CN114478326B - Synthesis method of saflufenacil key intermediate - Google Patents
Synthesis method of saflufenacil key intermediate Download PDFInfo
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Abstract
The invention belongs to the field of pesticide intermediate synthesis, and in particular relates to a synthesis method of carbamate derived from polysubstituted aromatic amine serving as a key intermediate of saflufenacil, which comprises the following specific steps: n- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide is taken as a raw material, and N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide with high yield and high selectivity is prepared in the presence of an additive; and then reacts with chloroformate to obtain the saflufenacil key intermediate. The synthesis method avoids the use of expensive raw materials, the whole route is economic and environment-friendly, and the product yield is high; the selectivity is good, the generation of chlorinated isomer is effectively controlled, the purity of the product is improved, the cost is greatly reduced, and the method is more beneficial to the industrial production of saflufenacil.
Description
Technical Field
The invention belongs to the field of pesticide intermediate synthesis, and in particular relates to a synthesis method of carbamate derived from a polysubstituted aromatic amine serving as a key intermediate of saflufenacil.
Background
Saflufenacil is a protoporphyrinogen oxidase (PPO) inhibitor, belongs to a novel uracil stem and leaf treatment agent, and has been called by basf as "new herbicide developed most successfully over 20 years", "representing a new level of broadleaf weed control". Firstly, the novel cultivation method can be suitable for various production systems and non-cultivated lands, and can be used after or before seedling emergence; secondly, the plant is suitable for more than 30 crops including grains, corns, cottons, paddy rice, sorghum, soybeans, fruit trees and the like; again, the broad spectrum control is able to control over 90 broad leaved weeds, including some weeds that are resistant to triazines, glyphosate and acetolactate synthase inhibitors; meanwhile, the saflufenacil has various characteristics of quick control effect, long residual effect period and the like.
The main industrial production route of saflufenacil is as follows:
wherein the polysubstituted aromatic amine derived carbamate is a core intermediate of this route. Patent CN101351443a discloses the formation of an intermediate N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropylsulfonamide (formula B) by condensation and hydrogenation of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (formula D) and N-methyl-N-isopropylsulfamide; patent CN101821233a discloses that the compound of formula B is urethanized to the corresponding carbamate intermediate (formula C); patent CN1989111A, CN101180277a discloses that the compound of formula C is subjected to subsequent cyclization and methylation reactions to produce the final pesticide saflufenacil.
Currently, there are two main synthetic routes for the starting material 2-chloro-4-fluoro-5-nitrobenzoyl chloride in the above process route:
patent CN1344258A discloses that 2-chloro-4-fluorobenzoic acid solid is used as a starting material, but the purchase price of 2-chloro-4-fluorobenzoic acid industrial products is very expensive, the price of polling is 55 ten thousand per ton, which obviously increases the original drug cost of saflufenacil. In addition, in the nitration reaction process, a 3-position nitrated isomer (formula I') is generated, and corresponding impurity removal measures are needed to eliminate the isomer, otherwise, impurities of the final product are easy to exceed standards.
The patent CN101948390A and the patent WO2018/141642A1 adopt 2-chloro-4-fluorotrichlorotoluene as raw materials to prepare 2-chloro-4-fluoro-5-nitrobenzoyl chloride, which needs to undergo multi-step reactions such as nitration, hydrolysis, acyl chlorination and the like, has poor safety, cannot avoid the problem of nitrated isomers, also needs subsequent impurity removal measures, improves the process complexity and also increases the cost of industrialized raw materials and equipment.
In order to solve the problem of excessive raw material cost, basf corporation disclosed a method of producing the corresponding aromatic urethane derivative using a non-chlorobenzoic acid derivative as a starting material in patent CN1989111 a. In the method, the aryl carbamate derivative is subjected to chlorination by one-step chlorination reaction, and finally the fluorine-chlorine substituted aryl carbamate compound (formula C) is generated. Specifically, 4-fluoro-3-nitrobenzoyl chloride (formula K) is condensed with sulfonamide, then hydrogenated and urethanized to generate a carbamate intermediate (formula N), and then chloridized with sulfonyl chloride to generate a compound of formula C. The initial raw material (formula K) in the process route can be obtained by nitrifying and acyl chloridizing p-fluorobenzoic acid which is low in cost and easy to obtain, the yield of the nitrifying process is high, the phenomenon of nitrifying isomers does not exist, and the process cost is reduced. However, the yield of the chlorination product generated by the chlorination reaction of the carbamate raw material under the condition of sulfonyl chloride is between 71 and 75 percent, and the inventor discovers that the chlorination selectivity problem exists when sulfonyl chloride is adopted as a chlorinating agent and a solvent in the process of reducing the synthesis method, and the obtained product still has 6 to 10 percent of chloro isomer (formula C ') and 2 to 3 percent of dichloro impurity (formula C'); effective impurity removal measures are required in the post-treatment process, which inevitably further reduces the reaction yield.
For those skilled in the art, if non-chlorine raw materials are used to reduce the industrial production cost of saflufenacil, proper chlorination route and scheme must be supported, so a method for synthesizing multi-substituted aromatic amine 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 synthesis method of a multi-substituted aromatic amine derived carbamate serving as a key intermediate of saflufenacil.
The technical scheme for solving the technical problems is as follows:
the invention provides a method for synthesizing a key intermediate of saflufenacil, which is characterized by comprising the following steps:
(1) Reacting N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide 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 N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide can be prepared from p-fluorobenzoic acid serving as a starting material through nitration, acyl chlorination, sulfonamide and hydrogenation reactions;
further, the chlorinating agent in the step (1) is selected from NCS, cuCl, HCl, cl 2 One 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 agent is 1:1-4, preferably 1:2.5-3;
further, R in the disulfide compound in the step (1) 1 And R is 2 Identical or different and are each independently selected from alkyl or aryl; the R is 1 And R is 2 The sum of the number of carbon atoms of the alkyl groups is 16 or less;
preferably, the disulfide compound is selected from one or more of dimethyl disulfide, diethyl disulfide, dipropyl disulfide, dibutyl disulfide, dipentyl 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 di (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 selected from one or more of N, N-dimethylacetamide, N-dimethylformamide, NMP, DMSO, toluene, acetonitrile, dichloromethane, dichloroethane, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tertiary butanol or 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 ℃, preferably 20-30 ℃;
further, R of the chloroformate reagent in the step (2) 3 Selected from alkyl or aryl; the R is 3 The number of carbon atoms of the alkyl group 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, 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, preferably 1:1.3;
further, the step (2) further 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, preferably pyridine;
furthermore, the step (2) can be carried out without adding an acid binding agent under the condition of heating;
further, the reaction temperature in the step (2) is 0-150 ℃, preferably 0-100 ℃;
further, the molar ratio of 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, preferably 1:1.3.
The Chinese naming of the compound in the invention conflicts with the structural formula, and the structural formula is taken as the reference; except for obvious structural errors.
The invention has the beneficial effects that:
according to the invention, a non-chlorine raw material N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide is adopted, and in the presence of an additive, the preparation of high-yield and high-selectivity N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide under a mild condition can be realized; and then reacts with chloroformate to obtain the saflufenacil key intermediate. Wherein, the non-chlorine raw material can be prepared from p-fluorobenzoic acid in advance, avoiding the use of expensive raw materials of 2-chloro-4-fluorobenzoic acid and 2-chloro-4-fluorobenzene in the existing route. The whole route is economic and environment-friendly, and the product yield is high; the selectivity is good, the generation of chlorinated isomer is effectively controlled, the purity of the product is improved, the cost is greatly reduced, and the method is more beneficial to the industrial production of saflufenacil.
Detailed Description
The invention is illustrated but not limited by the following examples. Simple alternatives and modifications of the invention will be apparent to those skilled in the art and are within the scope of the invention as defined by the appended claims.
Example 1: synthesis of raw materials for selective chlorination reaction
(1) Synthesis of N- (3-nitro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
N-methyl-N-isopropyl amino sulfonamide (16.74 g,0.11 mol), catalyst dimethylaminopyridine (72.0 mg,0.6 mmol) and acid-binding agent triethylamine (24.5 g,0.24 mol) were added to 60ml of toluene, the mixture was stirred and dissolved, the temperature was raised to 70℃and a toluene solution of 3-nitro-4-fluorobenzoyl chloride (20.4 g,0.10 mol) was added dropwise to the reaction system under nitrogen atmosphere for 1 hour, and after the addition, the suspension was cooled to room temperature and stirred for 2 hours. The mixture was acidified by addition of concentrated hydrochloric acid and stirred for 1 hour, the precipitated salts were filtered, washed once with 1N HCl solution and the resulting wet solid was recrystallized from 50g chlorobenzene. Finally, filtration and drying under reduced pressure gave 27.5g of the targetThe compound, the product is yellow crystal, the yield is 86%, the HPLC purity is 98%, 1 H-NMR(500MHz,DMSO-d 6 )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(CH 3 ) 2 ),2.95(s,CH 3 ),1.15(d,CH(CH 3 ) 2 )。
(2) Synthesis of N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide
N- (3-nitro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide (16.5 g,51.7 mmol) and 0.5g of 1% Pt/C catalyst solid were added to a hydrogenation reactor, then 100mL of methanol was added and replaced three times with nitrogen, the hydrogenation pressure of the system was maintained at 2MPa, and the temperature was raised to 50℃for 6 hours to drive out the remaining hydrogen with nitrogen. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure, and the solid product was dried to finally give 14.4g of the objective 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
N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropylsulfonamide (2.89 g,10mmol,1.0 eq) and N-chlorosuccinimide (4.05 g,30mmol,3.0 eq) were added to the reaction flask, and then 100mL of acetonitrile was added thereto for dissolution and stirring for 30min; dimethyl disulfide (1.22 g,13.0mmol,1.3 eq) was added under nitrogen at room temperature 25 ℃. After the generated product is stirred and reacted for 0.5 to 1 hour (LC monitoring) at room temperature under the nitrogen atmosphere, the reaction is basically converted, the reaction is carried out under negative pressure, the solution is removed and concentrated, and the residual liquid is subjected to column chromatography (PE: EA=1:2) to obtain 2.90g of target compound with the melting point of 160 to 162 ℃, wherein the product is a pale 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
N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropylsulfonamide (2.89 g,10mmol,1.0 eq) and N-chlorosuccinimide (4.05 g,30mmol,3.0 eq) were added to the reaction flask, and then 100mL of methylene chloride was added thereto for dissolution and stirring for 30min; dimethyl disulfide (1.22 g,13.0mmol,1.3 eq) was added under nitrogen at room temperature 25 ℃. Stirring the generated product at room temperature under nitrogen atmosphere for reaction for 0.5-1 h (LC monitoring), after the reaction is basically converted, carrying out negative pressure desolventizing and concentrating, adopting column chromatography (PE: EA=1:2) to obtain 2.87g of target compound with the melting point of 160-162 ℃, obtaining the product which is a pale yellow solid with the yield of 85 percent and the HPLC purity of 96 percent, 1 H-NMR(400MHz,DMSO-d 6 )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
N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropyl sulfonamide (2.89g,10mmol,1.0 eq) and N-chlorosuccinimide (3.38 g,25mmol,2.5 eq) were added to the reaction flask, and then 100mL of acetonitrile was added thereto for dissolution and stirring for 30min; dimethyl disulfide (1.22 g,13.0mmol,1.3 eq) was added under nitrogen at room temperature 25 ℃. After the generated product is stirred and reacted for 0.5 to 1 hour (LC monitoring) at room temperature under the nitrogen atmosphere, the reaction is basically converted, the reaction is carried out under negative pressure, the solution is removed and concentrated, and the residual liquid is subjected to column chromatography (PE: EA=1:2) to obtain 2.87g of target compound with the melting point of 160 to 162 ℃, wherein the product is a pale 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
N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropylsulfonamide (2.89 g,10mmol,1.0 eq) and N-chlorosuccinimide (4.05 g,30mmol,3.0 eq) were added to the reaction flask, and then 100mL of acetonitrile was added thereto for dissolution and stirring for 30min; dimethyl disulfide (1.41 g,15.0mmol,1.5 eq) was added under nitrogen at room temperature 25 ℃. After the generated product is stirred and reacted for 0.5 to 1 hour (LC monitoring) at room temperature under the nitrogen atmosphere, the reaction is basically converted, the reaction is carried out under negative pressure, the solution is removed and concentrated, and the residual liquid is subjected to column chromatography (PE: EA=1:2) to obtain 2.81g of target compound with the melting point of 160 to 162 ℃, wherein the product is a pale 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' -isopropyl-sulfonamide
Pyridine (3.18 g,40.2 mmol) was added dropwise to a solution of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropylsulfonamide (10.0 g,30.9 mmol) in 100mL of dichloromethane at room temperature 25℃and the mixture was subsequently cooled. Methyl chloroformate (3.80 g,40.2 mmol) 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 removed from the organic phase with 10% diluted hydrochloric acid and water. Then, desolventizing under negative pressure, drying the solid to obtain 11.56g of the target compound, with 98% yield and 98% HPLC purity, 1 H-NMR(400MHz,DMSO-d 6 )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' -isopropyl-sulfonamide
Pyridine (3.18 g,40.2 mmol) was added dropwise to a solution of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropylsulfonamide (10.0 g,30.9 mmol) in 100mL of dichloromethane at room temperature 25℃and the mixture was subsequently cooled. Ethyl chloroformate (4.36 g,40.2 mmol) 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 removed from the organic phase with 10% diluted hydrochloric acid and water. Subsequently, desolventizing under negative pressure, drying the solid gave 11.86g of the target compound in 97% yield and 98% purity by HPLC.
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 ] sulphonyl } benzamide
N- { 2-chloro-4-fluoro-5- [ (ethoxycarbonyl) amino group at room temperature]Benzoyl } -N '-methyl-N' -isopropyl sulfonamide (39.6 g,0.10 mol) was dissolved in 200g DMF and ethyl 3-amino-4, 4-trifluoro-2-butenoate (18.9 g,0.10 mol) was added thereto, followed by stirring and heating. A solution of sodium methoxide (37.8 g,0.21 mol) was added dropwise at 110-120℃slowly over a period of 3-4 hours, during which time the low-boiling methanol and ethanol mixture was distilled off. Stirring the mixture for 30min, cooling to room temperature, adding dilute sulfuric acid water solution into the reaction system, and regulating 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 give 43.8g of the title compound in 90% yield with 97% purity by HPLC, 1 H-NMR(400MHz, DMSO-d 6 )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 ] sulphonyl } benzamide
N- { 2-chloro-4-fluoro-5- [ (methoxycarbonyl) amino ] benzoyl } -N '-methyl-N' -isopropylsulfonamide (38.1 g,0.10 mol) was dissolved in 200g of DMF at room temperature and ethyl 3-amino-4, 4-trifluoro-2-butenoate (18.9 g,0.10 mol) was added thereto with stirring and heated. A solution of sodium methoxide (37.8 g,0.21 mol) was added dropwise at 110-120℃slowly over a period of 3-4 hours, during which time the low-boiling methanol and ethanol mixture was distilled off. The mixture was stirred for another 30min, cooled to room temperature, diluted aqueous hydrochloric acid was added to the reaction system, the pH of the reaction mixture was adjusted to <2, and during this time, a solid precipitate was found to gradually precipitate, and stirred for 30min at room temperature. The solid was filtered off, washed 3 times with water and then dried to give 43.3g of the title compound as off-white in 89% yield with 97% HPLC purity and melting point 228-229 ℃.
Example 10: synthesis of saflufenacil
First, 38mL of toluene, 15mL of tetrahydrofuran and 23mL of water were added to a four-necked flask, and the solvent was stirred uniformly, and then 2-chloro-5- [3, 6-dihydro-3-methyl-2, 6-dioxo-4- (trifluoromethyl) -1- (2H) -pyrimidinyl having a purity of 97% was stirred at 25 ℃]-4-fluoro-N- { [ methyl- (1-methylethyl) amino group]Sulfonyl } benzamide (10.0 g,19.9 mmol), tetrabutylammonium bromide (0.625 g, 1.94 mmol), and dimethyl sulfate (3.40 g,26.9 mmol) were added sequentially 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 38-42 ℃, the pH of the reaction is controlled to be 4-5 by continuously dripping 10% NaOH aqueous solution in the process, and the TLC is controlled until the reaction is finished. After the reaction was completed, the organic phase was washed twice with water, dried, and then a part of the solvent was removed. Cooling the reaction solution for crystallization, filtering, washing with a small amount of cold toluene, drying to obtain 8.68g of the target compound saflufenacil product, the yield is 85%, the HPLC purity is 97.5%, 1 H-NMR(400MHz, DMSO-d 6 )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
N- (4-fluoro-3-aminobenzoyl) -N '-methyl-N' -isopropylsulfonamide (2.89 g,10mmol,1.0 eq) and N-chlorosuccinimide (4.05 g,30mmol,3.0 eq) were added to the reaction flask, and then 100mL of acetonitrile was added thereto for dissolution and stirring for 30min; stirring and reacting at room temperature of 25 ℃ for 0.5-1 h (LC monitoring) under the nitrogen atmosphere at room temperature of 25 ℃, wherein the reaction is basically unconverted, a large amount of raw materials remain, the negative pressure desolventizing and concentrating are carried out, the product conversion rate is less than 3%, and no post treatment is carried out.
Comparative example 2: synthesis of N- { 2-chloro-4-fluoro-5- [ (methoxycarbonyl) amino ] benzoyl } -N '-methyl-N' -isopropyl-sulfonamide
NaH (0.96 g,40.2 mmol) was added dropwise to a solution of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropylsulfonamide (10.0 g,30.9 mmol) in 100mL of dichloromethane at 25℃and the mixture was subsequently cooled. Methyl chloroformate (3.80 g,40.2 mmol) 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 removed from the organic phase with 10% diluted hydrochloric acid and water. Subsequently, desolventizing under negative pressure, drying the solid gave 10.24g of the target compound in 86.8% yield and 95% purity by HPLC.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.
Claims (6)
1. The synthesis method of the saflufenacil key intermediate is characterized by comprising the following specific reaction steps:
the method comprises the following steps:
(1) Reacting N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide 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 dimethyl disulfide; the chlorinating agent in step (1) is selected from NCS; the molar ratio of the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to the chlorinating agent is 1:1-4; the reaction temperature of the step (1) is 10-40 ℃;
(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; r of chloroformate reagent in the step (2) 3 Selected from alkyl or aryl; the R is 3 The number of carbon atoms of the alkyl group is 10 or less.
2. The method according to claim 1, wherein the molar ratio of N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to dimethyl disulfide in the step (1) is 1:0.5-3.
3. The synthetic method according to claim 1, wherein the reaction solvent in the step (1) is selected from one or more of N, N-dimethylacetamide, N-dimethylformamide, NMP, DMSO, toluene, acetonitrile, dichloromethane, dichloroethane, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, t-butanol, or water; the mass ratio of the reaction solvent to the N- (3-amino-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide is 1-50:1.
4. The method according to claim 1, wherein the molar ratio of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to chloroformate reagent in step (2) is 1:0.9-2.
5. The method of synthesis according to claim 1, wherein step (2) further 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.
6. The method according to claim 5, wherein the molar ratio of N- (5-amino-2-chloro-4-fluorobenzoyl) -N '-methyl-N' -isopropyl sulfonamide to acid-binding agent in the step (2) is 1:0-2.
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| CN1989111A (en) * | 2004-07-22 | 2007-06-27 | 巴斯福股份公司 | Method for the production of 3-phenyl(thio)uracils and dithiouracils |
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