CN116253658B - Synthesis method of aforana intermediate - Google Patents
Synthesis method of aforana intermediate Download PDFInfo
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- CN116253658B CN116253658B CN202211491600.3A CN202211491600A CN116253658B CN 116253658 B CN116253658 B CN 116253658B CN 202211491600 A CN202211491600 A CN 202211491600A CN 116253658 B CN116253658 B CN 116253658B
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- trifluoroethyl
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims abstract description 23
- DOCFRBZXXQJPBD-UHFFFAOYSA-N 4-acetylnaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)C)=CC=C(C(O)=O)C2=C1 DOCFRBZXXQJPBD-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 29
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 21
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 abstract description 6
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 abstract description 3
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 28
- -1 3-chloro-5- (trifluoromethyl) phenyl Chemical group 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000367775 Amietia Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 230000000749 insecticidal effect Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241001414720 Cicadellidae Species 0.000 description 1
- 241000927584 Frankliniella occidentalis Species 0.000 description 1
- 241000255967 Helicoverpa zea Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000256251 Spodoptera frugiperda Species 0.000 description 1
- 240000006677 Vicia faba Species 0.000 description 1
- 235000010749 Vicia faba Nutrition 0.000 description 1
- 235000002098 Vicia faba var. major Nutrition 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of an aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalamide. The method synthesizes 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthoic acid from easily obtained industrial raw material glycine methyl ester and 4-acetyl-1-naphthoic acid, replaces expensive 2-amino-N- (2, 2-trifluoroethyl) acetamide hydrochloride, and carries out condensation under EDCl and HOBT effect, which is simpler and more convenient than N, N-Carbonyl Diimidazole (CDI) reaction, and has more economic benefit.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of an aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalamide.
Background
Aforana is an isoxazoline insecticide and acaricide that acts on ligand-gated chloride ion channels, particularly inhibits neurotransmitter gamma-aminobutyric acid (GABA) -gated channels, thereby blocking the transfer of chloride ions from the presynaptic membrane to the postsynaptic membrane, resulting in increased neuronal activity and overexcitation in insects. The afrana is safe to mammals, has high insecticidal activity, and has excellent insecticidal activity to pests such as spodoptera frugiperda, cotton bollworms, broad bean leafhoppers, frankliniella occidentalis and the like.
4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino group]Ethyl } -1-naphthamide is an important intermediate for synthesizing aforana, and has a chemical formula of C 17 H 15 F 3 N 2 O 3 Cas. No:1125812-54-5, the structural formula is as follows:
patent WO2012047543A1 discloses a process for the synthesis of 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide by adding anhydrous acetonitrile to 4-acetyl-1-naphthamic acid and N, N-Carbonyldiimidazole (CDI), stirring the solution at 25 ℃ for 5.75 hours, and then heating to 30 ℃. An aqueous solution of 2-amino-N- (2, 2-trifluoroethyl) acetamide hydrochloride was added over 6 minutes, the reaction mixture was stirred at 30 ℃ for 16.3 hours, then cooled to 20 ℃, water was added to the resulting slurry, and then an aqueous sodium carbonate solution was added over about 1 hour. The reaction mixture was stirred overnight at 20-25 ℃, maintained at 0-8 ℃ for 2.25 hours, and then filtered. The residue was washed 3 times with water and dried in a vacuum oven at 50 ℃ with nitrogen purge to give the desired product as an off-white solid in 87.7% yield. The reaction route is as follows:
the price of 2-amino-N- (2, 2-trifluoroethyl) acetamide hydrochloride in the reaction is high (7500 yuan/kg), and the price of the free base 2-amino-N- (2, 2-trifluoroethyl) acetamide is more than 2 times (18000 yuan/kg) of that of the hydrochloride, so that the cost is difficult to reduce by adopting the route for large-scale production process.
Disclosure of Invention
The invention solves the technical problem of providing a low-cost synthesis method of an aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalamide. The process adopts methyl glycinate as a raw material to react with 4-acetyl-1-naphthoic acid, and the target product is obtained after condensation, hydrolysis and condensation reaction, the reaction steps are simple, the price of the used materials is within thousands yuan, and the cost is greatly reduced.
The invention is realized by the following technical scheme:
a synthesis method of an aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalenamide, which comprises the following steps:
(1) Adding 4-acetyl-1-naphthoic acid into ethyl acetate, sequentially adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, stirring and reacting for 2 hours, adding glycine methyl ester hydrochloride, stirring and heating to 40-45 ℃ after the addition is finished, reacting for 2 hours, cooling, adding water and 20% hydrochloric acid, stirring for 30 minutes, standing and layering, heating a water layer to 50-55 ℃, stirring and reacting for 1.5-2 hours, regulating pH=9-10 by using 20% sodium hydroxide solution, precipitating solid, centrifuging, and drying for later use;
(2) Adding the solid obtained in the step (1) into a reaction kettle, adding ethyl acetate, 2-trifluoroethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, stirring and heating to 60-65 ℃, reacting for 4 hours, cooling to room temperature, washing reaction liquid by adopting 10% sodium hydroxide solution and saturated sodium chloride solution in sequence, concentrating under reduced pressure and evaporating to remove the solvent, adding ethyl acetate with the weight of 2.5 times of that of 4-acetyl-1-naphthoic acid, heating and refluxing for 2 hours, cooling to 15-20 ℃ for crystallization for 8 hours, centrifuging, drying to obtain a 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthoamide refined product,
the above-mentioned aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide synthesis method, wherein the molar ratio of 4-acetyl-1-naphthamic acid to 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in the step (1) is 1:1.2-1.5.
The molar ratio of the 4-acetyl-1-naphthoic acid to the 1-hydroxybenzotriazole in the step (1) is 1:0.5-0.7. Preferably 1:0.6.
The molar ratio of the 4-acetyl-1-naphthoic acid to the glycine methyl ester hydrochloride in the step (1) is 1:1.1-1.5.
The dosage of the 2, 2-trifluoroethylamine in the step (2) is 1.1-1.5 times of the molar quantity of the 4-acetyl-1-naphthoic acid.
The dosage of the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in the step (2) is 1.1-1.3 times of the molar quantity of the 4-acetyl-1-naphthoic acid.
The dosage of the 1-hydroxybenzotriazole in the step (2) is 0.5 time of the molar quantity of the 4-acetyl-1-naphthoic acid.
The amount of ethyl acetate in the step (1) is 4-5 times of the weight of the 4-acetyl-1-naphthoic acid.
Ethyl acetate, 2-trifluoroethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole are added in the step (2), and the amount of the ethyl acetate is 2.5-4 times of the weight of the 4-acetyl-1-naphthoic acid.
The reaction route of the invention is as follows:
in the technical scheme of the invention, EDCI is short for 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, HOBT is short for 1-hydroxybenzotriazole.
A synthesis method of aforana comprises the following steps:
(1) Placing cesium fluoride 4 into a reaction kettle, sequentially adding ethyl propionate, 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethyl ketone and g 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalenamide into the reaction kettle, fully stirring at room temperature, heating and refluxing for reaction for 12 hours, cooling, sequentially washing with water and 10% sodium chloride solution, and distilling and concentrating to obtain an intermediate (Z) 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4, 4-trifluoro but-2-enoyl) -N- (2-oxo-2- ((2, 2-trifluoroethyl) amino) ethyl) -1-naphthalenamide;
(2) Adding an intermediate (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4, 4-trifluoro-but-2-enoyl) -N- (2-oxo-2- ((2, 2-trifluoroethyl) amino) ethyl) -1-naphthamide and dichloromethane into a reaction kettle, and uniformly stirring; sequentially adding 50% hydroxylamine aqueous solution and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and stirring at 25 ℃ for reaction for 3 hours; after the reaction, adding water into the reaction solution, and extracting with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate, filtered, and the organic solvent was recovered by distillation to give aforana.
The above synthesis method of aforana comprises the following steps:
45kg of cesium fluoride is placed in a reaction kettle, 150kg of ethyl propionate, 100kg of 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethanone and 106kg of 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalenamide are sequentially added into the reaction kettle, after the mixture is fully stirred at room temperature, the mixture is heated and refluxed for 12 hours, cooled, washed by water and 10% sodium chloride solution in sequence, and distilled and concentrated to obtain an intermediate (Z) 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4, 4-trifluoro but-2-enoyl) -N- (2-oxo-2- ((2, 2-trifluoro ethyl) amino) ethyl) -1-naphthalimide with the yield of 92% and the purity of 98.1%.
55kg of an intermediate (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4, 4-trifluoro-but-2-enoyl) -N- (2-oxo-2- ((2, 2-trifluoroethyl) amino) ethyl) -1-naphthamide and 250kg of dichloromethane are added into a reaction kettle and stirred uniformly; 12kg of 50% aqueous hydroxylamine solution and 21kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were added in this order, and the mixture was stirred at 25℃for 3 hours. After the reaction, adding water into the reaction solution, and extracting with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate, filtered, and the organic solvent was recovered by distillation to obtain 49.7kg of aforana.
In the technical scheme of the invention, the 20% hydrochloric acid is hydrochloric acid with the mass percentage concentration of 20%. The 10% sodium hydroxide solution is 10% sodium hydroxide solution by mass percent concentration. The 10% sodium chloride solution is 10% sodium chloride solution by mass percent. The 50% aqueous hydroxylamine solution is a 50% aqueous hydroxylamine solution by mass percent concentration.
The beneficial technical effects are as follows:
according to the method for synthesizing the afrana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalamide, industrial raw materials methyl glycinate which are easy to obtain and 4-acetyl-1-naphthoic acid are used for synthesizing 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalamide, expensive 2-amino-N- (2, 2-trifluoroethyl) acetamide hydrochloride is replaced, condensation is carried out under the action of EDCl and HOBT, and the method is simpler and more convenient than the method adopting N, N-Carbonyl Diimidazole (CDI), has economic benefits, and the raw material production cost is 80.5% of that of comparative document 1.
Detailed Description
The present invention will be further described with reference to the following embodiments, so that those skilled in the art can more understand the present invention, but the present invention is not limited thereto.
Example 1:
adding 107kg of 4-acetyl-1-naphthoic acid into a reaction kettle, pumping into 450kg of ethyl acetate, sequentially adding 114.9kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 40.5kg of 1-hydroxybenzotriazole, stirring and reacting for 2 hours, adding 69kg of glycine methyl ester hydrochloride in batches, stirring and heating to 40-45 ℃ after 1 hour, reacting for 2 hours, cooling, adding water and 20% hydrochloric acid, stirring for 30 minutes, standing and layering, heating a water layer to 50-55 ℃, stirring and reacting for 1.5-2 hours, adjusting pH=9-10 by using 20% sodium hydroxide solution, precipitating solids, centrifuging, and drying for later use;
adding the solid sodium salt obtained in the above steps into a reaction kettle, adding 300kg of ethyl acetate, 54.4kg of 2, 2-trifluoroethylamine, 105.3kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 33.8kg of 1-hydroxybenzotriazole, stirring and heating to 60-65 ℃, cooling to room temperature after reacting for 4 hours, washing the reaction liquid by adopting 200kg of 10% sodium hydroxide solution and 200kg of saturated sodium chloride solution in sequence, concentrating under reduced pressure and steaming to remove the solvent, adding 268kg of ethyl acetate, heating and refluxing for 2 hours, cooling to 15-20 ℃ for crystallization for 8 hours, centrifuging, and drying to obtain 154.5kg of 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide refined product, wherein the total yield is 87.8%, and the purity is 98.2%.
Example 2:
adding 107kg of 4-acetyl-1-naphthoic acid into a reaction kettle, pumping into 450kg of ethyl acetate, sequentially adding 143.6kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 40.5kg of 1-hydroxybenzotriazole, stirring and reacting for 2 hours, adding 94.1kg of glycine methyl ester hydrochloride in batches, stirring and heating to 40-45 ℃ after 1 hour, cooling, adding water and 40kg of 20% hydrochloric acid, stirring for 30 minutes, standing and layering, heating a water layer to 50-55 ℃, stirring and reacting for 1.5-2 hours, adjusting pH=9-10 by using 20% sodium hydroxide (about 75 kg) solution, separating out solids, centrifuging, and drying for later use;
adding the solid sodium salt obtained in the above steps into a reaction kettle, adding 300kg of ethyl acetate, 54.4kg of 2, 2-trifluoroethylamine, 105.3kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 33.8kg of 1-hydroxybenzotriazole, stirring and heating to 60-65 ℃, cooling to room temperature after reacting for 4 hours, washing the reaction liquid by adopting 200kg of 10% sodium hydroxide solution and 200kg of saturated sodium chloride solution in sequence, concentrating under reduced pressure and steaming to remove the solvent, adding 268kg of ethyl acetate, heating and refluxing for 2 hours, cooling to 15-20 ℃ for crystallization for 8 hours, centrifuging, and drying to obtain 155.4kg of 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide fine product with the total yield of 88.3% and the purity of 98.7%.
Example 3:
107kg of 4-acetyl-1-naphthoic acid is added into a reaction kettle, the mixture is pumped into 450kg of ethyl acetate, 143.6kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 40.5kg of 1-hydroxybenzotriazole are sequentially added, after stirring and reacting for 2 hours, 94.1kg of glycine methyl ester hydrochloride is added in batches, after the addition of the mixture is completed for 1 hour, stirring and heating to 40-45 ℃, after reacting for 2 hours, cooling, adding water and 20% hydrochloric acid, stirring for 30 minutes, standing and layering, after the water layer is heated to 50-55 ℃, stirring and reacting for 1.5-2 hours, adjusting pH=9-10 by using 20% sodium hydroxide solution, separating out solids, centrifuging, and drying for later use;
adding the solid sodium salt obtained in the above steps into a reaction kettle, adding 300kg of ethyl acetate, 74.2kg of 2, 2-trifluoroethylamine, 105.3kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 33.8kg of 1-hydroxybenzotriazole, stirring and heating to 60-65 ℃, cooling to room temperature after reacting for 4 hours, washing the reaction liquid by adopting 200kg of 10% sodium hydroxide solution and 200kg of saturated sodium chloride solution in sequence, concentrating under reduced pressure and steaming to remove the solvent, adding 268kg of ethyl acetate, heating and refluxing for 2 hours, cooling to 15-20 ℃ for crystallization for 8 hours, centrifuging, and drying to obtain 156.1kg of 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide fine product with the total yield of 88.7% and the purity of 98.5%.
Embodiment 4: synthesis of aforana
45kg of cesium fluoride is placed in a reaction kettle, 150kg of ethyl propionate, 100kg of 1- (3-chloro-5- (trifluoromethyl) phenyl) -2, 2-trifluoroethanone and 106kg of 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalenamide are sequentially added into the reaction kettle, after the mixture is fully stirred at room temperature, the mixture is heated and refluxed for 12 hours, cooled, washed by water and 10% sodium chloride solution in sequence, and distilled and concentrated to obtain an intermediate (Z) 4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4, 4-trifluoro but-2-enoyl) -N- (2-oxo-2- ((2, 2-trifluoro ethyl) amino) ethyl) -1-naphthalimide with the yield of 92% and the purity of 98.1%.
55kg of an intermediate (Z) -4- (3- (3-chloro-5- (trifluoromethyl) phenyl) -4, 4-trifluoro-but-2-enoyl) -N- (2-oxo-2- ((2, 2-trifluoroethyl) amino) ethyl) -1-naphthamide and 250kg of dichloromethane are added into a reaction kettle and stirred uniformly; 12kg of 50% aqueous hydroxylamine solution and 21kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were added in this order, and the mixture was stirred at 25℃for 3 hours. After the reaction, adding water into the reaction solution, and extracting with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate, filtered, and the organic solvent was recovered by distillation to give afrana 49.7kg, yield 88.2%, purity 98.2%.
The cost of example 11 of the present invention and comparative document 1 was checked as follows:
table 1 comparative document 1 example 11 cost accounting
TABLE 2 cost accounting for example 2 of the invention
The cost of the synthesis of 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide in this invention is 80.5% of that of comparative document 1, relative to that of the synthesis of the arformrana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide in comparative document 1.
Claims (10)
1. A synthesis method of an aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalenamide, which comprises the following steps: (1) Adding 4-acetyl-1-naphthoic acid into ethyl acetate, sequentially adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, stirring and reacting for 2 hours, adding glycine methyl ester hydrochloride, stirring and heating to 40-45 ℃ after the addition is finished, reacting for 2 hours, cooling, adding water and 20% hydrochloric acid, stirring for 30 minutes, standing and layering, heating a water layer to 50-55 ℃, stirring and reacting for 1.5-2 hours, regulating pH=9-10 by using 20% sodium hydroxide solution, precipitating solid, centrifuging, and drying for later use; (2) Adding the solid obtained in the step (1) into a reaction kettle, adding ethyl acetate, 2-trifluoroethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, stirring and heating to 60-65 ℃, reacting for 4 hours, cooling to room temperature, washing reaction liquid by adopting 10% sodium hydroxide solution and saturated sodium chloride solution in sequence, concentrating under reduced pressure and evaporating to remove the solvent, adding ethyl acetate with the weight of 2.5 times of that of 4-acetyl-1-naphthoic acid, heating and refluxing for 2 hours, cooling to 15-20 ℃ for crystallization for 8 hours, centrifuging and drying to obtain a 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthoamide fine product.
2. The method for synthesizing aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide according to claim 1, wherein the molar ratio of 4-acetyl-1-naphthamic acid to 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in step (1) is 1:1.2-1.5.
3. The method for synthesizing aforamide intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide according to claim 1, wherein the molar ratio of 4-acetyl-1-naphthamic acid to 1-hydroxybenzotriazole in the step (1) is 1:0.5-0.7.
4. A process for the synthesis of the aforamide intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide according to claim 3, wherein the molar ratio of 4-acetyl-1-naphthamic acid to 1-hydroxybenzotriazole in step (1) is 1:0.6.
5. The method for synthesizing aforamide intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide according to claim 1, wherein the molar ratio of 4-acetyl-1-naphthamic acid to glycine methyl ester hydrochloride in the step (1) is 1:1.1-1.5.
6. The method for synthesizing aforamide intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalenic acid according to claim 1, wherein the amount of 2, 2-trifluoroethylamine used in the step (2) is 1.1 to 1.5 times the molar amount of 4-acetyl-1-naphthalenic acid.
7. The method for synthesizing aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide according to claim 1, wherein the amount of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride used in the step (2) is 1.1 to 1.3 times the molar amount of 4-acetyl-1-naphthamic acid.
8. The method for synthesizing aforamide intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide according to claim 1, wherein the amount of 1-hydroxybenzotriazole used in the step (2) is 0.5 times the molar amount of 4-acetyl-1-naphthamic acid.
9. The method for synthesizing aforamide intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthalenic acid according to claim 1, wherein the amount of ethyl acetate used in the step (1) is 4 to 5 times by weight of 4-acetyl-1-naphthalenic acid.
10. The method for synthesizing aforana intermediate 4-acetyl-N- { 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] ethyl } -1-naphthamide according to claim 1, wherein ethyl acetate, 2-trifluoroethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole are added in the step (2) in an amount of 2.5 to 4 times by weight as much as 4-acetyl-1-naphthamic acid.
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