CN111333513B - Preparation method of 2,4-difluoro-3-nitrobenzoic acid - Google Patents

Preparation method of 2,4-difluoro-3-nitrobenzoic acid Download PDF

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CN111333513B
CN111333513B CN202010305745.4A CN202010305745A CN111333513B CN 111333513 B CN111333513 B CN 111333513B CN 202010305745 A CN202010305745 A CN 202010305745A CN 111333513 B CN111333513 B CN 111333513B
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CN111333513A (en
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李安排
叶东伟
高德华
王玉乐
徐怀亮
赵小华
吴正华
张家庆
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Jiangsu Hengrun Pharmaceutical Co ltd
Jiangsu Hengpei Pharmaceutical Technology Co ltd
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    • 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
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Abstract

The invention discloses a preparation method of 2,4-difluoro-3-nitrobenzoic acid; the technical key points are as follows: carrying out amino protection on 2, 6-difluoroaniline to obtain a compound V; reacting the compound five with a halogenated reagent in a solvent to obtain a compound four; reacting the compound IV with carbon monoxide under a palladium catalyst to obtain a compound III or a compound III'; hydrolyzing the compound III or the compound III' to remove the protecting group on the amino group, and hydrolyzing the generated carboxylic ester or amide to obtain a compound II; and finally, oxidizing the compound II to obtain the compound I. The invention aims to provide a preparation method of 2,4-difluoro-3-nitrobenzoic acid; can realize the large-scale industrial production of the 2,4-difluoro-3-nitrobenzoic acid.

Description

Preparation method of 2,4-difluoro-3-nitrobenzoic acid
Technical Field
The invention relates to a preparation method of 2,4-difluoro-3-nitrobenzoic acid, belonging to the field of medical technology (organic synthesis).
Background
2,4-difluoro-3-nitrobenzoic acid, CAS accession No.: 1425174-31-7, the English name is: 2,4-difluoro-3-nitrobenzoic acid.
The structural formula is as follows:
Figure BDA0002455735100000011
the 2,4-difluoro-3-nitrobenzoic acid contains two fluorine atoms, nitro and carboxyl in the structure, can be used for constructing a new medicine molecular structure, and is a novel medicine synthesis intermediate.
2,4-difluoro-3-nitrobenzoic acid can be used to synthesize drug candidate compounds such as: HEPAREGENIX GMBH + PCT int.appl. (2019), WO 2019243315A1[ DE ] Tricyclic protein kinase inhibitors for promoting expression or reduction or prevention of platelet death, and drugs with good biological activity are screened and tested, and are shown in the following structural formula I and structural formula II.
Figure BDA0002455735100000012
For example: PCT int.appl. (2012), WO 2012171488a1 provides a novel coumarin derivative or a pharmaceutically acceptable salt or solvate thereof having anti-tumor and anti-inflammatory activities, and a pharmaceutical composition comprising the derivative, such as the following structural formula III having good anti-tumor activity.
Figure BDA0002455735100000013
For example: PCT int.appl. (2019), WO2019053426a1 inventions relate to novel compounds and ingredients, and their use in the treatment of hyperglycemia and diseases characterized by hyperglycemia, such as type II diabetes. The following structural formula IV and formula V both show good hypoglycemic bioactivity.
Figure BDA0002455735100000021
The series of compounds can be prepared by chemical synthesis by using 2,4-difluoro-3-nitrobenzoic acid as a starting raw material, and the reaction process conditions are relatively mild due to the existence of nitro.
From the structure, the target compound 1 is a tetra-substituted phenyl structure, and because four groups are close to each other and the groups have high chemical activity, the compound is difficult to synthesize. The synthesis of 2,4-difluoro-3-nitrobenzoic acid is not reported in the literature at present, and even the synthesis literature of similar structures is not abundant. In patent WO2019053426a1, a process for the preparation of 3-acetamido-2, 4-difluorobenzoic acid is disclosed, the reaction formula of which is as follows:
Figure BDA0002455735100000022
through investigation, the route does not supply 3-amino-2, 4-difluorotoluene as a starting material in the market at present, and a synthetic literature report is not available, so that the synthetic difficulty and the cost are high.
In Chemistry Open 2019,8, 166-172, a method for preparing m-nitrobenzoate is provided, the reaction formula of the preparation method is as follows:
Figure BDA0002455735100000023
the preparation method needs to use a specially prepared catalyst, and iodine is used as a starting material, so that the problems of high cost, low selectivity, low yield and the like exist.
Therefore, the development of a preparation method of 2,4-difluoro-3-nitrobenzoic acid which has wide raw material source, low cost, high yield, simple and convenient operation and is beneficial to realizing industrialization has extremely high practical value.
Disclosure of Invention
The invention aims to provide a method for synthesizing 2,4-difluoro-3-nitrobenzoic acid aiming at the defects of the prior art.
The present invention provides novel compounds of formula 1:
Figure BDA0002455735100000031
the technical scheme of the invention is as follows: a preparation method of 2,4-difluoro-3-nitrobenzoic acid takes 2, 6-difluoroaniline (compound 6) with wide source and low cost as a starting material, and obtains a compound 5 after amino protection; then reacting the compound 5 with a halogenated reagent in a proper solvent to obtain a compound 4; reacting the compound 4 with carbon monoxide in the presence of a palladium catalyst under mild conditions to obtain a compound 3 or a compound 3'; removing a protecting group on an amino group from the compound 3 or the compound 3' through alkaline or acidic hydrolysis, and hydrolyzing the generated carboxylic ester or amide to obtain 3-amino-2, 4-difluorobenzoic acid (a compound 2); finally, the compound 2 is oxidized to obtain 2,4-difluoro-3-nitrobenzoic acid (compound 1) according to the following reaction formula:
Figure BDA0002455735100000032
the method comprises the following steps:
step 1: preparation of Compound 5
Amino protection:
Figure BDA0002455735100000033
wherein R is1Represents alkyl acyl, alkoxy carbonyl, aromatic acyl or substituted aromatic acyl of C1-C6.
Step 1: preparation of compound 5: under the protection of nitrogen, adding 2, 6-difluoroaniline and a solvent into a reaction bottle, dropwise adding an amino protective reagent at the controlled temperature of 0-100 ℃ under stirring, and continuing to keep the reaction after the dropwise adding is finished; after the reaction is finished, obtaining a compound 5 through desolventizing crystallization;
the solvent used in the reaction is toluene, water, acetic acid, dichloromethane or alkane, preferably toluene.
The reaction temperature is 0-100 ℃, preferably 0-20 ℃.
The amino protecting reagent used in the reaction is chloroformate of C1-C6, alkyl acyl chloride of C1-C6, alkyl acid anhydride of C1-C6 and substituted or unsubstituted aromatic acyl chloride, preferably acetyl chloride and acetic anhydride.
Step 2: preparation of Compound 4
Halo moiety:
Figure BDA0002455735100000041
wherein, X represents chlorine, bromine and iodine; r1Represents alkyl acyl, alkoxy carbonyl, aromatic acyl or substituted aromatic acyl of C1-C6.
Preparation of compound 4: adding the compound 5 and a solvent into a reaction bottle, and stirring until the system is completely dissolved; adding halogenated reagent in several times, heating to 20-40 deg.C, stirring for 4 hr, slowly pouring the reaction liquid into ice water, and stirring to separate out solid. Filtering, and drying the solid under reduced pressure to obtain a compound 4;
the solvent adopted in the reaction is sulfuric acid, acetic acid and trifluoroacetic acid, and the sulfuric acid is preferred.
The reaction temperature is 0-100 ℃, preferably 20-40 ℃.
The halogenating agent used in the reaction is bromine, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), N-chlorosuccinimide (NCS) and dibromohydantoin (DBDMH), preferably NBS.
And step 3: preparation of compound 3 or compound 3'.
Wherein, X represents chlorine, bromine and iodine; r1Alkyl acyl representing C1-C6, substituted aromatic acyl, etc. R2Represents a hydrogen atom, a C1-C6 alkyl group, a phenyl group, a substituted phenyl group. R3And R4Represents a hydrogen atom, a C1-C3 alkyl group, or a phenyl group.
Preparation of compound 3 or compound 3': putting the compound 4 into a high-pressure kettle, adding alkali, a solvent, a palladium catalyst and a phosphine ligand at one time, covering the kettle cover, and vacuumizing and replacing for three times; introducing carbon monoxide gas, heating to 50-80 ℃, and keeping the reaction for 8 hours. After the reaction is finished, cooling the material to room temperature, replacing carbon monoxide with nitrogen, filtering to remove insoluble substances, and performing reduced pressure desolventizing on the filtrate to obtain a compound 3 or a compound 3';
the reaction temperature is 20-200 ℃, preferably 50-80 ℃.
The alkali used in the reaction is sodium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, ammonia, monomethylamine and dimethylamine, preferably triethylamine.
The solvent used in the reaction is methanol, ethanol, propanol, isopropanol, butanol, pentanol, phenol, or water and toluene, N-dimethylformamide, N-dimethylacetamide, acetonitrile, or the like, preferably methanol or water and toluene, and most preferably methanol.
The palladium used in the reaction is palladium acetate, palladium carbon or palladium chloride, preferably palladium acetate.
The phosphine ligands used in the reaction are 1,1 '-bis (diphenylphosphino) ferrocene, triphenylphosphine, 1, 3-bis (diphenylphosphino) propane, 1, 3-bis (diphenylphosphino) butane and 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene, preferably 1,1' -bis (diphenylphosphino) ferrocene.
Figure BDA0002455735100000051
And 4, step 4: preparation of Compound 2
Figure BDA0002455735100000052
Wherein R is1Alkyl acyl representing C1-C6, substituted aromatic acyl, etc. R2Represents a hydrogen atom, a C1-C6 alkyl group, a phenyl group, a substituted phenyl group. R3And R4Represents a hydrogen atom, a C1-C3 alkyl group, or a phenyl group.
Preparation of compound 2: adding the compound 3, a solvent and an acid or an alkali into a reaction bottle, heating to 80-100 ℃, reacting for 8 hours, cooling to room temperature after the reaction is finished, adjusting the pH value to 8-9, adding the solvent for extraction, discarding an organic layer, and collecting a water layer. Adjusting the water layer to be acidic, adding a solvent for extraction, and performing decompression and desolventization on the organic layer to obtain a compound 2;
the reaction temperature is 20-200 ℃, preferably 80-100 ℃.
The base used in the hydrolysis reaction is a metal base, such as sodium carbonate, sodium hydroxide, potassium carbonate, lithium hydroxide, preferably sodium hydroxide.
The acid used in the hydrolysis reaction is sulfuric acid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid and acetic acid, preferably sulfuric acid.
And 5: preparation of Compound 1
Figure BDA0002455735100000061
Preparation of compound 1: adding a certain proportion of oxidant into a reaction bottle, controlling the temperature to be not more than 20 ℃, and dropwise adding 3-amino-2, 4-difluorobenzoic acid; after the dropwise addition is finished, heating to react until the reaction liquid is qualified, slowly pouring the reaction liquid into ice water, adding a solvent for extraction, collecting an organic layer, and performing decompression and desolventization on the organic layer until the organic layer is dried to obtain the 2,4-difluoro-3-nitrobenzoic acid (compound 1).
The reaction temperature is 20-100 ℃, preferably 20-40 ℃.
The oxidant used in the reaction is hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid and peroxytrifluoroacetic acid, and hydrogen peroxide is preferred.
In the above, the compound 1 is 2,4-difluoro-3-nitrobenzoic acid; the compound 2 is 3-amino-2, 4-difluorobenzoic acid; the compound 3 is amino-2, 4-difluorobenzoic acid or benzoate protected by 3-acyl; compound 3' is 3-acyl protected amino-2, 4-difluorobenzamide; compound 4 is 3-acyl protected amino-2, 4-difluorohalobenzene (X represents chlorine, bromine and iodine); the compound 5 is acyl protected 2, 6-difluoroaniline; the compound 6 is 2, 6-difluoroaniline.
A preparation method of 2,4-difluoro-3-nitrobenzoic acid comprises the following steps:
firstly, carrying out amino protection on a compound VI to obtain a compound V;
then, reacting the compound five with a halogenated reagent in a solvent to obtain a compound four;
secondly, reacting the compound IV with carbon monoxide under a palladium catalyst to obtain a compound III or a compound III';
thirdly, hydrolyzing the compound III or the compound III' to remove the protecting group on the amino group, and hydrolyzing the generated carboxylic ester or amide to obtain a compound II;
finally, oxidizing the compound II to obtain a compound I;
wherein the first compound is 2,4-difluoro-3-nitrobenzoic acid;
wherein the compound II is 3-amino-2, 4-difluorobenzoic acid;
wherein the compound III is 3-acyl protected amino-2, 4-difluorobenzoic acid or benzoate;
wherein the compound tri' is amino-2, 4-difluorobenzamide protected by 3-acyl;
wherein the compound IV is 3-acyl protected amino-2, 4-difluorohalogenobenzene (X represents chlorine, bromine and iodine);
wherein the compound five is acyl-protected 2, 6-difluoroaniline;
wherein the compound six is 2, 6-difluoroaniline.
A preparation method of 2,4-difluoro-3-nitrobenzoic acid comprises the following steps:
step 1: taking a compound six as a raw material, and carrying out amino protection reaction in a solvent to obtain a compound five;
step 2: carrying out halogenation reaction on the compound V and a halogenating reagent in an acidic solvent to obtain a compound IV;
and step 3: the compound IV is subjected to an insertion carbonyl reaction by carbon monoxide under the catalysis of a palladium catalyst and a phosphine ligand, and then is subjected to esterification, hydrolysis or amidation reaction with alcohol, water or amine to obtain a compound III or a compound III'(in alkaline Environment)；
And 4, step 4: carrying out hydrolysis reaction on a compound III or a compound III' to obtain a compound II;
and 5: and carrying out oxidation reaction on the compound II in an acid solvent to obtain the compound I.
Wherein the first compound is 2,4-difluoro-3-nitrobenzoic acid;
wherein the compound II is 3-amino-2, 4-difluorobenzoic acid;
wherein the compound III is 3-acyl protected amino-2, 4-difluorobenzoic acid or benzoate;
wherein the compound tri' is amino-2, 4-difluorobenzamide protected by 3-acyl;
wherein the compound IV is 3-acyl protected amino-2, 4-difluorohalogenobenzene (X represents chlorine, bromine and iodine);
wherein the compound five is acyl-protected 2, 6-difluoroaniline;
wherein the compound six is 2, 6-difluoroaniline.
Further, the solvent used in step 1 is any one of toluene, water, acetic acid, dichloromethane and alkane.
Further, the reaction temperature used in the step 1 is 0-100 ℃, and the reaction temperature used in the step 2 is 0-100 ℃.
Further, an amino protecting agent is used in the step 1 to realize amino protection; the amino protection reagent is any one of chloroformate of C1-C6, alkyl acyl chloride of C1-C6, alkyl acid anhydride of C1-C6 and substituted or unsubstituted aromatic acyl chloride.
Further, the acidic solvent used in step 2 is any one of sulfuric acid, acetic acid and trifluoroacetic acid.
Further, the halogenating agent used in step 2 is any one of bromine, N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), N-chlorosuccinimide (NCS) and dibromohydantoin (DBDMH).
Further, the reaction temperature for the step 3 is 20-200 ℃.
Further, the alkali used in step 3 is any one of sodium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, ammonia gas, monomethylamine and dimethylamine.
Further, the solvent used in step 3 is methanol, ethanol, propanol, isopropanol, butanol, pentanol, phenol or water and toluene, N-dimethylformamide, N-dimethylacetamide, acetonitrile.
Further, the palladium catalyst used in the step 3 is palladium acetate, palladium carbon or palladium chloride; the phosphine ligand used in the step 3 is any one of 1,1' -bis (diphenylphosphino) ferrocene, triphenylphosphine, 1, 3-bis (diphenylphosphino) propane, 1, 3-bis (diphenylphosphino) butane and 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene.
Further, the reaction temperature for the step 4 is 20-200 ℃.
Further, the hydrolysis reaction in the step 4 is an alkaline environment, wherein the alkali used in the alkaline environment is a metal alkali, such as any one of sodium carbonate, sodium hydroxide, potassium carbonate and lithium hydroxide;
or,
the hydrolysis reaction in the step 4 is an acid environment, wherein the acid adopted in the acid environment is any one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid and acetic acid.
Further, the reaction temperature for the step 5 is 20-100 ℃.
Further, the oxidation reaction in step 5 is realized by adding an oxidizing agent; the oxidant used in the step 5 is any one of hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid and peroxytrifluoroacetic acid.
The invention has the beneficial effects that:
the invention relates to a novel and simple synthetic method for preparing 3-nitro-2, 4-difluorobenzoic acid, which has the advantages of wide raw material source, low cost, high yield, simple and convenient operation and capability of realizing large-scale industrialization.
Secondly, the synthetic route is not reported in documents, toxic and harmful substances are avoided in the synthetic process, and cheap and high-quality 2,4-difluoro-3-nitrobenzoic acid synthetic intermediates are provided for designing and screening new drugs.
Drawings
The invention will be further described in detail with reference to examples of embodiments shown in the drawings to which, however, the invention is not restricted.
FIG. 1 shows the confirmation of the structure of Compound 1 of example 11H-NMR spectrum.
FIG. 2 shows structural confirmation of Compound 1 of example 113C-NMR spectrum.
Fig. 3 is an HPLC chromatogram for purity detection of compound 1 of example 1.
Detailed Description
The following examples will help those skilled in the art to understand the gist of the preparation technique of the present invention, but are not intended to limit the scope of the present invention.
Example 1
Step 1: synthesis of 2, 6-difluoroacetamidobenzene (5)
Adding 100g (0.77mol) of 2, 6-difluoroaniline and 600mL of toluene into a reaction bottle, dropwise adding 87g (0.85mol) of acetic anhydride at the controlled temperature of 0-20 ℃ under stirring, keeping the reaction for 4 hours after the dropwise adding is finished, cooling to 0-10 ℃, keeping stirring for 1 hour, filtering, and drying the solid under reduced pressure to obtain 125g of 2, 6-difluoroacetaminophenyl (5) with the yield of 94%.
Step 2: synthesis of 3-bromo-2, 6-difluoroacetamidobenzene (4)
55g (0.32mol) of 2, 6-difluoroacetamidobenzene and 660g of concentrated sulfuric acid were added to the reaction flask, and the mixture was stirred until the system was completely dissolved. 63g (0.35mol) of NBS are added in portions at 20-40 ℃ and stirred for reaction for 5 h.
After the reaction is qualified, the reaction solution is slowly poured into 1000g of ice water, and white solid is separated out by stirring. Filtering to obtain a crude product of the 3-bromo-2, 6-difluoroacetaminophenyl. Adding 220mL of isopropyl acetate into the 3-bromo-2, 6-difluoroacetamidobenzene crude product, heating to reflux, stirring for 2 hours, cooling to 0-10 ℃, and stirring for 1 hour. Filtration and drying under reduced pressure gave 69g of 3-bromo-2, 6-difluoroacetaminophenyl (4) in 86% yield.
And step 3: synthesis of methyl 3-acetamido-2, 4-difluorobenzoate (3)
20g (0.08mol) of 3-bromo-2, 6-difluoroacetamidobenzene were placed in an autoclave and 57g of triethylamine, 200mL of methanol, 0.1g of palladium acetate and 0.4g of 1,1' -bis (diphenylphosphino) ferrocene were added in one portion. Covering the kettle cover, and vacuumizing and replacing for three times; introducing carbon monoxide gas, heating to 50-80 ℃, and keeping the reaction for 8 hours.
After the reaction, the reaction mixture was cooled to room temperature, carbon monoxide was replaced with nitrogen, and then the mixture was filtered, and the filtrate was desolventized under reduced pressure to obtain 16.7g of methyl 3-acetylamino-2, 4-difluorobenzoate (3) in a yield of 93%.
And 4, step 4: synthesis of 3-amino-2, 4-difluorobenzoic acid (2)
32g (0.14mol) of methyl 3-acetamido-2, 4-difluorobenzoate, 260g of 20% sulfuric acid and 60mL of toluene were charged into a reaction flask, and the reaction was stirred at 80-100 ℃ for 4 hours. After the reaction is finished, controlling the temperature not to exceed 30 ℃, dropwise adding a sodium hydroxide solution, and adjusting the pH value to 8-9. 100mL of toluene was added for extraction. The water layer is dripped with sulfuric acid, and the pH value is adjusted to 3.0-3.5. 600mL of isopropyl acetate was added and extracted. The resulting mixture was desolventized under reduced pressure to give 21.5g of 3-amino-2, 4-difluorobenzoic acid (2) in a yield of 90%.
And 5: synthesis of 2,4-difluoro-3-nitrobenzoic acid (1)
Adding 40g of 30% hydrogen peroxide into a reaction bottle, controlling the temperature not to exceed 20 ℃, dropwise adding a solution prepared from 10g (0.06mol) of 3-amino-2, 4-difluorobenzoic acid and 50g of trifluoroacetic acid, finishing dropwise adding, and controlling the temperature to be 20-40 ℃ to keep reacting for 5 hours.
After the reaction is finished, slowly pouring the reaction liquid into 200g of ice water, stirring and heating to 20-30 ℃, adding 200g of isopropyl acetate for extraction, adding activated carbon, stirring for 30 minutes, filtering, decompressing and desolventizing the filtrate to dryness, adding 5mL of isopropyl acetate and 50mL of heptane, heating to 40-50 ℃, stirring for 0.5 hour, then cooling to 0-5 ℃, and stirring for 1 hour.
Then, the mixture was filtered and dried under reduced pressure to obtain 10.3g of 2,4-difluoro-3-nitrobenzoic acid (1) in 88% yield and 99.7% purity.1H NMR(DMSO-d6),400MHz，δ13.91(s,2H)，δ8.23-8.17(m,1H)，δ7.56-7.52(t,1H)。
Wherein, of Compound 11H-NMR and13and C-NMR and HPLC spectrograms for purity detection are shown in figures 1, 2 and 3.
Example 2
Synthesis of 2, 6-difluoroacetamidobenzene (5)
The procedure was followed in step 1 of example 1 except that the reaction solvents were toluene, acetic acid, dichloromethane and hexane, respectively, and the other operating conditions were the same.
The yields of 2, 6-difluoroacetamidobenzene (5) and data for different solvents are given in table 1.
TABLE 1
Reaction solvent Reaction time (h) The reaction yield%
Toluene
4 94
Acetic acid 4 80
Methylene dichloride 4 90
Hexane (C) 8 60
Example 3
Synthesis of 2, 6-difluoroacetaminophenyl (5).
The procedure was followed in step 1 of example 1 except that the reaction temperatures were 0 to 20 deg.C, 20 to 40 deg.C and 60 to 80 deg.C, respectively, and the other operating conditions were the same. Data on the yield of 2, 6-difluoroacetaminophenyl (5) and different temperatures are shown in Table 2.
TABLE 2
Reaction temperature (. degree.C.) Reaction time (h) The reaction yield%
0-20 4 94
20-40 4 92
60-80 4 88
Example 4
Synthesis of acyl protected 2, 6-difluoroaniline (5).
The procedure is as in step 1 of example 1 except that the amino protecting groups are acetic anhydride, acetyl chloride, methyl chloroformate and benzoyl chloride, respectively, and the other operating conditions are the same. The yield of acyl protected 2, 6-difluoroaniline (5) is shown in Table 3 along with data for the various amino protecting groups.
TABLE 3
Amino protecting group Reaction time (h) The reaction yield%
Acetic anhydride 4 94
Acetyl chloride 4 93
Chloroformic acid methyl ester 4 88
Benzoyl chloride 4 92
Example 5
3-bromo-2, 6-difluoroacetaminophenyl (4).
The procedure is followed in step 2 of example 1 except that the halogenating agents are N-bromosuccinimide, bromine and dibromohydantoin, respectively, and the other operating conditions are the same. The yield of 3-bromo-2, 6-difluoroacetamidobenzene (4) and the data for the halogenating reagent are shown in Table 4.
TABLE 4
Halogenated agents Reaction time (h) The reaction yield%
N-bromosuccinimide 5 86
Bromine compound 5 80
Dibromo hydantoin 5 76
Example 6
3-bromo-2, 6-difluoroacetaminophenyl (4).
The procedure was followed in step 2 of example 1 except that the reaction solvents were concentrated sulfuric acid, acetic acid and trifluoroacetic acid, respectively, and the other operating conditions were the same. The yields of 3-bromo-2, 6-difluoroacetamidobenzene (4) and the data for the different reaction solvents are given in Table 5.
TABLE 5
Reaction solvent Reaction time (h) The reaction yield%
Concentrated sulfuric acid 5 86
Acetic acid 5 60
Trifluoroacetic acid 5 65
Example 7
3-bromo-2, 6-difluoroacetaminophenyl (4).
The procedure was followed in step 2 of example 1 except that the reaction temperatures were 0 to 20 deg.C, 20 to 40 deg.C and 60 to 80 deg.C, respectively, and the other operating conditions were the same. The yield of 3-bromo-2, 6-difluoroacetamidobenzene (4) is shown in Table 6 with data for different reaction temperatures.
TABLE 6
Reaction temperature Reaction time (h) The reaction yield%
0-20 5 75
20-40 5 86
60-80 5 55
Example 8
Synthesis of methyl 3-acetamido-2, 4-difluorobenzoate (3).
The procedure was followed as in step 3 of example 1 except that the catalysts were palladium acetate, 5% palladium on carbon and palladium chloride, respectively, and the other operating conditions were the same. The yields of methyl 3-acetamido-2, 4-difluorobenzoate (3) and data for different catalysts are shown in Table 7.
TABLE 7
Catalyst and process for preparing same Reaction time (h) The reaction yield%
Palladium acetate 8 93
5% Palladium on carbon 8 60
Palladium chloride 8 88
Example 9
Synthesis of methyl 3-acetamido-2, 4-difluorobenzoate (3).
The procedure was followed in step 3 of example 1 except that the phosphine ligands were 1,1' -bis (diphenylphosphino) ferrocene, triphenylphosphine and 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene, respectively, and the other operating conditions were the same. The yields of methyl 3-acetamido-2, 4-difluorobenzoate (3) and data for the different phosphine ligands are given in Table 8.
TABLE 8
Phosphine ligands Reaction time (h) Yield of the reaction％
1,1' -bis (diphenylphosphino) ferrocene 8 93
Triphenylphosphine 8 80
4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene 8 90
Example 10
Synthesis of methyl 3-acetamido-2, 4-difluorobenzoate (3).
The procedure was followed in step 3 of example 1 except that triethylamine, diisopropylethylamine and sodium carbonate were used as bases for the reaction, respectively, and the other operating conditions were the same. The yields of methyl 3-acetamido-2, 4-difluorobenzoate (3) are given in table 9 together with data on the various bases.
TABLE 9
Base used in the reaction Reaction time (h) The reaction yield%
Triethylamine 8 93
Diisopropylethylamine 8 92
Sodium carbonate 8 85
Example 11.
Synthesis of methyl 3-acetamido-2, 4-difluorobenzoate (3).
The procedure was followed in step 3 of example 1 except that the reaction temperatures were 20-40 deg.C, 50-80 deg.C, 80-100 deg.C and 140-160 deg.C, respectively, and the other operating conditions were the same. The yields of methyl 3-acetamido-2, 4-difluorobenzoate (3) and the data for the different reaction temperatures are given in Table 10.
Watch 10
Reaction temperature Reaction time (h) The reaction yield%
20-40 8 60
50-80 8 93
80-100 8 92
140-160 8 79
Example 12
Synthesis of 3-acetamido-2, 4-difluorobenzamide (3').
20g (0.08mol) of 3-bromo-2, 6-difluoroacetamidobenzene were placed in an autoclave, and 50g of ammonia gas, 200mL of toluene, 0.1g of palladium acetate and 0.4g of 1,1' -bis (diphenylphosphino) ferrocene were introduced in one portion. Covering the kettle cover, and replacing nitrogen for three times; introducing carbon monoxide gas, heating to 50-80 ℃, and keeping the reaction for 8 hours. After the reaction, the material was cooled to room temperature, carbon monoxide was replaced with nitrogen, and then the mixture was filtered, and the filtrate was desolventized under reduced pressure to obtain 15.4g of 3-acetamido-2, 4-difluorobenzamide, with a yield of 90%.
Example 13
And (3) synthesizing 3-acetamido-2, 4-difluorobenzoic acid.
20g (0.08mol) of 3-bromo-2, 6-difluoroacetamidobenzene were placed in an autoclave, and 57g of triethylamine, 100mL of water, 100g of toluene, 0.1g of palladium acetate and 0.4g of 1,1' -bis (diphenylphosphino) ferrocene were added in one portion. Covering the kettle cover, and vacuumizing and replacing for three times; introducing carbon monoxide gas, heating to 50-80 ℃, and keeping the reaction for 8 hours. After the reaction is finished, cooling the materials to room temperature, replacing carbon monoxide with nitrogen, filtering, and carrying out decompression desolventizing on the filtrate to obtain 15.5g of a product with the yield of 90%.
Example 14
And (3) synthesizing 3-amino-2, 4-difluorobenzoic acid (2).
The procedure was followed in step 4 of example 1 except that the reaction temperatures were 20 to 40 deg.C, 40 to 60 deg.C and 80 to 100 deg.C, respectively, and the other operating conditions were the same. The yields of 3-amino-2, 4-difluorobenzoic acid (2) and the data for the different reaction temperatures are shown in Table 11.
TABLE 11
Reaction temperature Reaction time (h) The reaction yield%
20-40 20 60
40-60 15 70
80-100 4 90
Example 15
And (3) synthesizing 3-amino-2, 4-difluorobenzoic acid (2).
TABLE 12
Hydrolysis reaction reagent Reaction time (h) The reaction yield%
Sulfuric acid 4 90
Hydrochloric acid 7 80
Trifluoromethanesulfonic acid 4 87
Acetic acid 15 40
Sodium hydroxide 5 30
Potassium carbonate 5 50
Conditions for example 15: the procedure was followed in step 4 of example 1 except that sulfuric acid, hydrochloric acid, trifluoromethanesulfonic acid, acetic acid, sodium hydroxide and potassium carbonate were used as reagents for the hydrolysis reaction, and the other operating conditions were the same. The yields of 3-amino-2, 4-difluorobenzoic acid (2) and the data for the different hydrolysis reagents are given in Table 12.
Example 16
Synthesis of 2,4-difluoro-3-nitrobenzoic acid (1).
The procedure was followed in step 5 of example 1 except that the oxidation reaction temperatures were 0 to 20 deg.C, 20 to 40 deg.C, 40 to 60 deg.C and 60 to 80 deg.C, respectively, and the other operating conditions were the same. Data for yield of 2,4-difluoro-3-nitrobenzoic acid (1) with different temperatures are shown in Table 13.
Watch 13
Reaction temperature (. degree.C.) Reaction time (h) The reaction yield%
0-20 10 65
20-40 5 88
40-60 5 82
60-80 4 60
As can be seen from Table 13, the reaction temperature has a large influence on the reaction yield, and when the reaction temperature is 0-20 ℃, the reaction yield after 10 hours of reaction time is still only 65%;
and when the reaction temperature is between 20 and 40 ℃, the reaction yield is 88 percent after 10 hours of reaction time.
As can be seen from table 13, the effect of the reaction temperature on the reaction yield was increased and then decreased; that is, after the temperature is higher than a certain value, it is disadvantageous to the reaction.
Example 17
Synthesis of 2,4-difluoro-3-nitrobenzoic acid (1).
The operation is carried out according to the step 5 of the embodiment 1, except that the oxidants are respectively hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid and peroxytrifluoroacetic acid, and other operation conditions are consistent;
the yields of 2,4-difluoro-3-nitrobenzoic acid (1) are shown in Table 14 together with data on the various oxidizing agents.
TABLE 14
Oxidizing agent Reaction time (h) The reaction yield%
Hydrogen peroxide solution 5 88
Tert-butyl hydroperoxide 5 80
Peroxyacetic acid 5 40
Perfluorotrifluoroacetic acid 5 50
From table 14, it can be seen that: the reaction yield of the hydrogen peroxide is the highest and can reach 88%; tert-butyl hydroperoxide reaches 80 percent; and peroxytrifluoroacetic acid and peroxyacetic acid are relatively poor and are only 50% and 40% respectively.
It should be noted that the product purity test of the present invention (product produced in example 1) employs the HPLC conditions shown in Table 15.
Watch 15
Figure BDA0002455735100000151
The above-mentioned embodiments are only for convenience of description, and are not intended to limit the present invention in any way, and those skilled in the art will understand that the technical features of the present invention can be modified or changed by other equivalent embodiments without departing from the scope of the present invention.

Claims (14)

1. A preparation method of 2,4-difluoro-3-nitrobenzoic acid is characterized by comprising the following steps:
firstly, carrying out amino protection on a compound VI to obtain a compound V;
then, reacting the compound five with a halogenated reagent in a solvent to obtain a compound four;
secondly, mixing the compound IV with alkali, a solvent, a palladium catalyst and a phosphine ligand, and then introducing carbon monoxide gas to react to obtain a compound III or a compound III'; the alkali is any one of sodium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, ammonia gas, monomethylamine and dimethylamine;
thirdly, hydrolyzing the compound III or the compound III' to remove the protecting group on the amino group, and hydrolyzing the generated carboxylic ester or amide to obtain a compound II;
finally, oxidizing the compound II to obtain a compound I;
wherein the first compound is 2,4-difluoro-3-nitrobenzoic acid;
wherein the compound II is 3-amino-2, 4-difluorobenzoic acid;
wherein the compound III is 3-acyl protected amino-2, 4-difluorobenzoic acid or benzoate;
wherein the compound tri' is 3-acyl protected amino-2, 4-difluorobenzamide, and the 3-acyl protected amino-2, 4-difluorobenzamide is:
Figure FDA0003168183900000011
r1 represents C1-C6 alkanoyl, alkoxycarbonyl, aroyl or substituted aroyl; r3 and R4 represent a hydrogen atom, a C1-C3 alkyl group, a phenyl group;
wherein the compound IV is amino-2, 4-difluoro halogenobenzene protected by 3-acyl;
wherein the compound five is acyl-protected 2, 6-difluoroaniline;
wherein the compound six is 2, 6-difluoroaniline.
2. A preparation method of 2,4-difluoro-3-nitrobenzoic acid is characterized by comprising the following steps:
step 1: taking a compound six as a raw material, and carrying out amino protection reaction in a solvent to obtain a compound five;
step 2: carrying out halogenation reaction on the compound V and a halogenating reagent in an acidic solvent to obtain a compound IV;
and step 3: mixing the compound IV with alkali, a solvent, a palladium catalyst and a phosphine ligand, and then introducing carbon monoxide gas to react to obtain a compound III or a compound III'; the alkali is any one of sodium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, ammonia gas, monomethylamine and dimethylamine;
and 4, step 4: carrying out hydrolysis reaction on a compound III or a compound III' to obtain a compound II;
and 5: carrying out oxidation reaction on the compound II in an acid solvent to obtain a compound I;
wherein the first compound is 2,4-difluoro-3-nitrobenzoic acid;
wherein the compound II is 3-amino-2, 4-difluorobenzoic acid;
wherein the compound III is 3-acyl protected amino-2, 4-difluorobenzoic acid or benzoate;
wherein the compound tri' is 3-acyl protected amino-2, 4-difluorobenzamide, and the 3-acyl protected amino-2, 4-difluorobenzamide is:
Figure FDA0003168183900000021
r1 represents C1-C6 alkanoyl, alkoxycarbonyl, aroyl or substituted aroyl; r3 and R4 represent a hydrogen atom, a C1-C3 alkyl group, a phenyl group;
wherein the compound IV is amino-2, 4-difluoro halogenobenzene protected by 3-acyl;
wherein the compound five is acyl-protected 2, 6-difluoroaniline;
wherein the compound six is 2, 6-difluoroaniline.
3. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the solvent used in the step 1 is any one of toluene, water, acetic acid, dichloromethane and alkane.
4. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the reaction temperature used in the step 1 is 0-100 ℃, and the reaction temperature used in the step 2 is 0-100 ℃.
5. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: in the step 1, an amino protection reagent is used for realizing amino protection; the amino protection reagent is any one of chloroformate of C1-C6, alkyl acyl chloride of C1-C6, alkyl acid anhydride of C1-C6 and substituted or unsubstituted aromatic acyl chloride.
6. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the acidic solvent used in the step 2 is any one of sulfuric acid, acetic acid and trifluoroacetic acid.
7. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the halogenating reagent used in the step 2 is any one of bromine, N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide and dibromohydantoin.
8. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the reaction temperature for the step 3 is 20-200 ℃.
9. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the solvent used in the step 3 is methanol, ethanol, propanol, butanol, pentanol, phenol, water, toluene, N-dimethylformamide, N-dimethylacetamide or acetonitrile.
10. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the palladium catalyst used in the step 3 is palladium acetate, palladium carbon or palladium chloride; the phosphine ligand used in the step 3 is any one of 1,1' -bis (diphenylphosphino) ferrocene, triphenylphosphine, 1, 3-bis (diphenylphosphino) propane, 1, 3-bis (diphenylphosphino) butane and 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene.
11. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the reaction temperature for the step 4 is 20-200 ℃.
12. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the hydrolysis reaction in the step 4 is an alkaline environment, wherein the alkali adopted in the alkaline environment is any one of sodium carbonate, sodium hydroxide, potassium carbonate and lithium hydroxide;
or,
the hydrolysis reaction in the step 4 is an acid environment, wherein the acid adopted in the acid environment is any one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid and acetic acid.
13. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the reaction temperature for the step 5 is 20-100 ℃.
14. The process for preparing 2,4-difluoro-3-nitrobenzoic acid according to claim 2, which comprises the steps of: the oxidation reaction in the step 5 is realized by adding an oxidant; the oxidant used in the step 5 is any one of hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid and peroxytrifluoroacetic acid.
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