A preparation method of methyl 3,4-diaminobenzoate

Abstract

The present invention discloses a preparation method of methyl 3,4-diaminobenzoate, which is characterized by comprising the following steps: condensing methyl 4-chloro-3-nitrobenzoate and dibenzylamine in a solvent to obtain methyl 3-nitro-4-dibenzylaminobenzoate; carrying out one-pot nitro reduction and debenzylation of methyl 3-nitro-4-dibenzylaminobenzoate under catalytic and hydrogenation conditions to obtain methyl 3,4-diaminobenzoate. The present invention uses dibenzylamine as a reagent for introducing an amino group, reduces the generation of dimer by-products, the one-pot method optimizes the process operation, reduces the operation steps, and has relatively mild condensation and hydrogenation conditions, which better ensures the safety of the production process.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthetic chemistry, and relates to a carbocyclic compound containing amino and carboxyl groups, and specifically relates to a preparation method of methyl 3,4-diaminobenzoate. Background Art

[0002] Methyl 3,4-diaminobenzoate is an important pharmaceutical synthesis intermediate. It can be used in the preparation of anticancer drugs and benzimidazole derivatives, and can also be used in the production of various drugs such as gastrointestinal drugs, amide benzoyl derivatives, and influenza neuraminidase inhibitors.

[0003] The CAS number of methyl 3,4-diaminobenzoate is [36692-49-6], and its molecular structural formula is as follows:

[0004] 。

[0005] When considering the synthesis of methyl 3,4-diaminobenzoate from methyl 4-chloro-3-nitrobenzoate, the available routes in the prior art are as follows:

[0006] Reference Route 1: In the reference Arch. Pharm. Chem. Life Sci. 2007, 340, 607 – 611, see Chart 2. Using methyl 4-chloro-3-nitrobenzoate as the starting material, esterifying with methanol, and then condensing with p-chlorobenzylamine in the solvent tetrahydrofuran. After the reaction is completed, the solvent is removed, water is added for crystallization, filtered and dried to obtain the intermediate, and then the nitro group is reduced to obtain methyl 3-amino-4-(4-chlorobenzyl)aminobenzoate. The reaction process is as follows:

[0007]

[0008] In the reference, the above-mentioned methyl 3-amino-4-(4-chlorobenzyl)aminobenzoate is used as an intermediate for the preparation of benzimidazole derivatives. However, if it is further catalytically debenzylated, methyl 3,4-diaminobenzoate can be obtained.

[0009] This process uses p-chlorobenzylamine as the amino group introducing reagent, and the three-step yield is 58%, with a relatively low yield.

[0010] Reference Route 2: In Chinese Patent Invention CN106458934 A, the reaction of methyl 4-fluoro-3-nitrobenzoate with 4-methoxybenzylamine is mentioned as an intermediate. See paragraph

[0753] , and the reaction process is as follows:

[0011]

[0012] According to the disclosure in paragraphs

[0757] and

[0759] , (4-methoxyphenyl)methanamine (23.0 g, 168 mmol) was added to a solution of methyl 3-fluoro-4-nitrobenzoate (25.0 g, 126 mmol) and TEA (37.0 g, 366 mmol) in DMF (200 mL). The mixture was stirred at 85 °C for 2 h. After cooling, the mixture was poured into crushed ice (300 g). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and concentrated in vacuo to give methyl 3-[(4-methoxybenzyl)amino]-4-nitrobenzoate (39.0 g, 98%) as an orange solid. At -78 °C, iron powder (22.5 g, 402 mmol) was added to a solution of methyl 3-[(4-methoxybenzyl)amino]-4-nitrobenzoate (30.0 g, 94.9 mmol) in EtOH (500 mL), followed by the addition of a solution of NH 4 Cl (50.0 g, 935 mmol) in water (280 mL). The mixture was refluxed for 2 h. After cooling, the insoluble material was removed by filtration through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to remove EtOH. The residue was suspended in a saturated aqueous solution of NaHCO 3 and then extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO 4 and concentrated in vacuo to give crude methyl 4-amino-3-[(4-methoxybenzyl)amino]benzoate (26.7 g) as a viscous orange oil.

[0013] On this basis, methyl 3,4-diaminobenzoate can also be obtained.

[0014] This process uses p-methoxybenzylamine as an amino group-introducing reagent and has a relatively high yield. However, it uses iron powder reduction in nitro reduction, which causes great environmental pollution, and the reaction is carried out at -78 °C, and the conditions are relatively harsh.

[0015] Therefore, it is necessary to seek a new synthesis method for methyl 3,4-diaminobenzoate to reduce pollution during the synthesis while increasing the yield. Summary of the Invention

[0016] The object of the present invention is to provide a method for preparing methyl 3,4-diaminobenzoate with simple operation, less pollution and low cost.

[0017] To achieve the above object of the invention, the technical solution adopted by the present invention is: a method for preparing methyl 3,4-diaminobenzoate, comprising the following steps:

[0018] (1) Condensing methyl 4-chloro-3-nitrobenzoate and dibenzylamine in a solvent to obtain methyl 3-nitro-4-dibenzylaminobenzoate;

[0019] (2) Methyl 3-nitro-4-dibenzylaminobenzoate is subjected to one-pot nitro reduction and debenzylation under catalytic hydrogenation conditions to obtain methyl 3,4-diaminobenzoate.

[0020] The above method is represented by the following chemical reaction:

[0021]

[0022]

[0023] In the above technical solution, the specific method of step (1) is to dissolve methyl 4-chloro-3-nitrobenzoate in a condensation solvent, then add dibenzylamine, stir evenly, heat for a condensation reaction. After the reaction is completed, water is added for cooling, crystallization, suction filtration, and drying to obtain a pale yellow crystal, which is methyl 3-nitro-4-dibenzylaminobenzoate;

[0024] Among them, the mass ratio of methyl 4-chloro-3-nitrobenzoate to the condensation solvent is 1:4 to 15; the molar ratio of methyl 4-chloro-3-nitrobenzoate to dibenzylamine is 1:1 to 3; the temperature of the condensation reaction is 50 to 120 °C, and the reaction time is 10 to 24 hours.

[0025] In a preferred technical solution, the mass ratio of methyl 4-chloro-3-nitrobenzoate to the condensation solvent is 1:7 to 10.

[0026] In the above technical solution, the condensation solvent is selected from DMF, DMSO or tetrahydrofuran. The condensation solvent is preferably DMSO.

[0027] In a preferred technical solution, the temperature of the condensation reaction is 60 to 80 °C, the reaction time is 12 to 15 hours. The molar ratio of methyl 4-chloro-3-nitrobenzoate to dibenzylamine is 1:2.

[0028] In the above technical solution, the specific method of step (2) is to add methyl 3-nitro-4-dibenzylaminobenzoate, a solvent and a catalyst to an autoclave. The catalyst is a palladium / carbon catalyst; hydrogen is introduced for one-pot hydrogenation reaction to obtain methyl 3,4-diaminobenzoate;

[0029] Among them, the mass ratio of methyl 3-nitro-4-dibenzylaminobenzoate to the catalyst is 1:0.02 to 0.1; the hydrogenation reaction temperature is 40 to 150 °C, the pressure is 2.0 to 8.0 MPa, and the reaction time is 2 to 10 hours; the solvent is selected from methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane.

[0030] In the above technical solution, the palladium / carbon catalyst contains 10% by weight of palladium.

[0031] In the preferred technical solution, the mass ratio of methyl 3-nitro-4-dibenzylaminobenzoate to the catalyst is 1:0.05. The hydrogenation reaction temperature is 50-80 °C, the pressure is 2.5-3.5 MPa, and the reaction time is 4-5 hours.

[0032] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0033] 1. The present invention uses methyl 4-chloro-3-nitrobenzoate and dibenzylamine as starting materials to carry out a condensation reaction, and then uses palladium-carbon catalyst for hydrogenation to carry out a one-pot method for nitro reduction and debenzylation to obtain the target product methyl 3,4-diaminobenzoate. The present invention uses dibenzylamine as the amino group introducing reagent, reducing the generation of dimer by-products. The one-pot method optimizes the process operation and reduces the operation steps. The relatively mild condensation and hydrogenation conditions better ensure the safety of the production process.

[0034] 2. By using the method of the present invention, the catalyst can be reused repeatedly and the yield is increased, reducing the production cost and improving the product quality. It provides a preparation method suitable for industrial production of methyl 3,4-diaminobenzoate for preparing anti-cancer drug intermediates. Embodiment

[0035] The present invention will be further described below in conjunction with the embodiments:

[0036] Example 1: Preparation of methyl 3,4-diaminobenzoate, including the following steps:

[0037] (1) Add 19.8 g (0.092 mol) of methyl 4-chloro-3-nitrobenzoate and 150 ml of dimethyl sulfoxide into a 500 ml four-necked flask, and stir evenly. Add 36.3 g (0.184 mol) of dibenzylamine, and stir for 10 min. Then heat to 60-80 °C and stir the reaction for about 12 hours.

[0038] Take a sample for GC analysis: the normalized content of the raw material is 0.5%, and the reaction ends. Cool to room temperature, add water and stir for crystallization for 1 hr. Filter by suction, and dry the solid to obtain 32.86 g of intermediate methyl 3-nitro-4-dibenzylaminobenzoate. The content is 99.3% and the yield is 95%.

[0039] (2) In a 500 ml autoclave, add 32.86 g of weighed methyl 3-nitro-4-dibenzylaminobenzoate, add 300 ml of ethanol and 1.65 g of 10% palladium-carbon. Seal the autoclave, displace with nitrogen three times, displace with hydrogen three times, and pressurize with hydrogen to 25 KG. Start stirring, heat the material temperature to 50-80 °C, and start the hydrogenation reaction at a hydrogen pressure of 25 KG until the hydrogen pressure does not drop, and then keep it at 50-80 °C and a hydrogen pressure of 25 KG for 3 hours.

[0040] Sampling analysis, the raw material is less than 0.2%. After the reaction is completed, stop stirring, let it stand for 1 hour, relieve the pressure, suck out all the substances in the reaction kettle, rinse the reaction kettle with ethanol, suck out the rinsing solution and filter it, collect the filtrate, recycle the palladium-carbon (reuse), distill under reduced pressure to remove all ethanol and toluene, cool the residual liquid to room temperature, add 165 g of n-heptane, stir and heat to 60 - 70 °C, stir until the material dissolves, keep warm for 30 minutes, cool, filter at 0 °C, dry the solid, and obtain 13.78 g of methyl 3,4-diaminobenzoate.

[0041] After testing, the yield is 95% and the HPLC content is 99.6%. Example 2

[0042] On the basis of Example 1, adjust the molar ratio of methyl 4-chloro-3-nitrobenzoate to dibenzylamine to 1:1, and keep the other conditions unchanged. Obtain 25 g of methyl 3-nitro-4-dibenzylaminobenzoate.

[0043] After testing, the content is 96% and the yield is 72.3%. Example 3

[0044] On the basis of Example 1, increase the condensation solvent DMSO to 198 ml, and keep the other conditions unchanged. Obtain 32.8 g of methyl 3-nitro-4-dibenzylaminobenzoate.

[0045] After testing, the content is 99.3% and the yield is 94.8%. Example 4

[0046] On the basis of Example 1, extend the reaction time to 15 hours, and keep the other conditions unchanged. Obtain 32.5 g of methyl 3-nitro-4-dibenzylaminobenzoate.

[0047] After testing, the content is 99.2% and the yield is 93.95%. Example 5

[0048] On the basis of Example 2, raise the reaction temperature to 100 - 150 °C, and keep the other conditions unchanged. Obtain 11.5 g of methyl 3,4-diaminobenzoate.

[0049] After testing, the yield is 79.3% and the HPLC content is 96.6%. Example 6

[0050] On the basis of Example 2, raise the reaction pressure to 4.0 - 8.0 MPa, and keep the other conditions unchanged. Obtain 13.5 g of methyl 3,4-diaminobenzoate.

[0051] After testing, the yield is 93.1% and the HPLC content is 99.%.

Claims

1. A preparation method of methyl 3,4-diaminobenzoate, characterized in that, it comprises the following steps: (1) Condensation reaction of methyl 4-chloro-3-nitrobenzoate and dibenzylamine in a solvent to obtain methyl 3-nitro-4-dibenzylaminobenzoate; (2) One-pot nitro reduction and debenzylation of methyl 3-nitro-4-dibenzylaminobenzoate under catalytic hydrogenation conditions to obtain methyl 3,4-diaminobenzoate; The specific method of step (2) is to add methyl 3-nitro-4-dibenzylaminobenzoate, a solvent and a catalyst into a pressure reactor, and the catalyst is palladium / carbon catalyst; hydrogen is introduced for one-pot hydrogenation reaction to obtain methyl 3,4-diaminobenzoate; wherein, the mass ratio of methyl 3-nitro-4-dibenzylaminobenzoate to the catalyst is 1:0.02 - 0.1; the hydrogenation reaction temperature is 40 - 150 °C, the pressure is 2.0 - 8.0 MPa, and the reaction time is 2 - 10 hours; the solvent is selected from methanol, ethanol, propanol, isopropanol, n-hexane, n-heptane.

2. The preparation method of methyl 3,4-diaminobenzoate according to claim 1, characterized in that: The specific method of step (1) is to dissolve methyl 4-chloro-3-nitrobenzoate in a condensation solvent, then add dibenzylamine, stir evenly, heat for condensation reaction, after the reaction is completed, add water to cool, crystallize, filter by suction, and dry to obtain a pale yellow crystal, which is methyl 3-nitro-4-dibenzylaminobenzoate; wherein, the mass ratio of methyl 4-chloro-3-nitrobenzoate to the condensation solvent is 1:4 - 15; the molar ratio of methyl 4-chloro-3-nitrobenzoate to dibenzylamine is 1:1 - 3; the temperature of the condensation reaction is 50 - 120 °C, and the reaction time is 10 - 24 hours.

3. The preparation method of methyl 3,4-diaminobenzoate according to claim 2, characterized in that: The mass ratio of methyl 4-chloro-3-nitrobenzoate to the condensation solvent is 1:7 - 10.

4. The preparation method of methyl 3,4-diaminobenzoate according to claim 2, characterized in that: The condensation solvent is selected from DMF, DMSO or tetrahydrofuran.

5. The preparation method of methyl 3,4-diaminobenzoate according to claim 2, characterized in that: The temperature of the condensation reaction is 60 - 80 °C, and the reaction time is 12 - 15 hours.

6. The preparation method of methyl 3,4-diaminobenzoate according to claim 2, characterized in that: The molar ratio of methyl 4-chloro-3-nitrobenzoate to dibenzylamine is 1:

2.

7. The preparation method of methyl 3,4-diaminobenzoate according to claim 1, characterized in that: The mass ratio of methyl 3-nitro-4-dibenzylaminobenzoate to the catalyst is 1:0.

05.

8. The preparation method of methyl 3,4-diaminobenzoate according to claim 1, characterized in that: The hydrogenation reaction temperature is 50 - 80 °C, the pressure is 2.5 - 3.5 MPa, and the reaction time is 4 - 5 hours.

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