reaction is performed in a solvent, for example, the solvent is at least one of methanol and ethanol, preferably methanol. Further, the mass ratio of the solvent to the compound of formula I is (6-10):1, e.g., (7-9):1, illustratively 8: 1.

Wherein, in step S2, the feeding sequence of the compound of formula I and sodium methyl mercaptide is: dispersing the compound of the formula I in a solvent until the system is clear, controlling the temperature of the system to be 0-20 ℃, and adding sodium methyl mercaptide into the system to adjust the pH value of the system to be alkaline (for example, the pH value is 8-9). Further, the sodium thiomethoxide may be added in portions, for example, in 2 portions.

Wherein, in step S2, the reaction temperature is 15-25 ℃, for example 18-23 ℃; the reaction time is from 1 to 4 hours, for example from 1.5 to 3 hours.

Wherein, in step S2, when the content of the compound of formula I in the system is less than 1%, the reaction is considered to be finished.

In step S2, the post-treatment includes at least one extraction, which may be at least two extractions, and the extraction process includes: adopting purified water and ethyl acetate to carry out first extraction on a reaction product, adjusting the pH of a system to 2-3 by using an acid solution (such as a hydrochloric acid solution, preferably a hydrochloric acid solution prepared by hydrochloric acid and water according to a mass ratio of 1 (2-4)) before extraction, stirring, standing for layering, and collecting an organic phase and a water phase; and (3) carrying out secondary extraction on the collected water phase by using ethyl acetate, stirring, standing for layering, collecting organic phases, and combining the organic phases obtained by the two extractions. Preferably, the temperature of the system is controlled not to exceed 15 ℃ during the process of adjusting the pH of the system by the acid solution. Preferably, the temperature of the system is reduced to below 15 ℃ before the first extraction.

Further, the post-treatment also includes washing, drying and redissolving. For example, the organic phase obtained by extraction is washed with a saturated sodium chloride solution, and the organic phase is collected after washing is completed; drying the organic phase (e.g., drying the organic phase with anhydrous sodium sulfate) to a moisture content of 2% or less; and then carrying out suction filtration, washing the obtained solid product with ethyl acetate, carrying out suction filtration until no liquid flows out basically, and collecting filtrate.

Further, the post-treatment also comprises concentration under reduced pressure: and (3) concentrating the filtrate under reduced pressure at the temperature of not more than 40 ℃ until no condensate flows out, and collecting the concentrate to obtain the compound of the formula I.

According to the present invention, the compound of formula I may be prepared by step S3: adding copper bromide into a system containing ethyl acetate, trichloromethane and o-hydroxyacetophenone for reaction, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a compound shown in the formula I;

wherein, in step S3, the mass ratio of the ethyl acetate, the trichloromethane and the o-hydroxyacetophenone is (4-9): (8-15):1, such as (5-8): (9-12):1, exemplary 6.72:11.17: 1.

Wherein, in step S3, the mass ratio of the copper bromide to the o-hydroxyacetophenone is (2-6):1, such as (3-5):1, and exemplary is 4.45: 1. Further, the copper bromide needs to be added slowly.

Wherein, in step S3, the temperature of the reaction is 70-80 ℃, such as 72-78 ℃, exemplary 75 ℃; further, the reaction time is 6-15h, such as 8-12h, exemplary 10 h.

In step S3, the reaction is considered to be completed when the content of the compound of formula I in the system is greater than 70.0%.

Wherein, in step S3, the post-treatment comprises at least one washing of the reaction product, for example with chloroform and water. Illustratively, cooling the system to 30-40 ℃, filtering, washing the solid obtained by filtering with chloroform, filtering until no liquid flows out basically, and collecting the filtrate; then washing with water, stirring, standing for layering, and collecting an organic phase.

Further, the post-treatment also comprises the steps of carrying out reduced pressure filtration on the collected organic phase (controlling the temperature to be not more than 55 ℃) until the organic phase is concentrated under reduced pressure until no condensate drips out basically, and collecting the concentrate.

Further, the post-treatment also comprises a refining process of the concentrate, for example, dissolving the concentrate in absolute ethyl alcohol, adding n-hexane at 20-30 ℃, cooling to 5-15 ℃ after stirring, preserving heat and stirring for 0.5-3h, cooling to-5 ℃, preserving heat and stirring for 1-4h, filtering, washing the solid obtained by filtering with n-hexane, filtering until no liquid flows out basically, and collecting the solid. Further, drying, e.g. vacuum drying, preferably at a temperature of 25-35 ℃, e.g. at a temperature of 27-32 ℃, the collected solid matter; the vacuum drying time is 2-6h, for example 3-5 h.

According to the invention, in step (1), the alkaline conditions can be obtained by adding a strong base, for example potassium hydroxide and/or sodium hydroxide. Further, the mass ratio of the strong base to the compound of formula III is (0.1-0.6):1, e.g., (0.2-0.5):1, illustratively 0.34: 1.

According to the present invention, in step (1), the reaction is carried out in a solvent, for example, N-dimethylformamide. Further, the mass ratio of the solvent to the compound of formula III is (5-10):1, e.g., (6-9):1, illustratively 7.58: 1.

According to the invention, in step (1), the temperature of the reaction is in the range of 25 to 35 deg.C, such as 27 to 32 deg.C, and exemplary 25 deg.C, 26 deg.C, 28 deg.C, 30 deg.C, 33 deg.C, 35 deg.C. Further, the reaction time is 2-5h, such as 2.5-4.5h, exemplary 3h, 4 h. Further, when the mass content of the compound of formula III in the reaction system is less than or equal to 0.1%, the reaction is considered to be finished.

According to the invention, in step (1), the compound of formula III, bromopentane, solvent, and strong base are added in the order: adding strong base and the compound shown in the formula III into the solvent in sequence, mixing uniformly, and adding bromopentane.

According to the present invention, in step (1), the extraction may include at least one extraction, for example, at least two extractions, and exemplarily, the extraction process includes: extracting the reaction product by adopting water and methyl tert-butyl ether, and separating to obtain an organic phase and a water phase; extracting the water phase by using methyl tert-butyl ether, separating to obtain an organic phase, and combining the organic phases obtained by two extractions; the combined organic phases were extracted with water and the organic phase was collected. And further, drying and filtering the collected organic phase until no liquid flows out basically, and collecting filtrate to obtain the organic product.

According to the invention, in step (1), the hydrogen chloride is added in the form of a solution, for example in the form of a hydrogen chloride/absolute ethanol solution; further, the mass ratio of the hydrogen chloride/absolute ethanol solution to the compound of formula III is (1.4-1.80):1, for example (1.45-1.70):1, preferably (1.54-1.60): 1. Further, in the hydrogen chloride/anhydrous ethanol solution, the mass ratio of hydrogen chloride to anhydrous ethanol is (0.2-0.3):1, for example, (0.21-028):1, and preferably, (0.22-0.26): 1.

According to the invention, in step (1), the temperature of the reaction to form the salt is 10-20 ℃, for example 10-15 ℃, exemplary 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃. Further, the reaction time to form the salt is 2 to 6 hours, such as 3 to 5 hours, illustratively 4 hours. Further, the reaction salt formation is carried out under the protection of an inert atmosphere, for example, nitrogen, helium or argon, preferably nitrogen. Further, after the reaction salt formation is completed, post-treatment, such as suction filtration, washing and drying, can be performed on the reaction product; illustratively, the post-processing includes: and (3) carrying out suction filtration on the reaction product, washing (such as stirring and washing) a filter cake obtained by suction filtration by using methyl tert-butyl ether until no liquid flows out basically, collecting the filter cake, and carrying out vacuum drying on the filter cake until the loss on drying is less than or equal to 1.0%. Wherein the vacuum drying temperature is 40-50 ℃, and the vacuum drying time is 3-6 h.

According to the present invention, in the step (2), the number of times of the reflux purification is at least one, and preferably two. Wherein, the reagents for the two heating reflux processes are the same or different, for example, the first heating reflux reagent is a mixed solvent of absolute ethyl alcohol and methyl tert-butyl ether (wherein, the volume ratio of the absolute ethyl alcohol and the methyl tert-butyl ether can be (0.5-1.5):1, such as 1:1), and the second heating reflux reagent is methyl tert-butyl ether. Further, in the reflux refining process, the volume ratio of the absolute ethyl alcohol to the methyl tert-butyl ether is 1 (2.5-3.5), preferably 1: 3. Further, the mass ratio of the first heating reflux reagent and/or the second heating reflux reagent to the crude product of the nyconazole hydrochloride is (1-2):1, for example (1.2-1.6):1, exemplary is 1.35:1, 1.5: 1. Illustratively, the first reflow heating operation includes: and adding the crude product of the nyconazole hydrochloride into a mixed solvent of absolute ethyl alcohol and methyl tert-butyl ether, heating to reflux, filtering while hot after the system is dissolved clearly, and collecting filtrate. The second heating reflux operation comprises: adding the filtrate collected by the first heating reflux into methyl tert-butyl ether, heating to reflux, slowly cooling (for example, firstly cooling to 40-45 ℃, preserving heat for 10-30min, then cooling to 30-35 ℃, preserving heat for 10-30min) to 15-20 ℃, preserving heat and stirring for reaction (for example, the reaction time is 3-6h, and the exemplary reaction time is 4h) under the protection of inert atmosphere, and performing post-treatment on the product after the reaction is finished; for example, the product is subjected to at least one filtration (e.g., suction filtration) and washing (e.g., whisking or rinsing), and drying. Illustratively, the product is filtered with suction, the filter cake is stirred and washed with methyl tert-butyl ether, then filtered again with suction, the filter cake is rinsed with methyl tert-butyl ether, and after washing, the filter cake is vacuum dried (e.g., vacuum drying at 40-50 ℃ for 4 hours); preferably, vacuum drying is carried out until the weight loss is less than or equal to 0.5 percent.

According to an embodiment of the present invention, the preparation method of the naphthoconazole hydrochloride comprises the following steps:

(1) adding copper bromide into a system containing ethyl acetate, trichloromethane and o-hydroxyacetophenone for reaction, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a compound shown in a formula I;

(2) taking the compound shown in the formula I and sodium methyl mercaptide as reaction raw materials, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a compound shown in a formula II;

(3) taking the compound of the formula II, imidazole and thionyl chloride as reaction raw materials, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a crude product of the compound of the formula III;

(4) refining the crude compound of the formula III in methanol and water to obtain a refined compound of the formula III;

(5) reacting the refined compound shown in the formula III and bromopentane serving as reaction raw materials under an alkaline condition, and extracting a product obtained by the reaction; reacting the extracted and separated organic product with hydrogen chloride to form salt, and obtaining a crude product of the nyconazole hydrochloride;

(6) and carrying out reflux refining on the crude product of the naphthoconazole hydrochloride to obtain the naphthoconazole hydrochloride.

Advantageous effects

According to the method, the reaction conditions (such as reaction temperature and reaction time) for preparing each intermediate, the intermediate post-treatment process (such as reagent selection and purification operation) and the nyconazole hydrochloride refining process (such as selection and volume ratio of a reflux reagent) are strictly controlled, so that the prepared nyconazole hydrochloride has high purity, and the content of residual solvents and impurities is very low. The obtained nyconazole hydrochloride also has excellent stability. The method is suitable for industrial large-scale production, and is beneficial to obtaining products with excellent and stable quality through precise process control.

Drawings

Fig. 1 is a nuclear magnetic resonance hydrogen spectrum of a refined product of nyconazole hydrochloride obtained in example 1.

Fig. 2 is a nuclear magnetic resonance carbon spectrum of the refined naphthoconazole hydrochloride obtained in example 1.

FIG. 3 is a nuclear magnetic resonance DEPT spectrum of the refined nyconazole hydrochloride obtained in example 1.

Fig. 4 is a nuclear magnetic resonance two-dimensional correlation spectrum (COSY) of the refined nyconazole hydrochloride obtained in example 1.

FIG. 5 shows the nuclear magnetic resonance HSQC of the refined nyconazole hydrochloride obtained in example 1.

FIG. 6 shows the nuclear magnetic resonance HMBC of the refined product of the naphthoconazole hydrochloride obtained in example 1.

FIG. 7 is the NMR rewater exchange chart of the refined naphthoconazole hydrochloride obtained in example 1.

Fig. 8 is a mass spectrum of a refined naphthoconazole hydrochloride product obtained in example 1.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

Example 1 preparation of Nalconazole hydrochloride

1. Preparation of Nalconazole hydrochloride intermediate I (compound of formula I)

The reaction equation is as follows:

adding 92kg of ethyl acetate, 153kg of trichloromethane and 13.7kg of o-hydroxyacetophenone into a 300L glass-lined reaction tank, starting stirring, slowly adding 61kg of copper bromide, heating to 70-80 ℃ after the addition is finished, carrying out heat preservation reaction for 10 hours, then carrying out sampling detection (1 time of sampling detection every 5 hours) until the intermediate I is detected to be more than 70.0% by HPLC (high performance liquid chromatography), and finishing the reaction. Cooling the system to 30-40 ℃, filtering, leaching the filter cake for 1 time by using 34kg of trichloromethane, filtering until no liquid flows out basically, and collecting the filtrate.

Adding the filtrate into a 300L glass-lined reaction tank, starting stirring, washing the system with purified water for 3 times, wherein the dosage is 50.0kg each time, stirring for 30min each time, standing for layering, separating liquid, and collecting an organic phase. And putting the organic phase in a 300L glass-lined reaction tank, controlling the temperature not to exceed 55 ℃, concentrating under reduced pressure until no condensate basically drips out, and finishing concentrating under reduced pressure. 26.8kg of absolute ethyl alcohol is added, stirred and dissolved.

Transferring the solution into a 100L glass lining reaction tank, starting stirring, cooling to 20-30 ℃, adding 23kg of n-hexane, stirring for 10min, cooling to 5-15 ℃, stirring for 1h, slowly cooling to-5 ℃, keeping the temperature and stirring for 2h, filtering, leaching a filter cake with 5kg of n-hexane, filtering until no liquid flows out basically, and collecting the filter cake.

And (3) spreading the filter cake in a vacuum drier, controlling the temperature to be 25-35 ℃, and carrying out vacuum drying for 4h to obtain the intermediate I of the naphthoconazole hydrochloride. The yield of the intermediate I is 30-50%, and the purity is more than or equal to 98%. Sampling, detecting, and storing at 10 deg.C under sealed condition.

The structure of the intermediate I is confirmed:

A. mass spectrum (GC-MS): intermediate I structural formula C₈H₇BrO₂The theoretical molecular weight is: 215.05, respectively; the mass spectrum peaks determined for the samples were (m/z: 214.0, 216.0), possible fragment ion peaks (m/z: 121.0), consistent with the molecular formula.

Test sample	Molecular formula	Theoretical molecular weight	Measured value
				Intermediate I	C₈H₇BrO₂	215.05	214.0

B. Nuclear magnetic resonance hydrogen spectrum (¹H-NMR)

And (3) testing conditions are as follows: the solvent is CDCl₃(ii) a The internal standard is TMS.

The nuclear magnetic resonance hydrogen spectrum data and the attribution of the intermediate I are as follows:

the nuclear magnetic resonance hydrogen spectrum characteristics of the sample accord with the chemical structure of the intermediate I.

C. Nuclear magnetic resonance carbon Spectroscopy (13C-NMR)

The nuclear magnetic resonance carbon spectrum data and the attribution of the intermediate I are shown in the following table:

the nuclear magnetic resonance carbon spectrum characteristics of the sample accord with the chemical structure of the intermediate I.

2. Preparation of intermediate II of nyconazole hydrochloride (compound of formula II)

The reaction equation is as follows:

preparation of hydrochloric acid solution: 0.19kg/kg of hydrochloric acid was slowly added to 0.49kg/kg of purified water, and mixed by stirring for use.

Preparation of saturated sodium chloride solution: 0.23kg/kg of sodium chloride was added to 0.6kg/kg of purified water, and dissolved by stirring for use.

Adding 8.0kg/kg of methanol and 1.0kg/kg of intermediate I into a 200L glass lining reaction tank, starting stirring, controlling the temperature to be 0-20 ℃ after the system is dissolved, adjusting the pH value of the system to be 8-9 (wide pH test paper) by using a proper amount of 20% sodium methyl mercaptide solution (firstly slowly adding 1.95kg/kg, and if the pH value is less than 8, supplementing a proper amount of 20% sodium methyl mercaptide solution until the pH value of the system is 8-9), and controlling the temperature to be not more than 20 ℃ in the adjusting process. After the adjustment is finished, heating to 15-25 ℃, keeping the temperature for reaction for 2 hours, sampling and detecting (sampling and detecting for 1 time every 1 hour) until the content of the intermediate I is less than 1.0 percent through HPLC detection, and finishing the reaction.

Controlling the temperature not to exceed 40 ℃, and concentrating under reduced pressure until no liquid flows out basically. Cooling the system to below 15 ℃, adding 4.0kg/kg of purified water and 2.8kg/kg of ethyl acetate, adjusting the pH value of the system to 2-3 (wide pH test paper) by using a proper amount of hydrochloric acid solution (about 0.28kg/kg), stirring for 30min, re-measuring the pH value (2-3), and controlling the temperature to be not more than 15 ℃ in the adjusting process. Standing for layering, separating liquid, and collecting an aqueous phase and an organic phase. Extracting the water phase with 1.4kg/kg ethyl acetate for 1 time, stirring for 30min, standing for layering, separating, collecting the combined organic phases.

Adding the organic phase into a 100L glass-lined reaction tank, starting stirring, washing the organic phase with 0.6kg/kg saturated sodium chloride solution for 1 time, stirring for 30min, standing for layering for 30min, separating, and collecting the organic phase. Adding 1.0kg/kg of anhydrous sodium sulfate into the organic phase, stirring and drying for 3 hours, sampling and detecting for 1 time every 2 hours until the detected water content is less than or equal to 2%, performing suction filtration, stirring and washing the filter cake for 1 time by using 2.8kg/kg of ethyl acetate, performing suction filtration until no liquid flows out basically, and collecting filtrate.

And transferring the filtrate to a 100L glass-lined reaction tank, controlling the temperature to be not more than 40 ℃, concentrating under reduced pressure until no condensate flows out basically, and collecting the concentrate to obtain a naphthoconazole hydrochloride intermediate II.

After sampling, 5.3kg/kg of methylene chloride was added to the obtained concentrate, and the mixture was dissolved by stirring and sealed in the dark for use.

3. Preparation of crude product of intermediate III of nyconazole hydrochloride (compound of formula III)

The reaction equation is as follows:

adding 48.46kg/kg of dichloromethane and 2.65kg/kg of imidazole into a 500L glass lining reaction tank under the protection of nitrogen in a dark place, starting stirring, cooling to 0-10 ℃, slowly adding 1.15kg/kg of thionyl chloride, and controlling the temperature to be not more than 25 ℃ in the adding process. After the addition, the temperature is controlled to be 15-25 ℃, the heat preservation and the stirring are carried out for 20min, the intermediate II dichloromethane solution is slowly added, and the temperature is controlled not to exceed 25 ℃ in the adding process. After the addition, the temperature is controlled to be 20-30 ℃, the reaction is carried out for 4h, and sampling detection is carried out (1 time for every 1 h) until the intermediate II is less than 5 percent through HPLC detection according to the completion of the reaction.

Removing the nitrogen protection, cooling the system to below 10 ℃, slowly adding 7.0kg/kg of purified water, and controlling the temperature to be not more than 25 ℃ in the adding process. Stirring for 30min after the addition is finished, standing for layering, separating liquid, and collecting an organic phase. Transferring the organic phase into a 300L glass lining reaction tank, controlling the temperature not to exceed 40 ℃, keeping out of the sun, concentrating under reduced pressure until no condensate flows out basically, adding 31.4kg/kg of trichloromethane, heating to the temperature of the system to reflux (60-70 ℃), stirring for 3 hours under reflux, cooling to 30-40 ℃, stirring for 5 hours under heat preservation, filtering, pulping the filter cake twice with an appropriate amount of trichloromethane, with the dosage of 2.92kg/kg each time, filtering until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 45-55 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time for every 1 h) until the drying weight loss is less than or equal to 1.0% by detection (a rapid moisture determinator: 105 ℃, 15min), and obtaining the intermediate product, namely the intermediate III crude product of the naphthoconazole hydrochloride.

4. Preparation of intermediate product-intermediate III of nyconazole hydrochloride

And (3) keeping out of the sun, adding 1.0kg/kg of crude intermediate III and 25.0kg/kg of methanol into a 300L glass lining reaction tank, starting stirring, heating to 60-70 ℃, keeping the temperature and stirring for 1h, cooling to 45-55 ℃, slowly adding 20.0kg/kg of purified water, and controlling the temperature to be not lower than 45 ℃ in the adding process. After the addition, the mixture is heated to 55-65 ℃, kept warm and stirred for 2h, cooled to 10-20 ℃. Filtering, leaching the filter cake with 2.0kg/kg chloroform for 1 time, filtering until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 45-55 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time for every 1 h) until the drying weight loss is less than or equal to 1.0% by detection (a rapid moisture determinator: 105 ℃, 15min), and obtaining the intermediate product, namely the intermediate III, of the naphthoconazole hydrochloride.

The structure of the intermediate III is confirmed:

A. mass spectrum (GC-MS): intermediate III structural formula C₁₂H₁₂N₂OS, theoretical molecular weight: 232.30 of the total weight of the mixture; the mass spectrum peak determined for the sample was (m/z: 232.9), consistent with the molecular formula.

Test sample	Molecular formula	Theoretical molecular weight	Measured value
				Intermediate I	C₁₂H₁₂N₂OS	232.07	232.90

B. Nuclear magnetic resonance hydrogen spectrum (¹H-NMR)

The nuclear magnetic resonance hydrogen spectrum data and the attribution of the intermediate III are as follows:

the nuclear magnetic resonance hydrogen spectrum characteristics of the sample accord with the chemical structure of the intermediate III.

C. Nuclear magnetic resonance carbon spectrum (¹³C-NMR)

The nuclear magnetic resonance carbon spectrum data and attribution of the intermediate III are as follows:

the nuclear magnetic resonance carbon spectrum characteristics of the sample accord with the chemical structure of the intermediate III.

5. Preparation of crude product of nyconazole hydrochloride

The reaction equation is as follows:

a 50L double-layer glass reaction kettle and a 200L glass lining reaction tank are refluxed by ethanol and dried to ensure that the reaction kettle is dry and anhydrous; the reaction kettle needs to be protected from light.

Preparation of hydrogen chloride/absolute ethanol solution: introducing hydrogen chloride gas into 1.26kg/kg of absolute ethyl alcohol until the weight is increased by 0.28 kg/kg-0.32 kg for later use.

Adding 7.58kg/kg of N, N-dimethylformamide into a 50L double-layer glass reaction kettle, starting stirring, keeping out of the sun, sequentially adding 0.34kg/kg of powdered potassium hydroxide and 1.0kg/kg of intermediate III, stirring for 5min at a stirring speed of not less than 180r/mn, adding 0.79kg/kg of bromopentane, controlling the temperature to be 25-35 ℃, carrying out heat preservation reaction for 3h, then carrying out sampling detection (1 sampling detection every 1 h) until the intermediate III is detected by HPLC (high performance liquid chromatography) to be less than or equal to 0.1%, and finishing the reaction.

Transferring the reaction liquid to a 200L glass-lined reaction tank, sequentially adding 7.89kg/kg of purified water and 11.84kg/kg of methyl tert-butyl ether, stirring for 10min, standing for layering, separating liquid, respectively collecting an organic phase and an aqueous phase, extracting the aqueous phase for 1 time by using 11.84kg/kg of methyl tert-butyl ether, stirring for 10min, standing for layering, separating liquid, collecting the organic phase, combining all the organic phases, washing the organic phase for 1 time by using 7.89kg/kg of purified water, stirring for 10min, standing for layering, separating liquid, collecting the organic phase, drying for 30min by using 0.68kg/kg of anhydrous magnesium sulfate for the organic phase, performing suction filtration until no liquid flows out basically, and collecting filtrate.

Transferring the filtrate into a 200L glass lining reaction tank, starting stirring, controlling the temperature to be 10-20 ℃ under the protection of nitrogen, adding 1.37kg/kg of prepared hydrogen chloride/absolute ethyl alcohol solution, keeping the temperature and stirring for 4 hours, carrying out suction filtration, stirring and washing a filter cake for 1 time by using 5.0kg/kg of methyl tert-butyl ether, carrying out suction filtration until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 40-50 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time for every 1 h) until the drying weight loss is less than or equal to 1.0% by detection (a rapid moisture content determinator: 70 ℃, 15min), and obtaining the crude product of the naphthoconazole hydrochloride.

6. Preparation of intermediate product-refined product of Nalconazole hydrochloride

Refluxing 20L and 50L double-layer glass reaction kettles with ethanol, and drying to ensure dryness and no water; the reaction kettle needs to be protected from light.

Adding 0.8kg/kg of anhydrous ethanol and 0.75kg/kg of methyl tert-butyl ether into a 20L double-layer glass reaction kettle, starting stirring, adding 1.0kg/kg of crude product, heating to reflux, filtering while the system is hot after being dissolved, transferring the filtrate into a 50L double-layer glass reaction kettle, starting stirring, adding 1.5kg/kg of methyl tert-butyl ether, heating to reflux, slowly cooling (firstly cooling to 40-45 ℃, keeping the temperature for 15min, then cooling to 30-35 ℃, keeping the temperature for 15min) to 20 ℃, stirring for 4h under the protection of nitrogen, carrying out suction filtration, washing a filter cake for 1 time by using 2.0kg/kg of methyl tert-butyl ether, carrying out suction filtration, leaching the filter cake once by using 0.75kg/kg of methyl tert-butyl ether, carrying out suction filtration until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 40-50 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time of sampling detection every 1 h) until the drying weight loss is less than or equal to 0.5% by detection (a rapid moisture determinator: 70 ℃, 15min), and obtaining a refined product of the naphthoconazole hydrochloride.

Fig. 1-8 are the confirmation of the structure of refined products of nyconazole hydrochloride:

A. mass spectrum (fig. 8): the structure of the nyconazole hydrochloride C₁₇H₂₃ClN₂OS, theoretical molecular weight: 338.89, HCl contained in the sample is not shown in the mass spectrum, the theoretical molecular weight is as follows except HCl: 302.14, respectively; the mass spectrum peak determined for the sample was (m/z: 302.14), consistent with the molecular formula.

B. Nuclear magnetic resonance hydrogen spectrum (fig. 1):

and (3) testing conditions are as follows: the solvent is DMSO-d 6; the internal standard is TMS.

The nuclear magnetic resonance hydrogen spectrum data of the nyconazole hydrochloride and the attribution are as follows:

C. nuclear magnetic resonance carbon spectrum (fig. 2):

The nuclear magnetic resonance carbon spectrum data of the nyconazole hydrochloride and the attribution are as follows:

the nuclear magnetic resonance carbon spectrum characteristics of the sample accord with the chemical structure of the naphthoconazole hydrochloride.

The product obtained in this example was designated as sample S1.

The above procedures were repeated to prepare refined S2 sample and S3 sample of nyconazole hydrochloride.

Comparative example 1

Effect of reaction temperature on intermediate I preparation

Adding 92g of ethyl acetate, 153g of trichloromethane and 13.7g of o-hydroxyacetophenone into a 500ml reaction bottle, starting stirring, slowly adding 61g of copper bromide, heating to 55-65 ℃ after the addition is finished, carrying out heat preservation reaction for 10 hours, then carrying out sampling detection (1 time for every 5 hours) until the intermediate I is more than 70.0% by HPLC detection, and finishing the reaction. Cooling the system to 30-40 ℃, filtering, leaching the filter cake for 1 time by 34g of trichloromethane, filtering until no liquid flows out basically, and collecting the filtrate.

Adding the filtrate into a 500ml reaction bottle, starting stirring, washing the system with purified water for 3 times, wherein the dosage is 50.0g each time, stirring for 30min each time, standing for layering, separating liquid, and collecting an organic phase. The organic phase is controlled at a temperature not higher than 55 ℃, and is concentrated under reduced pressure until no condensate drips out basically, and the reduced pressure concentration is finished. 26.8g of absolute ethyl alcohol is added, stirred and dissolved.

Transferring the solution into a 100L glass lining reaction tank, starting stirring, cooling to 20-30 ℃, adding 23g of n-hexane, stirring for 10min, cooling to 5-15 ℃, stirring for 1h, slowly cooling to-5 ℃, keeping the temperature and stirring for 2h, filtering, leaching a filter cake with 5g of n-hexane, filtering until no liquid flows out basically, and collecting the filter cake.

Controlling the temperature to be 25-35 ℃, and drying for 4h in vacuum to obtain the intermediate I of the naphthoconazole hydrochloride. The yield of the intermediate I is 8.17 percent, and the purity is more than or equal to 97.12 percent. Sealing and storing at below 10 deg.C.

It can be seen that lowering the reaction temperature significantly reduces the yield of intermediate I.

Comparative example 2 Effect of reaction time on intermediate I purity

Adding 92g of ethyl acetate, 153g of trichloromethane and 13.7g of o-hydroxyacetophenone into a 500ml reaction bottle, starting stirring, slowly adding 61g of copper bromide, heating to 70-80 ℃ after the addition is finished, carrying out heat preservation reaction for 10h, 22h, 30h, 46h and 52h, then respectively sampling and detecting, wherein the detection results are shown in Table 1.

TABLE 1

The content of the impurity intermediate IZ2 gradually increases with the increase of the reaction time, and the content of the intermediate I in the reaction liquid begins to decrease with the increase of the reaction time after reaching 76.18 percent, so that the reaction progress needs to be monitored by HPLC in the process, and the reaction is stopped by limiting the content of the intermediate I in the reaction liquid to be more than 70 percent.

Example 2

The preparation process of the intermediate III comprises the following steps:

adding 480g of dichloromethane and 20g of imidazole into a 1L reaction bottle in a dark place under the protection of nitrogen, starting stirring, cooling to 0-10 ℃, slowly adding 11.5g of thionyl chloride, and controlling the temperature to be not more than 25 ℃ in the adding process. After the addition, the temperature is controlled to be 15-25 ℃, the temperature is kept and the stirring is carried out for 20min, 20ml of dichloromethane solution (containing 10g of intermediate II) of the intermediate I is slowly added, and the temperature is controlled not to exceed 25 ℃ in the adding process. After the addition, the temperature is controlled to be 20-30 ℃, the reaction is carried out for 4h, and sampling detection is carried out (1 time for every 1 h) until the intermediate I is less than 5% by HPLC detection, and the reaction is finished.

Removing the nitrogen protection, cooling the system to below 10 ℃, slowly adding 70g of purified water, and controlling the temperature to be not more than 25 ℃ in the adding process. Stirring for 30min after the addition is finished, standing for layering, separating liquid, and collecting an organic phase. Controlling the temperature to be not more than 40 ℃, keeping out of the sun, concentrating under reduced pressure until no condensate flows out basically, adding 314g of trichloromethane, heating and raising the temperature until the system flows back (60-70 ℃), stirring for 3 hours under reflux, cooling to 30-40 ℃, stirring for 5 hours under heat preservation, filtering, pulping a filter cake twice with a proper amount of trichloromethane, using 29.2g of the filter cake each time, filtering until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 45-55 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time per 1 h) until the drying weight loss is less than or equal to 1.0% by detection (a rapid moisture determinator: 105 ℃, 15min), and obtaining 6.2g of a crude product of the intermediate product, namely the intermediate III of the similar white nyconazole hydrochloride, with the yield of 48.7%. The purity is more than 99%.

Comparative example 3

The preparation process of the intermediate III comprises the following steps:

adding 240g of dichloromethane and 20g of imidazole into a 1L reaction bottle in a dark place under the protection of nitrogen, starting stirring, cooling to 0-10 ℃, slowly adding 11.5g of thionyl chloride, and controlling the temperature to be not more than 25 ℃ in the adding process. After the addition, the temperature is controlled to be 15-25 ℃, the temperature is kept and the stirring is carried out for 20min, 20ml of dichloromethane solution (containing 10g of the intermediate II) of the intermediate II is slowly added, and the temperature is controlled not to exceed 25 ℃ in the adding process. After the addition, the temperature is controlled to be 20-30 ℃, the reaction is carried out for 4h, and sampling detection is carried out (1 time for every 1 h) until the intermediate II is less than 5 percent through HPLC detection according to the completion of the reaction.

Removing the nitrogen protection, cooling the system to below 10 ℃, slowly adding 70g of purified water, and controlling the temperature to be not more than 25 ℃ in the adding process. Stirring for 20min, separating out solid, stirring for 5h, filtering, washing the filter cake with purified water twice (30 g each time), filtering until no liquid flows out, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 45-55 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time per 1 h) until the drying weight loss is less than or equal to 1.0% by detection (a rapid moisture determinator: 105 ℃, 15min), and obtaining 2.63g of the intermediate III crude product of the off-white Naoconazole hydrochloride intermediate product, wherein the yield is 20.7%.

As can be seen from the example 2 and the comparative example 3, in the preparation process of the intermediate III, the organic phase is dried by decompression concentration and spinning, and the chloroform is selected for pulping, which is beneficial to improving the yield of the intermediate III.

Comparative example 4

1. The intermediate I is not separated, and the intermediate II is prepared by directly feeding:

preparation of 2-hydroxyacetophenone/chloroform solution: slowly adding 4.0kg of 2-hydroxyacetophenone into 45.0kg of chloroform, stirring and mixing, and standing for later use.

Adding 27.0kg of ethyl acetate into a 200L glass-lined reaction tank, starting stirring, slowly adding 18.1kg of copper bromide, adding 49.0kg of the prepared 2-hydroxyacetophenone/chloroform solution, heating until the system reflows (75-85 ℃), keeping the temperature for reaction for 20 hours, sampling and detecting (sampling and detecting for 1 time every 2 hours) until SMa (2-hydroxyacetophenone) is detected by HPLC (simple substance analysis) to be less than 6%, and finishing the reaction. Cooling the system to 35-45 ℃, filtering and collecting filtrate. The filter cake was rinsed once with 10kg of chloroform and filtered until substantially no liquid flowed out, and the filtrate was collected.

Adding the filtrate into a 100L glass-lined reaction tank, starting stirring, washing the system with purified water for 2 times, wherein the dosage of the purified water is 19.0kg each time, standing for layering, separating liquid, and collecting organic phases (weighing the organic phase and the water phase). And putting the organic phase in a 100L glass-lined reaction tank, controlling the temperature to be not more than 55 ℃, concentrating under reduced pressure until no condensate drips out basically, and collecting the concentrate to obtain the intermediate product, namely the intermediate I, of the naphthoconazole hydrochloride.

And adding 24kg of methanol into the obtained concentrate, stirring until the system is clear, and sealing for later use.

2. Preparation of intermediate product-intermediate II of nyconazole hydrochloride

Preparation of hydrochloric acid solution: 0.63kg of hydrochloric acid was slowly added to 1.6kg of purified water, and mixed with stirring for use.

Preparation of saturated sodium chloride solution: 1.1kg of sodium chloride was added to 3.0kg of purified water, and mixed by stirring for use.

Adding the intermediate I methanol solution into a 100L glass lining reaction tank, starting stirring, adjusting the pH value of the system to 9-10 (precision pH test paper) by using a proper amount of 20% sodium methyl mercaptide solution (firstly slowly adding 12.8kg, and if the pH value is less than 9, supplementing a proper amount of 20% sodium methyl mercaptide solution until the pH value of the system is 9-10), and controlling the temperature to be not more than 20 ℃ in the adjusting process. After the adjustment is finished, heating to 15-25 ℃, after the reaction is carried out for 3 hours under the condition of heat preservation, sampling and detecting (sampling and detecting for 1 time every 1 hour) until the content of the intermediate I is less than 1.0 percent through HPLC detection, and finishing the reaction.

Controlling the temperature not to exceed 40 ℃, and concentrating under reduced pressure until no liquid flows out basically. Cooling the system to below 15 ℃, adding 26.0kg of purified water and 11.0kg of ethyl acetate, adjusting the pH value of the system to 2-3 (precision pH paper) by using a proper amount of hydrochloric acid solution (about 2.14L), stirring for 15min, repeatedly measuring the pH value (2-3), and controlling the temperature to be not more than 15 ℃ in the adjusting process. Standing for layering, separating liquid, and collecting an aqueous phase and an organic phase. The aqueous phase was extracted 1 time with 3.6kg ethyl acetate, separated, allowed to stand for layering, separated, and the combined organic phases were collected.

Adding the organic phase into a 50L double-layer glass reaction kettle, starting stirring, washing the organic phase for 1 time by using 3.0kg of saturated sodium chloride solution, standing for layering, separating liquid, and collecting the organic phase. And drying the organic phase for 8 hours by using 5.3kg of anhydrous sodium sulfate, performing suction filtration, washing a filter cake for 1 time by using 10.0kg of ethyl acetate, performing suction filtration until no liquid flows out basically, and collecting filtrate.

And transferring the filtrate to a 50L rotary evaporator, controlling the temperature to be not more than 40 ℃, concentrating under reduced pressure until no condensate flows out basically, and collecting the concentrate to obtain the intermediate product, namely the intermediate II of the naphthoconazole hydrochloride.

To the resulting concentrate was added 27kg of methylene chloride, and the mixture was dissolved with stirring and sealed for use.

3. Preparation of intermediate product-intermediate III of nyconazole hydrochloride

Adding 133kg of dichloromethane and 12.0kg of imidazole into a 200L glass lining reaction kettle in a dark place under the protection of nitrogen, starting stirring, cooling to below 5 ℃, slowly adding 5.2kg of thionyl chloride, and controlling the temperature to be not more than 25 ℃ in the adding process. After the addition, the temperature is controlled to be 15-25 ℃, the heat preservation and the stirring are carried out for 20min, the intermediate II dichloromethane solution is slowly added, and the temperature is controlled not to exceed 25 ℃ in the adding process. After the addition, the temperature is controlled to be 20-30 ℃, the reaction is carried out for 20h, and sampling detection is carried out (1 time for every 1 h) until the content of the intermediate II is less than 5% through HPLC detection according to the completion of the reaction.

Removing the nitrogen protection, cooling the system to below 10 ℃, slowly adding 24.0kg of purified water, and controlling the temperature not to exceed 25 ℃ in the adding process (the time for adding the purified water is not more than 0.5h, the time is long, and solids are likely to be separated out). Stirring for 30min after the addition is finished, standing for layering, separating liquid, and collecting an organic phase and a water phase. The aqueous phase is extracted with dichloromethane for 2 times, the dosage is 8.0kg each time, the mixture is kept stand for layering, separated, collected and combined with organic phase. Transferring the organic phase to a 100L glass-lined reaction tank, controlling the temperature to be not more than 40 ℃, keeping out of the sun, concentrating under reduced pressure until no condensate flows out basically, and collecting the concentrate.

Adding 90kg of trichloromethane and the concentrate into a 100L glass-lined reaction tank, starting stirring, heating to raise the temperature until the system flows back (60-65 ℃), stirring for 3h, cooling to 10-20 ℃, stirring for 1h while keeping the temperature, filtering, leaching a filter cake for 2 times by using the trichloromethane, wherein the dosage is 3.3kg each time, filtering until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 40-50 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time of sampling detection every 1 h) until the drying weight loss is less than or equal to 1.0% by detection (a rapid moisture determinator: 105 ℃, 15min), and obtaining the intermediate product, namely the intermediate III crude product of the naphthoconazole hydrochloride.

Refining: the following charge amounts are based on the amount of the crude product of the intermediate III

And (3) keeping out of the sun, adding 1.0kg/kg of crude intermediate III and 25.0kg/kg of methanol into a 200L glass lining reaction tank, starting stirring, heating to 60-65 ℃, keeping the temperature and stirring for 1h, cooling to 50-55 ℃, slowly adding 20.0kg/kg of purified water, and controlling the temperature to be not lower than 50 ℃ in the adding process. After the addition, heating to reflux (60-65 ℃), keeping the temperature and stirring for 2h, and cooling to 10-20 ℃. Filtering, leaching the filter cake with 3.0kg/kg chloroform for 1 time, filtering until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 40-50 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time of sampling detection every 1 h) until the drying weight loss is less than or equal to 1.0% by detection (a rapid moisture determinator: 105 ℃, 15min), and obtaining 1.8kg of intermediate product namely intermediate III of the naphthoconazole hydrochloride. The purity is more than 99 percent, and no isomer is detected.

In the comparative example, the intermediate I is directly fed without separation, and contains more unreacted SMa, the SMa does not participate in the reaction in the preparation process of the intermediate II, but more impurities of the intermediate IIIZ1 are generated in the preparation process of the intermediate III, and the impurities are difficult to be refined to be below 0.10 percent, so that the yield of the intermediate III is influenced.

Examples 3-5 Effect of the volume ratio of Anhydrous ethanol and methyl t-butyl Ether on the product when refining crude Nalconazole hydrochloride

Example 3 Anhydrous ethanol/methyl t-butyl ether volume ratio 1:2

Adding 40g of absolute ethyl alcohol and 37.5g of methyl tert-butyl ether into a glass reaction bottle, starting stirring, adding 50g of crude product, heating and heating to reflux, filtering when the system is clear, transferring the filtrate into a 50L double-layer glass reaction kettle, starting stirring, adding 37.5g of methyl tert-butyl ether, heating and heating to reflux, slowly cooling (firstly cooling to 40-45 ℃, keeping the temperature for 15min, then cooling to 30-35 ℃ and keeping the temperature for 15min) to 15-20 ℃, stirring for 4h under the protection of nitrogen, carrying out suction filtration, stirring and washing a filter cake for 1 time by using 100g of methyl tert-butyl ether, carrying out suction filtration, leaching the filter cake once by using 37.5g of methyl tert-butyl ether, carrying out suction filtration until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 40-50 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time of sampling detection every 1 h) until the drying weight loss is less than or equal to 0.5% by detection (a rapid moisture determinator: 70 ℃, 15min), and obtaining a refined product of the naphthoconazole hydrochloride. Yield: 47.3%, purity: 99.91 percent.

Example 4 volume ratio of Anhydrous ethanol/methyl t-butyl Ether 1:3

Adding 40g of absolute ethyl alcohol and 37.5g of methyl tert-butyl ether into a glass reaction bottle, starting stirring, adding 50g of crude product, heating and heating to reflux, filtering when the system is clear, transferring the filtrate into a 50L double-layer glass reaction kettle, starting stirring, adding 75g of methyl tert-butyl ether, heating and heating to reflux, slowly cooling (firstly cooling to 40-45 ℃, keeping the temperature for 15min, then cooling to 30-35 ℃ and keeping the temperature for 15min) to 15-20 ℃, keeping the temperature and stirring for 4h under the protection of nitrogen, carrying out suction filtration, stirring and washing a filter cake for 1 time by using 100g of methyl tert-butyl ether, carrying out suction filtration, leaching the filter cake once by using 37.5g of methyl tert-butyl ether, carrying out suction filtration until no liquid flows out basically, and collecting.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 40-50 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time of sampling detection every 1 h) until the drying weight loss is less than or equal to 0.5% by detection (a rapid moisture determinator: 70 ℃, 15min), and obtaining a refined product of the naphthoconazole hydrochloride. Yield: 71.0%, purity: 99.91 percent.

Example 5 volume ratio of Anhydrous ethanol/methyl t-butyl Ether 1:4

Adding 40g of absolute ethyl alcohol and 37.5g of methyl tert-butyl ether into a glass reaction bottle, starting stirring, adding 50g of crude product, heating and heating to reflux, filtering when the system is clear, transferring the filtrate into a 50L double-layer glass reaction kettle, starting stirring, adding 112.5g of methyl tert-butyl ether, heating and heating to reflux, slowly cooling (firstly cooling to 40-45 ℃, keeping the temperature for 15min, then cooling to 30-35 ℃ and keeping the temperature for 15min) to 15-20 ℃, stirring for 4h under the protection of nitrogen, carrying out suction filtration, stirring and washing a filter cake for 1 time by using 100g of methyl tert-butyl ether, carrying out suction filtration, leaching the filter cake once by using 37.5g of methyl tert-butyl ether, carrying out suction filtration until no liquid flows out basically, and collecting the filter cake.

And (3) placing the filter cake in a vacuum drier, controlling the temperature to be 40-50 ℃, carrying out vacuum drying for 4h, then carrying out sampling detection (1 time of sampling detection every 1 h) until the drying weight loss is less than or equal to 0.5% by detection (a rapid moisture determinator: 70 ℃, 15min), and obtaining a refined product of the naphthoconazole hydrochloride. Yield: 75.0%, purity: 99.80 percent.

Examples 3-5 the results of the experiments are shown in table 2.

TABLE 2

Examples 3 to 5 show that the volume ratio of absolute ethanol to methyl t-butyl ether affects the yield and purity of the product during the refining of nyconazole hydrochloride.

Example 6 stability test of Nalconazole hydrochloride

(I) accelerated test

Accelerated experiments were performed on samples from S1 to S3 under the following conditions: 40 ℃ plus or minus 2 ℃ and RH75 percent plus or minus 5 percent. The results of the experiments are shown in tables 3-5.

TABLE 3 accelerated test results of S1 sample

TABLE 4 accelerated test results for S2 sample

TABLE 5 accelerated test results of S3 sample

Tables 3-5 the results show that: three pilot test batches of samples are inspected for 6 months under accelerated conditions (40 ℃ plus or minus 2 ℃ and RH75 percent plus or minus 5 percent), the properties, the acidity, related substances, the drying weight loss and the content are not obviously changed, the clarity and the color of the solution accord with the regulations, and the samples are relatively stable.

(II) Long term experiments

Long-term experiments were performed on samples from S1 to S3 under the following experimental conditions: 25 ℃ plus or minus 2 ℃ and RH60 percent plus or minus 5 percent. The results of the experiments are shown in tables 6-8.

TABLE 6 Long-term test results for S1 sample

TABLE 7 Long-term test results for S2 sample

TABLE 8 Long-term test results for S3 sample

Tables 6-8 the results show that: three batches of samples are inspected for 36 months under long-term conditions (25 ℃ plus or minus 2 ℃ and RH60 percent plus or minus 5 percent), the properties, acidity, related substances, drying weight loss and content are not obviously changed, the clarity and color of the solution meet the regulations, and the samples are relatively stable.

The detection methods for the relevant substances and residual solvents in tables 3 to 8 are as follows:

(1) the relevant substances are protected from light. Taking a proper amount of the product, adding ethanol to dissolve and dilute the product into a solution containing about 1.0mg in each 1ml as a test solution; precisely measuring 1ml, placing in a 100ml measuring flask, diluting with ethanol to scale, and shaking to obtain control solution. The measurement is carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition of the general rules 0512 in four parts). Octadecylsilane bonded silica gel as filler [ e.g. Aglient Poroshell 120ECC18(2.7 μm. times.4.6 mm. times.150 mm) or equivalent column](ii) a Taking 0.05mol/L sodium hydrogen tartrate solution-methanol (45:55) as a mobile phase; the column temperature is 40 ℃; the detection wavelength was 286nm and the flow rate was 0.8 ml/min. Taking appropriate amount of reference sample of Nalconazole hydrochloride, adding mobile phase to dissolve and dilute to obtain solution containing 1.0mg per 1ml, and keeping total illumination (sum of illumination after several hours of illumination under certain illumination) at 10⁵After being destroyed by Lux hr light, 10 mul of the solution is injected into a liquid chromatograph as a system applicability solution, the peak sequence is the nyconazole and the nyconazole Z isomer, and the resolution is not less than 1.5. The number of theoretical plates is not less than 2000 calculated according to the peak of the naphthoconazole. Taking 1ml of the control solution, placing the control solution in a 20ml measuring flask, diluting the control solution to a scale with ethanol, shaking up the control solution to serve as a sensitivity solution, and taking 10 mu l of the sensitivity solution to inject into a liquid chromatograph, wherein the signal-to-noise ratio of the sensitivity solution is not less than 10; precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main peak is 3 times. If the chromatogram of the test solution has impurity peaks, the Z isomer content should not exceed 0.15%, the single impurity peak area should not be larger than 0.1 times (0.10%) of the main peak area of the control solution, and the sum of the impurity peak areas is not larger than the main peak area (1.0%) of the control solution.

(2) Residual solvent

(a) Taking about 1.0g of the product from ethanol, dichloromethane and tert-butyl methyl ether, precisely weighing, placing in a 10ml measuring flask, adding dimethylformamide for dissolving and diluting to scale, and shaking up to obtain a test solution; an appropriate amount of each of ethanol, dichloromethane and tert-butyl methyl ether was precisely weighed, diluted with dimethylformamide to give a mixed solution containing about 500. mu.g of ethanol, 60. mu.g of dichloromethane and 500. mu.g of tert-butyl methyl ether per 1ml, and shaken up to give a control solution. According to the residual solvent determination method (0861 in the four-part general rules of the Chinese pharmacopoeia 2015 edition), a capillary column using (6%) cyanopropylphenyl- (94%) dimethyl siloxane (or similar polarity) as a stationary liquid is used as a chromatographic column [ such as DB-624(30m × 0.530mm × 3 μm) or an equivalent column ]; temperature programming: the initial temperature is 40 ℃, the temperature is maintained for 4 minutes, the temperature is increased to 180 ℃ at the rate of 30 ℃ per minute, the temperature is maintained for 1 minute, and then the operation is carried out for 200 ℃ and the temperature is maintained for 2 minutes; the detector is a hydrogen Flame Ionization Detector (FID), and the temperature of the detector is 300 ℃; the injection port temperature is 200 ℃, the carrier gas is nitrogen, the flow rate is 4.0ml per minute, and the split ratio is 20: 1. Precisely measuring 1.0 μ l of reference solution, directly injecting sample, recording chromatogram, and sequentially taking peak appearance: ethanol, dichloromethane and tert-butyl methyl ether, and the separation degree between peaks is in accordance with the requirement. Precisely measuring the sample solution and the reference solution by 1.0 μ l respectively, injecting into a gas chromatograph, recording chromatogram, and calculating according to external standard method by peak area, wherein ethanol content is not more than 0.5%, dichloromethane content is not more than 0.06%, and tert-butyl methyl ether content is not more than 0.5%.

(b) Taking trichloromethane and dimethylformamide, precisely weighing about 0.2g, placing into a 20ml headspace bottle, adding dimethyl sulfoxide to dissolve, sealing, and shaking to obtain a sample solution. Taking appropriate amount of trichloromethane and dimethylformamide, precisely weighing, adding dimethyl sulfoxide to dissolve and dilute to prepare solutions containing trichloromethane 12 μ g and dimethylformamide 176 μ g in each 1 ml. 1ml of the solution was measured precisely, and the solution was placed in a 20ml headspace bottle and sealed to prepare a control solution. A capillary column with (6%) cyanopropylphenyl- (94%) dimethicone (or similar polarity) as a stationary liquid [ e.g., DB-624(60m × 0.320mm × 1.8 μm) or equivalent column ] as determined by residual solvent assay (second method 0861, fourth general rule of chinese pharmacopoeia 2015 edition); the initial column temperature was 60 ℃, maintained for 10 minutes, ramped to 200 ℃ at a rate of 30 ℃ per minute, maintained for 3 minutes; the temperature of the FID detector is 250 ℃; the carrier gas is nitrogen; the flow rate is 3.0 ml/min; the temperature of a sample inlet is 200 ℃; the headspace equilibrium temperature is 90 ℃, and the equilibrium time is 20 min; the split ratio is 5: 1; precisely measuring a reference solution for sample injection, recording a chromatogram, wherein the peak output sequence sequentially comprises: trichloromethane and dimethylformamide, and the separation degree between each peak is in accordance with the requirement. Precisely measuring a reference substance solution and a test substance solution, injecting into a gas chromatograph, recording a chromatogram, and calculating according to an external standard method by using peak area, wherein the content of trichloromethane is not more than 0.006 percent, and the content of dimethylformamide is not more than 0.088 percent.

The Z isomer ((Z) -1- (2- (methylthio) -1- (2- (pentyloxy) phenyl) vinyl) -1H-imidazole) described in the examples and comparative examples has the following structure:

intermediate IZ2(α, α -dibromo-o-hydroxyacetophenone) has the following structure:

intermediate IIIZ1(2- [1- (1H-imidazol-1-yl) vinyl ] phenol) has the following structure:

the embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of the nyconazole hydrochloride is characterized by comprising the following steps:

optionally, further comprising step (2): and refining the obtained naphthoconazole hydrochloride.

2. The preparation method according to claim 1, wherein in the step (1), the mass ratio of the compound of formula III to bromopentane is 1 (0.5-1.0);

preferably, in step (1), the compound of formula III is obtained by purifying and refining the crude compound of formula III in an alcohol solvent and water.

3. The method of claim 1 or 2, wherein the crude compound of formula III is prepared in step S1: taking a compound of a formula II, imidazole and thionyl chloride as reaction raw materials, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a crude product of the compound of the formula III;

4. the method of claim 3, wherein in step S1, the post-treatment comprises adding water to quench: removing the inert atmosphere, adding water into the system after the temperature of the system is reduced, and quenching the reaction.

Preferably, the post-treatment further comprises extraction: after the water is added, stirring, standing for layering, separating liquid, and collecting an organic phase.

Preferably, the post-treatment further comprises concentration under reduced pressure, and the collected organic phase is concentrated under reduced pressure at a temperature not higher than 40 ℃ and under the condition of keeping away from light until no condensate flows out basically.

Preferably, the post-treatment further comprises heating reflux: and adding trichloromethane into the product after the pressure reduction and concentration, heating and raising the temperature until the system reflows, cooling after the reflowing is finished, and filtering.

Preferably, the post-treatment further comprises pulping: pulping the solid obtained by filtering with trichloromethane until no liquid flows out basically, and collecting the solid product.

5. The process according to any one of claims 2 to 4, wherein the compound of formula II is prepared in step S2: taking a compound shown in a formula I and sodium methyl mercaptide as reaction raw materials, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a compound shown in a formula II;

6. the method of claim 5, wherein the compound of formula I is prepared in step S3: adding copper bromide into a system containing ethyl acetate, trichloromethane and o-hydroxyacetophenone for reaction, and after the reaction is finished, carrying out post-treatment on a reaction product to obtain a compound shown in the formula I;

7. the method of claim 6, wherein the reaction temperature is 70-80 ℃ in step S3; preferably, the reaction time is 6-15 h;

preferably, the reaction is considered complete when the content of the compound of formula I in the system is > 70.0%.

Preferably, in step S3, the post-treatment comprises at least one washing of the reaction product, for example with chloroform and water.

Preferably, the post-treatment further comprises filtering the collected organic phase under reduced pressure until the organic phase is concentrated under reduced pressure until substantially no condensate drips out, and collecting the concentrate.

Preferably, the post-treatment further comprises a process of refining the concentrate.

8. The production method according to any one of claims 1 to 7, wherein in the step (1), the temperature of the reaction is 25 to 35 ℃ and the time of the reaction is 2 to 5 hours;

preferably, the reaction is considered to be completed when the mass content of the compound of formula III in the reaction system is 0.1% or less.

9. The production method according to any one of claims 1 to 8, wherein in the step (2), the number of times of the reflux refining is at least one, preferably two;

preferably, the reagents for the two heating reflux processes are the same or different, preferably, the first heating reflux reagent is a mixed solvent of absolute ethyl alcohol and methyl tert-butyl ether, and the second heating reflux reagent is methyl tert-butyl ether.

Preferably, the volume ratio of the absolute ethyl alcohol to the methyl tert-butyl ether in the reflux refining process is 1 (2.5-3.5).

10. The production method according to any one of claims 1 to 9, characterized by comprising the steps of: