CN1332930C - Method for preparing precursor of cycloprothrin - Google Patents

Abstract

The present invention relates to a convenient and low-cost process for synthesizing cycloprothrin and the precursor thereof. The process conveniently and cheaply prepares a key intermediate compound, namely 4-ethoxy phenyl lactate ester dehydrated under the acid condition to obtain corresponding methyl acrylate. 2-(4-ethoxy) phenyl methyl acrylate reacts with dichloro carbene to generate dichlor carbene ternary ring of which the compound is conventionally saponified into acid. After being chloridized, acylation reacts with cyanohydrin to obtain the cycloprothrin.

Description

Process for preparing promethrin precursor

Technical field:

The invention relates to a new process for promethrin precursor.

Background technique:

Cycloprothrin is a synthetic pyrethroid insecticide that is low-toxic to fish and other aquatic organisms and can be used in paddy fields. Its structural formula is as follows:

The literature synthesis method is to start from p-hydroxyphenylacetic acid, obtain ethyl p-ethoxyphenylacetate through etherification and esterification, then condense with formaldehyde to obtain 2-(p-ethoxyphenyl) acrylate, and then react with dichloro The carbene is reacted to form a three-membered ring, then saponified into an acid, and finally made into an acyl chloride and then reacted with cyanohydrin to obtain promethrin. The route is as follows:

The above process route is long, the yield is low, and most of the intermediates are oily liquids with high boiling points, which need to be purified by high vacuum distillation, which is difficult to purify, resulting in high cost. The specific documents are: 1.US4262014; 2.AU502950; 3.EP0003670.

Invention content:

The problem to be solved in the present invention is to prepare the key intermediate of 4-ethoxyphenyl lactate conveniently and at low cost, and then provide a convenient and low-cost process for synthesizing promethrin and its precursor . The structure of 4-ethoxyphenyl lactate is:

Wherein R is a straight-chain or branched-chain alkane with 1-6 carbons.

4-Ethoxyphenyl lactate was prepared by phenetole and pyruvate under the following reaction conditions. Such compounds can be used for the convenient and low-cost synthesis of promethrin.

The reaction formula of synthetic 4-ethoxyphenyl lactate is:

In the formula, R is as described above.

进行傅克反应制备上述的2-芳基乳酸酯。所述路易斯酸推荐为：三氯化铝，氯化锌，氯化铁，四氯化钛，氯化镍，四氯化锡，四氯化锆，二氯化锡，三氟化硼乙醚，三甲基氯硅烷，三氟甲磺酸锌，三氟甲磺酸铜，三氟甲磺酸铋。所述的碱是三乙胺，二乙胺，吡啶，哌啶，二异丙基乙胺、碱金属的碳酸盐、碱金属的氢氧化物、金属氧化物。所述的反应推荐在如下有机溶剂中进行：四氢呋喃，二氯甲烷，硝基苯，氯苯，二氯乙烷，甲基叔丁基醚，硝基甲烷，苯，四氯化碳，或者以上溶剂的混合物。所述的反应物之间物质的量的比例推荐为：苯乙醚∶丙酮酸酯∶碱∶路易斯酸＝1.0∶1.0～1.5∶1.0～3.0∶0.5～2.5。推荐的反应步骤如下：That is, under the action of a Lewis acid, with or without adding a base, the electron-rich position of phenetole directly interacts with the pyruvate

The Friedel-Crafts reaction was carried out to prepare the 2-aryl lactate described above. The recommended Lewis acid is: aluminum trichloride, zinc chloride, ferric chloride, titanium tetrachloride, nickel chloride, tin tetrachloride, zirconium tetrachloride, tin dichloride, boron trifluoride ether, Chlorotrimethylsilane, zinc triflate, copper triflate, bismuth triflate. The base is triethylamine, diethylamine, pyridine, piperidine, diisopropylethylamine, alkali metal carbonate, alkali metal hydroxide, metal oxide. The described reaction is recommended to be carried out in the following organic solvents: tetrahydrofuran, dichloromethane, nitrobenzene, chlorobenzene, dichloroethane, methyl tert-butyl ether, nitromethane, benzene, carbon tetrachloride, or the above mixture of solvents. The ratio of the amount of substances among the reactants is recommended to be: phenetole:pyruvate:base:Lewis acid=1.0:1.0-1.5:1.0-3.0:0.5-2.5. The recommended reaction steps are as follows:

1. Add phenetole, pyruvate and base to organic solvent

2. Then cool the system to minus 50 degrees to zero degrees, and start adding Lewis acid under stirring;

3. React between minus 50°C and 5°C. After the reaction is complete, add the reaction mixture into stirred water at 0-5°C to quench the reaction;

4. Concentrating the extract and distilling under reduced pressure to remove the solvent to obtain the product aryl lactate.

The present invention provides a new method for synthesizing promethrin and its precursor, which can conveniently and low-cost synthesize the precursor dichlorocarbene three-membered ring compound of promethrin:

1. Phenethyl ether reacts with pyruvate under the above conditions to obtain 4-ethoxyphenyl lactate:

2.4-ethoxyphenyl lactate is operated under acidic conditions according to routine (recommended to add p-toluenesulfonic acid and hydroquinone, further recommended to add (1-10)% p-toluenesulfonic acid and (0.1- 5) % hydroquinone, said percentage is relative to the weight percentage of lactic acid ester, and the reaction temperature is recommended to be heated to reflux) dehydration to generate the corresponding acrylate:

3.2-(4-ethoxyphenyl) acrylate and chloroform carry out dichlorocarbene reaction under the action of alkali to generate dichlorocarbene three-membered ring:

This step reaction further recommends that there are two methods to better control the thermal effect during the scale-up production of the process, thereby improving the shortcomings of the original process that are difficult to control due to the intense heat release of the carbene reaction, and the reaction yield is greatly improved. The methods are:

1) Add an organic solvent to the carbene reaction system to make the two-phase reaction proceed smoothly. The recommended organic solvent is toluene, and the amount of the organic solvent is recommended to be 0.5 to 6 times that of the substrate acrylate weight

2) The alkali that produces carbene is changed into potassium fluoride/alumina by sodium hydroxide, and the reaction proceeds very smoothly at room temperature;

The specific steps of the first method are recommended as follows: dehydration of 4-ethoxyphenyl lactate under acidic conditions to generate the corresponding acrylate dissolved in chloroform, and then add a phase transfer catalyst and 0.5 to 6 relative to the substrate acrylate Double the weight of toluene, and then dropwise add 50% concentrated sodium hydroxide solution between 40-65 degrees of temperature control. After the addition, react between 40-60 until the raw materials disappear. The phase transfer catalyst is a quaternary ammonium salt, recommended as tetramethylammonium hydroxide, tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride , Benzyltriethylammonium bromide, especially recommended as benzyltriethylammonium chloride.

The specific steps of the second method are recommended as follows: dehydrate 4-ethoxyphenyl lactate under acidic conditions to generate the corresponding acrylate, dissolve it in acetonitrile, and then add potassium fluoride 5 to 15 times as much as the substrate acrylate /alumina and a small amount of water, and finally chloroform was added, and the reaction was stirred at room temperature until the raw materials disappeared.

The above-mentioned three-membered ring compound of dichlorocarbene is subjected to conventional saponification to acid, and reacted with cyanohydrin to obtain promethrin, see 1.US4262014; 2.AU502950; 3.EP0003670.

The present invention provides a kind of convenient and low-cost process for synthesizing promethrin, which overcomes the low yield of previous technologies, and most of the intermediates are oily liquids with high boiling points, which need to be purified by high vacuum distillation, which is difficult to purify, resulting in Costly technical difficulties. In addition, the present invention further optimizes the reaction conditions to better control the thermal effect of the scale-up production of the process, improves the shortcomings of the previous process that is difficult to control due to the severe heat release of the carbene reaction, and greatly improves the reaction yield.

Detailed ways

The following examples help to understand this patent but the protection scope of this patent is not limited thereto.

Example 1

Add 40 grams of phenetole and 40 grams of ethyl pyruvate to 400 milliliters of dichloromethane, then add 31 grams of aluminum oxide, then cool the system to minus 45 degrees, start adding titanium tetrachloride, and keep the temperature from minus 45 to minus 20 degrees, and then react at this temperature. Gas chromatographic tracking until the reaction raw materials no longer decreased. React between minus 10 degrees and 5 degrees. After the reaction is complete, add the reaction mixture into stirred water at 0-5 degrees to quench the reaction. The extract was concentrated and evaporated under reduced pressure to remove the solvent to obtain 43 g of the product aryl lactate, with a yield of 55%. Compound Characterization Data:

FTIR (neat): 3506, 2983, 1728, 1247cm ^-1 ; ¹ H NMR (CDCl ₃ , 300MHz) δ = 7.46 (d, J = 9.0Hz, 2H), 6.87 (d, J = 8.7Hz, 2H), 4.25(q, J=7.1Hz, 2H), 4.02(q, J=7.0Hz, 2H), 3.77(s, 3H), 3.72(s, 1H), 1.75(s, 3H), 1.41(t, J = 7.0Hz, 3H), 1.27 (t, J = 7.1Hz, 3H); ¹³ C NMR (CDCl ₃ , 75MHz) δ = 175.6, 158.3, 134.7, 126.3, 113.9, 75.1, 63.2, 62.0, 26.5, 14.6, 13.9; MS (EI) m/e 238 (M+, 3.5), 165 (100), 43 (59.7); Anal. Calcd for C ₁₃ H ₁₈ O ₄ : C, 65.53; H, 7.61. Found: C, 65.59; H, 7.66.

Example 2

Add 40 grams of phenetole and 40 grams of methyl pyruvate to 400 milliliters of dichloromethane, then add 31 grams of barium oxide, then cool the system to minus 45 degrees, start adding titanium tetrachloride, and keep the temperature from minus 45 to minus 20 degrees, and then react at this temperature. Gas chromatographic tracking until the reaction raw materials no longer decreased. React between minus 10 degrees and 5 degrees. After the reaction is complete, add the reaction mixture into stirred water at 0-5 degrees to quench the reaction. The extract was concentrated and evaporated under reduced pressure to remove the solvent to obtain 41 g of the product aryl lactate, with a yield of 51%.

FTIR (neat): 3523, 2983, 1721, 1245cm ^-1 ; ¹ H NMR (CDCl ₃ , 300MHz) δ = 7.45 (d, J = 9.0Hz, 2H), 6.87 (d, J = 8.7Hz, 2H), 4.02(q, J=7.0Hz, 2H), 3.76(s, 3H), 3.72(s, 1H), 1.76(s, 3H), 1.41(t, J=7.0Hz, 3H); ¹³ C NMR (CDCl ₃ , 75MHz) δ=176.2, 158.4, 134.5, 126.3, 113.9, 75.3, 63.2, 53.0, 26.5, 14.7; MS (EI) m/e 224 (M+, 5.9), 165 (100), 43 (36.9); Anal. Calcd for C ₁₂ H ₁₆ O ₄ : C, 64.27; H, 7.19. Found: C, 64.11; H, 7.11.

Example 3

500 grams of 4-ethoxyphenyl ethyl lactate was added to 2000 milliliters of chloroform, then 2.5 grams of hydroquinone and 20 grams of p-toluenesulfonic acid were added, the water was separated under reflux, and the gas phase followed the reaction until the raw material was less than 1%. A total of 1000 ml of chloroform was distilled off. Cool, wash twice with 400 ml of 10% sodium hydroxide, and then add 3.6 g of benzyltriethylammonium chloride. The system was heated to 55 degrees, and 1800 grams of 50% sodium hydroxide aqueous solution was added dropwise, and the temperature was controlled at 50-65 degrees. The reaction during the dropwise addition was very violent and difficult to control. There have been three occurrences of flushing. If the dropwise addition is too slow, there will be saponification of the raw material acrylate. After adding, keep warm between 50-60 degrees until the raw material is less than 1%. Add 2000 ml of dichloroethane, separate the phases, and extract once with 1000 ml of dichloroethane. The oil phases are combined, dried and concentrated to remove the solvent to obtain a dichlorocarbene three-membered ring product, which can be saponified directly in the next step without purification and then purified. The percent yield is 41%, and the HPLC purity is 98%.

Example 4

500 grams of 4-ethoxyphenyl ethyl lactate was added to 2000 milliliters of chloroform, then 2.5 grams of hydroquinone and 20 grams of p-toluenesulfonic acid were added, the water was separated under reflux, and the gas phase followed the reaction until the raw material was less than 1%. A total of 1000 ml of chloroform was distilled off. Cool, wash twice with 400 ml of 10% sodium hydroxide, then add 2000 ml of toluene and 3.6 g of benzyltriethylammonium chloride. The system was heated to 55 degrees, and 1800 grams of 50% sodium hydroxide aqueous solution was added dropwise, and the temperature was controlled at 50-65 degrees. After adding, keep warm between 50-60 degrees until the raw material is less than 1%. Add 2000 ml of dichloroethane, separate the phases, and extract once with 1000 ml of dichloroethane. The oil phases are combined, dried and concentrated to remove the solvent to obtain a dichlorocarbene three-membered ring product, which can be saponified directly in the next step without purification and then purified. The percent yield is 90%, and the HPLC purity is 98%.

Example 5

500 grams of 4-ethoxyphenyl ethyl lactate was added to 2000 milliliters of chloroform, then 2.5 grams of hydroquinone and 20 grams of p-toluenesulfonic acid were added, the water was separated under reflux, and the gas phase followed the reaction until the raw material was less than 1%. A total of 1000 ml of chloroform was distilled off. Cool, wash twice with 400 ml of 10% sodium hydroxide, then add 500 ml of toluene and 3.6 g of benzyltriethylammonium chloride. The system was heated to 55 degrees, and 1800 grams of 50% sodium hydroxide aqueous solution was added dropwise, and the temperature was controlled at 50-65 degrees. Saponification was found before the addition was completed. After adding, keep warm between 50-60 degrees until the raw material is less than 1%. Add 2000 ml of dichloroethane, separate the phases, and extract once with 1000 ml of dichloroethane. The oil phases are combined, dried and concentrated to remove the solvent to obtain a dichlorocarbene three-membered ring product, which can be saponified directly in the next step without purification and then purified. 25% discount rate

Example 6

Add 50 grams of 4-ethoxyphenyl ethyl lactate to 200 milliliters of chloroform, then add 0.25 grams of hydroquinone and 2 grams of p-toluenesulfonic acid, heat to reflux to separate water, and follow the reaction in the gas phase until the raw materials are less than 1%. A total of 100 ml of chloroform was distilled off. Cool and wash twice with 40 ml of 10% sodium hydroxide, then add 300 ml of toluene and 0.36 g of tetrabutylammonium bromide. The system was heated to 55 degrees, and 180 grams of 50% sodium hydroxide aqueous solution was added dropwise, and the temperature was controlled at 50-65 degrees. The reaction takes about 3 to 4 hours. After adding, keep warm between 50-60 degrees until the raw material is less than 1%. Add 200 ml of dichloroethane, separate the phases, and extract once with 50 ml of dichloroethane. The oil phases are combined, dried and concentrated to remove the solvent to obtain a dichlorocarbene three-membered ring product, which can be saponified directly in the next step without purification and then purified. 36% discount rate

Example 7

Add 20 grams of 4-ethoxyphenyl ethyl lactate to 80 milliliters of chloroform, then add 0.1 gram of hydroquinone and 0.8 gram of p-toluenesulfonic acid, heat to reflux to separate water, and follow the reaction until the raw material is less than 1%. A total of 40 ml of chloroform was distilled off. Cool, wash twice with 40 ml of 10% sodium hydroxide, then add 200 ml of acetonitrile and 5.4 g of water. Another 100 g of potassium fluoride/alumina was added. Finally 12 mL of chloroform was added. The reaction system was stirred and reacted at room temperature (25-30 degrees). GC followed the reaction to less than 1% starting material. Filter, add 200 ml of dichloroethane and 100 ml of water to the filtrate, separate the phases, and extract once with 50 ml of dichloroethane. The oil phases are combined, washed once with water, dried and concentrated to remove the solvent to obtain a dichlorocarbene three-membered ring product, which can be saponified directly in the next step without purification and then purified. The percent yield is 66%, and the HPLC purity is 97%.

Example 8

Add 20 grams of 4-ethoxyphenyl ethyl lactate to 80 milliliters of chloroform, then add 0.1 gram of hydroquinone and 0.8 gram of p-toluenesulfonic acid, heat to reflux to separate water, and follow the reaction until the raw material is less than 1%. A total of 40 ml of chloroform was distilled off. Cool, wash twice with 40 ml of 10% sodium hydroxide, then add 200 ml of acetonitrile and 5.4 g of water. Another 150 grams of potassium fluoride/alumina was added. Finally 12 mL of chloroform was added. The reaction system was stirred and reacted at room temperature (25-30 degrees). GC followed the reaction to less than 1% starting material. Filter, add 200 ml of dichloroethane and 100 ml of water to the filtrate, separate the phases, and extract once with 50 ml of dichloroethane. The oil phases are combined, washed once with water, dried and concentrated to remove the solvent to obtain a dichlorocarbene three-membered ring product, which can be saponified directly in the next step without purification and then purified. The percent yield is 90%, and the HPLC purity is 97%.

Example 9

Add the three-membered cyclic ester after the carbene reaction into a 10-liter reactor, and dissolve it with 2.0L ethanol; add the pre-configured 4% NaOH (dissolved in 4.8L water) solution to the system, and start the reaction after heating and reflux for 1 hour Sampling was followed by HPLC analysis until the reaction of the raw materials was complete, concentrated to remove most of the ethanol, and cooled. After the remaining aqueous solution was washed with dichloroethane (2×2 L), hydrochloric acid was added to acidify the solution to pH=2 while cooling in an ice-water bath, and a solid precipitated out. Suction filtration, the filter cake was washed with water until the eluate was neutral. The filter cake was refluxed with 4 L of toluene for dehydration; until no more water was taken out, 1 L of toluene (remainder 3 L) was evaporated, cooled, and white flaky crystals were precipitated. Suction filtration, suction drying, weighing 740g product 1-(4-ethoxyphenyl)-2,2-dichlorocyclopropane-1-carboxylic acid, yield 90%. FTIR (KBr): 3218, 2990, 1732, 1515 cm ^-1 ; ¹ H NMR (CDCl ₃ , 300 MHz) δ = 11.3 (s, br, 1H), 7.36 (d, J = 8.5Hz, 2H), 6.88 (d, J=8.3Hz, 2H), 4.02(q, J=6.8Hz, 2H), 2.59(d, J=7.8Hz, 1H), 2.04(d, J=7.9Hz, 1H), 1.40(t , J=6.8Hz, 3H); ¹³ C NMR (CDCl ₃ , 75MHz) δ=173.8, 159.2, 131.9, 125.4, 114.1, 63.4, 61.8, 43.9, 30.6, 14.8; MS (EI) m/e 274 (M+ , 22.8), 239(100), 193(99.8), 165(99.3), 147(59.0), 131(63.5); Anal. Calcd for C ₁₂ H ₁₂ Cl ₂ O ₃ : C, 52.39; H, 4.40. Found: C, 52.34; H, 4.43.

Example 10

27.5 g of 1-p-ethoxyphenyl-2,2-dichlorocyclopropane-1-acid was added to 30 ml of thionyl chloride, heated to reflux for one hour, almost no hydrogen chloride was released. Then the excess thionyl chloride was distilled off under reduced pressure. After cooling, 50 ml of toluene was added. A solution of m-phenoxy-α-cyanobenzyl alcohol (24.8 g) and 12 g of pyridine in 30 ml of toluene was then added dropwise. React at room temperature for 12 hours. Wash with sodium carbonate aqueous solution, water, and saturated brine successively. Then dry and concentrate. 48 g of promethrin was obtained, and the HPLC purity was 99%.

Claims (13)

1. A new process for the precursor dichlorocarbene three-membered ring compound of synthetic promethrin, characterized in that the dehydration of 4-ethoxyphenyl lactate generates corresponding 2-(4 -ethoxyphenyl) acrylate; 2-(4-ethoxyphenyl) acrylate and chloroform carry out dichlorocarbene reaction under the effect of alkali to generate dichlorocarbene three-membered ring: Wherein R is a straight chain or branched chain alkane with 1 to 6 carbons. 2. The method according to claim 1, further comprising the reaction of phenetole and pyruvate to obtain 4-ethoxyphenyl lactate:

Wherein R is a straight chain or branched chain alkane with 1 to 6 carbons. 3. according to the described method of claim 1 and 2, it is characterized in that under Lewis acid effect, under the condition of adding or not adding alkali, the electron-rich position of phenetole is directly with pyruvate Carrying out the Friedel-Crafts reaction to prepare the above-mentioned 4-ethoxyphenyl lactate; the Lewis acid is: aluminum trichloride, zinc chloride, ferric chloride, titanium tetrachloride, nickel chloride, tin tetrachloride , zirconium tetrachloride, tin dichloride, boron trifluoride ether, trimethylchlorosilane, zinc trifluoromethanesulfonate, copper trifluoromethanesulfonate or bismuth trifluoromethanesulfonate; the base is three Ethylamine, diethylamine, pyridine, piperidine, diisopropylethylamine, alkali metal carbonates, alkali metal hydroxides or metal oxides. 4. method according to claim 3 is characterized in that described Friedel-Crafts reaction is carried out in following organic solvent: tetrahydrofuran (THF), methylene dichloride, nitrobenzene, chlorobenzene, ethylene dichloride, methyl tert-butyl Ether, nitromethane, benzene, carbon tetrachloride, or a mixture of the above solvents; the ratio of the amount of substances between the reactants is: phenetole: pyruvate: base: Lewis acid=1.0: 1.0～1.5 : 1.0~3.0: 0.5~2.5. 5. method according to claim 3, is characterized in that described Friedel-Crafts reaction comprises the steps: 1). Add phenetole, pyruvate and alkali to the organic solvent; 2). Then cool the system to minus 50 degrees to zero degrees, and start adding Lewis acid under stirring; 3). React between minus 50 degrees and 5 degrees. After the reaction is complete, add the reaction mixture to the stirring 0-5 degrees of water to quench the reaction; 4). Concentrating the extract and distilling under reduced pressure to remove the solvent to obtain the product 4-ethoxyphenyl lactate. 6. according to the described method of claim 1 or 2, it is characterized in that described acidic condition is to add p-toluenesulfonic acid and hydroquinone to carry out under acidic condition according to conventional operation. 7. The method according to claim 1 or 2, characterized in that toluene is added in the carbene reaction system. 8. The method according to claim 7, characterized in that 4-ethoxyphenyl lactate is dehydrated under acidic conditions to generate corresponding acrylate and is dissolved in chloroform, adding phase transfer catalyst and 0.5 to 6 times relative Add sodium hydroxide solution dropwise to the toluene of the weight of the substrate acrylate, and react at 40-65°C. 9. The method according to claim 8, characterized in that the phase transfer catalyst is a quaternary ammonium salt. 10. The method according to claim 1 or 2, characterized in that the base producing carbene is sodium hydroxide or potassium fluoride/aluminum oxide. 11. The method according to claim 10, characterized in that 4-ethoxyphenyl lactate is dehydrated under acidic conditions to generate corresponding acrylate and is dissolved in acetonitrile, adding 5 to 15 times relative to the substrate acrylic acid Ester weight potassium fluoride/alumina and water, add chloroform, react at room temperature. 12. The method according to claim 1 or 2, further comprising saponifying the obtained dichlorocarbene three-membered ring compound into an acid, and reacting with cyanohydrin to obtain promethrin after acid chlorination. 13. A compound having the structure: Wherein R is a straight chain or branched chain alkane with 1 to 6 carbons.