Preparation method and application of glutarimide compound

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method and application of glutarimide compounds, and the preparation method comprises the following steps: in the presence of formic acid, a compound II reacts with formamide to prepare a compound I. According to the preparation method, glutaric acid compounds and formamide are adopted as starting raw materials, and the yield of 80% or above can be obtained under the condition that no additional reaction solvent is used only by adding a catalytic amount of formic acid into a reaction system. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a preparation method and application of glutarimide compounds. Background Art

[0002] Alzheimer's disease is a progressive senile dementia in which obvious cerebral cortex atrophy can be observed due to the degeneration of nerve cells and the reduction of nerve cell number. At present, the research on drugs to treat this disease has also become a hot topic in the medical field.

[0003] Among them, WO2004085408A1 discloses that 4-(4-bromophenyl)piperidine-2,6-dione can be used as an intermediate of drugs for preventing and / or treating neurodegenerative diseases, and discloses a method for preparing 4-(4-bromophenyl)piperidine-2,6-dione: in the presence of acetic anhydride and ammonia, 3-(4-bromophenyl)pentanedioic acid is used to prepare 4-(4-bromo-phenyl)-piperidine-2,6-dione in a yield of 50%, which is relatively low.

[0004]

[0005] CN111533739A discloses a similar reaction, in which a glutaric acid derivative is used as a starting material and undergoes a ring-closing reaction with formamide, and the yield of the target product is 80%. However, the amount of formamide used in the reaction is 20-40 equivalents of the amount of the glutaric acid derivative used, and at the same time, a large amount of high-boiling point solvent is also required in the reaction, which also increases the difficulty in recovering a large amount of unreacted formamide and easily causes waste of materials.

[0006]

[0007] Therefore, exploring a method for preparing glutarimide compounds with high yield, convenient operation and environmental friendliness has become a technical problem that needs to be solved urgently. Summary of the invention

[0008] The present invention is made to solve the above problems, and aims to provide a preparation method and application of glutarimide compounds with high yield, convenient operation and environmental friendliness.

[0009] The present invention provides a method for preparing a glutarimide compound, which comprises the following steps:

[0010]

[0011] In the presence of formic acid, compound II reacts with formamide to obtain compound I;

[0012] Among them, A is C 6-10 Aryl; said C 6-10The aryl group is optionally substituted with one or more R 1 Replacement; the plurality is 2, 3, 4 or 5;

[0013] Each R 1 are independently halogen or C 1-6 alkyl.

[0014] In one embodiment, the C 6-10 Aryl may be phenyl or naphthyl.

[0015] In one embodiment, the C 1-6 The alkyl group may be C 1-4 Alkyl; for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0016] In one embodiment, A can be phenyl or R 1 Halogen or C 1-4 Alkyl; preferably, A is phenyl or R 1 is halogen; more preferably, A is R 1 It is a halogen.

[0017] In one embodiment, the molar ratio of the formamide to the compound II may be (4-7):1, preferably (4-6):1, for example 5.5:1.

[0018] In one embodiment, the molar ratio of the formic acid to the compound II may be (0.3-1):1, preferably (0.3-0.5):1, for example 0.34:1.

[0019] In one embodiment, the reaction temperature of the reaction may be 130-180°C, preferably 155-170°C.

[0020] In one embodiment, the reaction time of the reaction can be 12-24 hours.

[0021] In one embodiment, after the reaction is completed, the following post-treatment steps are further included: slurrying with solvent A or a mixed solvent consisting of solvent A and solvent B, filtering, and obtaining solids;

[0022] Wherein, the solvent A is selected from any one or more of tert-butyl methyl ether, isopropanol and tert-butyl alcohol;

[0023] The solvent B is an alkaline aqueous solution or water.

[0024] In one embodiment, the solvent A is preferably isopropanol, and the solvent B is preferably an alkaline aqueous solution; the mixed solvent of the solvent A and the solvent B is preferably a mixed solvent of isopropanol and an alkaline aqueous solution; preferably, the volume ratio of isopropanol to the alkaline aqueous solution is 1:1.

[0025] In one embodiment, the alkaline aqueous solution may be a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or a cesium hydroxide aqueous solution. In the post-treatment step, the alkaline aqueous solution may be an alkaline aqueous solution with a mass fraction of 10%.

[0026] In one embodiment, the preparation method of the glutarimide compound comprises the following steps:

[0027]

[0028] In the presence of formic acid, 3-(4-bromophenyl)glutaric acid and formamide react to obtain 4-(4-bromophenyl)piperidine-2,6-dione.

[0029] In one embodiment, the preparation method of the glutarimide compound comprises the following steps: in the presence of formic acid, 3-(4-bromophenyl)glutaric acid reacts with formamide at 140-180° C. for 12-24 hours, cooling, slurrying with isopropanol and sodium hydroxide solution, filtering, and taking solids to obtain 4-(4-bromophenyl)piperidine-2,6-dione.

[0030] The present invention provides an application of a glutarimide compound, wherein the application is a method for preparing a piperidine compound using the glutarimide compound as a raw material, and the method comprises the following steps:

[0031]

[0032] In an organic solvent, in the presence of sodium borohydride and boron trifluoride or a complex thereof, 4-(4-bromophenyl)piperidine-2,6-dione undergoes a reduction reaction to prepare 4-(4-bromophenyl)piperidine.

[0033] In one embodiment, the molar ratio of the sodium borohydride to the 4-(4-bromophenyl)piperidine-2,6-dione may be (2-4):1, preferably 3:1.

[0034] In one embodiment, the boron trifluoride complex may be a boron trifluoride tetrahydrofuran complex or a boron trifluoride ether complex.

[0035] In one embodiment, the molar ratio of the boron trifluoride or its complex to the 4-(4-bromophenyl)piperidine-2,6-dione may be (2-5):1, preferably 4:1.

[0036] In one embodiment, the organic solvent may be one or more of tetrahydrofuran, diethyl ether and diethylene glycol butyl ether, preferably tetrahydrofuran.

[0037] In one embodiment, the reaction temperature of the reduction reaction is 40-65°C, preferably 50-55°C.

[0038] In one embodiment, the reduction reaction takes 16-24 hours.

[0039] In one embodiment, after the reduction reaction is completed, the following post-treatment steps are further included: adding hydrochloric acid to quench the reaction, concentrating, adding water and methyl tert-butyl ether to extract, taking the aqueous phase, adding alkali solution to adjust the pH to 10-14, extracting with methyl tert-butyl ether, taking the organic phase, and concentrating.

[0040] In one embodiment, the preparation method of the piperidine compound comprises the following steps: in tetrahydrofuran, in the presence of sodium borohydride and boron trifluoride or its complex, 4-(4-bromophenyl)piperidine-2,6-dione is reacted at 40-65° C. for 16-24 hours, hydrochloric acid is added to quench the reaction, concentrated, water and methyl tert-butyl ether are added to extract, the aqueous phase is taken, alkali solution is added to adjust the pH to 10-14, methyl tert-butyl ether is extracted, the organic phase is taken, and concentrated to obtain 4-(4-bromophenyl)piperidine.

[0041] Functions and Effects of the Invention

[0042] The preparation method of glutarimide compounds involved in the present invention uses glutaric acid compounds and formamide as starting materials. The applicant unexpectedly found that only a catalytic amount of formic acid needs to be added to the reaction system to obtain a yield of more than 80% without using any additional reaction solvent.

[0043] The application of the glutarimide compounds involved in the present invention uses sodium borohydride and boron trifluoride or their complexes as reducing agents, so 4-(4-bromophenyl)piperidine-2,6-dione can be reduced to obtain 4-(4-bromophenyl)piperidine with a yield of about 70%. DETAILED DESCRIPTION

[0044] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below in conjunction with embodiments.

[0045] Example 1

[0046]

[0047] 86.2 g of formamide (1.9 mol, 5.5 eq), 5.4 g of formic acid (0.12 mol, 0.34 eq) and 100 g of 3-(4-bromophenyl)pentanedioic acid (0.35 mol, 1.0 eq) were placed in a reaction bottle, heated to 160°C, kept warm for reaction for 20 h, cooled to room temperature, 100 mL of isopropanol and 100 mL of 10 wt% NaOH solution were added, pulped for 1 h, filtered, and solids were taken to obtain 79.7 g of 4-(4-bromophenyl)piperidine-2,6-dione with a yield of 84.9% and a purity of 99.5%.

[0048] Example 2

[0049]

[0050] 153.1 g of formamide (3.4 mol, 5.4 eq), 9.7 g of formic acid (0.21 mol, 0.34 eq) and 180 g of 3-(4-bromophenyl)pentanedioic acid (0.63 mol, 1.0 eq) were placed in a reaction bottle, heated to 165°C, kept warm for reaction for 16 h, cooled to room temperature, 180 mL of isopropanol and 180 mL of water were added, slurried for 1 h, filtered, and solids were taken to obtain 141.0 g of 4-(4-bromo-phenyl)-piperidine-2,6-dione with a yield of 83.5% and a purity of 99.7%.

[0051] Example 3

[0052]

[0053] Control the temperature below 30°C, place 100g 4-(4-bromophenyl)piperidine-2,6-dione (0.37mol, 1.0eq), 1000mL tetrahydrofuran and 42g NaBH4 (1.11mol, 3.0eq) in a reaction flask, drop 208g BF3·THF (1.49mol, 4.0eq) and 400mL tetrahydrofuran in the reaction flask, keep warm for 1h, and then heat to 50-55°C for 20h. After the reaction is completed, add 400mL concentrated hydrochloric acid (mass fraction 37%) to quench the reaction, concentrate, and obtain a concentrated reaction solution. Add water and methyl tert-butyl ether to the concentrated reaction solution, extract, take the aqueous phase, drop 30wt% sodium hydroxide solution to neutralize to pH 10, add methyl tert-butyl ether for extraction, take the organic phase, and concentrate to obtain 63.3g of the product, with a yield of 71.2% and a purity of 99.7%.

[0054] Comparative Example 1

[0055]

[0056] 8.62 g of formamide (0.19 mol, 5.5 eq) and 10 g of 3-(4-bromophenyl)pentanedioic acid (0.035 mol, 1.0 eq) were placed in a reaction bottle, heated to 160°C, kept warm for reaction for 20 h, cooled to room temperature, 10 mL of isopropanol and 10 mL of 10 wt% NaOH solution were added, slurried for 1 h, filtered, and solids were obtained to obtain 5.1 g of 4-(4-bromophenyl)piperidine-2,6-dione with a yield of 54.4% and a purity of 98.3%.

[0057] Comparative Example 2

[0058] 10 g of 3-(4-bromophenyl)pentanedioic acid (0.035 mol, 1.0 eq) and 40 mL of formamide were added to 60 mL of dimethyl sulfoxide, and the mixture was reacted at 100° C. for 18 h. The mixture was cooled to room temperature, and 10 wt % aqueous sodium hydroxide solution and dichloromethane were added for extraction. The mixture was concentrated, filtered, and dried to obtain 6.7 g of a white solid with a yield of 71.4%.

[0059] The preparation method of glutarimide compounds involved in the above embodiments uses glutaric acid compounds and formamide as starting materials. The applicant unexpectedly found that only a catalytic amount of formic acid needs to be added to the reaction system to obtain a yield of more than 80% without using any additional reaction solvent.

[0060] Furthermore, the entire experimental process is easy to operate and the post-processing is simple, and the purity of more than 99% can be achieved by slurrying with a mixed solvent of sodium hydroxide solution and isopropanol.

[0061] The application of the glutarimide compounds involved in the above embodiments can reduce 4-(4-bromophenyl)piperidine-2,6-dione to obtain 4-(4-bromophenyl)piperidine with a yield of about 70% due to the use of sodium borohydride and boron trifluoride or its complex as reducing agents.

[0062] The above-mentioned embodiments are preferred examples of the present invention and are not intended to limit the protection scope of the present invention.

Claims

1. A method for preparing a glutarimide compound, characterized in that: It includes the following steps: In the presence of formic acid, compound II reacts with formamide to obtain compound I; Among them, A is C 6-10 Aryl; said C 6-10 The aryl group is optionally substituted with one or more R 1 Replacement; the plurality is 2, 3, 4 or 5; Each R 1 are independently halogen or C 1-6 of alkyl.

2. The preparation method according to claim 1, characterized in that The preparation method meets one or more of the following conditions: ① The molar ratio of the formamide to the compound II is (4-7):1; ② The molar ratio of the formic acid to the compound II is (0.3-1):1; ③ The reaction temperature of the reaction is 130-180°C; ④ The reaction time of the reaction is 12-24h; ⑤ After the reaction is completed, the following post-treatment steps are further included: slurrying with solvent A or a mixed solvent of solvent A and solvent B, filtering, and taking solids; Wherein, the solvent A is selected from any one or more of tert-butyl methyl ether, isopropanol and tert-butyl alcohol; and the solvent B is an alkaline aqueous solution or water.

3. The preparation method according to claim 2, characterized in that: The preparation method meets one or more of the following conditions: ① The molar ratio of the formamide to the compound II is (4-6):1; ② The molar ratio of the formic acid to the compound II is (0.3-0.5):1; ③ The reaction temperature of the reaction is 155-170°C; ④ The solvent A is isopropanol; ⑤ The solvent B is an alkaline aqueous solution.

4. The preparation method according to claim 1, characterized in that: The C 6-10 Aryl is phenyl or naphthyl; and / or, the C 1-6 Alkyl is C 1-4 alkyl.

5. The preparation method according to claim 4, characterized in that: A is phenyl or R 1 Halogen or C 1-4 alkyl.

6. The preparation method according to claim 5, characterized in that: A is phenyl or R 1 It is a halogen.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The preparation method of the glutarimide compound comprises the following steps: In the presence of formic acid, 3-(4-bromophenyl)glutaric acid and formamide react to obtain 4-(4-bromophenyl)piperidine-2,6-dione.

8. An application of a glutarimide compound, characterized in that: The application is a method for preparing a piperidine compound using a glutarimide compound as a raw material, which comprises the following steps: In an organic solvent, in the presence of sodium borohydride and boron trifluoride or a complex thereof, 4-(4-bromophenyl)piperidine-2,6-dione undergoes a reduction reaction to prepare 4-(4-bromophenyl)piperidine.

9. The use according to claim 8, characterized in that The preparation method of the piperidine compound satisfies one or more of the following conditions: ① The molar ratio of the sodium borohydride to the 4-(4-bromophenyl)piperidine-2,6-dione is (2-4):1; ② The boron trifluoride complex is a boron trifluoride tetrahydrofuran complex or a boron trifluoride ether complex; ③ The molar ratio of the boron trifluoride or its complex to the 4-(4-bromophenyl)piperidine-2,6-dione is (2-5):1; ④ The organic solvent is one or more of tetrahydrofuran, ether and diethylene glycol butyl ether; ⑤ The reaction temperature of the reduction reaction is 40-65°C; ⑥ The reaction time of the reduction reaction is 16-24h; ⑦ After the reduction reaction is completed, the following post-treatment steps are further included: adding hydrochloric acid to quench the reaction, concentrating, adding water and methyl tert-butyl ether to extract, taking the aqueous phase, adding alkali solution to adjust the pH to 10-14, extracting with methyl tert-butyl ether, taking the organic phase, and concentrating; ⑧The method for preparing 4-(4-bromophenyl)piperidine-2,6-dione is as described in the method for preparing glutarimide compounds according to any one of claims 1 to 7.

10. The use according to claim 9, characterized in that The preparation method of the piperidine compound satisfies one or more of the following conditions: ① The molar ratio of the sodium borohydride to the 4-(4-bromophenyl)piperidine-2,6-dione is 3:1; ② The molar ratio of the boron trifluoride or its complex to the 4-(4-bromophenyl)piperidine-2,6-dione is 4:1; ③ The organic solvent is tetrahydrofuran; ④ The reaction temperature of the reduction reaction is 50-55°C.

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