CN114716449B - Preparation method of 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline - Google Patents
Preparation method of 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline Download PDFInfo
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- CN114716449B CN114716449B CN202210379302.9A CN202210379302A CN114716449B CN 114716449 B CN114716449 B CN 114716449B CN 202210379302 A CN202210379302 A CN 202210379302A CN 114716449 B CN114716449 B CN 114716449B
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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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
Technical Field
The invention relates to a preparation method of a natural drug intermediate, in particular to a preparation method of 2-methoxy-6-glycol ketal-5, 7, 8-trihydroquinoline.
Background
Huperzine A (Huperzine A), under the trade name of habein, has the chemical name: (5R, 9R, 11E) -5-amino-11-ethylene-5, 8,9, 10-tetrahydro-7-methyl-5, 9-methylenecyclooctatetraene [ b ] pyridin-2- (1H) -one is a sesquiterpene alkaloid compound found and separated from Huperzia serrata by scientists in the eighth century. Pharmacological research shows that huperzine A is a high-efficiency reversible acetylcholinesterase inhibitor, has the advantages of high selectivity, good fat solubility, long acting time, easy passage through blood brain barrier, high oral bioavailability, less adverse reaction and the like, can obviously improve the cognition and behavior functions of people, and enhances the learning and memory effects. Is currently widely used for the treatment of myasthenia gravis and Alzheimer's disease.
The huperzine A raw material medicines sold in the market at present are almost all extracted from medicinal plant huperzia serrata. The preparation method for extracting huperzine A from medicinal plant huperzia serrata has fatal defects: (1) The growth cycle of the plant huperzia serrata is about 8-10 years, particularly because of the characteristics of the huperzia serrata, although scientists have carried out a great deal of research, artificial planting can not be realized until now, so the huperzia serrata for extracting huperzine A raw material medicines is collected in wild mode, resources are increasingly deficient, and the huperzine A is one of important factors for restricting the development of the huperzine A as a medicine; (2) huperzine A has very low content in huperzia serrata; (3) the whole extraction process is complex and has long period; (4) low yield and high cost; (5) A large amount of organic solvent is used in the extraction process, which is very easy to cause environmental pollution. Therefore, developing a huperzine A total synthesis process route which is environment-friendly, low in cost, high in yield and suitable for industrial production has good economic and social benefits.
The inverse synthetic analysis of huperzine A was as follows:
from the inverse synthetic analysis of huperzine A, 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline (compound 5) is a key intermediate for preparing huperzine A. In recent years, there have been some literature reports on the preparation of this key intermediate by chemical synthesis. In the comprehensive view, the synthesis method reported in the literature has low yield and high cost, and is extremely easy to cause environmental pollution. Therefore, the development of a process route of 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline which is environment-friendly, low in cost, high in yield and suitable for industrial production has good economic and social benefits.
Disclosure of Invention
The invention mainly provides a preparation method of a huperzine A intermediate 2-methoxy-6-glycol ketal-5, 7, 8-dihydroquinoline, 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-closing manner, the obtained product undergoes methylation reaction with methyl iodide, and finally removes methanesulfonyl under the action of magnesium metal to obtain a target product. Compared with the existing method, the preparation method has the advantages of safety, fewer steps, convenient operation, high yield and low cost.
The technical scheme of the invention is as follows:
the preparation method of the 2-methoxy-6-glycol ketal-5, 7, 8-trihydroquinoline comprises the following steps:
step 1: placing the compound 1 and DMF-DMA (N, N-dimethylformamide dimethyl acetal) in N, N-dimethylformamide, stirring at 70-90 ℃ for reaction, monitoring the reaction to be completed by TLC, and then evaporating the residual DMF-DMA and N, N-dimethylformamide under reduced pressure to obtain a compound 2;
the obtained compound 2 can be directly used for the next reaction without further purification;
step 2: adding the compound 2 and methanesulfonyl acetonitrile into absolute ethyl alcohol, stirring for reaction at 60-80 ℃, monitoring the reaction by TLC until the reaction is finished, and then carrying out post-treatment to obtain a compound 3;
the ratio of the amount of the compound 2 to the amount of the substance of the methanesulfonyl acetonitrile is 1:1.0-1:1.2;
the post-treatment method comprises the following steps: after the reaction is completed, naturally cooling to room temperature, separating out solids, filtering, washing a filter cake with cold (0-5 ℃) ethanol, and drying to obtain a compound 3;
step 3: adding the compound 3 and silver carbonate into dichloromethane, then adding methyl iodide, placing the mixture at 0-20 ℃ for light-proof reaction, monitoring the reaction by TLC until the reaction is completed, and then carrying out aftertreatment to obtain a compound 4;
the ratio of the amount of the compound 3 to the silver carbonate is 1:0.8-1:1.0;
the ratio of the amount of the compound 3 to the amount of the methyl iodide is 1:3-1:6;
the post-treatment method comprises the following steps: after the reaction is finished, filtering, washing a filter cake with dichloromethane, taking filtrate, decompressing, evaporating the solvent, and drying to obtain a compound 4;
step 4: mixing the compound 4 with magnesium metal, adding absolute methanol under the protection of nitrogen, heating to 40-60 ℃, stirring for reaction, monitoring the reaction by TLC until the reaction is completed, and then performing post-treatment to obtain a compound 5;
the ratio of the amount of the compound 4 to the amount of the metal magnesium is 1:3-1:6;
the post-treatment method comprises the following steps: after the reaction is completed, cooling to room temperature, dropwise adding 10% of dilute hydrochloric acid into the reaction liquid, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, and then decompressing, evaporating and drying the solvent to obtain a compound 5;
the synthetic route is as follows:
the beneficial effects of the invention are as follows: the invention provides a preparation method of huperzine A drug intermediate 2-methoxy-6-glycol ketal-5, 7, 8-trihydrogen quinoline, which 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.
Detailed Description
In order to clearly and fully describe the technical scheme of the invention, the following description will be made with reference to specific examples, and reagents involved in the invention are commercially available. The described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Synthesis of Compound 2:
1, 4-cyclohexanedione monoethylene ketal (Compound 1,23.4g,0.15 mol), N-dimethylformamide (150 mL) and N, N-dimethylformamide dimethyl acetal (26.8 g,0.225 mol) were sequentially added to a 500mL three-necked flask equipped with a condenser at room temperature. And (3) with uniform stirring, rapidly heating to 80 ℃, detecting the reaction progress by a TLC plate, and removing residual DMF-DMA (N, N-dimethylformamide dimethyl acetal) and N, N-dimethylformamide under reduced pressure after the reaction is finished to obtain the 2- ((dimethylamino) alkenyl) -1, 4-cyclohexanedione monoethylene glycol ketal (compound 2). The obtained compound 2 was used in the next reaction without further purification.
Synthesis of Compound 3:
at room temperature, compound 2 (0.15 mol, calculated according to the 100% conversion rate of the previous step), methanesulfonyl acetonitrile (19.6 g,0.165 mol) and 200mL of absolute ethyl alcohol obtained in the previous step are sequentially added into a 500mL three-port bottle provided with a reflux condenser, the mixture is rapidly heated to reflux, a TLC plate detects the reaction progress, after the reaction is completed, heating is stopped, the mixture is naturally cooled to room temperature, a large amount of solids are separated out at the moment, the solids are filtered, the filtered solids are washed with a small amount of cold ethyl alcohol (40 mL), and 25.1g of 2-carbonyl-3-methanesulfonyl-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline (compound 3) is obtained after drying, and the yield is 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:
compound 3 (28.5 g,0.1 mol), silver carbonate (22.1 g,0.08 mol) and methylene chloride (150 mL) were sequentially added to a 500mL reaction flask at room temperature, methyl iodide (85.2 g,0.6 mol) was then slowly added thereto, and the reaction was carried out at 20℃in the absence of light, and the TLC plate was used to detect the progress of the reaction. After the reaction is finished, filtering and washing the solid, decompressing the filtrate to remove redundant solvent, and drying to obtain 26.9g of 2-methoxy-3-methanesulfonyl-6-glycol ketal-5, 7, 8-trihydroquinoline (compound 4) with the yield of 90.2 percent.
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:
the compound 4 (20.9 g,0.0.07 mol) and magnesium metal (10.1 g,0.42 mol) obtained above were added into a reaction flask at room temperature, anhydrous methanol (150 mL) was added under nitrogen protection, the reaction progress was slowly warmed to 50 ℃, TLC plates were checked, after the reaction was completed, cooled to room temperature, then 10% of diluted hydrochloric acid was slowly added dropwise thereto, after the solid was completely dissolved, extraction was performed with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, and 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline (compound 5) 11.4g was obtained by drying, and the yield was 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 method for preparing 2-methoxy-6-glycol ketal-5, 7, 8-trihydroquinoline, which is characterized by comprising the following steps:
step 1: placing the compound 1 and DMF-DMA in N, N dimethylformamide, stirring at 70-90 ℃ for reaction, monitoring the reaction to be completed by TLC, and then decompressing and distilling off the residual DMF-DMA and N, N dimethylformamide to obtain a compound 2;
step 2: adding the compound 2 and methanesulfonyl acetonitrile into absolute ethyl alcohol, stirring for reaction at 60-80 ℃, monitoring the reaction by TLC until the reaction is finished, and then carrying out post-treatment to obtain a compound 3;
the ratio of the amount of the compound 2 to the amount of the substance of the methanesulfonyl acetonitrile is 1:1.0-1:1.2;
step 3: adding the compound 3 and silver carbonate into dichloromethane, then adding methyl iodide, placing the mixture at 0-20 ℃ for light-proof reaction, monitoring the reaction by TLC until the reaction is completed, and then carrying out aftertreatment to obtain a compound 4;
the ratio of the amount of the compound 3 to the silver carbonate is 1:0.8-1:1.0;
the ratio of the amount of the compound 3 to the amount of the methyl iodide is 1:3-1:6;
step 4: mixing the compound 4 with magnesium metal, adding absolute methanol under the protection of nitrogen, heating to 40-60 ℃, stirring for reaction, monitoring the reaction by TLC until the reaction is completed, and then performing post-treatment to obtain a compound 5;
the synthetic route is as follows:
2. the method for synthesizing 2-methoxy-6-ethyleneglycol ketal-5, 7, 8-dihydroquinoline according to claim 1 wherein in step 2, the post-treatment method comprises: and after the reaction is finished, naturally cooling to room temperature, separating out solids, filtering, washing a filter cake with cold ethanol, and drying to obtain the compound 3.
3. The method for synthesizing 2-methoxy-6-ethyleneglycol ketal-5, 7, 8-dihydroquinoline according to claim 1 wherein in step 3, the post-treatment method comprises: after the reaction is completed, filtering, washing a filter cake by using dichloromethane, taking filtrate, decompressing, evaporating the solvent, and drying to obtain the compound 4.
4. The method for synthesizing 2-methoxy-6-ethyleneglycol ketal-5, 7, 8-trihydroquinoline according to claim 1 wherein the ratio of the amount of the compound 4 to the amount of the magnesium metal in step 4 is 1:3 to 1:6.
5. The method for synthesizing 2-methoxy-6-ethyleneglycol ketal-5, 7, 8-dihydroquinoline according to claim 1 wherein in step 4, the post-treatment method comprises: after the reaction was completed, cooling to room temperature, dropwise adding 10% of diluted hydrochloric acid into the reaction solution, then extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and then evaporating the solvent under reduced pressure and drying to obtain compound 5.
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