Preparation method and application of a glutarimide compound

Abstract

The application relates to the field of organic synthesis, in particular to a preparation method and application of a glutarimide compound, which comprises the following steps: reacting a compound II and a formamide in the presence of formic acid to prepare a compound I. The preparation method adopts glutaric acid compounds and formamide as starting materials, only needs to add a catalytic amount of formic acid in a reaction system, and can obtain a yield of more than 80% without using any additional reaction solvent.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a preparation method and application of a glutarimide compound. BACKGROUND

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

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

[0004]

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

[0006]

[0007] Therefore, it is an urgent technical problem to explore a preparation method of a glutarimide compound with high yield, convenient operation and environmental friendliness. SUMMARY

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

[0009] The present application provides a preparation method of a glutarimide compound, which comprises the following steps:

[0010]

[0011] In the presence of formic acid, compound II and formamide undergo a reaction to prepare compound I;

[0012] wherein A is C 6-10 aryl; the C 6-10aryl is optionally substituted with 1 or more R 1 the number of R

[0013] each R 1 is independently halo or C 1-6 alkyl.

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

[0015] In one embodiment, the C 1-6 alkyl can be C 1-4 alkyl; for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or t-butyl.

[0016] In one embodiment, A can be phenyl or R 1 is halo or C 1-4 alkyl; preferably, A is phenyl or R 1 is halo; more preferably, A is R 1 is halo.

[0017] In one embodiment, the molar ratio of the formamide to the compound II can 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 can 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 can be 130-180°C, preferably 155-170°C.

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

[0021] In one embodiment, after the reaction, the following post-treatment steps are further included: beating with solvent A or a mixed solvent of solvent A and solvent B, filtering, and taking the solid;

[0022] wherein the solvent A is selected from any one or more of t-butyl methyl ether, isopropyl alcohol, and t-butyl alcohol;

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

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

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

[0026] In an embodiment, the method for preparing the glutarimide compound comprises the following steps:

[0027]

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

[0029] In an embodiment, the method for preparing the glutarimide compound comprises the following steps: in the presence of formic acid, 3-(4-bromophenyl) glutaric acid and formamide react at 140-180℃ for 12-24h, cooling, beating with isopropyl alcohol and sodium hydroxide solution, filtering, taking the solid, to produce 4-(4-bromophenyl) piperidine-2,6-dione.

[0030] The application provides an application of a glutarimide compound, which is a method for preparing a piperidine compound by taking a glutarimide compound as a raw material, comprising the following steps:

[0031]

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

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

[0034] In an embodiment, the boron trifluoride complex can be boron trifluoride tetrahydrofuran complex or boron trifluoride diethyl ether complex.

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

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

[0037] In an embodiment, the reaction temperature of the reduction reaction is 40-65℃, preferably 50-55℃.

[0038] In an embodiment, the reaction time of the reduction reaction is 16-24 hours.

[0039] In an embodiment, after the reduction reaction, the following post-processing steps are further included: adding hydrochloric acid to quench the reaction, concentrating, adding water and methyl tert-butyl ether to extract, taking the water phase, adding alkali to adjust the pH to 10-14, methyl tert-butyl ether extraction, taking the organic phase, concentrating, and it is ready.

[0040] In an embodiment, the method for preparing the piperidine compound includes the following steps: in the presence of sodium borohydride and boron trifluoride or its complex, 4-(4-bromophenyl) piperidine-2,6-dione is reacted in tetrahydrofuran 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 water phase is taken, alkali is added to adjust the pH to 10-14, methyl tert-butyl ether extraction is performed, the organic phase is taken, concentrated, and 4-(4-bromophenyl) piperidine is prepared.

[0041] Effects and advantages of the application

[0042] The method for preparing the glutarimide compound according to the application uses glutaric acid compounds and formamide as starting materials, and the applicant has unexpectedly found that only a catalytic amount of formic acid needs to be added to the reaction system to achieve a yield of more than 80% without using any additional reaction solvent.

[0043] The application of the glutarimide compound according to the application can reduce 4-(4-bromophenyl) piperidine-2,6-dione to obtain 4-(4-bromophenyl) piperidine with a yield of about 70% by using sodium borohydride and boron trifluoride or its complex as a reducing agent. DETAILED DESCRIPTION

[0044] In order to make the technical means, creative features, purposes and effects achieved by the application easy to understand, the application is specifically described below in combination with examples.

[0045] Example 1

[0046]

[0047] Put 86.2 g formamide (1.9 mol, 5.5 eq), 5.4 g formic acid (0.12 mol, 0.34 eq) and 100 g 3-(4-bromophenyl)pentandioic acid (0.35 mol, 1.0 eq) into a reaction bottle, heat to 160 °C, keep reaction for 20 h, drop to room temperature, add 100 mL isopropyl alcohol and 100 mL 10 wt% NaOH solution, beat for 1 h, filter, take solid to get 79.7 g 4-(4-bromophenyl)piperidine-2,6-dione, yield 84.9%, purity 99.5%.

[0048] Example 2

[0049]

[0050] Put 153.1 g formamide (3.4 mol, 5.4 eq), 9.7 g formic acid (0.21 mol, 0.34 eq) and 180 g 3-(4-bromophenyl)pentandioic acid (0.63 mol, 1.0 eq) into a reaction bottle, heat to 165 °C, keep reaction for 16 h, drop to room temperature, add 180 mL isopropyl alcohol and 180 mL water, beat for 1 h, filter, take solid to get 141.0 g 4-(4-bromo-phenyl)-piperidine-2,6-dione, yield 83.5%, purity 99.7%.

[0051] Example 3

[0052]

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

[0054] Comparative Example 1

[0055]

[0056] Put 8.62 g formamide (0.19 mol, 5.5 eq) and 10 g 3-(4-bromophenyl) glutaric acid (0.035 mol, 1.0 eq) in a reaction bottle, heat to 160°C, keep for 20 h, reduce to room temperature, add 10 mL isopropanol and 10 mL 10 wt% NaOH solution, beat for 1 h, filter, take the solid to get 5.1 g 4-(4-bromophenyl) piperidine-2,6-dione, yield 54.4%, purity 98.3%.

[0057] Comparative Example 2

[0058] Put 10 g 3-(4-bromophenyl) glutaric acid (0.035 mol, 1.0 eq) and 40 mL formamide into 60 mL dimethyl sulfoxide, react at 100°C for 18 h, reduce to room temperature, add 10 wt% aqueous sodium hydroxide solution and dichloromethane extraction, concentrate, filter, and dry to get 6.7 g white solid, yield 71.4%.

[0059] The preparation method of the glutarimide compound involved in the above examples 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 achieve a yield of more than 80% without using any additional reaction solvent.

[0060] Further, the whole experimental process is convenient to operate and simple to handle. A purity of more than 99% can be achieved by beating with a mixed solvent of sodium hydroxide solution and isopropanol.

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

[0062] The above embodiments are preferred cases of the present application and do not limit the protection scope of the present application.

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 prepare compound I; Where A is a phenyl or R 1 Halogen or C 1-4 alkyl, After the reaction is completed, the following post-processing steps are also included: pulping with solvent A or a mixture of solvent A and solvent B, filtering, and taking the solid; Solvent A is selected from any one or more of tert-butyl methyl ether, isopropanol, and tert-butanol; solvent B is an alkaline aqueous solution or water. The reaction temperature is 155-170℃.

2. The preparation method according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions: ① The molar ratio of formamide to compound II is (4-7):1; ② The molar ratio of formic acid to compound II is (0.3-1):1; ③ The reaction time is 12-24 hours.

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

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

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

6. The application of a glutarimide compound, characterized in that, The application is a method for preparing piperidine compounds using glutarimide compounds as raw materials, which includes the following steps: In an organic solvent, in the presence of sodium borohydride and boron trifluoride or their complexes, 4-(4-bromophenyl)piperidine-2,6-dione undergoes a reduction reaction to prepare 4-(4-bromophenyl)piperidine. The boron trifluoride complex is a boron trifluoride tetrahydrofuran complex or a boron trifluoride diethyl ether complex. The reduction reaction is carried out at a temperature of 40-65℃. The method for preparing the 4-(4-bromophenyl)piperidine-2,6-dione is as described in any one of claims 1-5.

7. The application as described in claim 6, characterized in that, The preparation method of the piperidine compound satisfies one or more of the following conditions: ① The molar ratio of sodium borohydride to 4-(4-bromophenyl)piperidine-2,6-dione is (2-4):1; ②The molar ratio of the boron trifluoride or its complex to the 4-(4-bromophenyl)piperidine-2,6-dione is (2-5):1; ③The organic solvent is one or more of tetrahydrofuran, diethyl ether, and diethylene glycol butyl ether; ④ The reaction time for the reduction reaction is 16-24 hours; ⑤ After the reduction reaction is completed, the following post-processing steps are also included: adding hydrochloric acid to quench the reaction, concentrating, adding water and methyl tert-butyl ether for extraction, taking the aqueous phase, adding alkaline solution to adjust the pH to 10-14, extracting with methyl tert-butyl ether, taking the organic phase, and concentrating.

8. The application as described in claim 7, characterized in that, The preparation method of the piperidine compound satisfies one or more of the following conditions: ① The molar ratio of sodium borohydride to 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; ③The organic solvent is tetrahydrofuran; ④ The reaction temperature of the reduction reaction is 50-55℃.

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