CN112250599A - Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester - Google Patents
Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester Download PDFInfo
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Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester. The invention takes a compound A as an initial raw material, and the compound A reacts with N-bromosuccinimide to form a compound B, and then the compound B reacts and other subsequent reactions to form 4-bromo-2-cyano-3-methyl fluorobenzoate.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester.
Background
At present, fluorine-containing fine chemicals are abnormally actively researched, and hundreds of fluorine-containing organic intermediates and fine chemicals are developed, particularly fluorine-containing fine chemicals are rapidly developed. Due to the special property of fluorine atoms, the organic fluorine compound has higher chemical stability, physiological activity, fat solubility and hydrophobicity, and is widely applied to the fields of medicines, pesticides, auxiliaries and the like.
Methyl 4-bromo-2-cyano-3-fluorobenzoate is one of fluorine-containing fine chemicals, and the property thereof is widely applied to the fields of pesticides, medicines and the like. As fluorine-containing fine chemicals, methyl 4-bromo-2-cyano-3-fluorobenzoate is an important intermediate for synthesizing medicines and pesticides. However, the synthesis method of methyl 4-bromo-2-cyano-3-fluorobenzoate is only reported in literature. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: aiming at the problems, the synthesis method of the 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthetic method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester comprises the following steps:
(1) mixing the compound A and acetic acid in a reactor, adding N-bromosuccinimide, and stirring to obtain a compound B
(2) Adding the compound B, iodine and DMF into a reactor, protecting with nitrogen, cooling, adding tert-butyl nitrite, stirring to obtain a compound C
(3) Adding the compound C, triethylamine, a catalyst and methanol into an autoclave, introducing CO, adjusting the pressure to 1.3-1.5 MPa, heating, and reacting to obtain a compound D, namely 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester
Preferably, in the step (1), the solid-to-liquid ratio g/mL of the compound A to acetic acid is 1:20, and the mass ratio of the compound A, N-bromosuccinimide is 1: 2-3.
Preferably, the solid-to-liquid ratio g/mL of the compound B, DMF in the step (2) is 1:20, and the mass ratio of the compound B, iodine and tert-butyl nitrite is 10: 16-17: 7-8.
Preferably, the catalyst in the step (3) is Pd (Dppf)2Cl2。
Preferably, the mass ratio of the compound C, triethylamine and the catalyst in the step (3) is 6: 4-5: 1-2, and the solid-liquid ratio g/mL of the compound C and methanol is 1: 50.
Compared with other methods, the method has the beneficial technical effects that:
(1) the method takes a compound A as an initial raw material, and comprises the steps of reacting the compound A with N-bromosuccinimide to form a compound B, and then carrying out subsequent reactions such as the reaction of the compound B to form 4-bromo-2-cyano-3-methyl fluorobenzoate, wherein the synthesis method of the 4-bromo-2-cyano-3-methyl fluorobenzoate is provided for the first time;
(2) the product obtained by the method has high yield and good purity.
Detailed Description
The catalyst is Pd (Dppf)2Cl2。
A synthetic method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester comprises the following steps:
(1) taking materials according to the solid-liquid ratio g/mL of the compound A to acetic acid of 1:20 and the mass ratio of the compound A, N-bromosuccinimide of 1: 2-3, putting the compound A and acetic acid into a reactor for mixing, adding N-bromosuccinimide, and stirring for 15-20 h at 28-35 ℃ to obtain a compound B;
(2) taking materials according to the solid-liquid ratio g/mL of the compound B, DMF of 1:20 and the mass ratio of the compound B, iodine and tert-butyl nitrite of 10: 16-17: 7-8, adding the compound B, iodine and DMF into a reactor, protecting with nitrogen, cooling to-1 ℃, adding the tert-butyl nitrite, and stirring for 23-26 h to obtain a compound C;
(3) according to the mass ratio of the compound C to the triethylamine to the catalyst of 6: 4-5: 1-2 and the solid-liquid ratio g/mL of the compound C to the methanol of 1:50, taking materials, adding the compound C, the triethylamine, the catalyst and the methanol into a high-pressure kettle, introducing CO for protection, adjusting the pressure to 1.3-1.5 MPa, heating to 100-105 ℃, and reacting for 1-2 hours to obtain a compound D, namely 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester.
Example 1
The catalyst is Pd (Dppf)2Cl2。
A synthetic method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester comprises the following steps:
(1) placing 20g of the compound A and 400mL of acetic acid into a reactor for mixing, adding 40g of N-bromosuccinimide, stirring for 15h at 28 ℃, detecting by TLC, adding 600mL of water after the raw materials react, extracting by ethyl acetate (600 mL of 2), concentrating to dryness, washing the solid by water (500 mL), filtering, and drying a filter cake to obtain 29.3g of white solid, thus obtaining a compound B, wherein the yield is 92.8%, and the purity is 95.8%;
(2) adding 20g of compound B, 32g of iodine and 400ml of DMF into a reactor, cooling to-1 ℃ under the protection of nitrogen, adding 14g of tert-butyl nitrite, stirring for 23h, detecting by TLC, and finishing the reaction of the raw materials. Pouring the reaction solution into ice water (200 mL), adding saturated sodium bicarbonate (200 mL), extracting with ethyl acetate (400 mL × 2), washing with saturated sodium thiosulfate (150 mL), concentrating, stirring, and passing through a column to obtain 28.2g of yellow solid, so as to obtain a compound C, wherein the yield is 93.0%, and the purity is 96.8%;
(3) adding 18g of the compound C, 12g of triethylamine, 3g of a catalyst and 900mL of methanol into an autoclave, introducing CO for protection, adjusting the pressure to 1.3MPa, heating to 100 ℃, reacting for 1h, detecting by TLC to find that the raw materials are completely reacted, concentrating the reaction solution, adding 200mL of ethyl acetate, filtering by using kieselguhr, concentrating, mixing the sample with silica gel, and passing through a column to obtain 13.6g of white solid, namely the compound D, namely the 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester, wherein the yield is 95.4% and the purity is 97.6%.
Characterization of methyl 4-bromo-2-cyano-3-fluorobenzoate: 1H NMR (d 6-DMSO) 8.23(t, J =7.8Hz, 1H), 7.85(d, J =8.7Hz, 1H), 3.94(s, 3H).
Example 2
The catalyst is Pd (Dppf)2Cl2。
A synthetic method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester comprises the following steps:
(1) placing 20g of the compound A and 400mL of acetic acid into a reactor for mixing, adding 50g of N-bromosuccinimide, stirring for 18h at 30 ℃, detecting by TLC, adding 600mL of water after the raw materials react, extracting by ethyl acetate (600 mL of 2), concentrating to dryness, washing the solid by water (500 mL), filtering, and drying a filter cake to obtain 30.1g of white solid, thus obtaining a compound B, wherein the yield is 95.3%, and the purity is 95.2%;
(2) adding 20g of compound B, 34g of iodine and 400mL of DMMF into a reactor, carrying out nitrogen protection, cooling to 0 ℃, adding 16g of tert-butyl nitrite, stirring for 25h, carrying out TLC detection, pouring the reaction solution into ice water (200 mL), adding saturated sodium bicarbonate (200 mL), extracting with ethyl acetate (400 mL x 2), washing with saturated sodium thiosulfate (150 mL), concentrating, mixing the sample, and carrying out column chromatography to obtain 28.9g of yellow solid, thus obtaining compound C, wherein the yield is 95.3%, and the purity is 96.5%;
(3) adding 18g of the compound C, 15g of triethylamine, 6g of a catalyst and 900mL of methanol into an autoclave, introducing CO for protection, adjusting the pressure to 1.4MPa, heating to 103 ℃, reacting for 1.5h, detecting by TLC to find that the raw materials are completely reacted, concentrating the reaction solution, adding 200mL of ethyl acetate, filtering by using kieselguhr, concentrating, mixing the sample with silica gel, and passing through a column to obtain 13.8g of white solid, namely the compound D, namely the 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester, wherein the yield is 96.8%, and the purity is 98.1%.
Characterization of methyl 4-bromo-2-cyano-3-fluorobenzoate: 1H NMR (d 6-DMSO) 8.23(t, J =7.8Hz, 1H), 7.85(d, J =8.7Hz, 1H), 3.94(s, 3H).
Example 3
The catalyst is Pd (Dppf)2Cl2。
A synthetic method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester comprises the following steps:
(1) according to the solid-liquid ratio g/mL of the compound A to acetic acid being 1:20 and the mass ratio of the compound A, N-bromosuccinimide being 1: 2-3, taking materials, putting 20g of the compound A and 400mL of acetic acid into a reactor for mixing, adding 40g of N-bromosuccinimide, stirring for 20 hours at 35 ℃, detecting by TLC, after the reaction of the raw materials is finished, adding 600mL of water, extracting by ethyl acetate (600 mL x 2), concentrating to dryness, washing the solid by water (500 mL), filtering, drying a filter cake to obtain 29.0g of white solid, obtaining a compound B, wherein the yield is 91.8%, and the purity is 95.2%;
(2) adding 20g of compound B, 34g of iodine and 400ml of DMF into a reactor, cooling to 1 ℃ under the protection of nitrogen, adding 16g of tert-butyl nitrite, stirring for 26h, detecting by TLC, and finishing the reaction of the raw materials. Pouring the reaction solution into ice water (200 mL), adding saturated sodium bicarbonate (200 mL), extracting with ethyl acetate (400 mL × 2), washing with saturated sodium thiosulfate (150 mL), concentrating, stirring, and passing through a column to obtain 28.0 yellow solid, so as to obtain a compound C, wherein the yield is 92.4%, and the purity is 95.7%;
(3) adding 18g of the compound C, 15g of triethylamine, 6g of a catalyst and 900mL of methanol into an autoclave, introducing CO for protection, adjusting the pressure to 1.3MPa, heating to 100 ℃, reacting for 1h, detecting by TLC to find that the raw materials are completely reacted, concentrating the reaction solution, adding 200mL of ethyl acetate, filtering by using kieselguhr, concentrating, mixing the sample with silica gel, and passing through a column to obtain 13.3g of white solid, namely the compound D, namely the 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester, wherein the yield is 93.3% and the purity is 94.9%.
Characterization of methyl 4-bromo-2-cyano-3-fluorobenzoate: 1H NMR (d 6-DMSO) 8.23(t, J =7.8Hz, 1H), 7.85(d, J =8.7Hz, 1H), 3.94(s, 3H).
Claims (5)
1. A synthetic method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester is characterized by comprising the following steps:
(1) mixing the compound A and acetic acid in a reactor, adding N-bromosuccinimide, and stirring to obtain a compound B
(2) Adding the compound B, iodine and DMF into a reactor, protecting with nitrogen, cooling, adding tert-butyl nitrite, stirring to obtain a compound C
(3) Adding the compound C, triethylamine, a catalyst and methanol into an autoclave, introducing CO, adjusting the pressure to 1.3-1.5 MPa, heating, and reacting to obtain a compound D, namely 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester
2. The synthesis method of methyl 4-bromo-2-cyano-3-fluorobenzoate according to claim 1, wherein the solid-to-liquid ratio g/mL of the compound A to acetic acid in the step (1) is 1:20, and the mass ratio of the compound A, N-bromosuccinimide is 1: 2-3.
3. The synthesis method of methyl 4-bromo-2-cyano-3-fluorobenzoate according to claim 1, wherein the solid-to-liquid ratio g/mL of the compound B, DMF in the step (2) is 1:20, and the mass ratio of the compound B, iodine and tert-butyl nitrite is 10: 16-17: 7-8.
4. The method for synthesizing methyl 4-bromo-2-cyano-3-fluorobenzoate according to claim 1, wherein the catalyst used in the step (3) is Pd (Dppf)2Cl2。
5. The synthesis method of methyl 4-bromo-2-cyano-3-fluorobenzoate according to claim 1, wherein the mass ratio of the compound C, triethylamine and the catalyst in the step (3) is 6: 4-5: 1-2, and the solid-to-liquid ratio g/mL of the compound C and methanol is 1: 50.
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Cited By (2)
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| CN112574040A (en) * | 2021-01-28 | 2021-03-30 | 阿里生物新材料（常州）有限公司 | Synthesis method of ethyl 2, 3-dichloro-4-nitrobenzoate |
| CN112707831A (en) * | 2021-02-05 | 2021-04-27 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3- (1-aminocyclopropyl) methyl benzoate |
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