CN111646922B - Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid - Google Patents

Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid Download PDF

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CN111646922B
CN111646922B CN202010703104.4A CN202010703104A CN111646922B CN 111646922 B CN111646922 B CN 111646922B CN 202010703104 A CN202010703104 A CN 202010703104A CN 111646922 B CN111646922 B CN 111646922B
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fluorophenyl
bromo
cyano
acetic acid
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CN111646922A (en
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许义波
王超
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Alibaba Biological New Materials Changzhou Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds

Abstract

The invention belongs to a medical intermediate, and particularly relates to a synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid. The invention provides a synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid for the first time, provides a synthetic route for the synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid, and has the advantages of short synthetic route, reasonable design, simple operation and easy control; the yield and the purity of the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid prepared by the method are high.

Description

Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid
Technical Field
The invention belongs to a medical intermediate, and particularly relates to a synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid.
Background
The phenylacetic acid derivative is an important medical intermediate, such as 3, 4-dimethoxyphenylacetic acid, which is used for preparing and synthesizing beta receptor blocker bevantolol (bevantolol) and antiarrhythmic drug verapamil (verapamil), and is also a key intermediate for synthesizing other alkaloids; p-methoxyphenylacetic acid, 3, 4, 5-trimethoxyphenylacetic acid are useful organic synthetic intermediates.
The synthesis methods of phenylacetic acid derivatives disclosed at present include the following methods:
the benzyl cyanide method: uses phenylacetonitrile as raw material, firstly modifies benzene ring to obtain target structure, and then hydrolyzes to obtain p-hydroxyphenylacetic acid (Shengweicheng, China journal of pharmaceutical industry, 1993,24 (6): 276-277). The method has the advantages of easily available raw materials, long reaction route, obvious side reaction and low reaction yield.
Chloral method: phenol and chloral are used as raw materials to generate electrochemical reaction to obtain p-hydroxy-beta, beta-dichlorostyrene, and the p-hydroxy-beta, beta-dichlorostyrene is hydrolyzed to obtain p-hydroxyphenylacetic acid (Penilin, etc., Zhejiang chemical industry 1997 (4): 22-23). The process has simple route and high product quality, but the raw material of chloral is not easy to obtain and has high price.
The compound 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid is one of phenylacetic acid derivatives, and the synthesis method and related derivatives thereof have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid is only reported in documents. 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 existing problems, the synthesis method of the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for synthesizing 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid, which has the following chemical reaction formula:
；
the synthesis comprises the following steps:
(1) mixing the compound A and concentrated sulfuric acid, cooling, adding N-iodosuccinimide, heating, stirring, and reacting to obtain compound B
；
(2) Uniformly mixing the compound B and methanol, dropwise adding concentrated sulfuric acid, heating, and reacting at a constant temperature to obtain a compound C
；
(3) Putting the compound C, zinc cyanide, palladium tetratriphenylphosphine and dimethylformamide into a reactor, uniformly mixing, using nitrogen for protection, heating and reacting to obtain a compound D
；
(4) Uniformly mixing the compound D and tetrahydrofuran, dropwise adding a lithium hydroxide aqueous solution with the mass fraction of 4.3%, and stirring for reaction to obtain a compound E, namely the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid
。
Preferably, in the step (1), the mass ratio of the compound A, N-iodosuccinimide is 1: 0.8-1.2, and the solid-liquid g/mL ratio of the compound A to concentrated sulfuric acid is 1: 16.
Preferably, the mass ratio of the compound B to concentrated sulfuric acid in the step (2) is 1: 0.5-0.8, and the solid-liquid g/mL ratio of the compound B to methanol is 1: 12.
Preferably, in the step (3), the mass ratio of the compound C, the zinc cyanide and the palladium tetratriphenylphosphine is 12: 3-4: 1-2, and the solid-liquid g/mL ratio of the compound C to the dimethylformamide is 1: 17.
Preferably, the solid-liquid g/mL ratio of the compound D and tetrahydrofuran is 1:7, and the volume ratio of the tetrahydrofuran and the lithium hydroxide aqueous solution with the mass fraction of 4.3% is 1: 1.
Compared with other methods, the method has the beneficial technical effects that:
(1) the invention provides a synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid for the first time, and provides a synthetic route for the synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid;
(2) the synthetic method of the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid provided by the invention is short in route, reasonable in design, simple to operate and easy to control;
(3) the yield and the purity of the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid prepared by the method are high.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.
A method for synthesizing 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid comprises the following steps:
(1) taking materials according to the mass ratio of A, N-iodosuccinimide of 1: 0.8-1.2 and the solid-liquid g/mL ratio of compound A to concentrated sulfuric acid of 1:16, mixing the compound A and the concentrated sulfuric acid, cooling to 0-3 ℃, adding N-iodosuccinimide, and adding the N-iodosuccinimide in three parts by mass at intervals of 5min, heating to 28-35 ℃, and stirring for reacting for 18h to obtain a compound B;
(2) taking materials according to the mass ratio of the compound B to concentrated sulfuric acid of 1: 0.5-0.8 and the solid-liquid g/mL ratio of the compound B to methanol of 1:12, uniformly mixing the compound B and methanol, dropwise adding concentrated sulfuric acid, heating to 80 ℃, and carrying out heat preservation reaction for 17 hours to obtain a compound C;
(3) taking materials according to the mass ratio of 12: 3-4: 1-2 of the compound C, zinc cyanide and tetratriphenylphosphine palladium and the solid-liquid g/mL ratio of 1:17 of the compound C and dimethylformamide, putting the compound C, zinc cyanide, tetratriphenylphosphine palladium and dimethylformamide into a reactor, uniformly mixing, using nitrogen for protection, heating to 100 ℃, and reacting for 15-18 hours to obtain a compound D;
(4) taking materials according to the solid-liquid g/mL ratio of the compound D to tetrahydrofuran of 1:7 and the volume ratio of the tetrahydrofuran to the 4.3% lithium hydroxide aqueous solution of 1:1, uniformly mixing the compound D and the tetrahydrofuran, dropwise adding the 4.3% lithium hydroxide aqueous solution, and stirring for reacting for 16h to obtain a compound E, namely the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid.
Example 1
A method for synthesizing 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid comprises the following steps:
(1) mixing 12.5g of compound A with 200mL of concentrated sulfuric acid, cooling to 0 ℃, adding 12g of N-iodosuccinimide, dividing the mixture into three parts by mass, adding the three parts in batches at intervals of 5min, heating to 30 ℃, stirring for reacting for 18h, detecting by TLC (thin layer chromatography), pouring the reaction solution into 500mL of ice water after the reaction of the raw materials is finished, extracting by ethyl acetate (300 mL of 2), and concentrating the organic phase to obtain 15.3g of yellow solid, namely compound B, wherein the purity is 98.8%, and the yield is 76.06%;
(2) uniformly mixing 15g of the compound B and 180mL of methanol, dropwise adding 7.5g of concentrated sulfuric acid, heating to 80 ℃, carrying out heat preservation reaction for 17h, detecting by TLC (thin layer chromatography), concentrating after the reaction of the raw materials is finished, removing the methanol, pouring the residue into ice water (100 mL), extracting with ethyl acetate (150 mL by 2), washing the ethyl acetate with saturated sodium bicarbonate (50 mL), and concentrating an organic phase to obtain 13.8g of yellow oily matter, namely the compound C, wherein the yield is 88.54% and the purity is 99.2%;
(3) putting 13g of the compound C, 3.5g of zinc cyanide, 1.5g of tetratriphenylphosphine palladium and 221mL of dimethylformamide into a reactor, uniformly mixing, heating to 100 ℃ under the protection of nitrogen, reacting for 16 hours, detecting by TLC, after the raw materials react, filtering, concentrating mother liquor, adding 200mL of ethyl acetate into the mother liquor concentrate, washing with saturated sodium bicarbonate (80 mL), filtering with diatomite, concentrating an organic phase, mixing with a silica gel sample, collecting a target product point, and concentrating to obtain 8.5g of white solid, namely the compound D, wherein the yield is 89.63% and the purity is 99.1%;
(4) uniformly mixing 8g of the compound D and 56mL of tetrahydrofuran, dropwise adding 56mL of lithium hydroxide aqueous solution with the mass fraction of 4.3%, stirring and reacting for 16h, detecting by TLC, concentrating after the reaction of the raw materials is finished, removing THF, adding 20 mL of water, extracting impurities (15 mL) by ethyl acetate, adjusting the pH value of a water phase by 4M hydrochloric acid to 3, separating out a large amount of white solid, filtering, washing by water (5 mL), and drying a filter cake to obtain 6.3g of white solid, namely the compound E, namely the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid, wherein the yield is 83.03% and the purity is 99.3%.
And (3) characterization: 1H NMR (d 6-DMSO): 12.74(brs, 1H), 8.03(d, J =7.2Hz, 1H), 7.93(d, J =9.3Hz, 1H), 3.70(s, 2H).
Example 2
A method for synthesizing 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid comprises the following steps:
(1) mixing 12g of compound A and 192mL of concentrated sulfuric acid, cooling to 1 ℃, adding 11.4g of N-iodosuccinimide, dividing the mixture into three parts by mass, adding the three parts in batches at intervals of 5min, heating to 28 ℃, stirring for reacting for 18h, detecting by TLC (thin layer chromatography), pouring the reaction solution into 500mL of ice water after the reaction of the raw materials is finished, extracting by ethyl acetate (300 mL of 2), and concentrating an organic phase to obtain 16.1g of yellow solid, namely compound B, wherein the purity is 99.1%, and the yield is 87.11%;
(2) uniformly mixing 18g of the compound B and 216mL of methanol, dropwise adding 9.8g of concentrated sulfuric acid, heating to 80 ℃, carrying out heat preservation reaction for 17h, detecting by TLC (thin layer chromatography), concentrating after the reaction of the raw materials is finished, removing the methanol, pouring the residue into ice water (100 mL), extracting with ethyl acetate (150 mL by 2), washing the ethyl acetate with saturated sodium bicarbonate (50 mL), and concentrating an organic phase to obtain 16.8g of yellow oily matter, namely the compound C, wherein the yield is 88.54% and the purity is 99.2%;
(3) putting 12g of the compound C, 3.8g of zinc cyanide, 1.7g of tetratriphenylphosphine palladium and 204mL of dimethylformamide into a reactor, uniformly mixing, heating to 100 ℃ under the protection of nitrogen, reacting for 16 hours, detecting by TLC, after the raw materials react, filtering, concentrating mother liquor, adding 200mL of ethyl acetate into the mother liquor concentrate, washing with saturated sodium bicarbonate (80 mL), filtering with diatomite, concentrating an organic phase, mixing with a silica gel sample, collecting target product points, and concentrating to obtain 7.9g of white solid, namely the compound D, wherein the yield is 90.25%, and the purity is 99.2%;
(4) uniformly mixing 3g of the compound D and 21mL of tetrahydrofuran, dropwise adding 21mL of lithium hydroxide aqueous solution with the mass fraction of 4.3%, stirring and reacting for 16h, detecting by TLC, concentrating after the reaction of the raw materials is finished, removing THF, adding 20 mL of water, extracting impurities (15 mL) by ethyl acetate, adjusting the pH value of a water phase by 4M hydrochloric acid to 3, separating out a large amount of white solid, filtering, washing by water (5 mL), and drying a filter cake to obtain 2.5g of white solid, namely the compound E, namely the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid, wherein the yield is 87.86% and the purity is 99.1%.
And (3) characterization: 1H NMR (d 6-DMSO): 12.74(brs, 1H), 8.03(d, J =7.2Hz, 1H), 7.93(d, J =9.3Hz, 1H), 3.70(s, 2H).
The present invention has been further described with reference to specific embodiments, but it should be understood that the detailed description should not be construed as limiting the spirit and scope of the present invention, and various modifications made to the above-described embodiments by those of ordinary skill in the art after reading this specification are within the scope of the present invention.

Claims (5)

1. A method for synthesizing 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid is characterized in that the chemical reaction formula of the synthesis is as follows:
；
the synthesis comprises the following steps:
(1) mixing the compound A and concentrated sulfuric acid, cooling, adding N-iodosuccinimide, heating, and stirring for reaction to obtain a compound B;
(2) uniformly mixing the compound B and methanol, dropwise adding concentrated sulfuric acid, heating, and carrying out heat preservation reaction to obtain a compound C; (3) putting the compound C, zinc cyanide, palladium tetratriphenylphosphine and dimethylformamide into a reactor, uniformly mixing, using nitrogen for protection, heating and reacting to obtain a compound D;
(4) and (3) uniformly mixing the compound D and tetrahydrofuran, dropwise adding a lithium hydroxide aqueous solution with the mass fraction of 4.3%, and stirring for reaction to obtain a compound E, namely the 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid.
2. The method for synthesizing 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid according to claim 1, wherein the mass ratio of the compound A, N-iodosuccinimide in the step (1) is 1: 0.8-1.2, and the solid-liquid g/mL ratio of the compound A to concentrated sulfuric acid is 1: 16.
3. The method for synthesizing 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid according to claim 1, wherein the mass ratio of the compound B to concentrated sulfuric acid in the step (2) is 1: 0.5-0.8, and the solid-liquid g/mL ratio of the compound B to methanol is 1: 12.
4. The synthesis method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid according to claim 1, wherein the mass ratio of the compound C, zinc cyanide and palladium tetratriphenylphosphine in the step (3) is 12: 3-4: 1-2, and the solid-liquid g/mL ratio of the compound C to dimethylformamide is 1: 17.
5. The method for synthesizing 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid according to claim 1, wherein the solid-liquid g/mL ratio of the compound D to tetrahydrofuran is 1:7, and the volume ratio of tetrahydrofuran to a 4.3% by mass aqueous solution of lithium hydroxide is 1: 1.
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CN112250599B (en) * 2020-11-24 2022-03-11 阿里生物新材料（常州）有限公司 Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester
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