CN117700321A - Synthesis method of 4-halogenated-2-carbonyl butyrate intermediate - Google Patents
Synthesis method of 4-halogenated-2-carbonyl butyrate intermediate Download PDFInfo
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- CN117700321A CN117700321A CN202211096083.XA CN202211096083A CN117700321A CN 117700321 A CN117700321 A CN 117700321A CN 202211096083 A CN202211096083 A CN 202211096083A CN 117700321 A CN117700321 A CN 117700321A
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- 239000007788 liquid Substances 0.000 claims abstract description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000013058 crude material Substances 0.000 claims abstract description 30
- -1 3-halogenated propionyl halide Chemical class 0.000 claims abstract description 29
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 22
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000002156 mixing Methods 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 17
- JQLHQBWQAFDAGK-UHFFFAOYSA-N propanoyl cyanide Chemical class CCC(=O)C#N JQLHQBWQAFDAGK-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000007864 aqueous solution Substances 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 12
- 238000006467 substitution reaction Methods 0.000 claims abstract description 12
- 239000004359 castor oil Substances 0.000 claims abstract description 8
- 235000019438 castor oil Nutrition 0.000 claims abstract description 8
- 150000002191 fatty alcohols Chemical class 0.000 claims abstract description 8
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 8
- 150000004714 phosphonium salts Chemical group 0.000 claims abstract description 8
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 150000004820 halides Chemical class 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 6
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- NLWVKWQAPXUNOS-UHFFFAOYSA-N 3-chloropropanoyl bromide Chemical compound ClCCC(Br)=O NLWVKWQAPXUNOS-UHFFFAOYSA-N 0.000 claims description 5
- 239000011260 aqueous acid Substances 0.000 claims description 5
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 4
- FRXLFVNGTPQFEJ-UHFFFAOYSA-N 3-bromopropanoyl bromide Chemical compound BrCCC(Br)=O FRXLFVNGTPQFEJ-UHFFFAOYSA-N 0.000 claims description 3
- IHBVNSPHKMCPST-UHFFFAOYSA-N 3-bromopropanoyl chloride Chemical compound ClC(=O)CCBr IHBVNSPHKMCPST-UHFFFAOYSA-N 0.000 claims description 3
- SITMIFRIVRPYOD-UHFFFAOYSA-N 3-chloropropanoyl iodide Chemical compound ClCCC(I)=O SITMIFRIVRPYOD-UHFFFAOYSA-N 0.000 claims description 3
- BVGKKICUUAFHFE-UHFFFAOYSA-N 3-iodopropanoyl chloride Chemical compound ClC(=O)CCI BVGKKICUUAFHFE-UHFFFAOYSA-N 0.000 claims description 3
- RVNUXWQUHSVKDZ-UHFFFAOYSA-N 3-iodopropanoyl iodide Chemical compound ICCC(I)=O RVNUXWQUHSVKDZ-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims 7
- 238000006243 chemical reaction Methods 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 16
- 239000000047 product Substances 0.000 description 11
- 239000002994 raw material Substances 0.000 description 7
- 239000012467 final product Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- CNRNYORZJGVOSY-UHFFFAOYSA-N 2,5-diphenyl-1,3-oxazole Chemical compound C=1N=C(C=2C=CC=CC=2)OC=1C1=CC=CC=C1 CNRNYORZJGVOSY-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000010587 phase diagram Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- FBWXUNCARHZYFO-UHFFFAOYSA-N C(=O)=C(C(=O)O)CCP(=O)(OCO)O Chemical compound C(=O)=C(C(=O)O)CCP(=O)(OCO)O FBWXUNCARHZYFO-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000004715 keto acids Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid Chemical compound CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000003512 Claisen condensation reaction Methods 0.000 description 2
- DWIFEYMXKLYISJ-UHFFFAOYSA-N OC(=O)C(=O)CCCl Chemical compound OC(=O)C(=O)CCCl DWIFEYMXKLYISJ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 239000005561 Glufosinate Substances 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- YHMDGPZOSGBQRH-UHFFFAOYSA-N PPO Natural products CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC YHMDGPZOSGBQRH-UHFFFAOYSA-N 0.000 description 1
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- GZBQGSURWYXEQF-UHFFFAOYSA-N ethoxy(methyl)phosphinous acid Chemical compound CCOP(C)O GZBQGSURWYXEQF-UHFFFAOYSA-N 0.000 description 1
- XOAXXVYLOZLMLP-UHFFFAOYSA-N ethyl 4-chloro-2-oxobutanoate Chemical compound CCOC(=O)C(=O)CCCl XOAXXVYLOZLMLP-UHFFFAOYSA-N 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Abstract
The invention provides a synthesis method of a 4-halogenated-2-carbonyl butyrate intermediate, which comprises the following steps: a) Mixing cyanide, a phase transfer catalyst and 3-halogenated propionyl halide, carrying out substitution reaction, and filtering to obtain 3-halogenated propionyl cyanide crude material liquid; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, poly fatty alcohol castor oil, quaternary ammonium salt and quaternary phosphonium salt; b) Mixing the 3-halogenated propionyl cyanide crude material liquid obtained in the step a) with an acid aqueous solution, performing hydrolysis reaction, and purifying to obtain 4-halogenated-2-carbonyl butyric acid crude material liquid; c) Mixing the crude material liquid of the 4-halogenated-2-carbonyl butyric acid obtained in the step b) with alcohol, carrying out esterification reaction, and purifying to obtain the intermediate of the 4-halogenated-2-carbonyl butyric acid ester. The synthesis method has simple process, mild and easily controlled conditions and higher yield.
Description
Technical Field
The invention relates to the technical field of fine chemical engineering, in particular to a method for synthesizing a pesticide intermediate 4-halogenated-2-carbonyl butyrate.
Background
4- (hydroxy methyl phosphono) -2-carbonyl butyric acid, PPO or keto acid for short, is an important intermediate in the synthesis process of glufosinate-ammonium, and the intermediate compound can be catalyzed by a biological enzyme method to obtain L-glufosinate-ammonium.
There are various methods for the synthesis of PPO. In 1980, the FBC company first filed patent US4399287A for preparing a keto acid intermediate, and 3- (ethoxymethylphosphono) propionate was subjected to a claisen condensation reaction to obtain the keto acid intermediate 4- (hydroxymethylphosphono) -2-carbonyl butyric acid, wherein the isolation yield of the target product is only about 30%.
In 1991, hoechest reported a chemical synthesis method (j.org.chem., 1991,56,1783-1788) of a 4-halo-2-carbonyl butyrate intermediate, wherein 3- (ethoxymethylphosphonyl) -ethyl propionate is prepared by michael addition reaction of monoethyl methylphosphonite and ethyl acrylate under the action of sodium ethoxide, then claisen ester condensation reaction is carried out between the ethyl propionate and diethyl oxalate under the action of sodium ethoxide at-50 ℃, and then the 4-halo-2-carbonyl butyrate intermediate is prepared by decarboxylation of hydrochloric acid; however, the method needs to be carried out at the temperature of minus 50 ℃, has lower overall yield and generates a large amount of wastewater, and meanwhile, the crystallization time of the product is as long as 48 hours, and the reaction formula is as follows:
from the above, in the reported PPO synthesis method, most of the raw materials used undergo claisen condensation or ring opening reaction steps, the synthesis conditions are harsh, the control is complex, and the yield is low. Therefore, it is necessary to efficiently and conveniently construct the key skeleton component of PPO from the raw material intermediate, thereby improving the synthesis yield.
Disclosure of Invention
In view of the above, the invention aims to provide a synthesis method of 4-halogeno-2-carbonyl butyrate intermediate, which has the advantages of simple process, mild condition, easy control and higher yield.
The invention provides a synthesis method of a 4-halogenated-2-carbonyl butyrate intermediate, which comprises the following steps:
a) Mixing cyanide, a phase transfer catalyst and 3-halogenated propionyl halide, carrying out substitution reaction, and filtering to obtain 3-halogenated propionyl cyanide crude material liquid; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, poly fatty alcohol castor oil, quaternary ammonium salt and quaternary phosphonium salt;
b) Mixing the 3-halogenated propionyl cyanide crude material liquid obtained in the step a) with an acid aqueous solution, performing hydrolysis reaction, and purifying to obtain 4-halogenated-2-carbonyl butyric acid crude material liquid;
c) Mixing the crude material liquid of the 4-halogenated-2-carbonyl butyric acid obtained in the step b) with alcohol, carrying out esterification reaction, and purifying to obtain the intermediate of the 4-halogenated-2-carbonyl butyric acid ester.
Preferably, the cyanide in step a) is selected from one or more of cuprous cyanide, sodium cyanide and hydrocyanic acid;
the 3-halogenopropionyl halide is selected from one or more of 3-chloropropionyl chloride, 3-chloropropionyl bromide, 3-chloropropionyl iodide, 3-bromopropionyl chloride, 3-bromopropionyl bromide, 3-bromopropionyl iodide, 3-iodopropionyl chloride, 3-iodopropionyl bromide and 3-iodopropionyl iodide.
Preferably, the phase transfer catalyst in step a) is added in an amount of 0.01% to 0.5% by mass of the 3-halopropionyl halide.
Preferably, the molar ratio of cyanide to 3-halopropionyl halide in step a) is (0.9 to 2.0): 1.
preferably, the temperature of the substitution reaction in step a) is between-10 ℃ and 110 ℃ and the time is between 0.5h and 18h.
Preferably, the aqueous acid in step b) is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid;
the molar ratio of the acid in the acid aqueous solution to the 3-halogenated propionyl cyanide is (1-10): 1.
preferably, the hydrolysis reaction in step b) is carried out at a temperature of 50 to 130 ℃ for a time of 1 to 24 hours.
Preferably, the alcohol in step c) is selected from one or more of methanol, ethanol, isopropanol and butanol;
the molar ratio of the alcohol to the 4-halogeno-2-carbonyl butyric acid is (0.9-3): 1.
preferably, the temperature of the esterification reaction in step c) is 70-105 ℃ and the time is 1-24 h.
Preferably, the purification treatment in step c) is specifically performed by:
adding 10-30wt% sodium hydroxide aqueous solution into the product obtained by the esterification reaction, neutralizing to pH 4-6, continuously decompressing and desolventizing to 50-120 ℃, cooling to room temperature, and filtering to remove insoluble solids to obtain the 4-halogenated-2-carbonyl butyric acid.
The invention provides a synthesis method of a 4-halogenated-2-carbonyl butyrate intermediate, which comprises the following steps: a) Mixing cyanide, a phase transfer catalyst and 3-halogenated propionyl halide, carrying out substitution reaction, and filtering to obtain 3-halogenated propionyl cyanide crude material liquid; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, poly fatty alcohol castor oil, quaternary ammonium salt and quaternary phosphonium salt; b) Mixing the 3-halogenated propionyl cyanide crude material liquid obtained in the step a) with an acid aqueous solution, performing hydrolysis reaction, and purifying to obtain 4-halogenated-2-carbonyl butyric acid crude material liquid; c) Mixing the crude material liquid of the 4-halogenated-2-carbonyl butyric acid obtained in the step b) with alcohol, carrying out esterification reaction, and purifying to obtain the intermediate of the 4-halogenated-2-carbonyl butyric acid ester. Compared with the prior art, the synthesis method provided by the invention takes 3-halogenopropionyl halide and cyanide as raw materials, 3-halogenopropionyl cyanide is obtained through reaction, cyano is hydrolyzed under an acidic condition to generate 4-halogeno-2-carbonyl butyric acid, and then the 4-halogeno-2-carbonyl butyric acid ester is further esterified with alcohol to generate a final product; the synthesis method has simple process, mild and easily controlled conditions and higher yield.
Drawings
FIG. 1 is a liquid phase diagram of the 4-chloro-2-oxo-butyric acid product of example 1 of the present invention;
FIG. 2 is a liquid phase diagram of a 4-chloro-2-oxo-butyric acid standard;
FIG. 3 is a gas chromatograph of the ethyl 4-chloro-2-oxo-butyrate product of example 1 of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a synthesis method of a 4-halogenated-2-carbonyl butyrate intermediate, which comprises the following steps:
a) Mixing cyanide, a phase transfer catalyst and 3-halogenated propionyl halide, carrying out substitution reaction, and filtering to obtain 3-halogenated propionyl cyanide crude material liquid; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, poly fatty alcohol castor oil, quaternary ammonium salt and quaternary phosphonium salt;
b) Mixing the 3-halogenated propionyl cyanide crude material liquid obtained in the step a) with an acid aqueous solution, performing hydrolysis reaction, and purifying to obtain 4-halogenated-2-carbonyl butyric acid crude material liquid;
c) Mixing the crude material liquid of the 4-halogenated-2-carbonyl butyric acid obtained in the step b) with alcohol, carrying out esterification reaction, and purifying to obtain the intermediate of the 4-halogenated-2-carbonyl butyric acid ester.
The invention provides a method for synthesizing a 4-halogeno-2-carbonyl butyrate intermediate, which takes 3-halogeno propionyl halide (shown in the formula I) and cyanide (shown in the formula II) as raw materials, obtains 3-halogeno propionyl cyanide (shown in the formula III) through reaction, hydrolyzes cyano under acidic condition to generate 4-halogeno-2-carbonyl butyrate (shown in the formula IV), and then further esterifies the 4-halogeno-2-carbonyl butyrate with alcohol (shown in the formula V) to generate a final product 4-halogeno-2-carbonyl butyrate (shown in the formula VI).
The invention has the innovation points that a carbon chain skeleton is constructed through carburetion reaction of 3-halogenopropionyl halide and sodium cyanide, and halogen atoms at the top end of the carbon chain can further bridge compounds such as alkyl phosphonate and the like, so that an important intermediate 4- (hydroxy methylphosphono) -2-carbonyl butyric acid of glufosinate can be efficiently and conveniently prepared; the substitution reaction is carried out in a solvent-free mode, the reaction is fully realized through a specific phase transfer catalyst, the residual solid raw materials and salt generated by the reaction can be directly filtered and removed, and the steps of separating and recovering the solvent are effectively reduced; and after the 3-halogeno propionyl cyanide is hydrolyzed to generate 4-halogeno-2-carbonyl butyric acid in acid, the system can remove excessive water and further catalyze the esterification reaction by using the residual acid.
The reaction formula of the synthesis method of the 4-halogenated-2-carbonyl butyrate intermediate provided by the invention is as follows:
the invention firstly mixes cyanide, phase transfer catalyst and 3-halogeno propionyl halide, carries out substitution reaction, and filters to obtain 3-halogeno propionyl cyanide crude material liquid.
In the present invention, the cyanide is preferably one or more selected from the group consisting of cuprous cyanide, sodium cyanide and hydrocyanic acid, more preferably cuprous cyanide; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compound, poly fatty alcohol castor oil, quaternary ammonium salt and quaternary phosphonium salt, preferably polyethylene glycol, crown ether compound, poly fatty alcohol castor oil, quaternary ammonium salt or quaternary phosphonium salt, more preferably polyethylene glycol or crown ether compound; the 3-halopropionyl halide is preferably one or more selected from 3-chloropropionyl chloride, 3-chloropropionyl bromide, 3-chloropropionyl iodide, 3-bromopropionyl chloride, 3-bromopropionyl bromide, 3-bromopropionyl iodide, 3-iodopropionyl chloride, 3-iodopropionyl bromide and 3-iodopropionyl iodide, more preferably 3-chloropropionyl chloride or 3-chloropropionyl bromide. The sources of the cyanide compound, the phase transfer catalyst and the 3-halopropionyl halide are not particularly limited, and commercially available products known to those skilled in the art may be used.
In the present invention, the addition amount of the phase transfer catalyst is preferably 0.01 to 0.5% by mass, more preferably 0.07 to 0.1% by mass, based on the mass of the 3-halopropionyl halide.
In the present invention, the molar ratio of the cyanide to the 3-halopropionyl halide is preferably (0.9 to 2.0): 1, more preferably (1 to 1.1): 1.
in the present invention, the process of mixing cyanide, phase transfer catalyst and 3-halopropionyl halide is preferably specifically:
cyanide (solid) is added to the reactor, and a phase transfer catalyst is added, followed by gradual addition of 3-halopropionyl halide (liquid); then heating and stirring to react.
In the present invention, the temperature of the substitution reaction is preferably-10 to 110 ℃, more preferably 50 to 70 ℃; the time for the substitution reaction is preferably 0.5 to 18 hours, more preferably 3 to 6 hours.
In the invention, the filtration mode is preferably suction filtration, and the purpose is to remove insoluble solids, so as to obtain 3-halogenated propionyl cyanide crude liquid.
After the 3-halogenated propionyl cyanide crude material liquid is obtained, the obtained 3-halogenated propionyl cyanide crude material liquid is mixed with an acid aqueous solution for hydrolysis reaction, and the 4-halogenated-2-carbonyl butyric acid crude material liquid is obtained after purification.
In the present invention, the aqueous acid solution is preferably one or more selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, more preferably hydrochloric acid. The source of the aqueous acid solution is not particularly limited, and commercially available products known to those skilled in the art may be used.
In the present invention, the molar ratio of the acid in the aqueous acid solution to 3-halopropionyl cyanide is preferably (1 to 10): 1, more preferably (3 to 4): 1.
in the present invention, the temperature of the hydrolysis reaction is preferably 50 to 130 ℃, more preferably 90 to 110 ℃; the hydrolysis reaction time is preferably 1 to 24 hours, more preferably 3 to 10 hours.
In the present invention, the purification process is preferably specifically:
and (3) removing excessive water from the product obtained by the hydrolysis reaction under reduced pressure, cooling to room temperature, and filtering out insoluble salt solids to obtain crude 4-halogeno-2-carbonyl butyric acid feed liquid.
In the present invention, the temperature for removing excess water under reduced pressure is preferably 50 to 150 ℃, more preferably 90 to 100 ℃.
After the crude material liquid of the 4-halogenated-2-carbonyl butyric acid is obtained, the obtained crude material liquid of the 4-halogenated-2-carbonyl butyric acid is mixed with alcohol for esterification reaction, and then the 4-halogenated-2-carbonyl butyric acid ester intermediate is obtained after purification treatment.
In the present invention, the alcohol is preferably one or more selected from methanol, ethanol, isopropanol and butanol, more preferably ethanol. The source of the alcohol is not particularly limited in the present invention, and commercially available products known to those skilled in the art may be used.
In the present invention, the molar ratio of the alcohol to 4-halogeno-2-carbonyl-butyric acid is preferably (0.9 to 3): 1, more preferably (1.1 to 1.5): 1.
in the present invention, the temperature of the esterification reaction is preferably 70 to 105 ℃, more preferably 75 to 90 ℃; the time of the esterification reaction is preferably 1 to 24 hours, more preferably 4 to 8 hours; the technical scheme of the heating reflux reaction which is well known to the person skilled in the art is adopted.
In the present invention, the purification treatment is preferably performed by:
adding 10-30wt% sodium hydroxide aqueous solution into the product obtained by the esterification reaction, neutralizing until the pH value is 4-6, continuously decompressing and desolventizing to 50-120 ℃, cooling to room temperature, and filtering to remove insoluble solids to obtain 4-halogenated-2-carbonyl ethyl butyrate;
more preferably:
and adding a 20wt% sodium hydroxide aqueous solution into the product obtained by the esterification reaction, neutralizing to pH 5, continuously decompressing and desolventizing to 105-110 ℃, cooling to room temperature, and filtering to remove insoluble solids to obtain the ethyl 4-halogeno-2-carbonyl butyrate.
The invention provides a synthesis method of a 4-halogenated-2-carbonyl butyrate intermediate, which comprises the following steps: a) Mixing cyanide, a phase transfer catalyst and 3-halogenated propionyl halide, carrying out substitution reaction, and filtering to obtain 3-halogenated propionyl cyanide crude material liquid; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, poly fatty alcohol castor oil, quaternary ammonium salt and quaternary phosphonium salt; b) Mixing the 3-halogenated propionyl cyanide crude material liquid obtained in the step a) with an acid aqueous solution, performing hydrolysis reaction, and purifying to obtain 4-halogenated-2-carbonyl butyric acid crude material liquid; c) Mixing the crude material liquid of the 4-halogenated-2-carbonyl butyric acid obtained in the step b) with alcohol, carrying out esterification reaction, and purifying to obtain the intermediate of the 4-halogenated-2-carbonyl butyric acid ester. Compared with the prior art, the synthesis method provided by the invention takes 3-halogenopropionyl halide and cyanide as raw materials, 3-halogenopropionyl cyanide is obtained through reaction, cyano is hydrolyzed under an acidic condition to generate 4-halogeno-2-carbonyl butyric acid, and then the 4-halogeno-2-carbonyl butyric acid ester is further esterified with alcohol to generate a final product; the synthesis method has simple process, mild and easily controlled conditions and higher yield.
In order to further illustrate the present invention, the following examples are provided. The raw materials used in the following examples of the present invention are all commercially available.
Example 1
(1) 50.3g of cuprous cyanide (0.55 mol) powder and 0.07g of polyethylene glycol are added into a 500ml four-necked flask, then 66.85g of 95% 3-chloropropionyl chloride (0.5 mol) is gradually added, and the temperature is raised to 60 ℃ for continuous reaction for 6 hours; insoluble solids in the system were removed by suction filtration to give 55.1g of a filtrate.
(2) 180g (1.5 mol) of 30% hydrochloric acid is continuously added into the feed liquid, after stirring and heating to 100 ℃ for full hydrolysis reaction for 6 hours, the pressure is further reduced, the temperature is further increased to 95 ℃ to remove acid water, the temperature is cooled to room temperature, insoluble salt solids are filtered out, 67.74g of 4-chloro-2-carbonyl butyric acid crude feed liquid is obtained, wherein the purity of 4-chloro-2-carbonyl butyric acid is 87.5%, the yield is 86.84% (0.434 mol), the liquid phase diagram is shown in fig. 1, and the other is: the liquid phase diagram of the standard sample of 4-chloro-2-carbonyl butyric acid is shown in figure 2.
(3) After the above feed liquid is cooled, 50.6g (1.1 mol) of absolute ethyl alcohol is continuously added, the temperature is raised to 75 ℃ and the mixture is stirred and refluxed for 6 hours, after the reaction is complete, 75.0g of 20% sodium hydroxide aqueous solution is slowly added until the pH is 5.0, the mixture is continuously decompressed and desolventized to 105 ℃, then cooled to room temperature and filtered to remove insoluble solids, 70.4g of final product is obtained, the purity of 4-chloro-2-carbonyl ethyl butyrate is 93.4% after gas phase analysis, the overall yield is 79.94% (0.400 mol), and the gas phase chromatogram is shown in FIG. 3.
Example 2
(1) 50.3g of cuprous cyanide (0.55 mol) powder and 0.07g of polyethylene glycol are added into a 500ml four-necked flask, then 90.26g of 95% 3-chloropropionyl bromide (0.5 mol) is gradually added, and the temperature is raised to 60 ℃ for continuous reaction for 6 hours; insoluble solids in the system were removed by suction filtration to give 56.1g of filtrate.
(2) 180g (1.5 mol) of 30% hydrochloric acid is continuously added into the feed liquid, after stirring and heating to 100 ℃ for full hydrolysis reaction for 6 hours, the pressure is further reduced, the temperature is further increased to 95 ℃ to remove acid water, the temperature is cooled to room temperature, insoluble salt solids are filtered out, 70.45g of 4-chloro-2-carbonyl butyric acid crude feed liquid is obtained, the purity of 4-chloro-2-carbonyl butyric acid is 85.9%, and the yield is 88.67% (0.443 mol).
(3) After the feed liquid is cooled, 50.6g (1.1 mol) of absolute ethyl alcohol is continuously added, the temperature is raised to 75 ℃ and the mixture is stirred and refluxed for 6 hours, after the reaction is complete, 74.3g of 20% sodium hydroxide aqueous solution is slowly added until the pH is 5.0, the mixture is continuously decompressed and desolventized to 105 ℃, then cooled to room temperature and filtered to remove insoluble solids, 70.7g of final product is obtained, and the purity of the ethyl 4-chloro-2-carbonyl butyrate is 93.6% and the overall yield is 80.46% (0.402 mol) through gas phase analysis.
Examples 3 to 9
The preparation method provided in example 1 was used, with the difference that: the types and amounts of the phase transfer catalysts were varied, and specific reaction conditions and experimental results are shown in table 1.
Reaction conditions and Experimental results in examples 3 to 9
Example 10
(1) Into a 500ml four-necked flask, 27.0g of sodium cyanide (0.55 mol) powder and 0.07g of polyethylene glycol were charged, followed by gradually adding 66.85g of 95% 3-chloropropionyl chloride (0.5 mol), and heating to 60℃for continuous reaction for 6 hours; insoluble solids in the system were removed by suction filtration to give 54.3g of filtrate.
(2) 180g (1.5 mol) of 30% hydrochloric acid is continuously added into the feed liquid, after stirring and heating to 100 ℃ for full hydrolysis reaction for 6 hours, the pressure is further reduced, the temperature is further increased to 95 ℃ for acid water removal, the temperature is cooled to room temperature, insoluble salt solids are filtered out, 65.70g of 4-chloro-2-carbonyl butyric acid crude feed liquid is obtained, the purity of 4-chloro-2-carbonyl butyric acid is 86.80%, and the yield is 83.56% (0.418 mol).
(3) After the feed liquid is cooled, 50.6g (1.1 mol) of absolute ethyl alcohol is continuously added, the temperature is raised to 75 ℃ and the mixture is stirred and refluxed for 6 hours, after the reaction is complete, 75.0g of 20% sodium hydroxide aqueous solution is slowly added until the pH is 5.0, the mixture is continuously decompressed and desolventized to 105 ℃, then cooled to room temperature and filtered to remove insoluble solids, 69.2g of final product is obtained, and the purity of 4-chloro-2-carbonyl ethyl butyrate is 91.2% and the overall yield is 76.73% (0.384 mol) through gas phase analysis.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A method for synthesizing a 4-halo-2-carbonyl butyrate intermediate, comprising the following steps:
a) Mixing cyanide, a phase transfer catalyst and 3-halogenated propionyl halide, carrying out substitution reaction, and filtering to obtain 3-halogenated propionyl cyanide crude material liquid; the phase transfer catalyst is selected from one or more of polyethylene glycol, crown ether compounds, poly fatty alcohol castor oil, quaternary ammonium salt and quaternary phosphonium salt;
b) Mixing the 3-halogenated propionyl cyanide crude material liquid obtained in the step a) with an acid aqueous solution, performing hydrolysis reaction, and purifying to obtain 4-halogenated-2-carbonyl butyric acid crude material liquid;
c) Mixing the crude material liquid of the 4-halogenated-2-carbonyl butyric acid obtained in the step b) with alcohol, carrying out esterification reaction, and purifying to obtain the intermediate of the 4-halogenated-2-carbonyl butyric acid ester.
2. The synthetic method according to claim 1, wherein the cyanide in step a) is selected from one or more of cuprous cyanide, sodium cyanide and hydrocyanic acid;
the 3-halogenopropionyl halide is selected from one or more of 3-chloropropionyl chloride, 3-chloropropionyl bromide, 3-chloropropionyl iodide, 3-bromopropionyl chloride, 3-bromopropionyl bromide, 3-bromopropionyl iodide, 3-iodopropionyl chloride, 3-iodopropionyl bromide and 3-iodopropionyl iodide.
3. The synthesis method according to claim 1, wherein the addition amount of the phase transfer catalyst in step a) is 0.01 to 0.5% by mass of the 3-halopropionyl halide.
4. The synthetic method according to claim 1, wherein the molar ratio of cyanide to 3-halopropionyl halide in step a) is (0.9 to 2.0): 1.
5. the method according to claim 1, wherein the substitution reaction in step a) is carried out at a temperature of-10 to 110 ℃ for a time of 0.5 to 18 hours.
6. The synthetic method according to claim 1, wherein the aqueous acid in step b) is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid;
the molar ratio of the acid in the acid aqueous solution to the 3-halogenated propionyl cyanide is (1-10): 1.
7. the synthetic method according to claim 1, wherein the hydrolysis reaction in step b) is carried out at a temperature of 50 ℃ to 130 ℃ for a time of 1h to 24h.
8. The synthetic method according to claim 1, wherein the alcohol in step c) is selected from one or more of methanol, ethanol, isopropanol and butanol;
the molar ratio of the alcohol to the 4-halogeno-2-carbonyl butyric acid is (0.9-3): 1.
9. the synthetic method according to claim 1, wherein the esterification reaction in step c) is carried out at a temperature of 70 to 105 ℃ for a time of 1 to 24 hours.
10. The synthetic method according to claim 1, wherein the purification treatment in step c) is specifically performed by:
adding 10-30wt% sodium hydroxide aqueous solution into the product obtained by the esterification reaction, neutralizing to pH 4-6, continuously decompressing and desolventizing to 50-120 ℃, cooling to room temperature, and filtering to remove insoluble solids to obtain 4-halogenated-2-carbonyl butyrate.
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