CN114478326A - Synthetic method of saflufenacil key intermediate - Google Patents
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Abstract
The invention belongs to the field of pesticide intermediate synthesis, and particularly relates to a synthetic method of a saflufenacil key intermediate polysubstituted arylamine derived carbamate, which comprises the following specific steps: preparing high-yield and high-selectivity N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide by taking N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide as a raw material in the presence of an additive; and then reacting with chloroformate to obtain the saflufenacil key intermediate. The synthesis method avoids the use of expensive raw materials, the whole route is economical and environment-friendly, and the product yield is high; the selectivity is good, the production of chlorinated isomers is effectively controlled, the product purity is improved, the cost is greatly reduced, and the industrial production of saflufenacil is facilitated.
Description
Technical Field
The invention belongs to the field of pesticide intermediate synthesis, and particularly relates to a synthetic method of a saflufenacil key intermediate polysubstituted arylamine derived carbamate.
Background
Saflufenacil is a protoporphyrinogen oxidase (PPO) inhibitor, belongs to a novel uracil stem and leaf treating agent, has been called as 'a new herbicide developed for more than 20 years by basf' and 'represents a new level for controlling broadleaf weeds'. Firstly, the method can be suitable for various production systems and non-cultivated land, and can be used after or before seedling; secondly, the fertilizer is suitable for more crops, and can be used for more than 30 crops including grains, corns, cotton, rice, sorghum, soybeans, fruit trees and the like; thirdly, the weeding composition has a broad control spectrum, and can control over 90 kinds of broadleaf weeds, including some weeds with resistance to triazine, glyphosate and acetolactate synthase inhibitors; meanwhile, the saflufenacil has the characteristics of quick control effect, long residual effect period and the like.
The main industrial production route of saflufenacil is as follows:
wherein, the carbamate derived from the polysubstituted arylamine is a core intermediate of the route. Patent CN101351443A discloses the condensation and hydrogenation of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (formula D) and N-methyl-N-isopropylaminosulfonamide to produce intermediate N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropylaminosulfonamide (formula B); patent CN101821233A discloses the formation of the corresponding carbamate intermediate (formula C) by carbamation of the compound of formula B; patents CN1989111A and CN101180277A disclose that the compound of formula C undergoes subsequent cyclization and methylation to produce the final product saflufenacil.
At present, the starting material 2-chloro-4-fluoro-5-nitrobenzoyl chloride in the process route mainly has two synthesis routes:
patent CN1344258A discloses that 2-chloro-4-fluorobenzoic acid solid is used as the starting material, but the procurement price of the 2-chloro-4-fluorobenzoic acid industrial product is very expensive, and is increased by 55 ten thousand per ton, which obviously increases the raw pesticide cost of saflufenacil. In addition, in the nitration reaction process, 3-position nitration isomer (formula I') is generated, corresponding impurity removal measures are required for eliminating the isomer, otherwise, the impurity of the final product is easy to exceed the standard.
In patents CN101948390A and WO2018/141642a1, 2-chloro-4-fluorotrichlorotoluene is used as a raw material to prepare 2-chloro-4-fluoro-5-nitrobenzoyl chloride, and the 2-chloro-4-fluoro-5-nitrobenzoyl chloride needs to undergo multi-step reactions such as nitration, hydrolysis, acyl chlorination and the like, so that the safety is poor, the problem of nitration isomers cannot be avoided, and subsequent impurity removal measures are also needed, so that the process complexity is increased, and the cost of industrial raw materials and equipment is also increased.
In order to solve the problem of excessive raw material cost, basf corporation disclosed a method for producing a corresponding arylaminocarboxylate derivative from a non-chlorobenzoic acid derivative as a starting material in patent CN 1989111A. In the method, the arylamine formate derivative is chlorinated through one-step chlorination reaction, and the fluorine-chlorine substituted arylamine formate compound (formula C) is finally generated. The preparation method specifically comprises the steps of condensing 4-fluoro-3-nitrobenzoyl chloride (formula K) and sulfamide, then carrying out hydrogenation and carbamation to generate a carbamate intermediate (formula N), and then carrying out chlorination reaction on the carbamate intermediate and sulfonyl chloride to generate a compound in a formula C. The starting material (formula K) in the process route can be obtained by nitration and acyl chlorination of cheap and easily available p-fluorobenzoic acid, the yield in the nitration process is high, the phenomenon of nitration isomers does not exist, and the process cost is reduced. However, the yield of the chlorinated product generated by chlorination reaction of the carbamate raw material under the sulfonyl chloride condition is 71-75%, and the inventor finds that chlorination selectivity is a problem when sulfonyl chloride is used as a chlorination reagent and a solvent in the reduction process of the synthetic method, and 6-10% of chloro isomer (formula C ') and 2-3% of dichloro impurity (formula C') still exist in the obtained product; therefore, effective impurity removal measures are required in the post-treatment process, which inevitably further reduces the yield of the reaction.
For those skilled in the art, if non-chlorine raw materials are used to reduce the cost of industrial production of saflufenacil, appropriate chlorination routes and schemes are necessary, and thus a method for synthesizing the polysubstituted arylamine derived carbamate with high yield and high selectivity still needs to be developed.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a method for synthesizing a polysubstituted arylamine derived carbamate as a saflufenacil key intermediate.
The technical scheme for solving the technical problems is as follows:
the invention provides a synthetic method of a saflufenacil key intermediate, which is characterized by comprising the following steps of:
(1) reacting N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide serving as a raw material with a chlorinating reagent in the presence of an additive to generate N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide; wherein the additive is a disulfide compound;
(2) reacting N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide with a chloroformate reagent to generate a compound shown in a formula I, namely a target product;
the specific route is as follows:
wherein the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide can be prepared by taking p-fluorobenzoic acid as a starting material and carrying out nitration, acyl chlorination, sulfonylation amination and hydrogenation reaction;
further, the chlorinating agent in the step (1) is selected from NCS, CuCl, HCl and Cl2One or more of hypochlorous acid, carbon subchloride, phosgene, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride, preferably NCS; the molar ratio of the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the chlorinating reagent is 1: 1-4, preferably 1: 2.5-3;
further, R of the disulfide compound in the step (1)1And R2Are the same or different and are each independently selected from alkyl or aryl; the R is1And R2Alkyl of (2)The sum of the numbers of basic carbon atoms is 16 or less;
preferably, the disulfide compound is selected from one or more of dimethyl disulfide, diethyl disulfide, dipropyl disulfide, dibutyl disulfide, diamyl disulfide, dihexyl disulfide, diheptyl disulfide, dioctyl disulfide, dinonyl disulfide, diphenyl disulfide, 4 '-dimethyl diphenyl disulfide, 4' -dichloro diphenyl disulfide, dibenzyl disulfide, difurfuryl disulfide, methylethyl disulfide, methylbenzyl disulfide, dicyclohexyl disulfide, ethylpropyl disulfide or bis (2-ethylhexyl) disulfide;
further, in the step (1), the molar ratio of the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the disulfide compound is 1: 0.5-3, preferably 1: 1.3-1.5;
further, the reaction solvent in the step (1) is one or more selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, NMP, DMSO, toluene, acetonitrile, dichloromethane, dichloroethane, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butanol and water, preferably acetonitrile or dichloromethane;
further, the mass ratio of the reaction solvent to the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide is 1-50: 1;
further, the reaction temperature in the step (1) is 10-40 ℃, and preferably 20-30 ℃;
further, R of the chloroformate reagent in said step (2)3Selected from alkyl or aryl; the R is3The number of carbon atoms of the alkyl group of (2) is 10 or less;
preferably, the chloroformate reagent is selected from methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, isoamyl chloroformate, or phenyl chloroformate;
further, in the step (2), the molar ratio of the N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the chloroformate reagent is 1: 0.9-2, and preferably 1: 1.3;
further, the step (2) also comprises adding an acid binding agent; the acid-binding agent is one or more of pyridine, 2, 6-lutidine, N-diisopropylethylamine, triethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate or sodium hydroxide, and pyridine is preferred;
further, in the step (2), under the condition of heating and temperature rise, no acid-binding agent is added;
further, the reaction temperature in the step (2) is 0-150 ℃, and preferably 0-100 ℃;
further, the molar ratio of the N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the acid-binding agent in the step (2) is 1: 0-2, and preferably 1: 1.3.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The invention has the beneficial effects that:
the invention adopts a non-chlorine raw material N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide, and can realize the preparation of the N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide with high yield and high selectivity under mild conditions in the presence of an additive; and then reacting with chloroformate to obtain the saflufenacil key intermediate. Wherein, the non-chlorine raw material can be prepared from p-fluorobenzoic acid in advance, thus avoiding the use of expensive raw materials of 2-chloro-4-fluorobenzoic acid and 2-chloro-4-fluorotoluene in the existing route. The whole route is economic and environment-friendly, and the product yield is high; the selectivity is good, the production of chlorinated isomers is effectively controlled, the product purity is improved, the cost is greatly reduced, and the industrial production of saflufenacil is facilitated.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1: synthesis of selective chlorination reaction starting material
(1) Synthesis of N- (3-nitro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
Adding N-methyl-N-isopropylaminosulfonamide (16.74g, 0.11mol), dimethylaminopyridine (72.0mg, 0.6mmol) as a catalyst and triethylamine (24.5g, 0.24mol) as an acid-binding agent into 60ml of toluene, stirring to dissolve, heating to 70 ℃, dropwise adding a toluene solution of 3-nitro-4-fluorobenzoyl chloride (20.4g, 0.10mol) into the reaction system under a nitrogen atmosphere, dropwise adding for 1h, cooling the suspension to room temperature after the dropwise adding is finished, and continuously stirring for 2 h. The mixture was acidified and stirred for 1 hour by adding concentrated hydrochloric acid, the precipitated salts were filtered off, washed once with 1N HCl solution and the wet solid obtained was recrystallized by adding 50g of chlorobenzene. Finally, filtration and drying under reduced pressure gave 27.5g of the title compound in the form of yellow crystals in a yield of 86% and a HPLC purity of 98%,1H-NMR(500MHz,DMSO-d6)δ12.3(br.s.,NH),8.85(d,Ar-H),8.40-8.45(m,Ar-H), 7.75(t,Ar-H),4.25(sept.,CH(CH3)2),2.95(s,CH3),1.15(d,CH(CH3)2)。
(2) synthesis of N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
Adding N- (3-nitro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide (16.5g, 51.7mmol) and 0.5g of 1% Pt/C catalyst solid into a hydrogenation reaction kettle, then adding 100mL of methanol, replacing with nitrogen three times, maintaining the hydrogenation pressure of the system at 2MPa, heating to 50 ℃ for reaction for 6h, and removing residual hydrogen by using nitrogen. The reaction mixture was filtered through silica gel with suction and the filtrate was concentrated under reduced pressure, and the solid product was dried to give 14.4g of the target compound in 96% yield and 98% purity by HPLC.
Example 2: synthesis of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
Adding N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropyl sulfonamide (2.89g,10mmol,1.0 eq) and N-chlorosuccinimide (4.05g, 30mmol, 3.0eq) into a reaction bottle, adding 100mL of acetonitrile, dissolving and stirring for 30 min; dimethyl disulfide (1.22g, 13.0mmol, 1.3eq) was added at room temperature at 25 ℃ under nitrogen. And (3) stirring the generated product at room temperature under the nitrogen atmosphere for reaction for 0.5-1 h (monitoring by LC), after the reaction is basically completed, performing negative pressure desolventizing and concentrating, and performing column chromatography (PE: EA is 1:2) on residual liquid to obtain 2.90g of a target compound with a melting point of 160-162 ℃, wherein the product is a light yellow solid, the yield is 87%, and the HPLC purity is 97%.
Example 3: synthesis of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
Adding N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropyl sulfonamide (2.89g,10mmol,1.0 eq) and N-chlorosuccinimide (4.05g, 30mmol, 3.0eq) into a reaction bottle, adding 100mL of dichloromethane, dissolving and stirring for 30 min; dimethyl disulfide (1.22g, 13.0mmol, 1.3eq) was added at room temperature at 25 ℃ under nitrogen. Stirring the generated product at room temperature in a nitrogen atmosphere for reaction for 0.5-1 h (LC monitoring), after the reaction is basically completed, performing negative pressure desolventizing concentration, performing column chromatography (PE: EA: 1:2) on residual liquid to obtain 2.87g of a target compound with a melting point of 160-162 ℃, wherein the product is a light yellow solid, the yield is 85%, the HPLC purity is 96%,1H-NMR(400MHz,DMSO-d6)δ11.91(br s,1H),7.26(d,J＝8.0 Hz,1H),6.85(d,J＝8.0Hz,1H),5.60(s,2H),4.10-4.06(m,1H),2.81(s,3H),1.12(d,J＝8.0Hz, 6H)。
example 4: synthesis of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
Adding N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropyl sulfonamide (2.89g,10mmol,1.0 eq) and N-chlorosuccinimide (3.38g, 25mmol, 2.5eq) into a reaction bottle, adding 100mL of acetonitrile, dissolving and stirring for 30 min; dimethyl disulfide (1.22g, 13.0mmol, 1.3eq) was added at room temperature at 25 ℃ under nitrogen. And (3) stirring the generated product in a nitrogen atmosphere at room temperature for reaction for 0.5-1 h (LC monitoring), after the reaction is basically completed, performing negative pressure desolventizing concentration, and performing column chromatography on residual liquid (PE: EA: 1:2) to obtain 2.87g of a target compound with a melting point of 160-162 ℃, wherein the product is a light yellow solid, the yield is 86% and the HPLC purity is 97%.
Example 5: synthesis of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
Adding N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropyl sulfonamide (2.89g,10mmol,1.0 eq) and N-chlorosuccinimide (4.05g, 30mmol, 3.0eq) into a reaction bottle, adding 100mL of acetonitrile, dissolving and stirring for 30 min; dimethyl disulfide (1.41g, 15.0mmol, 1.5eq) was added at room temperature 25 ℃ under nitrogen. And (3) stirring the generated product at room temperature under the nitrogen atmosphere for reaction for 0.5-1 h (LC monitoring), after the reaction is basically completed, performing negative pressure desolventizing and concentrating, and performing column chromatography (PE: EA: 1:2) on residual liquid to obtain 2.81g of a target compound with a melting point of 160-162 ℃, wherein the product is a light yellow solid, the yield is 85%, and the HPLC purity is 98%.
Example 6: synthesis of N- { 2-chloro-4-fluoro-5- [ (methoxycarbonyl) amino ] benzoyl } -N '-methyl-N' -isopropylsulfonamide
Pyridine (3.18g, 40.2mmol) was added dropwise to a solution of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropylsulfonamide (10.0g, 30.9mmol) in 100mL of dichloromethane at room temperature at 25 deg.C, followed by cooling the mixture. Methyl chloroformate (3.80g, 40.2mmol) was added dropwise to the reaction system at a temperature of 0 to 5 ℃ and the mixture was stirred for 60 minutes. The reaction mixture was poured into 100mL of water, the organic phase was separated by extraction, and the dichloromethane organic phase was washed with 10% dilute hydrochloric acid and water to remove the organic phase. Then, negative pressure desolventizing is carried out, the solid is dried to obtain 11.56g of target compound, the yield is 98 percent, the HPLC purity is 98 percent,1H-NMR(400MHz,DMSO-d6)δ11.90(s,1H),9.58(s,1H),8.24(d,J＝8.0Hz,1H), 7.37(m,1H),4.33-4.27(m,1H),3.70(s,3H),2.83(s,3H),1.08(d,J＝4.0Hz,6H)。
example 7: synthesis of N- { 2-chloro-4-fluoro-5- [ (ethoxycarbonyl) amino ] benzoyl } -N '-methyl-N' -isopropylsulfonamide
Pyridine (3.18g, 40.2mmol) was added dropwise to a solution of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropylsulfonamide (10.0g, 30.9mmol) in 100mL of dichloromethane at room temperature at 25 deg.C, followed by cooling the mixture. Ethyl chloroformate (4.36g, 40.2mmol) was added dropwise to the reaction system at a temperature of 0 to 5 ℃ and the mixture was stirred for 60 minutes. The reaction mixture was poured into 100mL of water, the organic phase was separated by extraction, and the dichloromethane organic phase was washed with 10% dilute hydrochloric acid and water to remove the organic phase. Subsequently, desolventizing under negative pressure and drying the solid to obtain 11.86g of the target compound, the yield is 97 percent and the HPLC purity is 98 percent.
Example 8: synthesis of 2-chloro-5- [3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1- (2H) -pyrimidinyl ] -4-fluoro-N- { [ methyl- (1-methylethyl) amino ] sulfonyl } benzamide
N- { 2-chloro-4-fluoro-5- [ (ethoxycarbonyl) amino group was reacted at room temperature]Benzoyl } -N '-methyl-N' -isopropylamide (39.6g, 0.10mol) was dissolved in 200g of DMF and ethyl 3-amino-4, 4, 4-trifluoro-2-butenoate (18.9g, 0.10mol) was added, and the temperature was raised with stirring. Dropwise adding (37.8g, 0.21mol) sodium methoxide solution at 110-120 ℃, slowly dropwise adding for 3-4 h, and evaporating a low-boiling methanol-ethanol mixture during the dropwise adding. Stirring the mixture for another 30min, cooling to room temperature, adding dilute sulfuric acid water solution into the reaction system, and adjusting pH of the reaction mixture<2, a solid precipitate was found in the process. The solid was filtered off, washed with water and then dried to yield 43.8g of whiteThe yield of the target compound is 90 percent, the HPLC purity is 97 percent,1H-NMR(400MHz, DMSO-d6)δ12.00(s,1H),8.08(m,2H),7.56(t,J＝8.0Hz,1H),6.44(s,1H),4.15(m,1H),2.84 (s,3H),1.10(d,J＝8.0Hz,6H)。
example 9: synthesis of 2-chloro-5- [3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1- (2H) -pyrimidinyl ] -4-fluoro-N- { [ methyl- (1-methylethyl) amino ] sulfonyl } benzamide
N- { 2-chloro-4-fluoro-5- [ (methoxycarbonyl) amino ] benzoyl } -N '-methyl-N' -isopropylsulfonamide (38.1g, 0.10mol) was dissolved in 200g of DMF at room temperature and ethyl 3-amino-4, 4, 4-trifluoro-2-butenoate (18.9g, 0.10mol) was added, and the temperature was raised with stirring. Dropwise adding (37.8g, 0.21mol) sodium methoxide solution at 110-120 ℃, slowly dropwise adding for 3-4 h, and evaporating a low-boiling methanol-ethanol mixture during the dropwise adding. Stirring the mixture for another 30min, cooling to room temperature, adding dilute hydrochloric acid water solution into the reaction system, adjusting pH of the reaction mixture to be less than 2, gradually finding solid precipitate in the process, and stirring at room temperature for 30 min. The solid was filtered off, washed 3 times with water and then dried to give 43.3g of off-white target compound in 89% yield, 97% HPLC purity and 228-229 ℃.
Example 10: synthesis of saflufenacil
38mL of toluene, 15mL of tetrahydrofuran and 23mL of water were first added to a four-necked flask, the solvent was stirred well, and then 2-chloro-5- [3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1- (2H) -pyrimidyl with a purity of 97% was added at 25 deg.C]-4-fluoro-N- { [ methyl- (1-methylethyl) amino]Sulfonyl benzamide (10.0g, 19.9mmol), tetrabutylammonium bromide (0.625g, 1.94mmol) and dimethyl sulfate (3.40g, 26.9mmol) were added successively to the mixed solvent, and the mixture was heated to 38-42 ℃. Then, the pH of the reaction mixture is controlled to be 4-5 by adding 10% NaOH aqueous solution, the reaction mixture is continuously stirred for 1 hour at the temperature of 38-42 ℃, and the 10% NaOH aqueous solution is continuously dripped in the processAnd controlling the pH value of the reaction to be kept at 4-5, and controlling by TLC until the reaction is finished. After the reaction is complete, the extraction is separated, the organic phase is washed twice with water, the organic phase is dried and part of the solvent is then removed. The reaction liquid is cooled and crystallized, filtered, washed by a small amount of cold toluene and dried to obtain 8.68g of the saflufenacil product of the target compound, the yield is 85 percent, the HPLC purity is 97.5 percent,1H-NMR(400MHz, DMSO-d6)δ12.03(s,1H),8.02(d,J＝7.2Hz,1H),7.54(t,J＝7.2Hz,1H),6.59(s,1H),4.11(m, 1H),3.43(s,3H),2.80(s,3H),1.08(d,J＝6.8Hz,6H)。
comparative example 1: synthesis of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
Adding N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropyl sulfonamide (2.89g,10mmol,1.0 eq) and N-chlorosuccinimide (4.05g, 30mmol, 3.0eq) into a reaction bottle, adding 100mL of acetonitrile, dissolving and stirring for 30 min; stirring and reacting for 0.5-1 h (LC monitoring) at room temperature of 25 ℃ and at room temperature of 25 ℃ in nitrogen atmosphere, wherein the reaction is basically not converted, a large amount of raw materials are remained, the reaction is subjected to negative pressure desolventizing and concentrating, the product conversion rate is less than 3%, and the product is not subjected to post-treatment.
Comparative example 2: synthesis of N- { 2-chloro-4-fluoro-5- [ (methoxycarbonyl) amino ] benzoyl } -N '-methyl-N' -isopropylsulfonamide
NaH (0.96g, 40.2mmol) was added dropwise to a solution of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropylsulfonamide (10.0g, 30.9mmol) in 100mL of dichloromethane at room temperature at 25 deg.C, followed by cooling the mixture. Methyl chloroformate (3.80g, 40.2mmol) was added dropwise to the reaction system at a temperature of 0 to 5 ℃ and the mixture was stirred for 60 minutes. The reaction mixture was poured into 100mL of water, the organic phase was separated by extraction, and the dichloromethane organic phase was washed with 10% dilute hydrochloric acid and water to remove the organic phase. Subsequently, desolventizing under negative pressure, and drying the solid to obtain 10.24g of the target compound, the yield is 86.8%, and the HPLC purity is 95%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A synthetic method of a saflufenacil key intermediate is characterized by comprising the following steps:
(1) reacting N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide serving as a raw material with a chlorinating reagent in the presence of an additive to generate N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide; wherein the additive is a disulfide compound;
(2) reacting N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide with a chloroformate reagent to generate a compound shown in a formula I, namely a target product;
the specific reaction route is as follows:
2. the synthesis process according to claim 1, wherein the chlorinating reagent in step (1) is selected from NCS, CuCl, HCl, Cl2One or more of hypochlorous acid, carbon subchloride, phosgene, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride; the molar ratio of the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the chlorinating reagent is 1: 1-4.
3. The method according to claim 1, wherein R in the disulfide compound in the step (1) is R1And R2Are the same or different and are each independently selected from alkyl or aryl; the R is1And R2The sum of the carbon atoms of the alkyl group(s) is 16 or less.
4. The synthesis method according to claim 1, wherein the molar ratio of the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the disulfide compound in the step (1) is 1: 0.5-3.
5. The synthesis method according to claim 1, wherein the reaction solvent in step (1) is one or more selected from the group consisting of N, N-dimethylacetamide, N-dimethylformamide, NMP, DMSO, toluene, acetonitrile, dichloromethane, dichloroethane, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butanol and water; the mass ratio of the reaction solvent to the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide is 1-50: 1.
6. The synthesis method according to claim 1, wherein the reaction temperature in the step (1) is 10-40 ℃.
7. The method of synthesizing of claim 1 wherein said R of the chloroformate reagent of step (2)3Selected from alkyl or aryl; the R is3The number of carbon atoms of the alkyl group (2) is 10 or less.
8. The synthesis method according to claim 1, wherein the molar ratio of the N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the chloroformate reagent in the step (2) is 1: 0.9-2.
9. The method of claim 1, wherein step (2) further comprises adding an acid scavenger; the acid-binding agent is one or more of pyridine, 2, 6-lutidine, N-diisopropylethylamine, triethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate or sodium hydroxide.
10. The synthesis method according to claim 9, wherein the molar ratio of the N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the acid-binding agent in the step (2) is 1: 0-2.
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