Preparation method of pyrethroid insecticide intermediate
By optimizing the asymmetric catalytic technology of nickel metal catalysts, the problem of reduced yield caused by optical isomers in the synthesis of pyrethroids was solved, and the preparation of intermediates with high ee value and low cost was achieved, which is suitable for the industrial production of pyrethroids.
Patent Information
- Application Number
- CN202510762596.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-09
- Publication Date
- 2025-09-23
AI Technical Summary
The existing pyrethroid synthesis process has the problem of reduced yield and increased production cost due to the generation of optical isomers, especially in the synthesis process of fenvalerate.
By using asymmetric catalytic technology involving nickel metal catalysts, which are inexpensive, abundant, and environmentally friendly, and optimizing reaction conditions, including selecting a suitable solvent and catalyst ratio and controlling reaction temperature and time, the team achieved the efficient preparation of ethyl (R)-2-(4-chlorophenyl)-3-methylbutanoate with an ee value of 91%.
The ee value of the pyrethroid intermediate was increased to 99%, the synthesis process was simplified, the production cost and waste emissions were reduced, and it was easy to apply in industry.
Smart Images
Figure CN120682094A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of pharmaceutical intermediate synthesis and relates to a pyrethroid intermediate ( R )-2-(4-chlorophenyl)-3-methylbutanoic acid ethyl ester. Background Art
[0002] Valerate, a pyrethroid insecticide, is highly effective and safe, with strong contact action, stomach poisoning, and repellent properties, resulting in strong knockdown. It is used to control cotton aphids, cotton bollworms, pink bollworms, cabbage aphids, diamondback moths, corn borers, Spodoptera litura, tea geometrids, tea moths, tea caterpillars, rice leaf rollers, citrus leafminers, and other pests.
[0003] The chemical structure of valerate is as follows:
[0004] In the original process, Valerate is synthesized through multiple steps. .
[0005] This route uses isopropyl benzenesulfonate as the alkylating agent, a readily available raw material. However, its high molecular weight (200.26) and the fact that only the isopropyl group is removed in the reaction result in a relatively high consumption quota. Bromine resources are limited when using isopropyl bromide. Industrial isopropyl chloride is currently unavailable. The starting material, p-chlorobenzyl cyanide, is of low purity and quality, directly affecting the quality of product (I). Therefore, the use of industrial p-chlorobenzyl cyanide requires redistillation and purification. Isopropyl benzenesulfonate is chemically unstable and decomposes in the presence of moisture or high temperatures. The acyl chlorination reaction requires dry, anhydrous conditions, and the temperature should be gradually increased with good stirring to avoid localized overheating. Considering the instability of product (III), it should not be stored for extended periods. The next step to produce cyanovalerate should be performed as soon as possible. If other impurities are present in m-phenoxybenzaldehyde, they could be introduced into the product and affect its quality. Purification can be achieved by sodium bisulfite addition or distillation.
[0006] Phenvalerate is a broad-spectrum, highly effective, and fast-acting pyrethroid. It primarily acts as a contact and stomach poison, with no systemic effects. It is ineffective against mites, but effective against lepidopteran larvae, Orthoptera, Hemiptera, and Diptera pests. It is used to control cotton aphids, leafhoppers, stink bugs, leaf rollers, cabbage loopers, soybean borers, wheat armyworms, pink bollworms, cotton bollworms, and citrus leafminer larvae.
[0007] The chemical structure of Phenvalerate is as follows:
[0008] In the original process .
[0009] Since racemic 2-(4-chlorophenyl)-3-methylbutyric acid is used in the synthesis of fenvalerate, optical isomers are inevitably produced, which will directly lead to a decrease in the yield of fenvalerate and an increase in production costs.
[0010] In order to obtain a single configuration of 2-(4-chlorophenyl)-3-methylbutanoic acid, this patent studies the asymmetric hydrogenation method to prepare chiral 3-phenoxybenzyl ( R The research team investigated the effects of various reaction conditions (reaction solvent, reducing agent system, catalyst type, and substrate / catalyst ratio (S / C)) on the yield and ee value of the resulting product. By comparing numerous asymmetric hydrogenation catalysts, identifying the optimal catalyst, and optimizing various reaction parameters, the present invention ultimately developed a stable process for synthesizing ethyl (R)-2-(4-chlorophenyl)-3-methylbutanoate with an ee value of 91%. This process is of great significance for reducing the production cost of Valerate and improving its synthesis efficiency. Summary of the Invention
[0011] The present invention provides a pyrethroid intermediate ( R The present invention is achieved through the following process scheme: A pyrethroid intermediate ( R )-2-(4-chlorophenyl)-3-methylbutanoic acid ethyl ester preparation synthesis process, the synthesis route includes:
[0012] In the present invention, the molecular structure of the preferred asymmetric hydrogenation catalyst is as follows:
[0013] In the present invention, the solvent of the catalyst used in the asymmetric hydrogenation process is preferably toluene (PhMe), trifluoroethanol (TFE), or hexafluoroisopropanol (HFIP).
[0014] In the present invention, the hydrogen source of the catalyst used in the asymmetric hydrogenation process is H2.
[0015] In the present invention, the ratio (molar ratio) of the two substances in the catalyst used in the asymmetric hydrogenation process is preferably 1:1.1.
[0016] In the present invention, the amount of the catalyst used is preferably 1%-5% equivalent relative to the reaction substrate, more preferably 5% equivalent.
[0017] In the present invention, the reaction temperature of the catalyst used in the asymmetric transfer hydrogenation process is preferably 20-50°C, more preferably 25°C.
[0018] In the present invention, the reaction time of the catalyst used in the asymmetric transfer hydrogenation process is preferably 6 h to 48 h.
[0019] The present invention also provides a method for synthesizing valpermethrin, including the method described above, and ( R )-2-(4-chlorophenyl)-3-methylbutanoic acid ethyl ester and (3-phenoxyphenyl)methanol are mixed in a solvent, N,N'-dicyclohexylcarbodiimide is added at 0-10°C, the temperature is raised to room temperature, and 4-dimethylaminopyridine is added to react to obtain valerate. The reaction formula is as follows: .
[0020] ( R The molar ratio of ethyl 2-(4-chlorophenyl)-3-methylbutanoate to (3-phenoxyphenyl)methanol is 3:0.5-1.5.
[0021] The present invention also provides a method for synthesizing fenvalerate, including the method described above, and ( R )-2-(4-chlorophenyl)-3-methylbutanoic acid ethyl ester and (S)-2-hydroxy-2-(3-phenoxyphenyl)acetonitrile are combined in a solvent, N,N'-dicyclohexylcarbodiimide is added at 0-10°C, and the temperature is raised to room temperature. Then, 4-dimethylaminopyridine is added to react to obtain valerate. The reaction formula is as follows: .
[0022] ( R The molar ratio of ethyl 2-(4-chlorophenyl)-3-methylbutanoate to (S)-2-hydroxy-2-(3-phenoxyphenyl)acetonitrile is 3:0.5-1.5.
[0023] Compared with the existing process routes, the process route of the present invention has the following advantages: the present invention adopts the asymmetric catalytic technology involving nickel metal catalysts, which are low-cost, abundant in reserves, and environmentally friendly. Compared with the existing similar intermediate preparation process methods, the present invention uses less catalyst, lower reaction temperature and higher catalytic efficiency. The product obtained by the process route of the present invention ( R The ee value of ethyl 2-(4-chlorophenyl)-3-methylbutanoate (II) is as high as 99%. Therefore, the present invention simplifies the overall synthesis process of the target product, reduces waste emissions, and lowers production costs. Therefore, the present invention is more amenable to industrial application. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 . HPLC spectrum of the racemic compound 2-(4-chlorophenyl)-3-methylbutyric acid ethyl ester of Example 2.
[0025] Figure 2 Example 1 Chiral Compound ( R HPLC spectrum of ethyl 2-(4-chlorophenyl)-3-methylbutanoate.
[0026] Figure 3 HPLC spectrum of the racemic compound 3-phenoxybenzyl-2-(4-chlorophenyl)-3-methylbutyrate of Example 3.
[0027] Figure 4 Example 31 Chiral Compound 3-phenoxybenzyl ( R HPLC spectrum of )-2-(4-chlorophenyl)-3-methylbutyrate.
[0028] Figure 5 Example 1 compound ( R )-2-(4-chlorophenyl)-3-methylbutanoic acid ethyl ester 1 H NMR spectrum.
[0029] Figure 6 Example 29 Compound 3-phenoxybenzyl ( R )-2-(4-chlorophenyl)-3-methylbutyrate 1 H NMR spectrum. DETAILED DESCRIPTION
[0030] In combination with the above process route scheme, the present invention will now be further described with reference to specific embodiments and drawings, but the embodiments of the present invention are not limited thereto.
[0031] Example 1 In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1..1×10 -2mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature for 12 hours to obtain a brown-red solution. 0.5 mL of this solution was added to compound I (0.2 mmol), followed by 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 20:1) was performed to obtain chiral product II. HPLC analysis of the product revealed an ee value of 99% and a yield of 99%. The synthetic route is shown below:
[0032] The present invention investigates the effects of different types of asymmetric hydrogenation catalysts on conversion (conv.) and enantiomeric selectivity (ee). 1 H NMR (400 MHz, CDCl3) δ 7.26 (s, 4H), 4.22 – 3.96 (m, 2H), 3.09(d, J = 10.6 Hz, 1H), 2.23-2.38 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H), 1.02 (d, J = 6.5Hz, 3H), 0.68 (d, J = 6.7 Hz, 3H). Example 2 In a high-purity argon atmosphere, [Rh(NBD)2]BF4 (1×10 -2 mmol) and ligand rac-BINAP (1..1×10 -2 mmol) was dissolved in dichloromethane (0.5 mL) and stirred at room temperature for 30 minutes to obtain a brown-red solution. 0.5 mL of this solution was added to compound I (0.2 mmol), followed by 0.5 mL of dichloromethane. The reaction system was placed in an autoclave and stirred at 50°C under H2 (50 bar) for 12 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 20:1) was used to obtain the racemic product. The synthetic route is shown below:
[0033] Example 3 In a high-purity argon atmosphere, [Rh(NBD)2]BF4 (1×10 -2 mmol) and ligand rac-BINAP (1..1×10 -2mmol) was dissolved in dichloromethane (0.5 mL) and stirred at room temperature for 30 minutes to obtain a brown-red solution. 0.5 mL of this solution was added to 3-phenoxybenzyl-2-(4-chlorophenyl)-3-methylbut-2-enoate (0.2 mmol) and 0.5 mL of dichloromethane. The reaction system was placed in an autoclave and stirred at 50°C under H2 (50 bar) for 12 hours. The solvent was removed under reduced pressure, and column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 20:1) was used to obtain the racemic product. The synthetic route is shown below:
[0034] Examples 4-11 The catalyst ligands in Example 1 were replaced by ( S )-Ph-BPE, ( S )-Segphos, ( S )-BINAP、( S, S )-Me-Duphos, ( R c, S p)- t Bu-Josiphos, ( S )-Binapine, ( R )-QuinoxP and ( S,S )-BenzP*.
[0035] The experimental results of the asymmetric reduction of ethyl 2-(4-chlorophenyl)-3-methylbut-2-enoate using different catalysts in Examples 4-11 are listed in Table 1 below; wherein, the conversion (conv.) and enantiomeric selectivity (ee) were obtained from the corresponding HPLC spectra.
[0036]
[0037] Table 1
[0038] Examples 12-19 In order to continue to investigate the effect of metal precursors on the asymmetric hydrogenation reaction, based on Example 1, the metal precursors were replaced with Ni(OAc)2·4H2O, Ni(OAc)2, NiCl2(DME), NiBr2(DME), Ni(OTf)2, Ni(OCOCF3)2·6H2O, Ni(acac), and NiI2 in sequence. The reaction temperature was 25°C, the reaction time was 48 h, and the hydrogen pressure was 50 bar. The following Examples 12-19 were carried out. The synthesis routes are shown below. The experimental results are shown in Table 2 below, where the conversion rate (conv.) and enantiomeric selectivity (ee) were obtained from the corresponding HPLC spectra.
[0039]
[0040] Table 2
[0041] Examples 20-27 In order to further investigate the effect of the reaction solvent on the asymmetric hydrogenation reaction, based on Example 12, hexafluoroisopropanol (HFIP) was replaced by tetrahydrofuran (THF), dichloromethane (DCM), toluene (PhMe), acetonitrile (MeCN), methanol (MeOH), isopropanol ( i The following Examples 20-27 were carried out using PrOH) and trifluoroethanol (TFE) at a reaction temperature of 25°C, a reaction time of 48 h, and a hydrogen pressure of 50 bar. The synthetic routes are shown below; the experimental results are shown in Table 3 below, where the conversion (conv.) and enantiomeric selectivity (ee) were obtained from the corresponding HPLC spectra.
[0042]
[0043] Table 3
[0044] The chemical structures of the catalysts Cat.1-8 in the above experiments are as follows:
[0045] It can be concluded that in the present invention, ethyl 2-(4-chlorophenyl)-3-methylbut-2-enoate (I) is used as the reaction substrate, HFIP is used as the reaction solvent, catalyst Cat.7 is used as the asymmetric hydrogenation catalyst, and H2 is used as the reaction hydrogen source. The target product with high conversion rate and high enantioselectivity can be obtained by reacting at 25°C for 48 h, which reflects the technical superiority of the patent of the present invention.
[0046] Implementation Example 28
[0047] We explored and determined the optimal hydrolysis conditions and obtained the target product with a yield of 80% and an ee value of 97% ( R )-2-(4-chlorophenyl)-3-methylbutanoic acid, the ee value decreased slightly during the hydrolysis process. R )-2-(4-chlorophenyl)-3-methylbutanoic acid ethyl ester (480 mg, 2 mmol) was added to a mixed solution of NaOH (10 mmol, 400 mg) in MeOH:THF:H2O=5:1:1 and reacted at 50°C for 12 h. After the reaction, the product was post-treated with dilute hydrochloric acid. A white solid precipitated after the addition of dilute hydrochloric acid, which was obtained by vacuum filtration.
[0048] Implementation Example 29
[0049] Add (3-phenoxyphenyl)methanol (600 mg, 3 mmol) and ( R To a solution of 2-(4-chlorophenyl)-3-methylbutanoic acid (212 mg, 1 mmol) in DCM was added DCC (412 mg, 2 mmol) at 0°C. The mixture was stirred for 10 minutes, then warmed to room temperature. DMAP (195 mg, 1.6 mmol) was added and stirred at room temperature for 6 hours. The mixture was washed with 0.5 M HCl solution and saturated NaHCO₃ solution, and extracted with ethyl acetate. Volatiles were removed, and the residue was purified by flash chromatography (1 / 20 (v / v) EtOAc / hexane) to yield a white oil. 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.32 (m, 2H), 7.31 – 7.21 (m, 5H), 7.16-7.11(m, J = 8.5, 7.1, 1.1 Hz, 1H), 7.02 – 6.97 (m, 3H), 6.97 – 6.90 (m, 2H), 5.19 –4.94 (m, 2H), 3.18 (d, J = 10.6 Hz, 1H), 2.41 – 2.18 (m, 1H), 1.00 (d, J = 6.5Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H). Implementation Example 30 (S)-2-hydroxy-2-(3-phenoxyphenyl)acetonitrile (675 mg, 3 mmol) and ( RTo a solution of 2-(4-chlorophenyl)-3-methylbutanoic acid (212 mg, 1 mmol) in DCM was added DCC (412 mg, 2 mmol) at 0°C. The mixture was stirred for 10 minutes, then warmed to room temperature. DMAP (195 mg, 1.6 mmol) was added and stirred at room temperature for 6 hours. The mixture was washed with 0.5 M HCl solution and saturated NaHCO₃ solution, and extracted with ethyl acetate. Volatiles were removed, and the residue was purified by flash chromatography (1 / 20 (v / v) EtOAc / hexane) to yield a light yellow oil.
[0050] Implementation Example 31
[0051] In a high-purity argon atmosphere, Ni(OAc)2·4H2O (1×10 -2 mmol) and ligand ( R,R )-QuinoxP*(1..1×10 -2 mmol) was dissolved in hexafluoroisopropanol (0.5 mL) and stirred at room temperature for 12 hours to obtain a brown-red solution. 0.5 mL of this solution was added to 3-phenoxybenzyl-2-(4-chlorophenyl)-3-methylbut-2-enoate (0.2 mmol) and 0.5 mL of hexafluoroisopropanol. The reaction system was placed in an autoclave and stirred at 25°C under H2 (50 bar) for 48 hours. The solvent was removed under reduced pressure, and the product was separated by column chromatography (silica gel column, eluent: petroleum ether:ethyl acetate = 20:1) to obtain the chiral product, Valerate. 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.32 (m, 2H), 7.31 –7.21 (m, 5H), 7.16-7.11 (m, J = 8.5, 7.1, 1.1 Hz, 1H), 7.02 – 6.97 (m, 3H), 6.97 – 6.90 (m, 2H), 5.19 – 4.94 (m, 2H), 3.18 (d, J = 10.6 Hz, 1H), 2.41 –2.18 (m, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H).
Claims
1. A method for preparing a pyrethroid intermediate, characterized in that: The steps include: (1) Preparation of the catalyst: The catalyst is prepared by mixing a metallic nickel compound with a diphosphorus chiral ligand in a solvent; (2) The compound represented by formula I is mixed in a solvent, the catalyst described in step (1) is added, and a high-pressure catalytic reaction is carried out under hydrogenation conditions to obtain a hydrogenated product represented by formula II; (3) The hydrogenated product of formula II is hydrolyzed to obtain ( R ) ethyl 2-(4-chlorophenyl)-3-methylbutanoate, a pyrethroid intermediate; The synthetic route is as follows: 。 2. The preparation method according to claim 1, characterized in that The molecular structure of the selected asymmetric hydrogenation catalyst is any one of the following: 。 3. The preparation method according to claim 1, characterized in that The solvent used in the hydrogenation process of the asymmetric hydrogenation catalyst is selected from any one of methanol, isopropanol, dichloromethane, tetrahydrofuran, acetonitrile, toluene, trifluoroethanol and hexafluoroisopropanol.
4. The preparation method according to claim 1, characterized in that The hydrogen source used in the hydrogenation process of the asymmetric hydrogenation catalyst is selected from H2, and the amount of the hydrogen source used is preferably 30 bar-80 bar, more preferably 50 bar.
5. The preparation method according to claim 1, characterized in that The catalyst is used in an amount of 1 wt % to 5 wt % equivalent to the reaction substrate, more preferably 5 wt % equivalent.
6. The preparation method according to claim 1, characterized in that The reaction temperature during the asymmetric hydrogenation process is 20-50°C, more preferably 25°C; the reaction time is 6h-48h, more preferably 48h.
7. A method for synthesizing valpermethrin, characterized in that: The method according to any one of claims 1 to 6, and the method prepared by the method ( R )-2-(4-chlorophenyl)-3-methylbutanoic acid ethyl ester and (3-phenoxyphenyl)methanol are mixed in a solvent, N,N'-dicyclohexylcarbodiimide is added at 0-10°C, the temperature is raised to room temperature, and 4-dimethylaminopyridine is added to react to obtain valerate. The reaction formula is as follows: 。 8. The method for synthesizing valpermethrin according to claim 7, wherein: ( R The molar ratio of ethyl 2-(4-chlorophenyl)-3-methylbutanoate to (3-phenoxyphenyl)methanol is 3:0.5-1.
5.
9. A method for synthesizing fenvalerate, characterized in that: Including the method according to any one of claims 1 to 6, and the method prepared by the method ( R )-2-(4-chlorophenyl)-3-methylbutanoic acid ethyl ester and (S)-2-hydroxy-2-(3-phenoxyphenyl)acetonitrile are combined in a solvent, N,N'-dicyclohexylcarbodiimide is added at 0-10°C, and the temperature is raised to room temperature. Then, 4-dimethylaminopyridine is added to react to obtain valerate. The reaction formula is as follows: 。 10. The method for synthesizing fenvalerate according to claim 9, wherein ( R The molar ratio of ethyl 2-(4-chlorophenyl)-3-methylbutanoate to (S)-2-hydroxy-2-(3-phenoxyphenyl)acetonitrile is 3:0.5-1.5.