CN111517975B - Preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide - Google Patents
Preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide Download PDFInfo
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- CN111517975B CN111517975B CN202010459411.2A CN202010459411A CN111517975B CN 111517975 B CN111517975 B CN 111517975B CN 202010459411 A CN202010459411 A CN 202010459411A CN 111517975 B CN111517975 B CN 111517975B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- WOBVZGBINMTNKL-UHFFFAOYSA-N 2-amino-5-chloro-n,3-dimethylbenzamide Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1N WOBVZGBINMTNKL-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 17
- 238000006722 reduction reaction Methods 0.000 claims abstract description 13
- DGDAVTPQCQXLGU-UHFFFAOYSA-N 5437-38-7 Chemical compound CC1=CC=CC(C(O)=O)=C1[N+]([O-])=O DGDAVTPQCQXLGU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 10
- 238000005886 esterification reaction Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- KOPXCQUAFDWYOE-UHFFFAOYSA-N 2-amino-5-chloro-3-methylbenzoic acid Chemical compound CC1=CC(Cl)=CC(C(O)=O)=C1N KOPXCQUAFDWYOE-UHFFFAOYSA-N 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WNAJXPYVTFYEST-UHFFFAOYSA-N 2-Amino-3-methylbenzoate Chemical compound CC1=CC=CC(C(O)=O)=C1N WNAJXPYVTFYEST-UHFFFAOYSA-N 0.000 claims description 22
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000007868 Raney catalyst Substances 0.000 claims description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 10
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000007098 aminolysis reaction Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 239000002699 waste material Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- PSOVNZZNOMJUBI-UHFFFAOYSA-N chlorantraniliprole Chemical compound CNC(=O)C1=CC(Cl)=CC(C)=C1NC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl PSOVNZZNOMJUBI-UHFFFAOYSA-N 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- 230000008901 benefit Effects 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000005886 Chlorantraniliprole Substances 0.000 description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- BOYQWVQNPIZDPU-UHFFFAOYSA-N methyl 2-amino-5-chloro-3-methylbenzoate Chemical compound COC(=O)C1=CC(Cl)=CC(C)=C1N BOYQWVQNPIZDPU-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000002910 solid waste Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- INHQWSPQWGUYBT-UHFFFAOYSA-N ethyl 2-amino-5-chloro-3-methylbenzoate Chemical compound CCOC(=O)C1=CC(Cl)=CC(C)=C1N INHQWSPQWGUYBT-UHFFFAOYSA-N 0.000 description 2
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- JOJSINBHIDDRFK-UHFFFAOYSA-N propan-2-yl 2-amino-5-chloro-3-methylbenzoate Chemical compound CC(C)OC(=O)C1=CC(Cl)=CC(C)=C1N JOJSINBHIDDRFK-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- -1 2-amino-5-chloro-3-methylbenzoic acid methyl ester Chemical class 0.000 description 1
- FBOWFVWOCBTBPH-UHFFFAOYSA-N 2-amino-n,3-dimethylbenzamide Chemical compound CNC(=O)C1=CC=CC(C)=C1N FBOWFVWOCBTBPH-UHFFFAOYSA-N 0.000 description 1
- 229910014265 BrCl Inorganic materials 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide. The preparation method comprises the following steps: 2-nitro-3-methyl benzoic acid is taken as an initial raw material, and the 2-amino-5-chloro-N, 3-dimethyl benzamide is obtained by reduction reaction, chlorination reaction, esterification reaction and ammonolysis reaction in sequence. The preparation method provides a new path for the synthesis of the 2-amino-5-chloro-N, 3-dimethylbenzamide, the yield of the whole route can reach more than 80%, the cost is obviously reduced, the reaction conditions of each step are mild, the quantity of three wastes is small, and the preparation method is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide.
Background
Chlorantraniliprole, the common name of which is Chlorantraniprole, is an anthranilamide pesticide successfully developed by DuPont in 2000, the trade names of which are Altaco, coragen, rynaxypyr, kang Kuan, KK technical and the like, and the chemical name of which is: 3-bromo-N- { 4-chloro-2-methyl-6- [ (methylamino) carbonyl]Phenyl } -1- (3-chloro-2-pyridyl) -1H-pyrazole-5-amide having CAS registry number 500008-45-7 and molecular formula C 18 H 14 BrCl 2 N 5 O 2 The chemical structural formula is as follows:
2-amino-5-chloro-N, 3-dimethyl benzamide is an important intermediate for synthesizing chlorantraniliprole, and the existing 2-amino-5-chloro-N, 3-dimethyl benzamide synthesis methods mainly comprise two methods. The first method comprises the following steps: o-toluidine is taken as a raw material, the o-toluidine is condensed with chloral hydrate and hydroxylamine hydrochloride to generate oxime, the oxime is dehydrated and subjected to ring closing under the action of concentrated sulfuric acid to obtain isatin, the isatin is oxidized by hydrogen peroxide to generate isatoic anhydride, the isatoic anhydride is subjected to ring opening by methylamine gas to obtain 2-amino-N, 3-dimethylbenzamide, and finally, the 2-amino-5-chloro-N, 3-dimethylbenzyl chloride is obtained by chlorination of sulfuryl chlorideAn amide. The whole route has the advantages that the starting material o-toluidine is cheaper, and the disadvantages that the total yield is lower and is only about 30 percent, and the total raw material cost is higher. And a large amount of Na is used in the reaction process 2 SO 4 And concentrated sulfuric acid, the three wastes are large. A specific synthetic route of the method is as follows:
the second method comprises the following steps: 2-amino-3-methylbenzoic acid is taken as a raw material, NCS chlorination is firstly carried out to obtain 2-amino-5-chloro-3-methylbenzoic acid, then solid phosgene cyclization is carried out to obtain a compound 11, and finally ring opening is carried out by methylamine gas to obtain an intermediate 2-amino-5-chloro-N, 3-dimethylbenzamide. The whole route has the advantage of high total yield of about 70%. The disadvantages are that the starting material 2-amino-3-methylbenzoic acid is expensive, NCS which is expensive and atom-uneconomical is used in chlorination reaction, and solid phosgene is used in cyclization, so that atoms are uneconomical, and a large amount of HCl generated needs to be neutralized by adding alkali, thereby generating a large amount of solid waste. The specific synthetic route of the second method is as follows:
the method I is used for preparing the 2-amino-5-chloro-N, 3-dimethyl benzamide, and has the advantages of lower total yield, higher total raw material cost and more three wastes; the preparation of 2-amino-5-chloro-N, 3-dimethylbenzamide by the second method has higher total cost and more solid wastes due to the more expensive starting materials and used reagents. Therefore, the development of a synthetic method which has high yield, low cost, high atom economy and environmental friendliness is of great significance for the industrialization of the 2-amino-5-chloro-N, 3-dimethylbenzamide.
Disclosure of Invention
The invention aims to provide a novel preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide, which has high yield, low cost, high atom economy and less three wastes.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide, which comprises the following steps:
K1. 2-nitro-3-methylbenzoic acid is used as an initial raw material to carry out reduction reaction to obtain 2-amino-3-methylbenzoic acid;
K2. performing chlorination reaction on 2-amino-3-methylbenzoic acid to obtain 2-amino-5-chloro-3-methylbenzoic acid;
K3. carrying out esterification reaction on 2-amino-5-chloro-3-methylbenzoic acid to obtain 2-amino-5-chloro-3-methylbenzoate;
K4. 2-amino-5-chloro-3-methylbenzoate is subjected to ammonolysis reaction to obtain 2-amino-5-chloro-N, 3-dimethylbenzoyl.
Preferably, the 2-nitro-3-methylbenzoic acid described in K1 is subjected to the reduction reaction with hydrogen in ethanol under the presence of a catalyst.
In the invention, the specific operation steps of the reduction reaction are as follows: dissolving 2-nitro-3-methylbenzoic acid in ethanol, placing the solution in a hydrogenation kettle, adding a catalyst, closing the hydrogenation kettle, introducing hydrogen, heating for reaction, filtering while the solution is hot after the reaction is finished, recovering the catalyst, and distilling the filtrate under reduced pressure to remove the solvent to obtain the 2-amino-3-methylbenzoic acid.
Preferably, the feeding mass ratio of the 2-nitro-3-methylbenzoic acid to the ethanol in the reduction reaction is 1: 4-6, preferably 1: 5.
Preferably, nitrogen is used for 1 to 3 times before the introduction of hydrogen.
Preferably, the catalyst is raney nickel.
Further preferably, the feeding mass ratio of the 2-nitro-3-methylbenzoic acid to the raney nickel is 1: 0.01-0.05.
More preferably, the hydrogen pressure is 0.1 to 1.5MPa.
Further preferably, the reaction temperature of the reduction reaction is 20 ℃ to 80 ℃.
More preferably, the reaction temperature of the reduction reaction is 50 ℃ to 70 ℃.
More preferably, the reaction time of the reduction reaction is 3 to 8 hours.
More preferably, the reaction time of the reduction reaction is 4 to 6 hours.
Preferably, the 2-amino-3-methylbenzoic acid described in K2 is subjected to the chlorination with chlorine in an organic solvent.
In the invention, the concrete operation steps of the chlorination reaction are as follows: placing 2-amino-3-methylbenzoic acid into a reaction container, adding an organic solvent, stirring and heating, introducing chlorine gas for reaction, cooling to room temperature after the reaction is finished, and filtering to obtain 2-amino-5-chloro-3-methylbenzoic acid.
The feeding mass ratio of the 2-amino-3-methylbenzoic acid to the organic solvent in the chlorination reaction is 1: 4-6, and preferably 1: 5.
Further preferably, the organic solvent includes but is not limited to one or more of chloroform, dichloroethane, acetonitrile, tetrahydrofuran.
More preferably, the solvent is dichloroethane.
Further preferably, the feeding molar ratio of the 2-amino-3-methylbenzoic acid to the chlorine gas is 1: 1-1.5.
Further preferably, the reaction temperature of the chlorination reaction is 20-80 ℃.
More preferably, the reaction temperature of the chlorination reaction is 50 ℃ to 60 ℃.
Further preferably, the reaction time of the chlorination reaction is 2-4 h.
Preferably, the esterification of 2-amino-5-chloro-3-methylbenzoic acid described in K3 with an alcohol is carried out under concentrated sulfuric acid.
In the invention, the esterification reaction comprises the following specific operation steps: placing 2-amino-5-chloro-3-methylbenzoic acid into a reaction container, adding alcohol, cooling in an ice water bath, dropwise adding concentrated sulfuric acid, heating for reflux reaction after dropwise adding is finished, distilling to remove alcohol after reaction is finished, adding water, pulping at room temperature, and filtering to obtain 2-amino-5-chloro-3-methylbenzoic acid methyl ester.
The feeding mass ratio of the 2-amino-5-chloro-3-methylbenzoic acid to the alcohol in the esterification reaction is 1: 4-6, preferably 1: 5.
Further preferably, the alcohol includes but is not limited to one or more of methanol, ethanol, isopropanol and n-butanol.
Further preferably, the feeding molar ratio of the 2-amino-5-chloro-3-methylbenzoic acid to the concentrated sulfuric acid is 1: 0.1-0.5.
Further preferably, the reaction time of the chlorination reaction is 4 to 10 hours.
Preferably, the 2-amino-5-chloro-3-methylbenzoate described in K4 is subjected to the aminolysis reaction with methylamine in an alcohol.
In the invention, the specific operation steps of the ammonolysis reaction are as follows: adding 2-amino-5-chloro-3-methyl benzoate and alcohol into a reaction container, stirring and heating, introducing methylamine gas for reaction, and distilling to remove the alcohol after the reaction is finished to obtain the 2-amino-5-chloro-N, 3-dimethyl benzamide.
The feeding mass ratio of the 2-amino-5-chloro-3-methyl benzoate to the alcohol in the ammonolysis reaction is 1: 3-5, preferably 1: 4.
Further preferably, the alcohol is one or more of methanol, ethanol, isopropanol and n-butanol.
Further preferably, the feeding molar ratio of the 2-amino-5-chloro-3-methylbenzoate to the methylamine is 1: 1-1.5.
Further preferably, the reaction temperature of the ammonolysis reaction is 20-60 ℃.
More preferably, the reaction temperature of the ammonolysis reaction is 45-60 ℃.
Further preferably, the reaction time of the ammonolysis reaction is 2 to 8 hours.
The reaction formula of the invention is as follows:
the preparation method provides a new path for the synthesis of the 2-amino-5-chloro-N, 3-dimethylbenzamide, the preparation method has the advantages of mild reaction conditions and high yield in each step, the total yield is more than 80%, the three wastes are less, no solid wastes are generated, the preparation method is environment-friendly and suitable for industrial production, the problems of low reaction yield, high cost, poor atom economy and more three wastes in the prior art are solved, and the production cost of the intermediate 2-amino-5-chloro-N, 3-dimethylbenzamide is greatly reduced, so that the production cost of the chlorantraniliprole is reduced, and convenience is provided for industrial production of the chlorantraniliprole.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the new preparation method of the 2-amino-5-chloro-N, 3-dimethylbenzamide has the advantages of high yield, low cost, high atom economy and less three wastes, and is suitable for industrial production.
Detailed Description
The technical solution of the present invention is further described below with reference to specific embodiments, but the present invention is not limited to the following embodiments. The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
Example 1
Preparation of K1, 2-amino-3-methylbenzoic acid
Dissolving 10g (55.2 mmol) of 2-nitro-3-methylbenzoic acid in 50g of ethanol, placing the mixture in a hydrogenation kettle, adding 0.4g of Raney nickel, closing the hydrogenation kettle, replacing with nitrogen for 3 times, introducing 0.2MPa hydrogen, starting stirring, heating to 50 ℃ and reacting for 4 hours. After the reaction, raney nickel was recovered by hot filtration, and the solvent was removed from the filtrate by distillation under reduced pressure to obtain 8.2g of 2-amino-3-methylbenzoic acid with a yield of 98.3%.
Preparation of K2, 2-amino-5-chloro-3-methylbenzoic acid
8g (53 mmol) of 2-amino-3-methylbenzoic acid are placed in a flask, 40g of dichloroethane are added, stirring is switched on, the temperature is raised to 50 ℃ and 4.5g (63.4 mmol) of chlorine are slowly passed through for reaction for 3h. After the reaction, the temperature was decreased to room temperature and filtration was conducted to obtain 9.6g of 2-amino-5-chloro-3-methylbenzoic acid (3) in 98.1% yield.
Preparation of K3.2-amino-5-chloro-3-methylbenzoic acid methyl ester
9g (48.6 mmol) of 2-amino-5-chloro-3-methylbenzoic acid is placed in a flask, 45g of methanol is added, stirring is started, an ice water bath is cooled to 5 ℃, 0.95g (9.7 mmol) of concentrated sulfuric acid is added dropwise, and after the dropwise addition is finished, the temperature is increased for reflux reaction for 8 hours. After the reaction, methanol was distilled off, 10g of water was added, and after beating at room temperature for 0.5 hour, methyl 2-amino-5-chloro-3-methylbenzoate was obtained by filtration in a yield of 95%.
Preparation of K4.2-amino-5-chloro-N, 3-dimethylbenzamide
After 9g (45.1 mmol) of methyl 2-amino-5-chloro-3-methylbenzoate was dissolved in 36g of methanol, the mixture was placed in a flask, stirred, heated to 45 ℃ and slowly charged with 1.7g (54.8 mmol) of methylamine gas to react for 6 hours. After the completion of the reaction, methanol was distilled off to obtain 8.7g of 2-amino-5-chloro-N, 3-dimethylbenzamide in a yield of 97.2%.
Example 2
Preparation of K1, 2-amino-3-methylbenzoic acid
40g (221 mmol) of 2-nitro-3-methylbenzoic acid is dissolved in 200g of ethanol and then placed in a hydrogenation kettle, 1.2g of Raney nickel is added, then the hydrogenation kettle is closed, nitrogen is replaced for 3 times, then 0.3MPa hydrogen is introduced, stirring is started, and the temperature is raised to 60 ℃ for reaction for 6 hours. After the reaction, raney nickel is recovered by hot filtration, and the filtrate is subjected to reduced pressure distillation to remove the solvent, so that 32g of 2-amino-3-methylbenzoic acid is obtained, and the yield is 95.9%.
Preparation of K2, 2-amino-5-chloro-3-methylbenzoic acid
30g (198.7 mmol) of 2-amino-3-methylbenzoic acid are placed in a flask, 150g of acetonitrile are added, stirring is started, the temperature is raised to 60 ℃, and 20.5g (288.7 mmol) of chlorine gas is slowly introduced for reaction for 4 hours. After the reaction, the temperature was decreased to room temperature and filtration was carried out to obtain 35.4g of 2-amino-5-chloro-3-methylbenzoic acid in a yield of 96%.
Preparation of K3.2-amino-5-chloro-3-methylbenzoic acid ethyl ester
30g (161.7 mmol) of 2-amino-5-chloro-3-methylbenzoic acid is placed in a flask, 150g of ethanol is added, stirring is started, an ice water bath is cooled to 5 ℃, 4.75g (48.5 mmol) of concentrated sulfuric acid is added dropwise, and after dropwise addition, the temperature is increased and reflux reaction is carried out for 6 hours. After the reaction is finished, ethanol is removed by reduced pressure distillation, 30g of water is added, pulping is carried out for 0.5h at room temperature, and then filtration is carried out to obtain 31.8g of ethyl 2-amino-5-chloro-3-methylbenzoate, wherein the yield is 92.1%.
Preparation of K4.2-amino-5-chloro-N, 3-dimethylbenzamide
30g (140.5 mmol) of ethyl 2-amino-5-chloro-3-methylbenzoate are dissolved in 120g of methanol and placed in a flask, stirring is started, the temperature is raised to 50 ℃, and then 5.7g (182.6 mmol) of methylamine gas is slowly introduced for reaction for 6h. After the reaction, ethanol was distilled off to obtain 26.6g of 2-amino-5-chloro-N, 3-dimethylbenzamide with a yield of 95.4%.
Example 3
Preparation of K1, 2-amino-3-methylbenzoic acid
Dissolving 90g (497.2 mmol) of 2-nitro-3-methylbenzoic acid in 450g of ethanol, placing the mixture in a hydrogenation kettle, adding 1.8g of Raney nickel, closing the hydrogenation kettle, replacing with nitrogen for 3 times, introducing 0.5MPa hydrogen, stirring, heating to 70 ℃, and reacting for 5 hours. And after the reaction is finished, filtering while the reaction is hot to recover raney nickel, and distilling the filtrate under reduced pressure to remove the solvent to obtain 73g of 2-amino-3-methylbenzoic acid with the yield of 97.2 percent.
Preparation of K2, 2-amino-5-chloro-3-methylbenzoic acid
70g (463.6 mmol) of 2-amino-3-methylbenzoic acid are dissolved in 350g of tetrahydrofuran and placed in a flask, stirring is started, the temperature is raised to 50 ℃, and then 46.1g (649.3 mmol) of chlorine gas is slowly introduced for reaction for 2 hours. After the reaction, the temperature was decreased to room temperature and filtration was carried out to obtain 82g of 2-amino-5-chloro-3-methylbenzoic acid in a yield of 95.4%.
Preparation of isopropyl K3.2-amino-5-chloro-3-methylbenzoate
Placing 80g (431.3 mmol) of 2-amino-5-chloro-3-methylbenzoic acid into a flask, adding 400g of isopropanol, starting stirring, cooling to 5 ℃ in an ice water bath, dropwise adding 10.6g (108 mmol) of concentrated sulfuric acid, and heating for reflux reaction for 6 hours after dropwise adding. After the reaction is finished, the isopropanol is removed by reduced pressure distillation, 80g of water is added, pulping is carried out for 0.5h at room temperature, and then filtration is carried out to obtain 93g of isopropyl 2-amino-5-chloro-3-methylbenzoate, wherein the yield is 94.8%.
Preparation of K4.2-amino-5-chloro-N, 3-dimethylbenzamide
90g (395.6 mmol) isopropyl 2-amino-5-chloro-3-methylbenzoate is dissolved in 360g isopropanol and placed in a flask, stirring is started, the temperature is raised to 60 ℃, and 17.2g (554.8 mmol) methylamine gas is slowly introduced for reaction for 7 hours. After the reaction, isopropanol was distilled off under reduced pressure to obtain 76g of 2-amino-5-chloro-N, 3-dimethylbenzamide with a yield of 96.8%.
The present invention is described in detail in order to make those skilled in the art understand the content and practice the present invention, and the present invention is not limited to the above embodiments, and all equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (6)
1. The preparation method of the 2-amino-5-chloro-N, 3-dimethylbenzamide is characterized by comprising the following steps:
K1. 2-nitro-3-methylbenzoic acid is used as an initial raw material to carry out reduction reaction to obtain 2-amino-3-methylbenzoic acid;
K2. performing chlorination reaction on 2-amino-3-methylbenzoic acid to obtain 2-amino-5-chloro-3-methylbenzoic acid;
K3. carrying out esterification reaction on 2-amino-5-chloro-3-methylbenzoic acid to obtain 2-amino-5-chloro-3-methylbenzoate;
K4. carrying out ammonolysis reaction on 2-amino-5-chloro-3-methylbenzoate to obtain 2-amino-5-chloro-N, 3-dimethylbenzamide;
the 2-nitro-3-methyl benzoic acid in the K1 and hydrogen are subjected to the reduction reaction in ethanol under the condition of a catalyst, the catalyst is Raney nickel, and the pressure of the hydrogen is 0.1MPa to 0.5MPa;
performing the chlorination reaction on the 2-amino-3-methylbenzoic acid and chlorine in K2 in an organic solvent, wherein the organic solvent is one or more of chloroform, dichloroethane, acetonitrile and tetrahydrofuran; the feeding molar ratio of the 2-amino-3-methylbenzoic acid to the chlorine is 1 to 1.5; the reaction temperature of the chlorination reaction is 50-60 ℃; the reaction time of the chlorination reaction is 2h to 4h.
2. The preparation method according to claim 1, wherein the mass ratio of the 2-nitro-3-methylbenzoic acid to the Raney nickel is 1; the reaction temperature of the reduction reaction is 20-80 ℃; the reaction time of the reduction reaction is 3h to 8h.
3. The process according to claim 1, wherein the esterification of 2-amino-5-chloro-3-methylbenzoic acid with an alcohol is carried out in the presence of concentrated sulfuric acid in K3.
4. The preparation method according to claim 3, wherein the alcohol is one or more selected from methanol, ethanol, isopropanol and n-butanol; the feeding molar ratio of the 2-amino-5-chloro-3-methylbenzoic acid to concentrated sulfuric acid is 1; the reaction time of the chlorination reaction is 4h to 10h.
5. The process according to claim 1, wherein the aminolysis reaction of 2-amino-5-chloro-3-methylbenzoate and methylamine in an alcohol is carried out in K4.
6. The preparation method according to claim 5, wherein the alcohol is one or more selected from methanol, ethanol, isopropanol and n-butanol; the feeding molar ratio of the 2-amino-5-chloro-3-methylbenzoate to the methylamine is 1 to 1.5; the reaction temperature of the ammonolysis reaction is 20-60 ℃; the reaction time of the ammonolysis reaction is 2h to 8h.
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| Title |
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