A method for synthesizing buthionine

Abstract

The application is a divisional application of application No. 202410786126.X and discloses a synthesis method of buthionine, which comprises the following steps: condensation reaction of a compound shown in formula (I) and a compound shown in formula (II) in the presence of an organic base to obtain buthionine. The application condenses the compound shown in formula (I) and the compound shown in formula (II) to prepare buthionine in the presence of an organic base, and the conversion rate and selectivity are high. Compared with the sodium thiocyanate method, the method provided by the application has short process steps, avoids high-temperature thermal decomposition reaction, improves process safety, is suitable for industrial production, and has a wide application prospect.

Description

[0001] This invention is a divisional application of Chinese application filed on June 18, 2024, with application number 202410786126.X and invention title "A method for synthesizing butyl ether urea". Technical Field

[0002] This invention relates to the field of pesticides, and more particularly to a method for synthesizing butyl urea. Background Technology

[0003] Butyl ether urea, chemically named 1-tert-butyl-3-(2,6-diisopropyl-4-phenoxyphenyl)thiourea, is a novel thiourea insecticide and acaricide. There are several main methods for synthesizing butyl ether urea: the thiophosgene method, the trimerizing phosgene method, and the sodium thiocyanate method. The sodium thiocyanate method is the most commonly used industrial method. This method uses 4-bromo-2,6-diisopropylaniline as a raw material. First, it reacts with bromine to generate 4-bromo-2,6-diisopropylaniline, then reacts with phenol and a base to generate 4-phenoxy-2,6-diisopropylaniline. Next, it condenses with NaSCN to generate a substituted thiourea (i.e., 4-phenoxy-2,6-diisopropylphenylthiourea), which is then thermally decomposed (generally at around 150℃) to obtain isothiocyanate, and finally reacts with tert-butylamine to obtain the target product.

[0004] However, the sodium thiocyanate method for preparing butyl ether urea still suffers from technical drawbacks such as a long process route, harsh reaction conditions, and high costs. To overcome these problems in existing methods for preparing butyl ether urea, a new method is needed. Summary of the Invention

[0005] Purpose of the invention

[0006] To overcome the above shortcomings, the present invention aims to provide a method for synthesizing butyl ether urea. In the presence of an organic base or organic carboxylic acid, the compound shown in formula (I) is condensed with the compound shown in formula (II) to prepare butyl ether urea, achieving high conversion and selectivity. The method of the present invention differs from the existing sodium thiocyanate route, avoiding the use of hazardous reagents such as sodium thiocyanate. Furthermore, compared to the sodium thiocyanate method, the method provided by the present invention has shorter process steps and avoids high-temperature thermal decomposition reactions, improving process safety and making it suitable for industrial production with broad application prospects. The method of the present invention has the advantages of mild reaction conditions, a shorter process route, and high conversion and selectivity.

[0007] Solution

[0008] To achieve the objectives of this invention, the technical solution adopted is as follows:

[0009] This invention provides a method for synthesizing butyl ether urea, the method comprising: in the presence of an organic acid or an organic base, subjecting a compound of formula (I) to a condensation reaction with a compound of formula (II) to obtain butyl ether urea.

[0010]

[0011] Firstly, in the presence of an organic acid, the compound shown in formula (I) undergoes a condensation reaction with the compound shown in formula (II) to obtain butyl ether urea.

[0012] Optionally, when an organic acid is present, the organic acid is a weak organic acid;

[0013] Optionally, the organic acid has a pKa ≥ 3.5 in water at 25°C, preferably a pKa of 3.5-5.0 (which can be 3.5, 3.8, 4.0, 4.2, 4.5, 4.6, 4.7, 4.8, 5.0 and any value between them).

[0014] Optionally, the organic acid is a C1-C10 organic carboxylic acid or an organic sulfonic acid, optionally a C1-C7 organic carboxylic acid or an organic sulfonic acid, optionally a C2-C7 organic carboxylic acid or an organic sulfonic acid;

[0015] Optionally, the organic acid is an organic carboxylic acid with the chemical formula R1COOH; optionally, R1 is one or more of the following: hydrogen-based, C1-C9 alkyl, C1-C9 hydroxy-substituted alkyl, C1-C9 amino-substituted alkyl, phenyl, and substituted phenyl; optionally, R1 is one or more of the following: hydrogen-based, C1-C5 alkyl, C1-C5 hydroxy-substituted alkyl, phenyl, and hydroxy-substituted phenyl; optionally, R1 is one or more of the following: hydrogen-based, C1-C3 alkyl, C1-C3 hydroxy-substituted alkyl, phenyl, and hydroxy-substituted phenyl; optionally, R1 is one or more of the following: hydrogen-based, C1-C2 alkyl, C1-C2 hydroxy-substituted alkyl, phenyl, and hydroxy-substituted phenyl.

[0016] Optionally, the organic acid is selected from one or more of formic acid, acetic acid, propionic acid, lactic acid, benzoic acid, trifluoroacetic acid, isobutyric acid, citric acid and p-toluenesulfonic acid;

[0017] Optionally, the organic acid is selected from one or more of formic acid, acetic acid, propionic acid, lactic acid, and benzoic acid.

[0018] Furthermore, when an organic acid is present, the molar ratio of the compound shown in formula (I) to the organic acid is 1:(1-10) (optionally 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and any value between them), optionally 1:(2-10), optionally 1:(3-10), optionally 1:(2-8), optionally 1:

[0019] (2-5), optionally 1: (3-5).

[0020] Optionally, when an organic acid is present, the condensation temperature is 30-100℃ (which can be 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, 100℃ and any value between them), optionally 40-90℃ (which can be 40℃, 50℃, 60℃, 70℃, 80℃, 90℃ and any value between them), optionally 40-80℃, optionally 40-75℃, optionally 40-70℃, optionally 50-80℃, optionally 50-70℃ (which can be 50℃, 55℃, 60℃, 65℃, 70℃ and any value between them).

[0021] Optionally, when an organic acid is present, the condensation reaction time is 5-20 h, optionally 5-18 h, optionally 8-18 h, or optionally 8-15 h.

[0022] Optionally, when an organic acid is present, the molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(1-10), optionally 1:(2-10), optionally 1:(3-10), optionally 1:(2-8), optionally 1:(2-5), optionally 1:(3-6), optionally 1:(4-6).

[0023] Optionally, when an organic acid is present, the condensation reaction is carried out in the absence of a solvent.

[0024] Secondly, when an organic base is present, the compound shown in formula (I) undergoes a condensation reaction with the compound shown in formula (II) to obtain butyl ether urea.

[0025] Furthermore, when an organic base is present, the organic base is a strong organic base.

[0026] Optionally, the pKa of the organic base in DMSO at 25°C is 8-25 (which can be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and any value between them).

[0027] Optionally, the organic base is selected from at least one of N-alkylimidazolium, fatty amine strong bases, bicyclic amidine strong bases, pyridine, and substituted pyridine.

[0028] Optionally, the alkyl group in the N-alkylimidazolium is selected from C1-C6 alkyl groups, and is optionally at least one of methyl, ethyl, and propyl.

[0029] Optionally, the strong base of the aliphatic amine is a C2-C14 aliphatic amine, or a C6-C14 aliphatic amine, or one or more of triethylenediamine, triethylamine, and N,N-diisopropylethylamine.

[0030] Optionally, the bicyclic amidine strong base is a C2-C10 bicyclic amidine strong base, and optionally it is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0031] Optionally, the substituents of the substituted pyridine are C1-C5 alkyl or hydroxyl groups.

[0032] Optionally, the organic base is selected from at least one of N-methylimidazole, N-ethylimidazole, N-propylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, triethylamine, N,N-diisopropylethylamine, 2-hydroxypyridine, 2,6-dimethylpyridine, and pyridine; wherein,

[0033] Optionally, the organic base is selected from at least one of N-methylimidazole, N-ethylimidazole, N-propylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylenediamine.

[0034] Furthermore, when an organic base is present, the molar ratio of the compound shown in formula (I) to the organic base is 1:(0.1-10) (optionally 1:0.1, 1:0.2, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 and any value between them), optionally 1:(0.2-5), optionally 1:(0.2-3), optionally 1:(1-5), optionally 1:(1-3), optionally 1:(1.5-3).

[0035] Furthermore, when an organic base is present, the condensation temperature is 30-100℃ (which can be 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, 100℃ and any value between them), optionally 40-90℃, optionally 40-80℃, optionally 40-75℃, optionally 40-60℃, optionally 45-60℃ (which can be 40℃, 45℃, 50℃, 55℃, 60℃ and any value between them), optionally 45-55℃, optionally 45-50℃.

[0036] Furthermore, when an organic base is present, the condensation reaction time is 1-20 h, optionally 5-18 h, optionally 8-18 h, or optionally 8-15 h.

[0037] Furthermore, when an organic base is present, the molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(1-10), optionally 1:(2-10), optionally 1:(3-10), optionally 1:(2-8), optionally 1:

[0038] (2-5), optionally 1: (3-6), optionally 1: (4-6).

[0039] Furthermore, when an organic base is present, the condensation reaction is carried out in the absence of a solvent.

[0040] In this invention, whether it is an organic carboxylic acid or a condensation reaction in the presence of an organic base, a small amount of the byproduct 4-phenoxy-2,6-diisopropylphenyl isothiocyanate will be produced.

[0041] Further, after the condensation reaction, the target product precipitates out, and is washed with organic solvent and / or water and dried to obtain butyl ether urea.

[0042] In this invention, the target product can be purified using methods conventional in the art. Preferably, it can be carried out as follows: the material containing the compound shown in formula (I) is washed with an organic solvent and then vacuum dried at 50-70°C to constant weight. The organic solvent used for washing can be selected from C1-C10 saturated monohydric alcohols and / or water, such as methanol, ethanol, propanol, and isopropanol. This invention does not impose a particular limitation on the amount of organic solvent used for washing, as long as it meets the requirements of this invention.

[0043] Optionally, the method for precipitating the target product is as follows: the compound shown in formula (II) is recovered by vacuum distillation (which can be recycled), and the target product solid is precipitated. Optionally, the temperature of vacuum distillation can be 50-70℃.

[0044] Beneficial effects

[0045] This invention prepares butyl ether urea by condensing the compound shown in formula (I) with the compound shown in formula (II) in the presence of an organic base or organic carboxylic acid, achieving high conversion and selectivity. The method of this invention differs from the existing sodium thiocyanate route, avoiding the use of hazardous reagents such as sodium thiocyanate. Furthermore, compared to the sodium thiocyanate method, the method provided by this invention has shorter process steps and avoids high-temperature thermal decomposition reactions, improving process safety and making it suitable for industrial production with broad application prospects. The method of this invention has the advantages of mild reaction conditions, a shorter process route, and high conversion and selectivity. Detailed Implementation

[0046] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0047] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In some embodiments, materials, methods, means, etc., well-known to those skilled in the art, are not described in detail in order to highlight the spirit of the present invention.

[0048] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0049] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0050] The present invention will be described in detail below through embodiments.

[0051] In this invention, there are no particular limitations on the preparation method of the compounds represented by formula (I) or formula (II), and they can be prepared by conventional methods in the art. For example, the compounds represented by formula (I) or formula (II) can be prepared by disclosed methods or are commercially available.

[0052]

[0053] In the following examples, unless otherwise specified, all raw materials used are commercially available products.

[0054] The content (purity) of reactants and products was determined by GC.

[0055] The conversion rate and selectivity of the reaction are calculated using the following formulas:

[0056] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%. The conversion rate in the following examples refers to the conversion rate of compound (I).

[0057] The selectivity of the target product = actual molar amount of the target product / theoretical molar amount of the target product × 100%. The theoretical molar amount of the target product refers to the theoretical value of the target product calculated based on the raw material conversion rate. For example, if the initial raw material molar amount is 1 mol and the residual raw material molar amount after the reaction is 0.2 mol, then the theoretical molar amount of the target product = ((1-0.2) / 1) × 1 = 0.8 mol. If the actual molar amount of the target product is 0.72 mol, then the selectivity of the target product = (0.72 / 0.8) × 100% = 90%.

[0058] The following examples illustrate the synthesis of butyl ether urea using the method of the present invention:

[0059] In a first aspect, the present invention provides a method for synthesizing butyl ether urea, the method comprising: in the presence of an organic carboxylic acid, subjecting a compound of formula (I) (4-phenoxy-2,6-diisopropylaniline) to a first contact with a compound of formula (II) (tert-butyl isothiocyanate) to undergo a condensation reaction, thereby preparing butyl ether urea. Examples of some embodiments are provided, such as Examples A1 to A10.

[0060]

[0061] Example A1

[0062] (1) 4-phenoxy-2,6-diisopropylaniline (13.5 g, 0.05 mol) and tert-butyl isothiocyanate (23.0 g, 0.2 mol) were added to a 150 mL single-necked round-bottom flask, and acetic acid (12 g, 0.2 mol) was added. The temperature was raised to 70 °C and stirred for 13 h for condensation reaction. HPLC analysis showed that the conversion rate of 4-phenoxy-2,6-diisopropylaniline was 99.5% and the selectivity was 97.3% (butyl ether urea was the product and 4-phenoxy-2,6-diisopropylphenyl isothiocyanate was the byproduct).

[0063] (2) Tert-butyl isothiocyanate was recovered by vacuum distillation at 60°C. The residual solid was washed with 60 mL of isopropanol and 60 mL of water. After filtration, the solid was dried under vacuum at 60°C to constant weight, yielding 17.3 g of off-white solid, with a yield of 90%.

[0064] The present invention also studied the effects of factors such as the type and amount of organic carboxylic acid, reaction temperature or reaction time, as shown in Examples A2-A10 and Comparative Example 1 in the table below. The operation steps of Examples A2-A10 and Comparative Example 1 are the same as those of Example A1, except that the materials used (type and amount of organic carboxylic acid) and reaction conditions (reaction temperature or reaction time) are different. The specific differences are shown in Table 1.

[0065] Table 1. Materials, reaction conditions, and results data for Examples A1-A10 and Comparative Example 1.

[0066]

[0067]

[0068] The results in Table 1 show that the target product can be obtained with high conversion rates using organic carboxylic acids such as acetic acid, propionic acid, benzoic acid, and lactic acid. Condensation can be effectively achieved at temperatures ranging from 50 to 80°C (preferably 50 to 75°C or 50 to 70°C).

[0069] Secondly, the present invention also provides a method for synthesizing butyl ether urea, the method comprising: in the presence of an organic base, subjecting a compound of formula (I) (4-phenoxy-2,6-diisopropylaniline) to a first contact with a compound of formula (II) (tert-butyl isothiocyanate) to a condensation reaction, thereby preparing butyl ether urea. Examples B1 to B10 are provided as partial embodiments.

[0070]

[0071] Example B1

[0072] (1) 4-phenoxy-2,6-diisopropylaniline (13.5 g, 0.05 mol) and tert-butyl isothiocyanate (23.0 g, 0.20 mol) were added to a 150 mL single-necked round-bottom flask, and N-methylimidazole (8.21 g, 0.1 mol) was added. The temperature was raised to 50 °C, and the mixture was stirred for 15 h for condensation reaction. HPLC analysis showed that the conversion rate of 4-phenoxy-2,6-diisopropylaniline was 98%, and the selectivity was 99% (butyl ether urea was the target product, and 4-phenoxy-2,6-diisopropylphenyl isothiocyanate was a byproduct).

[0073] (2) Tert-butyl isothiocyanate was recovered by vacuum distillation at 60°C. The residual solid was washed with 60 mL of isopropanol and 60 mL of water. After filtration, the solid was dried under vacuum at 60°C to constant weight, yielding 17.1 g of off-white solid, with a yield of 89%.

[0074] The present invention also studied the effects of factors such as the type and amount of organic base, reaction temperature or reaction time, as shown in Examples B2-B10 and Comparative Examples 2-4 in the table below. The operation steps of Examples B2-B10 and Comparative Examples 2-4 are the same as those of Example B1, except that the materials used (type and amount of organic base) and reaction conditions (reaction temperature or reaction time) are different. The specific differences are shown in Table 2.

[0075] Table 2. Materials, reaction conditions, and results data for Examples B2-B10 and Comparative Examples 2-4.

[0076]

[0077]

[0078] The results in Table 2 show that the target product can be obtained with high conversion rates using organic bases such as N-methylimidazole, N-ethylimidazole, N-propylimidazole, DABCO, and DBU. Condensation can be effectively achieved at temperatures ranging from 45 to 60 °C.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing butyl ether urea, characterized in that, The method includes: in the presence of an organic base, reacting the compound of formula (I) with the compound of formula (II) in a condensation reaction to obtain butyl ether urea. ； The organic base is selected from at least one of N-methylimidazolium, N-ethylimidazolium, N-propylimidazolium, 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylenediamine.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) to the organic base is 1:(0.1-10).

3. The synthesis method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) to the organic base is 1:(0.2-5).

4. The synthesis method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) to the organic base is 1:(0.2-3).

5. The synthesis method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) to the organic base is 1:(1-5).

6. The synthesis method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) to the organic base is 1:(1-3).

7. The synthesis method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) to the organic base is 1:(1.5-3).

8. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation temperature is 40-90℃.

9. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation temperature is 40-80℃.

10. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation temperature is 40-75℃.

11. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation temperature is 40-60℃.

12. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation temperature is 45-60℃.

13. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation temperature is 45-55℃.

14. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation temperature is 45-50℃.

15. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation reaction time is 1-20 hours.

16. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation reaction time is 5-18 hours.

17. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation reaction time is 8-18 hours.

18. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation reaction time is 8-15 hours.

19. The synthesis method according to any one of claims 1 to 7, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(1-10).

20. The synthesis method according to any one of claims 1 to 7, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(2-10).

21. The synthesis method according to any one of claims 1 to 7, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(3-10).

22. The synthesis method according to any one of claims 1 to 7, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(2-8).

23. The synthesis method according to any one of claims 1 to 7, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(2-5).

24. The synthesis method according to any one of claims 1 to 7, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(3-6).

25. The synthesis method according to any one of claims 1 to 7, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1:(4-6).

26. The synthesis method according to any one of claims 1 to 7, characterized in that, The condensation reaction is carried out in the absence of solvent.

27. The synthesis method according to any one of claims 1 to 7, characterized in that, Byproducts include 4-phenoxy-2,6-diisopropylphenyl isothiocyanate.

28. The synthesis method according to any one of claims 1 to 7, characterized in that, After the condensation reaction, the target product precipitates, and is washed with organic solvent and / or water and dried to obtain butyl ether urea.

29. The synthesis method according to any one of claims 1 to 7, characterized in that, The method for precipitating the target product is as follows: the compound shown in formula (II) is recovered by vacuum distillation, and the target product solid is precipitated.

30. The synthesis method according to any one of claims 1 to 7, characterized in that, The temperature for vacuum distillation is 50-70℃.

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