阅读说明：本技术 一种3-(2-氨基苯基)-2-丙烯酸酯的制备方法 (Preparation method of 3- (2-aminophenyl) -2-acrylate ) 是由 陈剑 余长泉 郭士超 沈秋华 于 2021-12-06 设计创作，主要内容包括：本发明涉及药物制备技术领域,尤其是一种3-(2-氨基苯基)-2-丙烯酸酯的制备方法,具体包括以下步骤：1)在碱的作用下,邻硝基苯甲醛与丙二酸酯衍生物在有机溶剂中进行Knoevenagel缩合反应,生成α,β-不饱和羰基化合物A；2)在盐的作用下,化合物A在有机溶剂和水中进行脱羧反应得到化合物B；3)在酸的作用下,还原金属试剂与化合物B在有机溶剂和水中进行硝基还原反应生成3-(2-氨基苯基)-2-丙烯酸酯,即化合物C；本发明中的3-(2-氨基苯基)-2-丙烯酸酯的制备方法原材料易得,成本低,工艺稳定,且制备的3-(2-氨基苯基)-2-丙烯酸酯化学纯度高。(The invention relates to the technical field of medicine preparation, in particular to a preparation method of 3- (2-aminophenyl) -2-acrylate, which specifically comprises the following steps: 1) under the action of alkali, carrying out Knoevenagel condensation reaction on o-nitrobenzaldehyde and malonate derivatives in an organic solvent to generate an alpha, beta-unsaturated carbonyl compound A; 2) under the action of salt, carrying out decarboxylation reaction on the compound A in an organic solvent and water to obtain a compound B; 3) under the action of acid, reducing metal reagent and compound B are subjected to nitro reduction reaction in organic solvent and water to generate 3- (2-aminophenyl) -2-acrylate, namely compound C; the preparation method of the 3- (2-aminophenyl) -2-acrylate has the advantages of easily available raw materials, low cost, stable process and high chemical purity of the prepared 3- (2-aminophenyl) -2-acrylate.)

1. A preparation method of 3- (2-aminophenyl) -2-acrylate is characterized in that: the chemical reaction formula is as follows:

r = methyl, ethyl, propyl, isopropyl;

the method specifically comprises the following steps:

1) under the action of alkali, carrying out Knoevenagel condensation reaction on o-nitrobenzaldehyde and malonate derivatives in an organic solvent to generate an alpha, beta-unsaturated carbonyl compound A;

2) under the action of salt, carrying out decarboxylation reaction on the compound A in an organic solvent and water to obtain a compound B;

3) under the action of acid, reducing metal reagent and compound B are subjected to nitro reduction reaction in organic solvent and water to generate 3- (2-aminophenyl) -2-acrylate, namely compound C;

the specific steps in the step 1) are as follows: adding o-nitrobenzaldehyde and alkali into an aprotic solvent, stirring at 20-30 ℃ for reaction for 0.5h, dropwise adding monomethyl malonate, continuing the reaction for 2h at 20-30 ℃ after the addition is finished, and performing post-treatment to obtain a compound A after the reaction is complete;

the alkali is organic alkali and is selected from one of triethylamine, pyridine and piperidine;

the organic solvent is an aprotic solvent and is selected from chlorobenzene, xylene, toluene and DMSO.

2. The method for preparing 3- (2-aminophenyl) -2-acrylate according to claim 1, wherein: the alkali is piperidine, and the molar ratio of the o-nitrobenzaldehyde to the piperidine to the monomethyl malonate is as follows: 1:2.5:1.

3. The method for preparing 3- (2-aminophenyl) -2-acrylate according to claim 1, wherein: the specific steps in the step 2) are as follows: adding DMSO and H into the reaction flask₂And stirring and heating the O, the lithium chloride and the compound A to 100 ℃ for reacting for 16h, cooling to below 30 ℃ after the reaction is safe, and carrying out post-treatment to obtain a compound B, wherein the molar ratio of the lithium chloride to the compound A is 1: 1.

4. The method for producing 3- (2-aminophenyl) -2-acrylic ester according to claim 3, characterized in that: the salt is selected from one of sodium chloride, potassium chloride and lithium chloride.

5. The method for producing 3- (2-aminophenyl) -2-acrylic ester according to claim 3, characterized in that: the organic solvent is one of DMF, DMSO and 1, 4-dioxane.

6. The method for preparing 3- (2-aminophenyl) -2-acrylate according to claim 1, wherein: the step 3) specifically comprises the steps of adding ethyl acetate, water and the compound B into a reaction bottle, stirring for dissolving, adding iron powder, dropwise adding acid while stirring, heating to reflux for 5 hours after dropwise adding, reacting completely, cooling the reaction liquid to 30 ℃, passing through diatomite, performing post-treatment to obtain a compound C,

the molar ratio of the compound B to the iron powder is 1: 3.5.

7. The method for producing 3- (2-aminophenyl) -2-acrylate according to claim 6, wherein: the acid is one of hydrochloric acid and acetic acid, and the organic solvent is one of methanol, ethanol and ethyl acetate.

Technical Field

The invention relates to the technical field of medicine preparation, in particular to a preparation method of 3- (2-aminophenyl) -2-acrylate.

Background

CN 108863899 discloses a synthetic method, which comprises the following steps:

the method adopts Wittig reaction, and the generated triphenylphosphine oxide is difficult to remove in the post-treatment process, and has low atomic effect and low yield.

Disclosure of Invention

The purpose of the invention is: overcomes the defects in the prior art, and provides a preparation method of 3- (2-aminophenyl) -2-acrylate, which has the advantages of low cost, stable process and high product purity.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows:

a preparation method of 3- (2-aminophenyl) -2-acrylate has the following chemical reaction formula:

r = methyl, ethyl, propyl, isopropyl;

the method specifically comprises the following steps:

1) under the action of alkali, carrying out Knoevenagel condensation reaction on o-nitrobenzaldehyde and malonate derivatives in an organic solvent to generate an alpha, beta-unsaturated carbonyl compound A;

2) under the action of salt, carrying out decarboxylation reaction on the compound A in an organic solvent and water to obtain a compound B;

3) under the action of acid, reducing metal reagent and compound B are made to produce nitro reducing reaction in organic solvent and water to produce 3- (2-aminophenyl) -2-acrylate, compound C.

The specific steps in the step 1) are as follows: adding o-nitrobenzaldehyde and alkali into an aprotic solvent, stirring and reacting for 0.5h at the temperature of 20-30 ℃, dropwise adding monomethyl malonate, continuing to react for 2h at the temperature of 20-30 ℃ after the addition is finished, and carrying out post-treatment to obtain a compound A after the reaction is complete.

The alkali is organic alkali selected from one of triethylamine, pyridine and piperidine.

The organic solvent is an aprotic solvent and is selected from chlorobenzene, xylene, toluene and DMSO.

Further, the alkali is piperidine, and the molar ratio of the o-nitrobenzaldehyde to the piperidine to the monomethyl malonate is as follows: 1:2.5:1.

Further, the specific steps in the step 2) are as follows: adding DMSO and H into the reaction flask₂And stirring and heating the O, the lithium chloride and the compound A to 100 ℃ for reacting for 16h, cooling to below 30 ℃ after the reaction is safe, and carrying out post-treatment to obtain a compound B, wherein the molar ratio of the lithium chloride to the compound A is 1: 1.

Further, the salt is selected from one of sodium chloride, potassium chloride, lithium chloride and lithium bromide.

Further, the organic solvent is one of DMF, DMSO and 1, 4-dioxane.

Further, the step 3) specifically comprises adding ethyl acetate, water and the compound B into a reaction bottle, stirring for dissolving, adding iron powder, dropwise adding acid while stirring, heating to reflux for 5 hours after dropwise adding, reacting completely, cooling the reaction solution to 30 ℃, passing through diatomite, performing post-treatment to obtain a compound C,

the molar ratio of the compound B to the iron powder is 1: 3.5.

Further, the acid is one of hydrochloric acid and acetic acid, and the organic solvent is one of methanol, ethanol and ethyl acetate.

The technical scheme adopted by the invention has the beneficial effects that:

the preparation method of the 3- (2-aminophenyl) -2-acrylate has the advantages of easily available raw materials, low cost, stable process and high chemical purity of the prepared 3- (2-aminophenyl) -2-acrylate.

Detailed Description

The preparation method of 3- (2-aminophenyl) -2-acrylate according to the present invention will be further described with reference to the following embodiments.

Example 1: synthesis of Compound A

The synthetic route is as follows:

adding 400ml of toluene, 100.0g (1.00 eq) of o-nitrobenzaldehyde and 140.9g (2.50 eq) of piperidine into a three-mouth reaction bottle, stirring and reacting for 0.5h at 20-30 ℃, dropwise adding 78.2g (1.00 eq) of monomethyl malonate, continuing to react for 2h at 20-30 ℃, monitoring no raw material residue by TLC, adding 500ml of water, stirring and separating liquid, removing impurities from an upper organic phase, adding 0.5M hydrochloric acid into a lower water phase to adjust the pH to be =2-3, adding 500ml of ethyl acetate, extracting for 2 times, combining organic phases, washing for 1 time by using 500ml of 20% sodium chloride solution, drying the organic phase by anhydrous magnesium sulfate, and then decompressing and desolventizing to obtain 154.6g of compound A, wherein the yield is as follows: 93.0%, HPLC: 97.50 percent.

Example 2: synthesis of Compound A

The synthetic route is as follows:

adding 400ml of toluene, 100.0g (1.00 eq) of o-nitrobenzaldehyde and 130.9g (2.50 eq) of pyridine into a three-mouth reaction bottle, stirring and reacting for 0.5h at 20-30 ℃, dropwise adding 78.2g (1.00 eq) of monomethyl malonate, continuing to react for 2h at 20-30 ℃ after the addition is finished, monitoring no raw material residue by TLC, adding 500ml of water, stirring and separating liquid, removing impurities from an upper organic phase, adding 0.5M hydrochloric acid into a lower water phase to adjust the pH to be =2-3, adding 500ml of ethyl acetate, extracting for 2 times, combining organic phases, washing for 1 time by using 500ml of 20% sodium chloride solution, drying the organic phase by anhydrous magnesium sulfate, and then decompressing and desolventizing to obtain 146.5g of compound A, wherein the yield is as follows: 88.1%, HPLC: 98.60 percent.

Example 3: synthesis of Compound B

The synthetic route is as follows:

250ml DMSO, 25ml H was added to a three-necked reaction flask₂O, 8.44g (1.00 eq) of lithium chloride, 50.00g (1.00 eq) of a compoundStirring the substance A, heating to 100 ℃ for reaction for 16h, monitoring by TLC (thin layer chromatography) that no raw material remains, cooling to below 30 ℃, adding 500ml of water, extracting 300ml of 2 times by using ethyl acetate, combining organic phases, washing 1 time by using 250ml of saturated sodium chloride solution, performing desolventization on the organic phases under reduced pressure, adding 100ml of ethanol into the concentrated solid, cooling to 15-20 ℃, pulping and purifying for 1h, filtering, and drying a filter cake at 50 ℃ to obtain 37.94g of a white solid compound B with yield: 92.0%, HPLC: 99.36 percent.

Example 4: synthesis of Compound B

The synthetic route is as follows:

250ml of DMF, 25ml of H was added to a three-necked reaction flask₂O, 17.29g (1.00 eq) lithium bromide, 50.00g (1.00 eq) compound A, stirring and heating to 120 ℃ for reaction for 12 hours, monitoring by TLC that no raw material remains, cooling to below 30 ℃, adding 500ml of water, extracting 300ml of 2 times by using ethyl acetate, combining organic phases, washing 3 times by using 250ml of saturated sodium chloride solution, decompressing and desolventizing the organic phase, adding 100ml of ethanol into the concentrated solid, cooling to 15-20 ℃, pulping and purifying for 1 hour, filtering, drying a filter cake at 50 ℃ to obtain 40.23g of white solid compound B, wherein the yield is as follows: 97.5%, HPLC: 99.58 percent.

Example 5: synthesis of Compound C

The synthetic route is as follows:

adding 1000ml of ethyl acetate, 400ml of water and 100.0g (1.00 eq) of compound B into a three-port reaction bottle, stirring for dissolving, adding 93.60g (3.50 eq) of iron powder, dropwise adding 20ml of concentrated hydrochloric acid while stirring, heating to reflux for 5 hours after dropwise adding, monitoring by HPLC (high performance liquid chromatography) until no raw materials are left, cooling the reaction solution to 30 ℃, passing through diatomite, leaching a filter cake by 100ml of EA, leaching by 100ml of water, merging filtrate, standing for layering, extracting an aqueous phase once by 200ml of EA, merging organic phases, washing once by 200ml of saturated sodium bicarbonate, washing once by 200ml of saturated sodium chloride, and washing by 200ml of saturated sodium chlorideWashing once, drying the organic phase with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure until no fraction is produced, adding 170ml of ethanol and 340ml of n-heptane into the concentrate, stirring and heating to 60 ℃, keeping the temperature for 1h, cooling to 25-30 ℃, stirring and crystallizing for 1h, continuously cooling to 0-5 ℃, stirring and crystallizing for 1h, filtering, leaching the filter cake with 50ml of n-heptane, and drying by air blowing at 40 ℃ to obtain 68.90g of yellow solid compound C, wherein the yield is as follows: 80.50%, HPLC: 99.28 percent of the total weight of the steel,¹H-NMR (400 MHz，DMSO-d6) δ 7.89 (d, J = 15.6 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.54 (t, J = 7.5 Hz, 1H), 6.37 (d, J = 15.7 Hz, 1H), 5.61 (s, 2H), 3.71 (s, 3H)。

example 6: synthesis of Compound C

The synthetic route is as follows:

adding 1000ml of absolute ethyl alcohol and 100.0g (1.00 eq) of compound B into a three-mouth reaction bottle, stirring for dissolving, adding 93.60g (3.50 eq) of iron powder, dropwise adding 20ml of concentrated hydrochloric acid while stirring, heating to reflux for 5h while stirring, monitoring by HPLC (high performance liquid chromatography) until no raw material is left, cooling the reaction solution to 30 ℃, passing through diatomite, leaching the filter cake with 100ml of ethanol, combining the filtrates, removing ethanol under reduced pressure at 50 ℃, adding 500ml of ethyl acetate into the concentrate for dissolving, washing once with 200ml of saturated sodium bicarbonate, washing once with 200ml of saturated sodium chloride, drying the organic phase anhydrous magnesium sulfate, filtering, concentrating under reduced pressure until no fraction is left, adding 170ml of ethanol and 340ml of n-heptane into the concentrate, stirring for heating to 60 ℃, preserving heat for 1h, cooling to 25-30 ℃, stirring for crystallizing for 1h, continuing cooling to 0-5 ℃, stirring for crystallizing for 1h, filtering, leaching the filter cake with 50ml of n-heptane, forced air drying at 40 ℃ gave 73.0g of Compound C as a yellow solid in yield: 85.30%, HPLC: 99.15 percent.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein, and any reference signs in the claims are not intended to be construed as limiting the claim concerned.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment contains only one independent claim, and such description is for clarity only, and those skilled in the art will be able to make the description as a whole, and the embodiments may be appropriately combined to form other embodiments understood by those skilled in the art.