CN114716449B - A kind of preparation method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline - Google Patents

Abstract

The invention discloses a preparation method of 2-methoxy-6-glycol ketal-5, 7, 8-trihydroquinoline, which takes 1, 4-cyclohexanedione monoethyl glycol ketal as a starting material, reacts with N, N-dimethylformamide dimethyl acetal under a heating condition to obtain a ketoenamine product, then further reacts with methanesulfonyl acetonitrile in a ring closure way, the obtained product reacts with methyl iodide in a methylation way, and finally removes methanesulfonyl under the action of magnesium metal to obtain a target product; the preparation method has the advantages of fewer reaction steps, mild reaction conditions, higher yield, simple operation, convenient product refining and low production cost, and is suitable for industrial production.

Description

A kind of preparation method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline

Technical field

The present invention relates to a preparation method of natural pharmaceutical intermediates, specifically to a preparation method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline.

Background technique

Huperzine A (Huperzine A), trade name is Huperzine, chemical name is: (5R,9R,11E)-5-amino-11-ethylene-5,8,9, 10-tetrahydro-7 -Methyl-5,9-methylenecyclooctatetraeno[b]pyridin-2-(1H)-one is a polypeptide isolated from the plant Huperzia serrata by Chinese scientists in the 1980s. Hemiterpene alkaloids. Pharmacological studies have shown that huperzine A is a highly efficient and reversible acetylcholinesterase inhibitor with the advantages of high selectivity, good fat solubility, long action time, easy passage through the blood-brain barrier, high oral bioavailability and few adverse reactions. , can significantly improve people's cognitive and behavioral functions, and enhance learning and memory. It is currently widely used to treat myasthenia gravis and Alzheimer's disease.

Almost all of the Huperzine A raw materials currently on the market are extracted from the medicinal plant Melaleuca. The preparation method of extracting huperzine A from the medicinal plant Melaleuca has fatal flaws: (1) The growth cycle of the plant Melaleuca is long, about 8-10 years. Especially due to the characteristics of the Melaleuca plant, Although scientists have conducted a lot of research, artificial cultivation is still not possible. Therefore, the melaleuca towers used to extract huperzine A raw materials are all collected from wild sources, and resources are increasingly scarce. This restricts the development of huperzine A as a drug. One of the important factors; (2) The content of huperzine A in Melaleuca Tower is extremely low; (3) The entire extraction process is complex and the cycle is long; (4) The yield is low and the cost is high; (5) During the extraction process A large amount of organic solvents are used in the process, which can easily cause environmental pollution. Therefore, developing a total synthesis process route for huperzine A that is environmentally friendly, low-cost, high-yield, and suitable for industrial production will have good economic and social benefits.

The retrosynthetic analysis of huperzine A is as follows:

From the retrosynthetic analysis of huperzine A, it can be seen that 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline (compound 5) is the key intermediate for the preparation of huperzine A. In recent years, there have been some literature reports on the use of chemical synthesis methods to prepare this key intermediate. Taken together, the synthesis methods reported in the literature have low yields, high costs, and can easily cause environmental pollution. Therefore, it will be economically feasible to develop a process route for 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline that is environmentally friendly, has low cost, has high yield and is suitable for industrial production. benefits and social benefits.

Contents of the invention

The present invention mainly provides a preparation method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline, an intermediate of huperzine A, which method uses 1,4-cyclohexane The diketone monoethylene glycol ketal is used as the starting material. It reacts with N,N-dimethylformamide dimethyl acetal under heating conditions to obtain the ketoenamine product, and then further undergoes a ring-closing reaction with methanesulfonyl acetonitrile. , the obtained product undergoes a methylation reaction with methyl iodide, and finally, under the action of metal magnesium, the methanesulfonyl group is removed to obtain the target product. Compared with existing methods, this preparation method is safe, has fewer steps, is easy to operate, has high yield and low cost.

The technical solution of the present invention is as follows:

A preparation method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline, including the following steps:

Step 1: Place compound 1 and DMF-DMA (N,N-dimethylformamide dimethyl acetal) in N,N dimethylformamide, stir the reaction at 70-90°C, and monitor by TLC. After the reaction is completed, the remaining DMF-DMA and N,N dimethylformamide are evaporated under reduced pressure to obtain compound 2;

The obtained compound 2 does not require further purification and can be directly used in the next reaction;

Step 2: Add compound 2 and methanesulfonyl acetonitrile into absolute ethanol, stir the reaction at 60-80°C, monitor with TLC until the reaction is completed, and then perform post-processing to obtain compound 3;

The ratio of the amounts of compound 2 to methanesulfonyl acetonitrile is 1:1.0 to 1:1.2;

The post-treatment method is: after the reaction is completed, naturally cool to room temperature, the solid is precipitated, filtered, and the filter cake is washed with cold (0-5°C) ethanol and dried to obtain compound 3;

Step 3: Add compound 3 and silver carbonate to methylene chloride, then add methyl iodide, and react at 0 to 20°C in the dark, monitor with TLC until the reaction is completed, and then perform post-processing to obtain compound 4;

The ratio of the amount of compound 3 to silver carbonate is 1:0.8 to 1:1.0;

The ratio of the amount of compound 3 to methyl iodide is 1:3 to 1:6;

The post-treatment method is: after the reaction is completed, filter, wash the filter cake with dichloromethane, take the filtrate, evaporate the solvent under reduced pressure, and dry to obtain compound 4;

Step 4: Mix compound 4 with metallic magnesium, add anhydrous methanol under nitrogen protection, raise the temperature to 40-60°C and stir the reaction, monitor with TLC until the reaction is completed, and then perform post-processing to obtain compound 5;

The ratio of the amount of compound 4 to metallic magnesium is 1:3 to 1:6;

The post-treatment method is: after the reaction is completed, cool to room temperature, add 10% dilute hydrochloric acid dropwise to the reaction solution, and then extract with ethyl acetate. The organic phase is dried with anhydrous sodium sulfate, and then evaporated under reduced pressure. Solvent and dry to obtain compound 5;

The synthesis route is as follows:

The beneficial effects of the present invention are: the present invention provides a method for preparing the huperzine A drug intermediate 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline. It has fewer reaction steps, mild reaction conditions, higher yield, simple operation, convenient product refining, low production cost, and is suitable for industrial production.

Detailed ways

In order to clearly and completely describe the technical solution of the present invention, a clear and complete description will be given below with reference to specific examples. The reagents involved in the present invention are all commercially available. The described embodiments are some, but not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present invention.

Example 1

Synthesis of compound 2:

At room temperature, 1,4-cyclohexanedione monoethylene glycol ketal (compound 1, 23.4g, 0.15mol), N,N-dimethylformamide (150mL) and N,N-dimethylformamide were added in sequence. Formamide dimethyl acetal (26.8g, 0.225mol) was added to a 500mL three-necked flask equipped with a condenser tube. Under uniform stirring, rapidly raise the temperature to 80°C, and check the reaction progress on a TLC plate. After the reaction is completed, remove the remaining DMF-DMA (N,N-dimethylformamide dimethyl acetal) and N,N-dimethylacetal under reduced pressure. Methyl formamide is used to obtain 2-((dimethylamino)methenyl)-1,4-cyclohexanedione monoethylene glycol ketal (compound 2). The obtained compound 2 did not require further purification and could be directly used in the next reaction.

Synthesis of compound 3:

At room temperature, add the compound 2 obtained in the previous step (0.15 mol, calculated according to the 100% conversion rate of the previous step), methanesulfonyl acetonitrile (19.6 g, 0.165 mol) and 200 mL of absolute ethanol in sequence into a 500 mL three-port equipped with a reflux condenser tube. In the bottle, quickly heat to reflux, and check the reaction progress with TLC plate. After the reaction is completed, stop heating and cool to room temperature naturally. At this time, a large amount of solid will precipitate. Filter the solid, wash it with a small amount of cold ethanol (40mL), and dry it. 25.1 g of 2-carbonyl-3-methanesulfonyl-6-ethylene glycol ketal-5,7,8-trihydroquinoline (compound 3), yield 58.7%.

The hydrogen spectrum of compound 3 is: ¹ H NMR (CDCl ₃ , 600MHz): δ12.87 (1H,s,NH), 8.01 (1H,s,CH), 4.03 (4H,m, 2×OCH ₂ ), 3.27 (3H,s,CH ₃ ),2.98(2H,t,J＝6.78Hz,CH ₂ ),2.77(2H,s,CH ₂ ),1.97(2H,t,J＝6.78Hz, CH ₂ ).

Synthesis of compound 4:

At room temperature, compound 3 (28.5g, 0.1mol), silver carbonate (22.1g, 0.08mol) and dichloromethane (150mL) were sequentially added to a 500mL reaction flask, and then methyl iodide (85.2g, 0.6 mol), place it at 20°C to avoid light, and monitor the reaction progress with a TLC plate. After the reaction is completed, filter and wash the solid, remove excess solvent from the filtrate under reduced pressure, and dry to obtain 2-methoxy-3-methanesulfonyl-6-ethylene glycol ketal-5,7,8-trihydroquin 26.9g of pholine (compound 4), yield 90.2%.

The hydrogen spectrum of compound 4 is: ¹ H NMR (CDCl ₃ , 600MHz): δ: 7.89 (1H, s, CH), 4.06 (3H, s, OCH ₃ ), 4.03 (4H, s, 2×OCH ₂ ), 3.18(3H,s,CH ₃ ), 3.06(2H,t,J＝6.84Hz,CH ₂ ), 2.94(2H,s,CH ₂ ), 2.03(2H,t,J＝6.84Hz, CH ₂ ).

Synthesis of compound 5:

At room temperature, add compound 4 (20.9g, 0.0.07mol) and metal magnesium (10.1g, 0.42mol) obtained above into the reaction bottle. Under nitrogen protection, add anhydrous methanol (150mL), slowly warm to 50°C, and perform TLC Check the progress of the reaction with a plate. After the reaction is completed, cool to room temperature, and then slowly drop 10% dilute hydrochloric acid into it. After the solid is completely dissolved, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and dry That is, 11.4 g of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline (compound 5) was obtained, with a yield of 73.6%.

The hydrogen spectrum of compound 5 is: ¹ H NMR (CDCl ₃ , 600MHz): δ: 7.23 (1H, d, J = 8.34Hz, CH), 6.581 (1H, d, J = 8.34Hz, CH), 4.03 (4H ,s,2×OCH ₂ ),3.88(3H,s,OCH ₃ ),3.01(2H,t,J＝6.78Hz,CH ₂ ),2.89(2H,s,CH ₂ ), 2.01((2H,t , J=6.84Hz, CH ₂ ).

Claims (5)

1. A preparation method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline, characterized in that the preparation method includes the following steps: Step 1: Place compound 1 and DMF-DMA in N,N dimethylformamide, stir the reaction at 70-90°C, monitor with TLC until the reaction is completed, and then evaporate the remaining DMF-DMA and N under reduced pressure. N dimethylformamide to obtain compound 2; Step 2: Add compound 2 and methanesulfonyl acetonitrile into absolute ethanol, stir the reaction at 60-80°C, monitor with TLC until the reaction is completed, and then perform post-processing to obtain compound 3; The ratio of the amounts of compound 2 to methanesulfonyl acetonitrile is 1:1.0 to 1:1.2; Step 3: Add compound 3 and silver carbonate to methylene chloride, then add methyl iodide, and react in the dark at 0 to 20°C. Monitor with TLC until the reaction is completed, and then perform post-processing to obtain compound 4; The ratio of the amount of compound 3 to silver carbonate is 1:0.8 to 1:1.0; The ratio of the amount of compound 3 to methyl iodide is 1:3 to 1:6; Step 4: Mix compound 4 with metallic magnesium, add anhydrous methanol under nitrogen protection, raise the temperature to 40-60°C and stir the reaction, monitor with TLC until the reaction is completed, and then perform post-processing to obtain compound 5; The synthesis route is as follows: 2. The synthetic method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline as claimed in claim 1, characterized in that, in step 2, the post-processed The method is: after the reaction is completed, cool to room temperature naturally, the solid will precipitate, filter, and the filter cake will be washed with cold ethanol and dried to obtain compound 3. 3. The synthetic method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline as claimed in claim 1, characterized in that, in step 3, the post-processed The method is: after the reaction is completed, filter, wash the filter cake with dichloromethane, take the filtrate, evaporate the solvent under reduced pressure, and dry to obtain compound 4. 4. The synthetic method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline as claimed in claim 1, characterized in that, in step 4, the compound 4 and The material quantity ratio of metallic magnesium is 1:3 to 1:6. 5. The synthetic method of 2-methoxy-6-ethylene glycol ketal-5,7,8-trihydroquinoline as claimed in claim 1, characterized in that, in step 4, the post-processed The method is: after the reaction is completed, cool to room temperature, add 10% dilute hydrochloric acid dropwise to the reaction solution, and then extract with ethyl acetate. The organic phase is dried with anhydrous sodium sulfate, and then the solvent is evaporated under reduced pressure and dried. Compound 5 is obtained.