Preparation method of pranoprofen intermediate

Abstract

The invention discloses a preparation method of a pranoprofen intermediate, and belongs to the technical field of medicines, and the preparation method comprises the following preparation steps: adding a raw material 5H-[1]-benzopyran [2, 3-b] pyridine-5-ketone into a reactor, adding an organic solvent, cooling the reaction system to-10-5 DEG C while stirring, and adding a catalytic amount of PdCl2; slowly adding sodium borohydride in batches into the reaction system at-10-5 DEG C, reacting for 1-2 hours, heating to room temperature, continuously reacting for 3-6 hours, heating to 50-55 DEG C, reacting for 2-4 hours, and adding activated carbon; and adding purified water into the filtrate to separate out a product, pulping at 50-55 DEG C for 2 hours, cooling to room temperature, carrying out suction filtration, and drying a filter cake in a drying box at 50-55 DEG C for 5-15 hours to obtain the pranoprofen intermediate 5H-[1]-benzopyran [2, 3-b] pyridine. The process operation and post-treatment are simple, the solvent cost, the labor cost and the power cost of the multi-step reaction are reduced, and remarkable economic benefits are achieved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for preparing pranoprofen intermediate 5H-[1]-benzopyrano[2,3-b]pyridine. Background Art

[0002] Pranoprofen is a tricyclic propionic acid derivative, with the chemical name 2-5H-[1]chromeno[2,3-b]pyridin-7-ylpropanoic acid (2-(5H-chromeno[2,3-b]pyridin-7-yl)propanoic acid) and the structural formula is as follows:

[0003]

[0004] Academician Chen Fener mentioned in "Organic Drug Synthesis" that in the process, 2-aminonicotinic acid is used as the starting material, and 2-chloronicotinic acid is prepared by diazotization and chlorination in sequence, and then 9-oxa-1-aza-anthracene is obtained after nucleophilic substitution reaction with phenol, dehydration by phosphorus oxychloride, and reduction with sodium amalgam, and then reacted with polyformaldehyde / hydrochloric acid, followed by nucleophilic substitution with potassium cyanide, and finally pranoprofen is obtained by sequentially reacting with diethyl carbonate, methyl iodide, and acid hydrolysis. The route is as follows:

[0005]

[0006] Jin Rongqing et al. reported an improved synthetic route in Fine Chemical Intermediates (2009, 39(3), 37-39) as follows:

[0007]

[0008] In this route, 2-chloronicotinic acid and phenol are used as raw materials, and 5H-[1]-benzopyrano[2,3-b]pyridine (4) is prepared through four steps of reaction, and then 2-chloropropionyl chloride is subjected to Friedel-Crafts acylation, and the carbonyl group is protected and then hydrolyzed, chlorinated, and acidolyzed to obtain pranoprofen. This route avoids highly toxic reagents such as mercury and potassium cyanide, and also avoids dangerous reagents such as sodium and phosphorus oxychloride. The overall reaction is relatively conventional, the raw materials are cheap and easy to obtain, the route reliability is high, and it is suitable for industrial production.

[0009] The above routes all use 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2) to obtain the key intermediate pranoprofen 5H-[1]-benzopyrano[2,3-b]pyridine (4) through two-step reduction. It has been verified that there is an obvious impurity in the reaction solution during the potassium borohydride reduction process. The impurity content is about 12% by liquid phase detection, and the yield of this step is about 78%. In the process of reducing the hydroxyl group in the isopropanol / hydrochloric acid system, the methylene group of 5H-[1]-benzopyrano[2,3-b]pyridine (4) has a certain reducing ability and participates in the competitive reaction to be oxidized to 5H-[1]-benzopyrano[2,3-b]pyridine

[0010] [2,3-b]pyridin-5-one (2), increasing the amount of isopropanol and reducing the concentration of reactants in this step can reduce the occurrence of side reactions, but about 15% of oxidation products are still produced. The mechanism is as follows:

[0011]

[0012] In order to control the product quality, both steps need to be refined before use, and the total yield is less than 50%, resulting in low atomic utilization and high production cost. To this end, the present invention provides a method for preparing a pranoprofen intermediate. Summary of the invention

[0013] The purpose of the present invention is to solve the shortcomings existing in the prior art and to propose a new method for preparing pranoprofen key intermediate 5H-[1]-benzopyrano[2,3-b]pyridine (4) from 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2) by a one-step reaction. The method has the advantages of high yield and good reproducibility, and meets the needs of laboratory research and large-scale chemical production in the pharmaceutical and chemical industries.

[0014] In order to achieve the above object, the present invention adopts the following technical solutions:

[0015] The present invention provides a method for preparing a pranoprofen intermediate, characterized in that it comprises the following preparation steps:

[0016] Step 1: Add the raw material 5H-[1]-benzopyrano[2,3-b]pyridin-5-one into the reactor, add an organic solvent and cool the reaction system to -10 to 5°C under stirring, and add a catalytic amount of PdCl2;

[0017] Step 2: Slowly add sodium borohydride in batches to the reaction system at a temperature of -10 to 5°C. After the addition is completed, the temperature is controlled at -10 to 5°C for reaction for 1 to 2 hours, then the temperature is raised to room temperature for further reaction for 3 to 6 hours, the temperature is raised to 50 to 55°C for reaction for 2 to 4 hours, and activated carbon is added;

[0018] Step 3: Filter while hot, add purified water to the filtrate to precipitate the product, slurry at 50-55°C for 2 hours, then cool to room temperature, filter, and dry the filter cake in a drying oven at 50-55°C for 5-15 hours to obtain pranoprofen intermediate 5H-[1]-benzopyrano[2,3-b]pyridine.

[0019] The reaction equation is as follows:

[0020]

[0021] Preferably, the organic solvent is methanol or ethanol.

[0022] Preferably, the mass volume ratio between the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one and the organic solvent is 1:4-8 (g / ml).

[0023] Preferably, the molar equivalent ratio of the activated carbon to the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one is 1.0 to 2.5.

[0024] Preferably, the molar equivalent ratio of PdCl2 to the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one is 0.005 to 0.05.

[0025] Preferably, the molar equivalent ratio of the sodium borohydride to the raw material 5H-[1]-benzopyrano[2,3-b]pyridin-5-one is 0.8 to 2.0.

[0026] Preferably, the molar equivalent ratio of the sodium borohydride to the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one is 1.0 to 2.0.

[0027] Preferably, the room temperature is 25°C±5°C.

[0028] The present invention has the following technical effects:

[0029] 1. The present invention uses only one step reaction to prepare pranoprofen key intermediate 5H-[1]-benzopyrano[2,3-b]pyridine (4) from 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2), with a yield of 84-92%, thereby improving the yield.

[0030] 2. The process operation and post-processing of the present invention are simple, which reduces the solvent, labor and power costs of multi-step reactions and has significant economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is the detection spectrum of HPLC of the pranoprofen intermediate of the present invention.

[0032] Figure 2 It is the nuclear magnetic spectrum of the hydrogen spectrum of the pranoprofen intermediate of the present invention. DETAILED DESCRIPTION

[0033] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] Example 1: A preparation process of a pranoprofen intermediate proposed in the present invention, 15.0 g of 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2) and 60 ml of methanol are added to a 250 ml three-necked reaction flask, stirred with a heat collecting constant temperature magnetic stirrer and cooled to -10°C with an ice-water bath, 0.067 g of PdCl2 is added, 2.25 g of sodium borohydride is slowly added in batches, the temperature is controlled at -10°C for reaction for 2 hours, then the temperature is raised to room temperature and the reaction is continued for 4 hours, the temperature is raised to 50°C for reaction for 4 hours, 0.91 g of activated carbon is added, the mixture is filtered, 200 ml of purified water is added to the filtrate to precipitate solids, the mixture is slurried at 50°C for 2 hours, the heating is turned off and the temperature is cooled to room temperature, the filter cake is dried in a 50°C forced air drying oven for 5 hours, and 11.7 g of 5H-[1]-benzopyrano[2,3-b]pyridine (4) is obtained, with a yield of 84%.

[0035] Example 2: A preparation process of a pranoprofen intermediate proposed in the present invention, 15.0 g of 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2) and 70 ml of methanol are added to a 250 ml three-necked reaction flask, stirred using a heat-collecting constant temperature magnetic stirrer and cooled to -5°C using an ice-water bath, 0.134 g of PdCl2 is added, 2.5 g of sodium borohydride is slowly added in batches, the temperature is controlled at -5°C for reaction for 2 hours, then the temperature is raised to room temperature and the reaction is continued for 4 hours, the temperature is raised to 53°C for reaction for 4 hours, 1.1 g of activated carbon is added, and the mixture is filtered with suction, 200 ml of purified water is added to the filtrate to precipitate solids, the mixture is slurried at 53°C for 2 hours, the heating is turned off and the mixture is cooled to room temperature, filtered with suction, and the filter cake is dried in a 50°C forced air drying oven for 8 hours to obtain 11.9 g of 5H-[1]-benzopyrano[2,3-b]pyridine (4), with a yield of 85.4%.

[0036] Example 3: A preparation process of a pranoprofen intermediate proposed in the present invention, 15.0 g of 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2) and 80 ml of methanol are added to a 250 ml three-necked reaction flask, stirred using a heat-collecting constant temperature magnetic stirrer and cooled to 0°C using an ice-water bath, 0.21 g of PdCl2 is added, 3.2 g of sodium borohydride is slowly added in batches, the temperature is controlled at 0°C for reaction for 2 hours, then the temperature is raised to room temperature and the reaction is continued for 4 hours, the temperature is raised to 53°C for reaction for 4 hours, 1.3 g of activated carbon is added, the mixture is filtered, 200 ml of purified water is added to the filtrate to precipitate solids, the mixture is slurried at 53°C for 2 hours, the heating is turned off and the temperature is cooled to room temperature, the filter cake is dried in a 50°C forced air drying oven for 8 hours, and 12.3 g of 5H-[1]-benzopyrano[2,3-b]pyridine (4) is obtained, with a yield of 88.2%.

[0037] Example 4: A preparation process of a pranoprofen intermediate proposed in the present invention, 15.0 g of 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2) and 90 ml of methanol are added to a 250 ml three-necked reaction flask, stirred using a heat collecting constant temperature magnetic stirrer and cooled to 0°C with an ice-water bath, 0.27 g of PdCl2 is added, 3.7 g of sodium borohydride is slowly added in batches, the temperature is controlled at -10 to 5°C for reaction for 2 hours, then the temperature is raised to room temperature and the reaction is continued for 4 hours, the temperature is raised to 53°C for reaction for 4 hours, 1.5 g of activated carbon is added, and the mixture is filtered with suction, 200 ml of purified water is added to the filtrate to precipitate solids, the mixture is slurried at 50 to 55°C for 2 hours, the heating is turned off and the mixture is cooled to room temperature, filtered with suction, and the filter cake is dried in a 50°C forced air drying oven for 8 hours to obtain 12.8 g of 5H-[1]-benzopyrano[2,3-b]pyridine (4), with a yield of 92%.

[0038] Example 5: A preparation process of a pranoprofen intermediate proposed in the present invention, 15.0 g of 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2) and 110 ml of methanol are added to a 250 ml three-necked reaction flask, stirred using a heat-collecting constant temperature magnetic stirrer and cooled to 0°C using an ice-water bath, 0.45 g of PdCl2 is added, 4.0 g of sodium borohydride is slowly added in batches, the temperature is controlled at 0°C for reaction for 2 hours, then the temperature is raised to room temperature and the reaction is continued for 4 hours, the temperature is raised to 53°C for reaction for 4 hours, 1.9 g of activated carbon is added, the mixture is filtered, 200 ml of purified water is added to the filtrate to precipitate solids, the mixture is slurried at 53°C for 2 hours, the heating is turned off and the temperature is cooled to room temperature, the filter cake is dried in a 50°C forced air drying oven for 10 hours, and 12.3 g of 5H-[1]-benzopyrano[2,3-b]pyridine (4) is obtained, with a yield of 88.2%.

[0039] Example 6: A preparation process of a pranoprofen intermediate proposed in the present invention, 15.0 g of 5H-[1]-benzopyrano[2,3-b]pyridine-5-one (2) and 120 ml of methanol are added to a 250 ml three-necked reaction flask, stirred using a heat-collecting constant temperature magnetic stirrer and cooled to 5°C with an ice-water bath, 0.67 g of PdCl2 is added, 4.44 g of sodium borohydride is slowly added in batches, the temperature is controlled at 5°C for reaction for 2 hours, then the temperature is raised to room temperature and the reaction is continued for 4 hours, the temperature is raised to 55°C for reaction for 4 hours, 2.28 g of activated carbon is added, the mixture is filtered, 200 ml of purified water is added to the filtrate to precipitate solids, the mixture is slurried at 55°C for 2 hours, the heating is turned off and the temperature is cooled to room temperature, the filter cake is dried in a 50°C forced air drying oven for 15 hours, and 12.0 g of 5H-[1]-benzopyrano[2,3-b]pyridine (4) is obtained, with a yield of 86.1%.

[0040] like Figure 1 and Figure 2As shown, the intermediate 5H-[1]-benzopyran[2,3-b]pyridine obtained in Example 4 of the present invention obtains the HPLC detection spectrum and the hydrogen spectrum nuclear magnetic spectrum by high performance liquid chromatography and nuclear magnetic resonance spectroscopy. It can be seen that the present invention only has one-step reaction, that is, 5H-[1]-benzopyran[2,3-b]pyridine-5-one (2) is used to prepare the key intermediate 5H-[1]-benzopyran[2,3-b]pyridine (4) of pranoprofen, and the yield is 84-92%, which improves the yield. The process operation and post-processing of the present invention are simple, and the solvent, labor and power costs of the multi-step reaction are reduced, and the economic benefits are significant.

[0041] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a pranoprofen intermediate, characterized in that: The method comprises the following preparation steps: Step 1: Add the raw material 5H-[1]-benzopyrano[2,3-b]pyridin-5-one into the reactor, add an organic solvent and cool the reaction system to -10 to 5°C under stirring, and add a catalytic amount of PdCl2; Step 2: Slowly add sodium borohydride in batches to the reaction system at a temperature of -10 to 5°C. After the addition is completed, the temperature is controlled at -10 to 5°C for reaction for 1 to 2 hours, then the temperature is raised to room temperature for further reaction for 3 to 6 hours, the temperature is raised to 50 to 55°C for reaction for 2 to 4 hours, and activated carbon is added; Step 3: Filter while hot, add purified water to the filtrate to precipitate the product, slurry at 50-55°C for 2 hours, then cool to room temperature, filter, and dry the filter cake in a drying oven at 50-55°C for 5-15 hours to obtain pranoprofen intermediate 5H-[1]-benzopyrano[2,3-b]pyridine.

2. The method for preparing a pranoprofen intermediate according to claim 1, wherein The organic solvent is methanol or ethanol.

3. The method for preparing a pranoprofen intermediate according to claim 1, wherein The mass volume ratio between the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one and the organic solvent is 1:4-8 (g / ml).

4. The method for preparing a pranoprofen intermediate according to claim 1, wherein The molar equivalent ratio of the activated carbon to the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one is 1.0 to 2.

5.

5. The method for preparing a pranoprofen intermediate according to claim 1, wherein The molar equivalent ratio of the PdCl2 to the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one is 0.005 to 0.

05.

6. The method for preparing a pranoprofen intermediate according to claim 1, wherein: The molar equivalent ratio of the sodium borohydride to the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one is 0.8 to 2.

0.

7. The method for preparing a pranoprofen intermediate according to claim 6, wherein: The molar equivalent ratio of the sodium borohydride to the raw material 5H-[1]-benzopyrano[2,3-b]pyridine-5-one is 1.0 to 2.

0.

8. The method for preparing a pranoprofen intermediate according to claim 1, wherein: The room temperature is 25°C±5°C.

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