CN115215793A - Synthesis method of fluopyram - Google Patents
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Abstract
The invention discloses a method for synthesizing fluopyram, which comprises the steps of taking 2-ethylcyano-3-chloro-5-trifluoromethylpyridine as a raw material, hydrolyzing cyano-group into carboxyl, reducing the carboxyl into alcohol under the action of a reducing agent to obtain 2-ethanol-3-chloro-5-trifluoromethylpyridine, converting the hydroxyl into amino, and finally condensing with 2-trifluoromethylbenzoic acid to generate fluopyram. The method avoids dangerous operation of pressure hydrogenation in the prior art, adopts a one-pot method for feeding in multiple steps through the synthesis process disclosed by the invention, can feed the related intermediate into subsequent reaction without purification, has safe and simple reaction overall operation and ideal yield, and has potential value of industrial amplification.
Description
Technical Field
The invention belongs to the technical field of pesticide raw material medicine preparation, and particularly relates to a synthesis method of fluopyram.
Background
Fluopyram (common name: fluopyram, CAS:658066-35-4, trade name: luofuda) is a new generation of SDHI (succinate dehydrogenase inhibitor) bactericide and nematicide developed by Bayer crop science. It acts on complex II on the mitochondrial respiratory electron transport chain, interfering with its respiratory action by inhibiting the activity of the target succinate dehydrogenase. After the nematodes are treated by the fluopyram, the bodies of the nematodes become needle-shaped and the activity is reduced rapidly. Fluopyram is the first nematicide acting on the target, represents a new action mechanism of nematicide, is also the first nematicide with low toxicity to users and environment, and is expected to become a support product in the strategy of nematode control in the future.
The fluopyram can be used for preventing and controlling alternaria leaf spot, gray mold, powdery mildew, sclerotinia, early blight and the like on vegetables such as grapes, pear trees, bananas, apples, cucumbers, tomatoes and the like and field crops, can be registered on various crops for preventing and controlling various nematodes, and is an efficient, green and low-toxicity nematicide. Fluopyram is not only a new generation of excellent nematicide, but also a broad-spectrum bactericide, a seed treatment agent, an agricultural product storage preservative and the like, and has multiple functions.
At present, the synthesis of fluopyram mainly uses 2, 3-dichloro-5-trifluoromethylpyridine and ethyl cyanoacetate as raw materials, and the raw materials are subjected to nucleophilic substitution to obtain an intermediate, then hydrolysis and decarboxylation are carried out under the hydrochloric acid condition to obtain [ 3-chloro-5- (trifluoromethyl) -2-pyridyl ] acetonitrile, then catalytic hydrogenation is carried out under Pd/C to generate acetate, hydrolysis is carried out under the acidic condition to obtain 3-chloro-5- (trifluoromethyl) -2- (2-aminoethyl) pyridine, and finally the acetate reacts with 2-trifluoromethylbenzoyl chloride to obtain the target product fluopyram, wherein the reaction process is shown in the following formula.
The synthesis route has low yield, a large amount of dechlorination impurities exist, especially, the one-step operation of reducing cyano by pressure hydrogenation is adopted, the yield is low and is difficult to control, the operation repeatability is poor, an amplification effect exists, the pressure hydrogenation also has danger, and the industrial production is not facilitated. At present, relevant patents reported around the method are EP1548007, WO200558828, WO2004016088, CN110437139A, CN111056997A, CN109293565B, CN114031551A, CN108947892A and CN108863915A, which do not completely solve the problem existing in the step of cyano reduction, and therefore, improvement of the existing synthetic method is urgently needed.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for synthesizing fluopyram.
The technical scheme adopted by the invention is as follows: the synthesis method of fluopyram comprises the steps of sequentially converting cyano in a compound of a formula 1 into carboxyl, hydroxyl and amino to obtain a compound of a formula 4, and reacting with a compound of a formula 5 to synthesize a compound of a formula 6, namely fluopyram;
preferably, the cyano group in the compound of formula 1 is converted to a carboxyl group to give a compound of formula 2, and the carboxyl group in the compound of formula 2 is reduced to a hydroxyl group to give a compound of formula 3;
preferably, the compound of formula 3 is converted to the compound of formula 4 in the following manner;
converting hydroxyl into an azide group, and reducing the azide group to obtain an amino;
or converting hydroxyl into a leaving group, and obtaining amino by using aminolysis substitution reaction;
alternatively, hydroxyl groups are converted to halogens to give amino groups by substitution reactions.
Preferably, the hydroxyl group is converted to an azide group, and the azide group is reduced to obtain an amino group, specifically:
converting the hydroxy group to a leaving group and converting the compound of formula 3 to a compound of formula 3 a; reacting with an azide reagent, performing substitution reaction on a leaving group and an azide group to obtain a compound shown as a formula 3b, and reducing the azide group to obtain an amino group shown as a formula 4;
wherein R is methylsulfonyl, p-toluenesulfonyl or trifluoromethylsulfonyl;
preferably, the azidation reagent is sodium azide or diphenylphosphoryl azide;
preferably, the reducing azide group employs triphenylphosphine, tin dichloride, lithium aluminum hydride, hydrazine hydrate in combination with raney nickel or sodium borohydride in combination with a lewis acid.
Preferably, hydroxyl is converted into leaving group, and amino is obtained by ammonolysis substitution reaction, specifically:
converting hydroxyl into leaving group, converting the compound shown in the formula 3 into a compound shown in the formula 3a, and obtaining amino by using ammonolysis substitution reaction, wherein the compound shown in the formula 4 is obtained;
wherein R is methylsulfonyl, p-toluenesulfonyl or trifluoromethylsulfonyl;
preferably, the reagent used for the ammonolysis substitution is ammonia in methanol or ammonia.
Preferably, the compound of formula 3a containing a leaving group is represented by a compound of formula 3a1 or a compound of formula 3a 2;
preferably, the hydroxyl group is converted to a halogen, which gives an amino group by a substitution reaction, in particular:
converting the hydroxy group to a halogen, converting the compound of formula 3 to a compound of formula 3c, aminolyzing the compound of formula 3 c;
in the ammonolysis process, the compound in the formula 3c reacts with phthalimide methyl salt, and then hydrazinolysis is carried out to obtain a compound in a formula 4;
or, in the ammonolysis process, the compound shown in the formula 3c and ammonia methanol are subjected to a dissolution reaction to obtain a compound shown in a formula 4;
or, in the ammonolysis process, the compound shown in the formula 3c reacts with acetamide or tert-butyl carbamate under the alkaline condition, and the protecting group on the amino group is removed to obtain the compound shown in the formula 4;
wherein X is a halogen atom; preferably a chlorine atom or a bromine atom;
preferably, the halogenation conditions may employ the reagents bromine, chlorine, thionyl chloride, elemental iodine in combination with triphenylphosphine, carbon tetrachloride in combination with triphenylphosphine, N-bromosuccinimide in combination with triphenylphosphine, or N-chlorosuccinimide in combination with triphenylphosphine.
Preferably, the reducing agent or combination of reducing agents used to convert the carboxyl group in the compound of formula 2 to the hydroxyl group in the compound of formula 3 is lithium aluminum hydride, zinc borohydride, ethylborane, a combination of sodium borohydride and elemental iodine, a combination of sodium borohydride and ethyl chloroformate, a combination of sodium borohydride and protonic acid, a combination of sodium borohydride and lewis acid, a combination of benzyltriethylammonium borohydride and trimethylchlorosilane, a combination of sodium borohydride and a carbene condensing agent, a combination of lithium borohydride and N, N '-dicyclohexylcarbodiimide, a combination of bromoborane and dimethylsulfide, a combination of N, N' -dimethylchloroimine hydrochloride and lithium tri-tert-butoxyaluminum hydride, a combination of samarium diiodide and protonic acid, or a combination of methylamine and lithium metal.
Preferably, the compound of formula 4 is condensed with the compound of formula 5 to obtain the compound fluopyram of formula 6, and the condensing agent is N, N ' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (7-azobenzotriazol) -N, N, N ' -tetramethyluronium Hexafluorophosphate (HATU), 1-Hydroxybenzotriazole (HOBT), benzotriazol-N, N, N ' -tetramethyluronium Hexafluorophosphate (HBTU), carbonyldiimidazole (CDI), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP).
Fluopyram synthesized by the method for synthesizing fluopyram.
The invention has the advantages and positive effects that: the synthesis scheme is suitable for feeding materials by a multi-step one-pot method, the related intermediate can be put into subsequent reaction without purification, the operation of pressure hydrogenation is avoided, the whole reaction operation is safe and simple, the yield is ideal, and the method is suitable for industrial amplification.
Drawings
Process for preparation of intermediate 3 of FIG. 1 1 H-NMR spectrum;
FIG. 2 of intermediate 4 1 H-NMR spectrum;
figure 3 MS spectrum of intermediate 4;
FIG. 4 of Fluopyram 1 H-NMR spectrum;
FIG. 5 MS spectrum of fluopyram;
FIG. 6 HPLC chromatogram of fluopyram.
Detailed Description
Embodiments of the present invention are described below with reference to the drawings.
The invention discloses a method for synthesizing fluopyram, which takes 2-acetonitrile-3-chlorine-5-trifluoromethyl pyridine as a raw material (the synthesis method is reported in many documents, and can refer to Bioorganic and Medicinal Chemistry,2021,29,115846, bioorganic and Medicinal Chemistry,2004,14, 2943), firstly, cyano is hydrolyzed into carboxyl, then the carboxyl is reduced into alcohol under the action of a reducing agent, so as to obtain 2-ethanol group-3-chlorine-5-trifluoromethyl pyridine, then the hydroxyl is converted into amino, and finally, the hydroxyl is condensed with 2-trifluoromethyl benzoic acid to obtain fluopyram, and the reaction process is as follows:
sequentially converting cyano groups in the compound of the formula 1 into carboxyl groups to obtain a compound of a formula 2, converting the carboxyl groups into hydroxyl groups to obtain a compound of a formula 3, converting the hydroxyl groups into amino groups to obtain a compound of a formula 4, and reacting with the compound of the formula 5 to synthesize a compound of a formula 6, namely fluopyram;
by adopting the synthesis strategy, raw materials required by the reaction can be sequentially added in the reaction process, and the intermediate purification process is omitted, so that the production cost is reduced, the pressure hydrogenation process in the prior art is avoided, and the reaction process is safer.
The method comprises the following steps: converting a cyano group in the compound of formula 1 to a carboxyl group to obtain a compound of formula 2;
the nitrile hydrolysis of step one is both acid hydrolysis and base hydrolysis, exemplified by the hydrolysis of the compound of formula 1 in concentrated sulfuric acid. The specific process is as follows: adding water and concentrated sulfuric acid into a reaction bottle, slowly adding the compound of the formula 1, and refluxing for overnight reaction; after the reaction is finished, adding ice blocks, and cooling with ice brine to separate out dark white solid, namely the compound of the formula 2. Filtering, extracting the filtrate with ethyl acetate, combining organic phases, washing twice, drying and rotary steaming the organic phases, and carrying out acid washing and decoloring to obtain a dark white solid compound of formula 2.
Step two: converting carboxyl in the compound of formula 2 into hydroxyl by a reducing agent to obtain a compound of formula 3;
a reducing agent or combination of reducing agents may be used, such as lithium aluminum hydride, zinc borohydride, ethylborane, sodium borohydride in combination with elemental iodine, sodium borohydride in combination with ethyl chloroformate, sodium borohydride in combination with protonic acid, sodium borohydride in combination with lewis acid, benzyltriethylammonium borohydride in combination with trimethylchlorosilane, sodium borohydride in combination with a carbene condensing agent, lithium borohydride in combination with N, N '-dicyclohexylcarbodiimide, borane bromide in combination with dimethylsulfide, N' -dimethylchloroimine hydrochloride in combination with lithium tri-tert-butoxyaluminum hydride, samarium diiodide in combination with protonic acid, or methylamine in combination with lithium metal;
wherein the protonic acid can be sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid or the like.
Step three: converting the hydroxy group of the compound of formula 3 to an amino group to obtain a compound of formula 4; one of the following three ways may be employed;
the method I comprises the following steps: converting hydroxyl into an azide group, and reducing the azide group to obtain an amino;
converting the hydroxy group to a leaving group (OR) and converting the compound of formula 3 to a compound of formula 3 a; then reacting with an azide reagent, carrying out substitution reaction on a leaving group and an azide group to obtain a compound shown as a formula 3b, and then reducing the azide group to obtain an amino group shown as a formula 4;
wherein R is methylsulfonyl, p-toluenesulfonyl or trifluoromethylsulfonyl;
wherein the azide reagent is sodium azide or diphenyl phosphorazidate; the reducing azide group can be triphenylphosphine, tin dichloride, lithium aluminum hydride, a combination of hydrazine hydrate and raney nickel, or a combination of sodium borohydride and lewis acid.
The second method comprises the following steps: converting hydroxyl into leaving group, and obtaining amino by ammonolysis substitution reaction;
firstly, converting hydroxyl into a leaving group, converting the compound shown in the formula 3 into a compound shown in the formula 3a, and then obtaining amino through aminolysis substitution reaction, namely a compound shown in a formula 4;
wherein R is methylsulfonyl, p-methylbenzenesulfonyl or trifluoromethylsulfonyl;
in certain embodiments of the invention, the leaving group-containing compound of formula 3a is a compound of formula 3a1 or a compound of formula 3a 2;
in this mode, the reagent used for the ammonolysis substitution is ammonia methanol solution or ammonia water.
The third method comprises the following steps: converting hydroxyl into halogen, and obtaining amino through substitution reaction;
converting hydroxyl into halogen, converting the compound shown in the formula 3 into a compound shown in the formula 3c, and then aminolyzing the compound shown in the formula 3 c;
wherein X is a halogen atom; preferably a chlorine atom or a bromine atom; the halogenation condition can adopt a reagent of bromine, chlorine, thionyl chloride, a combination of iodine elementary substance and triphenylphosphine, a combination of carbon tetrachloride and triphenylphosphine, a combination of N-bromosuccinimide and triphenylphosphine or a combination of N-chlorosuccinimide and triphenylphosphine;
in some embodiments of the invention, the ammonolysis process is hydrazinolysis of a compound of formula 3c after reaction with phthalimide methyl salt to give a compound of formula 4; alternatively, in some embodiments of the invention, the ammonolysis process is a substitution reaction of the compound of formula 3c with ammonia methanol to obtain a compound of formula 4; alternatively, in some embodiments of the invention, the aminolysis is performed by reacting the compound of formula 3c with acetamide or tert-butyl carbamate under basic conditions to remove the protecting group from the amino group to give the compound of formula 4.
Among the above synthetic strategies, the second and third modes are preferred.
Step four: condensing the compound of formula 4 with the compound of formula 5 to obtain fluopyram of formula 6, wherein the compound of formula 4: compound of formula 5 =1:0.9-1.2; the condensing agent is N, N ' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (7-azobenzotriazol) -N, N, N ' N ' -tetramethyluronium Hexafluorophosphate (HATU), 1-Hydroxybenzotriazole (HOBT), benzotriazol-N, N, N ' N ' -tetramethyluronium Hexafluorophosphate (HBTU), carbonyldiimidazole (CDI), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP).
In the reaction process, the protonic acid involved in the reaction conversion process can be sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or acetic acid and the like; the Lewis acid involved in the reaction conversion process is boron trifluoride, aluminum trichloride, zinc chloride, ferric trichloride or methyl trifluoromethanesulfonate and the like; the alkali used in the reaction conversion process can be sodium hydride, potassium carbonate, triethylamine, 4-Dimethylaminopyridine (DMAP), n-butyllithium, liHMDS or sodium hydroxide and the like; the solvent used in the reaction conversion process can be water, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, acetone, ethanol, methanol or toluene and the like.
The following describes the scheme of the present invention with reference to the accompanying drawings, wherein experimental methods without specific description of operation steps are all performed according to corresponding commercial specifications, and instruments, reagents and consumables used in the examples can be purchased from commercial companies without specific description.
Example 1
100g of the raw material 1 is placed in 500mL of methanol and stirred, then 100mL of concentrated hydrochloric acid is added, the system is heated and refluxed for 6h, TLC shows that the reaction is complete, the system is placed in an ice water bath for cooling, then 6M sodium hydroxide solution is gradually added, the pH of the system is adjusted to be neutral, then the methanol is removed by a rotary evaporator, 500mL of ethyl acetate is added into the residue for extraction, the extracted organic phase is washed by 500mL of water, then the organic extract phase is collected, and anhydrous sodium sulfate is added for drying overnight. After drying, removing ethyl acetate by using a rotary evaporator to obtain a yellowish dark white solid, namely a crude product of the intermediate 2, without further purification, placing the crude product in 500mL of tetrahydrofuran, stirring, placing the system in an ice-water bath for cooling, gradually dropping 20mL of concentrated sulfuric acid, after dropping, adding 34.5g of sodium borohydride in batches, after adding, continuing to stir for reaction for 3h, and after TLC shows that the reaction is complete, gradually adding 6M sodium hydroxide solution, adjusting the pH of the system to be neutral, removing tetrahydrofuran by using the rotary evaporator, adding 500mL of ethyl acetate into the residue for extraction, washing an extracted organic phase by using 500mL of water, collecting an organic extract phase, adding anhydrous sodium sulfate, and drying overnight. The dried ethyl acetate was removed by rotary evaporator to give a viscous oil which was recrystallized from isopropyl ether/ethanol to give 73.4g of a white solid, intermediate 3, 72% overall yield.
As shown in FIG. 1 for intermediate 3 1 H-NMR spectrum. 1 H-NMR(400MHz,Chloroform-d)δ8.70(s,1H),7.92(s,1H),4.12(t,J＝5.5Hz,1H),3.22(t,J＝5.4Hz,1H)。
Example 2
Weighing 50g of intermediate 3, placing the intermediate 3 in 50mL of tetrahydrofuran, stirring, adding 45g of triethylamine, placing the system in an ice water bath for cooling, gradually dropwise adding 38g of methylsulfonyl chloride, continuing stirring for 1h after dropwise adding is finished, TLC shows that the reaction conversion is complete, adding 50mL of water to quench the reaction, removing the tetrahydrofuran by using a rotary evaporator, adding dichloromethane for extraction, washing an organic extraction phase once by using saturated sodium bicarbonate, collecting an organic phase, adding anhydrous sodium sulfate for drying overnight, after drying is finished, spin-drying a system solvent to obtain a pale yellow oily substance, namely a crude intermediate 3a1, then adding 100mL of 7M ammonia methanol solution, heating at 60 ℃ for reaction until the conversion is complete, then spin-removing methanol, and fully stirring and washing the residue by using petroleum ether to obtain 41.3g of white solid, namely an intermediate 4, wherein the total yield is 83%.
As shown in FIG. 2 for intermediate 4 1 H-NMR spectrum, FIG. 3 isMS spectrum of intermediate 4. 1 H-NMR(600MHz,Deuterium Oxide)δ8.79(s,1H),8.28(s,1H),3.51(t,J＝6.9Hz,1H),3.43(t,J＝6.8Hz,1H).MS：calcd for[C 8 H 8 ClF 3 N 2 ,M+H] + :225.03,Found:225.04。
Example 3
Weighing 50g of intermediate 3, placing the intermediate 3 in 50mL of tetrahydrofuran, stirring, adding 45g of triethylamine, placing the system in an ice water bath for cooling, gradually dropwise adding 38g of methylsulfonyl chloride, continuing stirring for 1h after dropwise adding is finished, TLC shows that reaction conversion is complete, adding 50mL of water to quench the reaction, removing the tetrahydrofuran by using a rotary evaporator, adding dichloromethane for extraction, washing an organic extraction phase once by using saturated sodium bicarbonate, collecting an organic phase, adding anhydrous sodium sulfate for drying overnight, and after drying is finished, spin-drying a system solvent to obtain a pale yellow oily substance, namely a crude intermediate 3a 1. And then adding 100mL of sodium azide, heating to 100 ℃ for reaction for 4 hours after the solution is clear, adding 100mL of water after the system is cooled to room temperature, extracting twice with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and after drying is finished, spin-drying the solvent to obtain brown oily matter, namely a crude intermediate 3b 1. Then 150mL of methanol and 7g of 10% palladium carbon are added to react for 6h under 5bar of hydrogen, after the reaction is finished, the mixture is filtered by using kieselguhr, the methanol is removed by rotation, and the mixture is purified by a silica gel column to obtain 24.1g of white solid, namely the intermediate 4, with the total yield of 48%. 1 H-NMR(600MHz,Deuterium Oxide)δ8.79(s,1H),8.28(s,1H),3.51(t,J＝6.9Hz,1H),3.43(t,J＝6.8Hz,1H).MS：calcd for[C 8 H 8 ClF 3 N 2 ,M+H] + :225.03,Found:225.04。
Example 4
Weighing 50g of intermediate 3, reactingPlacing the mixture into 100mL of dichloromethane, stirring, sequentially adding 59g of N-bromosuccinimide and 87g of triphenylphosphine, stirring the system at room temperature for overnight reaction, detecting by TLC to show that the reaction is complete, filtering and removing insoluble substances after the reaction, then adding 100mL of anhydrous ethanol, stirring and dissolving, then adding 31g of zinc chloride, stirring for 1h, then filtering and removing the insoluble substances, collecting filtrate, removing ethanol by screwing, stirring the residue with N-hexane to obtain light yellow solid powder, namely a crude product of an intermediate 3c1, continuing to place the mixture into 100mL of DMF without further purification, stirring, then adding 42g of phthalimide potassium salt, heating the system to 90 ℃, reacting for 5h, detecting by TLC to show that the reaction is complete, removing DMF, adding ethanol into the residue, stirring and dissolving, then adding 22g of hydrazine hydrate, continuing to react at room temperature for 3h, detecting by TLC to show that the reaction is complete, then selecting a system solvent, adding 100mL of dichloromethane for extraction, then adding 50mL of dichloromethane for washing, collecting an organic extraction phase, drying by anhydrous, drying, removing dichloromethane after drying, purifying to obtain 37g of a white solid, namely an intermediate 4, namely an overnight silica gel column yield, 74 percent. 1 H-NMR(600MHz,Deuterium Oxide)δ8.79(s,1H),8.28(s,1H),3.51(t,J＝6.9Hz,1H),3.43(t,J＝6.8Hz,1H).MS：calcd for[C 8 H 8 ClF 3 N 2 ,M+H] + :225.03,Found:225.04。
Example 5
Weighing 50g of intermediate 3, placing the intermediate 3 in 100mL of dichloromethane, stirring, sequentially adding 59g of N-bromosuccinimide and 87g of triphenylphosphine, stirring the system at room temperature for reacting overnight, detecting by TLC to show complete reaction, filtering and removing insoluble substances after the reaction, adding 100mL of absolute ethyl alcohol, stirring and dissolving, adding 31g of zinc chloride, stirring for 1h, filtering and removing the insoluble substances, collecting filtrate, removing the ethyl alcohol by spinning, stirring the residue with N-hexane to obtain light yellow solid powder, namely the crude intermediate 3c1, adding 100mL of 7M ammonia methanol solution, heating at 60 ℃ for reaction until complete conversion, spinning off the methanol, and removing siliconPurification on a gel column gave 17.2g of a white solid, intermediate 4, in 34% overall yield. 1 H-NMR(600MHz,Deuterium Oxide)δ8.79(s,1H),8.28(s,1H),3.51(t,J＝6.9Hz,1H),3.43(t,J＝6.8Hz,1H).MS：calcd for[C 8 H 8 ClF 3 N 2 ,M+H] + :225.03,Found:225.04。
Example 6
Weighing 50g of intermediate 3, placing the intermediate in 100mL of dichloromethane, stirring, sequentially adding 59g of N-bromosuccinimide and 87g of triphenylphosphine, stirring the system at room temperature for overnight reaction, detecting by TLC to show complete reaction, filtering and removing insoluble substances after the reaction, then adding 100mL of absolute ethyl alcohol, stirring and dissolving, then adding 31g of zinc chloride, stirring for 1h, then filtering and removing the insoluble substances, collecting filtrate, removing the ethyl alcohol by spinning, stirring the remainder with N-hexane to obtain light yellow solid powder, namely a crude product of the intermediate 3c1, then adding 50mL of THF, after complete dissolution, slowly adding the mixture into THF (100 mL) dissolved with 20mL of acetamide and 41mL of pyridine through a constant pressure dropping funnel under ice water bath, transferring the mixture to room temperature for 6h after completion of the dropwise addition reaction, spin-drying the system, then adding 100mL of water, adjusting the pH of the system to 2 by concentrated hydrochloric acid, heating to 110 ℃, and refluxing overnight. After the reaction is finished, the PH value of the system is adjusted to 8-9 by using 1mol/L NaOH solution, the system is extracted three times by using ethyl acetate, washed by water and salt, dried by using anhydrous sodium sulfate, then the ethyl acetate is removed by spinning, and the white solid 10.6g, namely the intermediate 4, is obtained by silica gel column purification, and the total yield is 21%. 1 H-NMR(600MHz,Deuterium Oxide)δ8.79(s,1H),8.28(s,1H),3.51(t,J＝6.9Hz,1H),3.43(t,J＝6.8Hz,1H).MS：calcd for[C 8 H 8 ClF 3 N 2 ,M+H] + :225.03,Found:225.04。
Example 7
Weighing 20g of intermediate 4, placing the intermediate 4 in 100mL of dichloromethane, stirring, sequentially adding 17g of 2-trifluoromethylbenzoic acid, 18g of triethylamine, 26g of EDCI and 11g of DMAP, stirring the system at room temperature for reacting overnight, detecting by TLC to show that the reaction is complete, washing the reaction system by using 1M hydrochloric acid solution, washing by using saturated sodium bicarbonate solution, collecting an organic phase, drying by using anhydrous sodium sulfate overnight, then removing dichloromethane by spinning, recrystallizing by using isopropyl ether to obtain 30g of white solid, namely fluopyram, with the yield of 85%.
As shown in FIGS. 4-6, respectively, of Fluopyram obtained by the preparation 1 H-NMR spectrum, MS spectrum and HPLC spectrum; HPLC 99.3%; 1 H-NMR(400MHz,DMSO-d 6 )δ8.90(s,1H),8.58(t,J＝5.7Hz,1H),8.40(d,J＝2.0Hz,1H),7.72(dd,J＝18.2,7.7Hz,2H),7.62(t,J＝7.6Hz,1H),7.49(d,J＝7.5Hz,1H),3.70(q,J＝6.8Hz,2H),3.23(t,J＝7.0Hz,2H).MS：calcd for[C 16 H 11 ClF 6 N 2 O,M+H] + 397.71, found. The successful synthesis of fluopyram is proved.
The embodiments of the present invention have been described in detail, but the description is only for the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.
Claims (10)
1. The synthesis method of fluopyram is characterized by comprising the following steps: sequentially converting cyano in the compound of the formula 1 into carboxyl, hydroxyl and amino to obtain a compound of a formula 4, and reacting with a compound of a formula 5 to synthesize a compound of a formula 6, namely fluopyram;
2. the method for synthesizing fluopyram according to claim 1, wherein: converting cyano in the compound of formula 1 into carboxyl to obtain a compound of formula 2, and reducing carboxyl in the compound of formula 2 into hydroxyl to obtain a compound of formula 3;
3. the method for synthesizing fluopyram according to claim 2, wherein: the compound of formula 3 may be converted into the compound of formula 4 in the following manner;
converting hydroxyl into an azide group, and reducing the azide group to obtain an amino;
or converting hydroxyl into leaving group, and obtaining amino by ammonolysis substitution reaction;
alternatively, hydroxyl groups are converted to halogens to give amino groups by substitution reactions.
4. The method for synthesizing fluopyram according to claim 3, wherein: converting hydroxyl into an azide group, and reducing the azide group to obtain an amino group, which specifically comprises the following steps:
converting the hydroxy group to a leaving group and converting the compound of formula 3 to a compound of formula 3 a; reacting with an azide reagent, performing substitution reaction on a leaving group and an azide group to obtain a compound shown as a formula 3b, and then reducing the azide group to obtain an amino group shown as a formula 4;
wherein R is methylsulfonyl, p-toluenesulfonyl or trifluoromethylsulfonyl;
preferably, the azidation reagent is sodium azide or diphenylphosphoryl azide;
preferably, the reducing azide group employs triphenylphosphine, tin dichloride, lithium aluminum hydride, hydrazine hydrate in combination with raney nickel or sodium borohydride in combination with a lewis acid.
5. The method for synthesizing fluopyram according to claim 3, wherein: converting hydroxyl into a leaving group, and obtaining amino by using aminolysis substitution reaction, wherein the amino comprises the following specific steps:
converting hydroxyl into leaving group, converting the compound shown in the formula 3 into a compound shown in the formula 3a, and obtaining amino by using ammonolysis substitution reaction, wherein the compound shown in the formula 4 is obtained;
wherein R is methylsulfonyl, p-toluenesulfonyl or trifluoromethylsulfonyl;
preferably, the reagent used for the ammonolysis substitution is ammonia in methanol or ammonia.
6. The method for synthesizing fluopyram according to claim 5, wherein: the compound of formula 3a containing a leaving group is shown as a compound of formula 3a1 or a compound of formula 3a 2;
7. the method for synthesizing fluopyram according to claim 3, wherein: converting hydroxyl into halogen, and obtaining amino through substitution reaction, wherein the amino comprises the following specific steps:
converting the hydroxy group to a halogen, converting the compound of formula 3 to a compound of formula 3c, aminolyzing the compound of formula 3 c;
in the ammonolysis process, the compound shown in the formula 3c reacts with phthalimide methyl salt, and then hydrazinolysis is carried out to obtain a compound shown in the formula 4;
or in the ammonolysis process, the compound shown in the formula 3c and ammonia methanol are subjected to dissolution reaction and substituted to obtain a compound shown in the formula 4;
or, in the ammonolysis process, the compound shown in the formula 3c reacts with acetamide or tert-butyl carbamate under the alkaline condition, and the protecting group on the amino group is removed to obtain the compound shown in the formula 4;
wherein X is a halogen atom; preferably a chlorine atom or a bromine atom;
preferably, the halogenation conditions can employ the reagents bromine, chlorine, thionyl chloride, elemental iodine in combination with triphenylphosphine, carbon tetrachloride in combination with triphenylphosphine, N-bromosuccinimide in combination with triphenylphosphine, or N-chlorosuccinimide in combination with triphenylphosphine.
8. A process for the synthesis of fluopyram according to claims 1-7, which comprises: the reducing agent or the combination of reducing agents used for converting the carboxyl group in the compound of formula 2 into the hydroxyl group in the compound of formula 3 is lithium aluminum hydride, zinc borohydride, ethylborane, the combination of sodium borohydride and elemental iodine, the combination of sodium borohydride and ethyl chloroformate, the combination of sodium borohydride and protonic acid, the combination of sodium borohydride and lewis acid, the combination of benzyltriethylammonium borohydride and trimethylchlorosilane, the combination of sodium borohydride and a captivating agent, the combination of lithium borohydride and N, N '-dicyclohexylcarbodiimide, the combination of bromoborane and dimethylsulfide, the combination of N, N' -dimethylchloroimine hydrochloride and lithium tri-tert-butoxyaluminum hydride, the combination of samarium diiodide and protonic acid, or the combination of methylamine and metallic lithium.
9. A process for the synthesis of fluopyram according to any of claims 1 to 7, wherein: the compound of formula 4 and the compound of formula 5 are condensed to obtain the compound fluopyram of formula 6, and the condensing agent is N, N ' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (7-azobenzotriazol) -N, N, N ' -tetramethyluronium Hexafluorophosphate (HATU), 1-Hydroxybenzotriazole (HOBT), benzotriazol-N, N, N ' -tetramethyluronium Hexafluorophosphate (HBTU), carbonyldiimidazole (CDI), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP).
10. Fluopyram synthesized by the method for synthesizing Fluopyram according to any one of claims 1 to 9.
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