CN115626879A - Preparation method of 2-phenylalanyl-benzoic acid derivative - Google Patents

Preparation method of 2-phenylalanyl-benzoic acid derivative Download PDF

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CN115626879A
CN115626879A CN202211223770.3A CN202211223770A CN115626879A CN 115626879 A CN115626879 A CN 115626879A CN 202211223770 A CN202211223770 A CN 202211223770A CN 115626879 A CN115626879 A CN 115626879A
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benzoic acid
phenyl
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CN115626879B (en
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梁伟周
郑庆泉
张君浪
李俊宇
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Guangzhou Trojan Pharmatec Ltd
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines

Abstract

The invention provides a method for synthesizing a 2-phenylalanyl-benzoic acid derivative, which uses malonic diester derivative, anthranilate derivative and benzaldehyde derivative as raw materials, which are industrial basic raw materials; phenolic hydroxyl groups on benzene rings in all raw materials do not need to be protected, so that the production steps are reduced; a condensing agent or an acyl chlorination reagent is not used, so that the production cost is greatly reduced, and three wastes are reduced; no expensive reagents are used other than the noble metal catalysts that have to be used for the double bond reduction.

Description

Preparation method of 2-phenylalanyl-benzoic acid derivative
Technical Field
The invention relates to a 2- (3- (p-hydroxyphenyl) -propionamido) -benzoic acid derivative and a preparation method thereof, belonging to the fields of chemistry and chemical industry, cosmetics and medicinal chemicals.
Background
The 2-phenylpropionamide benzoic acid derivative is the main component of the avenanthramide, has multiple biological activities of oxidation resistance, inflammation resistance, itching relieving and the like, is widely applied to cosmetics and skin medicaments, and is known as dihydro avenanthramide D and tranilast
Figure BDA0003878658400000011
In the prior art, the synthesis methods of the compounds mainly comprise the following steps:
the method comprises the following steps: as disclosed in WO2005016870, CN106631865, the synthetic route is as follows:
Figure BDA0003878658400000012
the method is characterized in that: 1) The use of expensive condensation reagents such as dicarbonylimidazole, EDCI, DCC, and the like; 2) Large amounts of organic bases, such as pyridine, triethylamine, diisopropylethylamine, etc., are consumed; 3) Hydroxyl on a benzene ring of the raw material needs to be protected to ensure the yield; 4) If the carboxyl group is not esterified, the condensing agent is excessive or the temperature is too high, the impurity m1-BP-01 is easily generated. The three characteristics mean high cost of raw materials for production, complex steps and more three wastes.
The second method comprises the following steps: as disclosed in CN106631865, CN112939803, CN104418764 and WO2005016870, phenylpropionic acid derivatives are converted into acid chlorides, which are reacted with anthranilic acid derivatives under the action of a base to give the desired product. The method is a traditional method for synthesizing amide, and the synthetic route is as follows:
Figure BDA0003878658400000021
the method uses acyl chlorination reagents, such as common thionyl chloride, oxalyl chloride and the like, to prepare acyl chloride, and then uses the acyl chloride to prepare amide, so that the cost of raw materials is reduced compared with that of a condensing agent in the first method, but the acyl chlorination reagents are dangerous chemicals and highly toxic chemicals, byproducts comprise strongly acidic hydrogen chloride gas, toxic and harmful sulfur dioxide, carbon monoxide and the like, besides a great corrosion effect on equipment, the method also has a very serious threat on the personal safety of production personnel, and a large amount of three wastes are generated by treating the gases; the method also protects phenolic hydroxyl and carboxyl on benzene ring to esterify so as to ensure reaction yield, and also needs a large amount of organic base as an acid-binding agent, and pollutants and three wastes generated in the process are even more than those generated in the method.
The general synthetic method of the raw material phenylpropionic acid of the first method and the second method is as follows:
Figure BDA0003878658400000022
in conclusion, the initial raw materials used in the first method and the second method are benzaldehyde, malonic acid and anthranilic acid or ester, and the 2-phenylpropionamide benzoic acid is synthesized through 4-5 steps of condensation decarboxylation, hydrogenation, condensation amidation or acyl chloride amidation (2 steps), deprotection and the like. The process method uses expensive condensing agent or acyl chlorination reagent with great pollution, consumes a large amount of organic or inorganic alkali and generates a large amount of three wastes; if the phenol hydroxyl on benzene rings of benzaldehyde and the anthranilic acid derivative needs to be protected to react, two protection steps and at least one deprotection step need to be added in the whole process, and the process is more complicated.
And thirdly, reacting anthranilic acid with Meldrum's acid to generate 2- (carboxyl acetamido) -benzoic acid, condensing with benzaldehyde to generate decarboxylation to obtain 2-phenylpropenamidobenzoic acid, and reducing double bonds to obtain the target compound, as disclosed in CN10651110, CN106631865, ref 1 and Ref 2. The synthetic route is as follows:
Figure BDA0003878658400000031
Ref 1：Shrivallabh P Kamat，Sulaksha J Parab.A simple two-step synthesis of avenanthramides,constituents of oats(Avena sativa L)[J].Indian Journal of Chemistry Section B-organic Chemistry,vol 46B, 2074-2078
Ref 2：Inese Mierina,Agnese Stikute,Anatoly Mishnev&Mara Jure.An alternative way to analogues of avenanthramides and their antiradical activity[J].Monatshefte für Chemie-Chemical Monthly volume 150,85–101(2019)
in the prior art, the reaction yield of anthranilic acid (m-02) and meldrum's acid (m-07) in CN10651110 and CN106631865 is 85%, and the two-step yield of the reaction with benzaldehyde (m-04) is 70%; the yield of the reaction of Ref 1 with the Meldrum's acid (m-07) is 90 percent, and the yield of the reaction of Ref 1 with the benzaldehyde (m-04) in two steps is 60-80 percent; the reaction yield of Ref 2 and the Meldrum's acid (m-07) is 30-70%, the proportion of the byproduct m3-BP-01 is 2-18%, the condensation yield of the Ref 2 and the benzaldehyde (m-04) is 26-74%, and the decarboxylation yield is 45-88%. It can be seen from the disclosure of the prior art that the reaction repeatability is not very good, and the yield data varies greatly; m3-BP-01 impurity is easy to generate, which causes low yield and increases the difficulty of purification. The raw material of the method, namely the Meldrum's acid, is expensive, high in cost and unstable in yield, and is not a method suitable for industrial production.
In the fourth method, as disclosed in CN109553550, benzenepropanal and anthranilate are subjected to condensation oxidation by sodium persulfate under the action of 1, 4-dimethyltriazole chloride and cesium carbonate to generate 2-phenylamido-benzoate, and the 2-phenylamido-benzoate is obtained by hydrolysis, wherein the yield is 98%. The hydroxyl substituent in phenylpropyl aldehyde and anthranilate is protected by acetyl, propionyl and methyl. The synthetic route is as follows:
Figure BDA0003878658400000041
the method uses a few phenylpropyl aldehyde raw materials, does not have an industrial product at present, and needs autonomous production. The common phenylpropionaldehyde is prepared by reduction oxidation or conversion of phenylpropionic acid into acyl chloride or N, O-dimethylhydroxyamide; the phenolic hydroxyl on the benzene ring in the raw material must be protected, the total synthesis steps are long, and the cost is high; the used catalysts, namely triazole quaternary ammonium acid and cesium carbonate, are high in price, and although the reported yield is up to 98%, the production cost is high, so that the method is not a method suitable for industrial production.
The problems with the above four methods include:
1) The steps are various, and the protection and the deprotection of phenolic hydroxyl in raw materials are very complicated;
2) The condensing agent, the acyl chlorination reagent and a large amount of organic alkali are used in the first method and the second method, so that the cost of raw materials is increased, and a large amount of three wastes are generated;
3) The third method and the fourth method have high cost of raw materials or have no commercialized raw materials, such as the Meldrum's acid, the phenylpropionaldehyde reagent and the like, and have high independent production cost.
Disclosure of Invention
In order to solve the above problems, the present invention provides a novel method for synthesizing a 2-phenylamido-benzoic acid derivative, comprising the reaction steps of:
step 1: carrying out condensation reaction on the compound of the formula 1 and the compound of the formula 2 to generate a compound of a formula 3;
step 2: reacting a compound of formula 3 with a compound of formula 4 to produce a compound of formula 5;
and step 3: hydrolyzing the compound of formula 5 to obtain a compound of formula 6;
and 4, step 4: reducing the double bond of the compound shown in the formula 6 to obtain a compound shown in a formula 7;
and 5: decarboxylating the compound of formula 7 to obtain a 2-phenylamido-benzoic acid derivative of formula 8;
wherein, the structure of the compound of formula 1 is:
Figure BDA0003878658400000051
the structure of the compound of formula 2 is:
Figure BDA0003878658400000052
the structure of the compound of formula 3 is:
Figure BDA0003878658400000053
the structure of the compound of formula 4 is:
Figure BDA0003878658400000054
the structure of the compound of formula 5 is:
Figure BDA0003878658400000055
the structure of the compound of formula 6 is:
Figure BDA0003878658400000056
the structure of the compound of formula 7 is:
Figure BDA0003878658400000061
the structure of the compound of formula 8 is:
Figure BDA0003878658400000062
wherein R is 1 And R 2 Is C 1 -C 5 Alkyl of (C) 6 -C 20 Aryl radical, C 7 -C 25 Aralkyl, C 7 -C 25 An alkaryl group;
R 3 、R 4 and R 5 Is H, OH, halogen, C 1 -C 5 Alkyl and C 1 -C 5 Alkoxy group of (a);
with the proviso that R 3 、R 4 And R 5 At least one is OH or C 1 -C 5 Alkoxy group of (2).
The synthesis method is as follows:
Figure BDA0003878658400000063
the step 1 can adopt the prior art:
the synthesis described in Brown et al, australian Journal of Chemistry,1954, vol.7, p.348, 369 is carried out by directly heating the compound of formula 2 with the compound of formula 1 to produce the compound of formula 3, but the reaction will simultaneously produce the diester amidated by-product BP-01, with higher reaction temperatures giving greater proportions of by-product BP-01, and suitable reaction temperatures are 130-160 ℃. The property of the by-product BP-01 is similar to that of the compound shown in the formula 3, 2-4 times of crystallization is needed to obtain a pure product, the crystallization condition is complex, the repeatability is poor, and the final yield is only 50-70%.
The structure of the byproduct BP-01 is as follows:
Figure BDA0003878658400000071
in order to overcome the above disadvantages, the present invention also provides a method for preparing the compound of formula 3, wherein step 1 is performed using the method.
The method comprises the following steps:
step 1a: heating the compound shown in the formula 2 and an excessive compound shown in the formula 1 to 130-160 ℃ for reaction to generate a compound shown in the formula 3 and a byproduct BP-02P-01;
step 1b: after the reaction in the step 1a is finished, heating the reaction system to 190-200 ℃, and converting the byproduct BP-01 into a byproduct BP-02;
step 1c: cooling the reaction system to 60-80 ℃, filtering to remove a byproduct BP-02, and distilling to recover an excessive compound of the formula 1 to obtain a compound of the formula 3;
wherein the structure of the byproduct BP-02 is as follows:
Figure BDA0003878658400000072
we found that the by-product BP-01 is converted into the by-product BP-02 at a temperature of more than 190 ℃, the solubility of the by-product BP-02 in the reaction system is low, and the by-product BP-02 can be removed by filtration after the reaction is finished. The method has simple process conditions and high utilization rate of raw materials, the conversion rate of the compound in the formula 2 can reach 100 percent, and the yield is 80-90 percent.
The reaction temperature of the step 2 is 50-150 ℃, preferably 80-120 ℃;
the reaction solvent is selected from: heptane, hexane, petroleum ether, toluene, benzene, formic acid, acetic acid, and propionic acid, N-dimethylformamide, N-methylpyrrolidone;
preferably, the solvent is a mixed solvent of two or more of the above which can be azeotropically distilled off with water continuously by azeotropy during the reaction; the mixed solvent is selected from: formic acid-heptane, acetic acid-heptane, formic acid-hexane, acetic acid-hexane, N-dimethylformamide-heptane, N-methylpyrrolidone-heptane;
the catalyst is selected from piperidine, tetrahydropyrrole, piperazine, methyl piperazine and corresponding salts thereof, and the dosage of the catalyst is not less than 1%.
The reaction temperature in the step 3 is less than or equal to 60 ℃;
the reaction solution is a solvent which can be mutually dissolved with water and is selected from: methanol, ethanol, propanol, tetrahydrofuran, methyltetrahydrofuran;
after the reaction in the step 3 is finished, a product can be separated out from the reaction liquid and can also be obtained by an extraction method, the product in the step 3 contains cis-trans isomers, and the total purity is more than 95%;
the product of step 3 can be used directly in the next reaction or can be purified by crystallization.
Step 4 may employ any known double bond reduction reaction conditions,
the optional double bond reduction reaction is a catalytic hydrogenation reaction, and the catalyst of the reaction is selected from palladium carbon, raney nickel and a composite metal catalyst;
the optional double bond reduction reaction is a transfer hydrogenation reaction, the hydrogen source of the transfer hydrogenation reaction is selected from formic acid and formate, and the formate is selected from ammonium formate, potassium formate and sodium formate.
In the step 5, the reaction temperature is 80-150 ℃, preferably 80-130 ℃;
the higher the reaction temperature, the faster the reaction, but the temperature also causes side reactions to occur, such as intramolecular or intermolecular dehydration reactions;
the reaction solvent is selected from: formic acid, acetic acid, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, N-dimethylamide, N-methylpyrrolidone, preferably: formic acid, acetic acid, N-methylpyrrolidone;
the step 4 and the step 5 can be combined into one step, namely, the double bond of the compound shown in the formula 6 is reduced at the temperature of more than 80 ℃ to obtain the compound shown in the formula 7, and the target product, the compound shown in the formula 8, is directly decarboxylated without separation.
The raw materials used in the route of the invention are malonic diester derivatives, anthranilate derivatives and benzaldehyde derivatives which are all industrial basic raw materials; such as R 1 When the compound is methyl or ethyl, the compound in the formula 1 is dimethyl malonate or diethyl malonate, is a raw material for industrial large-scale production, and is widely used in the field of pharmaceutical chemicals; r 2 When the compound is methyl or ethyl, the compound in the formula 2 is methyl anthranilate or ethyl anthranilate, is a nontoxic raw material widely used in perfume essence, is low in price and is easy to obtain. Phenolic hydroxyl groups on benzene rings in all raw materials do not need to be protected, so that the production steps are reduced; a condensing agent or an acyl chlorination reagent is not used, so that the production cost is greatly reduced, and three wastes are reduced; no expensive reagents are used other than the noble metal catalysts that have to be used for the double bond reduction.
Detailed Description
The present invention will be described in further detail with reference to examples. It will also be understood that the following examples are included merely for purposes of further illustrating the invention and are not to be construed as limiting the scope of the invention, as the invention extends to insubstantial modifications and adaptations of the invention following in the light of the principles set forth herein. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can make a selection within suitable ranges through the description herein, and are not intended to be limited to the specific data of the following examples.
The first embodiment is as follows: synthesis of methyl 2- (2-methoxycarbonylacetamido) -benzoate (L1-3) (step one)
Figure BDA0003878658400000101
Mixing dimethyl malonate L1-1 (132.12g, 1.0 mol) and methyl anthranilate L1-2 (15.1 g,0.1 mol), heating to 150-160 ℃ for reaction for 12 hours, heating to 190 ℃ for reaction for 2 hours after the anthranilate completely reacts, cooling to 80-100 ℃ after the byproduct L1-BP-01 is completely converted into the byproduct L1-BP-02, and filtering to remove solids; the filtrate was concentrated to give L1-3.0 g of methyl 2- (2-methoxycarbonylacetamido) -benzoate.
Example two: synthesis of methyl 2- (2-ethoxycarbonylacetamido) -benzoate (L2-3) (step one)
Figure 1
Mixing diethyl malonate L2-1 (160.17g, 1.0 mol) and methyl anthranilate L1-1 (15.1g, 0.1mol), heating to 150-160 ℃ for reaction for 16h, heating to 190 ℃ for reaction for 2h after the methyl anthranilate completely reacts, cooling to 80-100 ℃ after L1-BP-01 is completely converted into L1-BP-02, and filtering to remove solids; the filtrate was concentrated to give L1-3.0 g of 2- (2-ethoxycarbonylacetamido) -benzoic acid methyl ester.
Example three: synthesis of 2- (2-methoxycarbonylacetamido) -5-hydroxy-benzoic acid methyl ester (L3-3) (step one)
Figure BDA0003878658400000111
Mixing dimethyl malonate L1-1 (132.12g, 1.0mol) and 2-amino-5-hydroxy-methyl benzoate L3-2 (16.7g, 0.1mol), heating to 130-140 ℃ for reacting for 8 hours, heating to 190 ℃ after phthalic acid completely reacts, reacting for 2hours, completely converting L3-BP-01 into L3-BP-02, cooling to 60-80 ℃, and filtering to remove solids; the filtrate was concentrated to give L3-3.5g of 2- (2-methoxycarbonylacetamido) -5-hydroxy-benzoic acid methyl ester.
Example four: synthesis of methyl 2- (3- (4-hydroxy-phenyl) -2-methoxycarbonyl-acrylamido) -benzoate (L4-2) (step 2)
2- (2-methoxycarbonylacetamido) -benzoic acid methyl ester L1-3 (25.1g, 100mmol), 4-hydroxybenzaldehyde L4-1 (12.8g, 105mol), acetic acid (100 ml) and piperidine (425mg, 5mmol) were mixed and heated to 100 ℃ to react for 12h, HPLC analysis showed that the conversion of L1-3 was 80%, acetic acid was recovered by distillation, ethyl acetate (200 ml) was added, washed with water and 1N hydrochloric acid, and concentrated to give a crude product of L4-2, 85% purity by HPLC.
EXAMPLE five Synthesis of methyl 2- (3- (4-hydroxy-phenyl) -2-methoxycarbonyl-acrylamido) -benzoate (L4-2) (step 2)
2- (2-methoxycarbonylacetamido) -benzoic acid methyl ester L1-3 (25.1g, 100mmol), 4-hydroxybenzaldehyde L4-1 (12.8g, 105mol), acetic acid (100 ml), heptane (100 ml) and piperidine (425 mg,5 mmol) were mixed, reflux water separation reaction was carried out for 12h, HPLC analysis gave 98% conversion of L1-3, acetic acid and heptane were recovered by distillation, ethyl acetate (200 ml) was added, washed with water and 1N hydrochloric acid, and concentrated to give crude L4-2, HPLC purity was 95%, methyl tert-butyl ether was used to crystallize 2- (3- (4-hydroxy-phenyl) -2-methoxycarbonyl-acrylamido) -benzoic acid methyl ester L4-2.5g.
Examples 4, 5 the reaction sequence is as follows:
Figure BDA0003878658400000121
example six: synthesis of 2- (3- (4-hydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid (L6-1) (step 3)
Figure BDA0003878658400000122
3- (3- (4-hydroxy-phenyl) -2-methoxycarbonyl-acrylamido) -benzoic acid methyl ester L4-2 (33.5g, 94.3mmol) was dissolved in methanol (150 ml), and 50% aqueous sodium hydroxide solution (38g, 471.5mmol) was added to complete the reaction, and after completion of the reaction, the reaction mixture was poured into 1N HCl to precipitate a solid, which was then filtered to obtain L6-1.9.
1 H-NMR(500MHz，DMSO-d6)：6.73-6.76(d，2H)，7.21(m，1H)，7.43-7.46(d， 2H)，7.59(s，1H)，7.67(t，1H)，7.95-7.80(m，1H)，8.63-8.66(m，1H)，10.09(s， 1H)，11.40(s，1H)，12.80(bs，1H)，13.50(bs，1H)。
MS ESI[M+1]：327.92
Example seven: synthesis of 2- (3- (4-hydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid (L7-1) (step 4)
Figure BDA0003878658400000131
Dissolving 2- (3- (4-hydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid L6-1 (30.9, 94.3 mmol) in methanol (500 ml), adding 5% Pd/C (1.5 g), reacting under normal pressure with hydrogen for 8h, filtering to recover Pd/C, and concentrating the filtrate to obtain 2- (3- (4-hydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid L7-1.0 g
1 H-NMR(500MHz，DMSO-d6)：3.01-3.05(m，2H)，3.60-3.65(m，1H)， 6.61-6.64(d，2H)，7.02-7.05(d，2H)，7.14-7.18(m，1H)，7.56-7.60(m，1H)， 7.96-8.00(m，1H)，8.42-8.50(m，1H)，9.15(s，1H)，11.34(s，1H)，12.90(bs， 1H)，13.50(bs，1H)。
MS ESI[M+1]：329.90。
Example eight: synthesis of 2- (3- (4-hydroxy-phenyl) -propionamido) -benzoic acid (8 a) (step 5)
Figure BDA0003878658400000141
2- (3- (4-hydroxy-phenyl) -2-carboxyl-propionamido) -benzoic acid L7-1 (31.0g, 94.3mmol) is dispersed in acetic acid (100 ml), heated to reflux for reaction for 3h, cooled to room temperature, and filtered to collect solid to obtain 24.1g of 2- (3- (4-hydroxy-phenyl) -propionamido) -benzoic acid 8a.
1 H-NMR(500MHz，DMSO-d6)：2.62-2.84(m，2H)，3.42-3.47(m，2H)， 6.65-6.67(d，2H)，7.03-7.05(d，2H)，7.12-7.15(m，1H)，7.56-7.60(m，1H)， 7.96-7.98(m，1H)，8.47-8.50(m，1H)，9.16(s，1H)，11.10(s，1H)，13.61(bs， 1H)。
MS ESI[M+1]：285.98。
Example nine: synthesis of 2- (3- (4-hydroxy-phenyl) -propionamido) -benzoic acid (8 a) (step 5)
2- (3- (4-hydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid L7-1 (10.0g, 30.4mmol) is dissolved in N-methylpyrrolidone (50 ml), the mixture is heated to 110 ℃ for reaction for 3h, the temperature is reduced to room temperature, water (200 ml) is added, and the solid is collected by filtration to obtain 8.3g of 2- (3- (4-hydroxy-phenyl) -propionamido) -benzoic acid.
Example ten: synthesis of 2- (3- (4-hydroxy-phenyl) -propionamido) -benzoic acid (8 a) (Steps 4, 5 combine)
2- (3- (4-hydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid L6-1 (10.0 g, 30.6 mmol) was dissolved in N-methylpyrrolidone (100 ml), 5% Pd/C (0.5 g) was added, ammonium formate (9.2g, 153mmol) was added, the reaction was heated to 100 ℃ for 12h, pd/C was recovered by filtration, and the filtrate was concentrated to give 2- (3- (4-hydroxy-phenyl) -propionamido) -benzoic acid 8a 8.4g.
Example eleven: synthesis of 2- (3, 4-dihydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid (L11-3) (Steps 2, 3)
Figure BDA0003878658400000151
2- (3, 4-dihydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid (L11-3) was synthesized by the procedure of examples four and six, using 3, 4-dihydroxy-benzaldehyde (L11-1) instead of 4-hydroxybenzaldehyde (L6-1)
1 H-NMR(500MHz，DMSO-d6)：6.74-6.77(d，1H)，6.95-6.97(d，1H)， 7.06-7.08(d，1H)，7.18-7.22(t，1H)，7.53(s，1H)，7.65-7.69(t，1H)， 8.00-8.03(d，1H)，8.71-8.74(d，1H)，9.18(bs，1H)，9.66(bs，1H)，11.44(s， 1H)，12.10-14.20(bs，2H)。
MS ESI[M+1]：343.81。
Example twelve: synthesis of 2- (3, 4-dihydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid (L12-1) (step 4)
Figure BDA0003878658400000161
2- (3, 4-dihydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid (L12-1) was synthesized by the procedure of example seven, substituting 2- (3, 4-dihydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid (L11-3) for 2- (3- (4-hydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid (L6-1).
1 H-NMR(500MHz，DMSO-d6)：2.96-2.98(m，2H)，3.55-3.59(m，1H)，6.47-6.49(d，1H)，6.58-6.60(d，1H)，6.62-6.63(d，1H)，7.14-7.17(t，1H)， 7.56-7.60(t，1H)，7,96-8.00(d，1H)，8.44-8.46(d，1H)，8.62(s，1H)，8.68(bs， 1H)，11.36(s，1H)，12.82(bs，1H)，13.62(bs，1H)。
MS ESI[M+1]：345.95。
Example thirteen: synthesis of 2- (3, 4-dihydroxy-phenyl) -propionamido) -benzoic acid (8 b) (step 5)
Figure BDA0003878658400000162
Synthesis of 2- (3, 4-dihydroxy-phenyl) -propionamido) -benzoic acid (8 b) by the procedure of example eight, substituting 2- (3, 4-dihydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid (L12-1) for 2- (3- (4-hydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid (L7-1)
1 H-NMR (500MHz, DMSO-d 6): 2.48-2.52 (m, 2H, DMSO residual superposition), 2.74-2.78 (m, 2H), 6.45-6.48 (d, 1H), 6.60-6.62 (m, 2H), 6.89-6.92 (t, 1H), 7.22-7.26 (t, 1H), 7.96-7.98 (d, 1H), 8.44-8.46 (d, 1H), 14.20 (s, 1H).
MS ESI[M+1]：301.95。
Example fourteen: synthesis of 2- (3, 4-dimethoxy-phenyl) -propionamido) -benzoic acid (8 c) (Steps 2-5)
Figure BDA0003878658400000171
2- (3, 4-dimethoxy-phenyl) -propionamido) -benzoic acid (8 c) was synthesized by the procedure of examples five, six, seven and nine, substituting 3, 4-dimethoxy-benzaldehyde (L14-1) for 4-hydroxybenzaldehyde.
Wherein, L14-3:2- (3, 4-dimethoxy-phenyl) -2-carboxy-acrylamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：3.76(s，6H)，6.95-7.00(m，1H)，7.15-7.25(m， 3H)，7.50-7.60(m，2H)，7.97-8.05(d，1H)，8.68-8.72(d，1H)，11.82s，1H)
MS ESI[M+1]：371.91
L14-4:2- (3, 4-dimethoxy-phenyl) -2-carboxy-propionamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：3.08-3.12(m，2H)，3.67(s，6H)，3.69-3.74(m， 1H)，6.74-6.81(m，2H)，6.88(s，1H)，7.13-7.17(t，1H)，7.55-7.59(t，1H)， 7.97-8.00(d，1H)，8.45-8.47(d，1H)，11.40(s，1H).
MS ESI[M+1]：373.95
8c
1 H-NMR(500MHz，DMSO-d6)：2.56-2.59(m，2H)，2.87-2.90(m，2H)，3.70(s， 6H)，6.74-6.77(m，1H)，6.82-6.84(m，1H)，6.90(s，1H)，6.92-6.93(m，1H)， 7.22-7.25(t，1H)，7.96-7.99(d，1H)，8.44-8.47(d，1H)，11.30(s，1H)。
MS ESI[M+1]：329.92
Example fifteen: synthesis of 2- (3- (3-methoxy-4-hydroxy-phenyl) -propionamido) -benzoic acid (8 d) (Steps 2-5)
Figure BDA0003878658400000181
Synthesis of 2- (3- (3-methoxy-4-hydroxy-phenyl) -propionamido) -benzoic acid (8 d) according to the procedure of examples five, six, seven and eight, with 3-methoxy-4-hydroxy-benzaldehyde (L15-1) replacing 4-hydroxybenzaldehyde
Wherein: l15-3:2- (3- (3-methoxy-4-hydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：3.48(s，3H)，6.74-6.79(m，1H)，7.05-7.08(m， 1H)，7.10-7.13(m，1H)，7.18(s，1H)，7.50-7.52(m，2H)，7.99-8.01(d，1H)， 8.67-8.69(d，1H)，12.81(bs，1H).
MS ESI[M+1]：357.81
L15-4:2- (3- (3-methoxy-4-hydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：3.05-3.08(s，2H)，3.58-3,68(m，4H)，6.64(m， 2H)，6.83(s，1H)，7.13-7.16(m，1H)，7.55-7.59(m，1H)，7.97-7.99(d，1H)， 8.46-8.48(d，1H)，8.70(bs,1H)，11.42(s，1H)，13.17(bs,1H).
MS ESI[M+1]：359.95
8d:2- (3- (3-methoxy-4-hydroxy-phenyl) -propionamido) -benzoic acid (8 d)
1 H-NMR(500MHz，DMSO-d6)：2.53-2.57(t，2H)，2.83-2.86(t，2H)，3.71(s， 3H)，6.61-6.69(m，2H)，6.81s，1H)，6.90-6.94(m，1H)，7.23-7.27(m，1H)， 7.97-7.99(d，1H)，8.46-8.48(d，1H)，8.74(bs,1H)，14.12(s，1H).
MS ESI[M+1]：315.94。
Example sixteen: synthesis of 2- (3- (4-hydroxy-phenyl) -propionamido) -5-hydroxy-benzoic acid (8 e) (Steps 2-5)
Figure BDA0003878658400000201
Synthesis of 2- (3- (4-hydroxy-phenyl) -propionamido) -5-hydroxy-benzoic acid (8 e) by substituting 2- (2-methoxycarbonylacetamido) -5-hydroxy-benzoic acid methyl ester (L3-3) for 2- (2-methoxycarbonylacetamido) -benzoic acid methyl ester (L1-3) according to the procedures of example five, six, seven and eight
L16-3:2- (3- (4-hydroxy-phenyl) -2-carboxy-acrylamido) -5-hydroxy-benzoic acid
1 H-NMR(500MHz,DMSO-d6):6.73-6.76(d,1H),7.05(d,1H),7.37(s,1H),7.43 -7.44(d,2H),7.54(s,1H),8.40(d,1H),9.65(s,1H),10.11(s,1H),11.05(s,1H) ,13.05-13.08(bs,2H)
MS ESI[M+1]：343.83
L16-4:2- (3- (4-hydroxy-phenyl) -2-carboxy-propionamido) -5-hydroxy-benzoic acid
1 H-NMR(500MHz，DMSO-d6)：2.99-3.02(m,2H),3.56(m,1H),6.60-6.64(d, 2H),6.90-7.00(d,1H),7.00-7.05(d,2H),7.34(s,1H),8.18-8.21(d,1H),9.13( s,1H),9.55(s,1H),10.92(s,1H),12.80-13.50(bs,2H)
MS ESI[M+1]：345.96
8e:2- (3- (4-hydroxy-phenyl) -propionamido) -5 hydroxy-benzoic acid (8 e)
1 H-NMR(500MHz，DMSO-d6)：2.55-2.60(t,2H),2.79-2.83(t,2H), 6.64-6.70(d,2H),6.95-7.00(d,1H),7.01-7.04(d,2H),7.34(s,1H), 9.10(s,1H),9.49(s,1H),10.65(s,1H),13.36(bs,1H)
MS ESI[M+1]：301.97。
Example seventeen: synthesis of 2- (3- (3-fluoro-4-hydroxy-phenyl) -propionamido) -benzoic acid (8 f) (step 2-5)
Figure BDA0003878658400000211
Synthesis of 2- (3- (3-fluoro-4-hydroxy-phenyl) -propionamido) -benzoic acid (8 f) by the procedure of examples five, six, seven and eight, substituting 3-fluoro-4-hydroxy-benzaldehyde (L18-1) for 4-hydroxybenzaldehyde
L18-3:2- (3- (3-fluoro-4-hydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：6.90-7.00(m，1H)，7.18-7.20(m，1H)， 7.25-7.30(m，1H)，7.35-7.40(m，1H)，7.55(s，1H)，7.65(t，1H)，7.93-7.98(m， 1H)，8.62-8.65(m，1H)，10.65(s，1H)，11.80(bs，1H).
MS ESI[M+1]：345.97
L18-4:2- (3- (3-fluoro-4-hydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：3.00-3.06(m，2H)，3.55-3.65(m，1H)， 6.78-6.89(m，2H)，7.00-7.05(m，1H)，7.21-7.23(m，1H)，7.65(t，1H)， 7.93-7.98(m，1H)，8.62-8.65(m，1H)，10.65(s，1H)，11.80(bs，1H).
MS ESI[M+1]：348.11
8f:2- (3- (3-fluoro-4-hydroxy-phenyl) -propionamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：2.60-2.80(m，2H)，3.45-3.48(m，2H)， 6.78-6.89(m，2H)，7.00-7.05(m，1H)，7.21-7.25(m，1H)，7.63(t，1H)， 7.90-7.95(m，1H)，8.60-8.65(m，1H)，9.55(s，1H)，11.05(s，1H)，13.60(s， 1H).
MS ESI[M+1]：304.12
Example eighteen: synthesis of 2- (3- (4-methyl-phenyl) -propionamido) -benzoic acid (8 g) (Steps 2-5)
Figure BDA0003878658400000221
Synthesis of 2- (3- (4-methyl-phenyl) -propionamido) -benzoic acid (8 g) by the procedure of examples five, six, seven and eight, using 4-methyl-benzaldehyde (L15-1) instead of 4-hydroxybenzaldehyde
L19-3:2- (3- (4-methyl-phenyl) -2-carboxy-acrylamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：2.23(s，3H)，7.20(m，1H)，7.40-7.45(d， 2H)，7.55-7.60(m，3H)，7.67(t，1H)，7.92-8.00(m，1H)，8.60-8.66(m，1H)， 11.20(s，1H)，12.70(bs，1H)，13.45(bs，1H).
MS ESI[M+1]：326.10
L19-4:2- (3- (4-methyl-phenyl) -2-carboxy-propionamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：2.20(s，3H)，3.00-3.05(m，2H)，3.61-3.64(m， 1H)，7.00-7.10(m，4H)，7.20(m，1H)，7.66(t，1H)，7.90-8.00(m，1H)， 8.60-8.66(m，1H)，11.20(s，1H)，12.70(bs，1H)，13.45(bs，1H).
MS ESI[M+1]：328.09
8g:2- (3- (4-methyl-phenyl) -propionamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：2.20(s，3H)，2.62-2.65(m，2H)，3.42-3.50(m， 2H)，6.98-7.08(m，4H)，7.20(m，1H)，7.66(t，1H)，7.90-8.00(m，1H)， 8.60-8.66(m，1H)，11.18(s，1H)，12.50(bs，1H).
MS ESI[M+1]：284.08。
Example nineteenth: synthesis of 2- (3, 5-dihydroxy-phenyl) -propionamido) -benzoic acid (8 h) (Steps 2-5)
Figure BDA0003878658400000241
Synthesis of 2- (3, 5-dihydroxy-phenyl) -propionamido) -benzoic acid (8 h) by the procedure of examples five, six, seven and eight, using 3, 5-dihydroxy-benzaldehyde (L17-1) instead of 4-hydroxybenzaldehyde
L17-3:2- (3, 5-dihydroxy-phenyl) -2-carboxy-acrylamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：6.30(s，1H)，6.55(s，2H)，7.18-7.23(m， 2H)，7.45(s，1H)，7.65(t，1H)，7.93-7.98(m，1H)，8.62-8.65(m，1H)，9.50(bs， 2H)，11.22(s，1H)，13.50(bs，2H).
MS ESI[M+1]：344.08
L17-4:2- (3, 5-dihydroxy-phenyl) -2-carboxy-propionamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：2.82-3.00(m，2H)，3.45-3.55(m，1H)，6.05(s， 1H)，6.10(s，2H)，7.10-7.15(m，1H)，7.65(t，1H)，7.93-7.98(m，1H)， 8.62-8.65(m，1H)，9.15(bs，2H)，11.20(s，1H)，13.50(bs，2H).
MS ESI[M+1]：346.08
8h:2- (3, 5-dihydroxy-phenyl) -propionamido) -benzoic acid
1 H-NMR(500MHz，DMSO-d6)：2.50-2.65(m，2H)，3.40-3.44(m，2H)，6.05(s， 1H)，6.10(s，2H)，7.10-7.15(m，1H)，7.65(t，1H)，7.93-7.98(m，1H)， 8.62-8.65(m，1H)，9.05(bs，2H)，11.20(s，1H)，13.50(bs，1H)。
MS ESI[M+1]：302.10
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims (10)

1. A method for synthesizing a 2-phenylamido-benzoic acid derivative, comprising the following reaction steps:
step 1: carrying out condensation reaction on a compound shown in a formula 1 and a compound shown in a formula 2 to generate a compound shown in a formula 3;
and 2, step: reacting a compound of formula 3 with a compound of formula 4 to produce a compound of formula 5;
and 3, step 3: hydrolyzing the compound of formula 5 to obtain a compound of formula 6;
and 4, step 4: reducing the double bond of the compound shown in the formula 6 to obtain a compound shown in a formula 7;
and 5: decarboxylating the compound of formula 7 to obtain a 2-phenylamido-benzoic acid derivative of formula 8;
wherein the compound of formula 1 has the structure:
Figure FDA0003878658390000011
the structure of the compound of formula 2 is:
Figure FDA0003878658390000012
the structure of the compound of formula 3 is:
Figure FDA0003878658390000013
the structure of the compound of formula 4 is:
Figure FDA0003878658390000014
the structure of the compound of formula 5 is:
Figure FDA0003878658390000015
the structure of the compound of formula 6 is:
Figure FDA0003878658390000021
the structure of the compound of formula 7 is:
Figure FDA0003878658390000022
the structure of the compound of formula 8 is:
Figure FDA0003878658390000023
wherein R is 1 And R 2 Is C 1 -C 5 Alkyl of (C) 6 -C 20 Aryl radical, C 7 -C 25 Aralkyl, C 7 -C 25 An alkaryl group;
R 3 、R 4 and R 5 Is H, OH, halogen, C 1 -C 5 Alkyl and C 1 -C 5 Alkoxy group of (a);
provided that R is 3 、R 4 And R 5 At least one is OH or C 1 -C 5 An alkoxy group of (2).
2. The method of claim 1, wherein the reaction conditions of step 1 are heating to 130-160 ℃.
3. The method of claim 1, wherein the reaction conditions of step 1 are heating to 130-160 ℃ and then heating to 190-200 ℃.
4. The method of claim 3, wherein the reaction step of step 1 is:
step 1a: heating the compound shown in the formula 2 and an excessive compound shown in the formula 1 to 140-150 ℃ for reaction to generate a compound shown in the formula 3 and a byproduct BP-01;
step 1b: after the reaction in the step 1a is finished, heating the reaction system to 190-200 ℃, and converting the byproduct BP-01 into a byproduct BP-02;
step 1c: cooling the reaction system to 60-80 ℃, filtering to remove a byproduct BP-02, and distilling to recover an excessive compound of the formula 1 to obtain a compound of the formula 3;
wherein the structures of the by-products BP-01 and BP-02 are as follows:
Figure FDA0003878658390000031
5. the method of claim 1, wherein the reaction solvent of step 2 is selected from the group consisting of: heptane, hexane, petroleum ether, toluene, benzene, formic acid, acetic acid, and propionic acid, N-dimethylformamide, N-methylpyrrolidone.
6. The method of claim 1, wherein the catalyst of step 2 is selected from the group consisting of piperidine, tetrahydropyrrole, piperazine, methylpiperazine and corresponding salts thereof.
7. The method of claim 1, wherein the reaction temperature of step 3 is 60 ℃ or less.
8. The method of claim 1, wherein the double bond reduction reaction of step 4 is a catalytic hydrogenation reaction with a catalyst selected from the group consisting of palladium on carbon, raney nickel, and composite metal catalysts; or a transfer hydrogenation reaction, wherein the hydrogen source of the transfer hydrogenation reaction is selected from formic acid and formate.
9. The method of claim 1, wherein in step 5, the reaction temperature is 80-150 ℃.
10. The method of claim 1, wherein step 4 and step 5 can be combined into one step at a reaction temperature of 80 ℃ or higher.
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