CN114716449A - Preparation method of 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline - Google Patents
Preparation method of 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline Download PDFInfo
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- CN114716449A CN114716449A CN202210379302.9A CN202210379302A CN114716449A CN 114716449 A CN114716449 A CN 114716449A CN 202210379302 A CN202210379302 A CN 202210379302A CN 114716449 A CN114716449 A CN 114716449A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—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
- 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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- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline, which takes 1, 4-cyclohexanedione monoethylene glycol ketal as a starting material, reacts with N, N-dimethylformamide dimethyl acetal under the heating condition to obtain a ketoenamine product, then further performs a ring closing reaction with methylsulfonyl acetonitrile, performs a methylation reaction on the obtained product and methyl iodide, and finally removes methylsulfonyl under the action of metal magnesium 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-ethylene ketal-5, 7, 8-trihydroquinoline.
Background
Huperzine A (Huperzine A) is sold under the trade name Haberein, and has the chemical name: the (5R,9R,11E) -5-amino-11-ethylidene-5, 8,9, 10-tetrahydro-7-methyl-5, 9-methylene cyclooctatetra [ b ] pyridine-2- (1H) -ketone is a sesquiterpene alkaloid compound discovered and separated from the plant huperzia serrata by Chinese scientists in the eighties of the last century. Pharmacological research shows that huperzine A is a highly-efficient reversible acetylcholinesterase inhibitor, has the advantages of high selectivity, good fat solubility, long action time, easiness in passing through a blood brain barrier, high oral bioavailability, few adverse reactions and the like, can obviously improve the cognitive and behavioral functions of people, and enhances the learning and memory effects. Is widely applied to the treatment of myasthenia gravis and Alzheimer's disease at present.
The huperzine A raw material medicine sold in the market at present is almost completely extracted from medicinal plant huperzine serrate. The preparation method for extracting huperzine A from the medicinal plant huperzine serrate has fatal defects: (1) the growth cycle of the plant huperzine serrate is long, about 8-10 years, especially because of the characteristics of huperzine serrate, although scientists have carried out a lot of research, still can not realize artificial planting so far, so the huperzine serrate which is used for extracting huperzine A raw material medicine at present is all wild acquisition, the resource is increasingly deficient, which is one of the important factors for restricting the development of huperzine A as medicine; (2) the content of huperzine A in the huperzine serrate is extremely low; (3) the whole extraction process is complex and has long period; (4) the yield is low and the cost is high; (5) a large amount of organic solvent is used in the extraction process, so that the environmental pollution is easily caused. Therefore, the development of 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 reverse synthesis analysis of huperzine A is as follows:
from the retrosynthetic analysis of huperzine A, it is known that 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline (compound 5) is a key intermediate for preparing huperzine A. In recent years, there are several literature reports on the chemical synthesis of this key intermediate. In conclusion, the synthesis method reported in the literature has low yield and high cost, and is very easy to cause environmental pollution. Therefore, the development of a process route of the 2-methoxy-6-ethylene 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 an intermediate 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline of huperzine A, which takes 1, 4-cyclohexanedione monoethylene ketal as a starting material, reacts with N, N-dimethylformamide dimethyl acetal under the heating condition to obtain a ketoenamine product, then further performs a ring closing reaction with methylsulfonyl acetonitrile, performs a methylation reaction on the obtained product and methyl iodide, and finally removes methylsulfonyl under the action of magnesium metal to obtain a target product. Compared with the existing method, the preparation method has the advantages of safety, few steps, convenient operation, high yield and low cost.
The technical scheme of the invention is as follows:
a preparation method of 2-methoxy-6-ethylene 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 for reaction at 70-90 ℃, monitoring by TLC until the reaction is completed, 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 methylsulfonyl acetonitrile into absolute ethyl alcohol, stirring and reacting at 60-80 ℃, monitoring by TLC (thin layer chromatography) until the reaction is finished, and performing post-treatment to obtain a compound 3;
the mass ratio of the compound 2 to the methylsulfonyl acetonitrile is 1: 1.0-1: 1.2;
the post-treatment method comprises the following steps: after the reaction is finished, 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;
and step 3: adding the compound 3 and silver carbonate into dichloromethane, then adding methyl iodide, placing at 0-20 ℃ in a dark place for reaction, monitoring by TLC (thin layer chromatography) until the reaction is finished, and then carrying out aftertreatment to obtain a compound 4;
the mass ratio of the compound 3 to the silver carbonate is 1: 0.8-1: 1.0;
the mass ratio of the compound 3 to the methyl iodide is 1:3 to 1: 6;
the post-treatment method comprises the following steps: after the reaction is finished, filtering, washing a filter cake by using dichloromethane, taking filtrate, decompressing, steaming and removing a solvent, and drying to obtain a compound 4;
and 4, step 4: mixing the compound 4 with magnesium metal, adding anhydrous methanol under the protection of nitrogen, heating to 40-60 ℃, stirring for reaction, monitoring by TLC (thin layer chromatography) until the reaction is finished, and performing post-treatment to obtain a compound 5;
the mass ratio of the compound 4 to the metal magnesium is 1:3 to 1: 6;
the post-treatment method comprises the following steps: after the reaction is finished, cooling to room temperature, dropwise adding 10% dilute hydrochloric acid into the reaction solution, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, and then evaporating under reduced pressure to remove the solvent and drying to obtain a compound 5;
the synthetic route is as follows:
the invention has the beneficial effects that: the invention provides a preparation method of a huperzine A drug intermediate 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline, which has the advantages of fewer reaction steps, mild reaction conditions, higher yield, simple operation, convenient product refining, low production cost and suitability for industrial production.
Detailed Description
For a clear and complete description of the technical solution of the present invention, the following embodiments are given for clear and complete description, and the reagents involved in the present invention are commercially available. The described embodiments are only some, but not all embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Synthesis of Compound 2:
1, 4-cyclohexanedione monoethylene ketal (compound 1,23.4g,0.15mol), N-dimethylformamide (150mL) and N, N-dimethylformamide dimethyl acetal (26.8g,0.225mol) were added sequentially to a 500mL three-necked flask equipped with a condenser tube at room temperature. And (3) rapidly heating to 80 ℃ under uniform stirring, detecting the reaction process by a TLC plate, and after the reaction is finished, removing the residual DMF-DMA (N, N-dimethylformamide dimethyl acetal) and N, N-dimethylformamide under reduced pressure to obtain the 2- ((dimethylamino) methylene) -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:
and at room temperature, sequentially adding the compound 2(0.15mol, calculated according to the 100% conversion rate of the previous step), methylsulfonyl acetonitrile (19.6 g, 0.165mol) and 200mL of absolute ethyl alcohol into a 500mL three-necked bottle with a reflux condenser tube, rapidly heating to reflux, detecting the reaction process by a TLC plate, stopping heating after the reaction is finished, naturally cooling to room temperature, precipitating a large amount of solid at the moment, filtering the solid, washing with a small amount of cold ethyl alcohol (40mL), and drying to obtain 25.1g of 2-carbonyl-3-methylsulfonyl-6-ethylene ketal-5, 7, 8-trihydroquinoline (compound 3) with the yield of 58.7%.
The hydrogen spectrum of compound 3 is:1H NMR(CDCl3,600MHz):δ12.87(1H,s,NH),8.01(1H,s,CH),4.03(4H,m, 2×OCH2),3.27(3H,s,CH3),2.98(2H,t,J＝6.78Hz,CH2),2.77(2H,s,CH2),1.97(2H,t,J＝6.78Hz, CH2).
synthesis of Compound 4:
compound 3(28.5g,0.1mol), silver carbonate (22.1g,0.08mol) and methylene chloride (150mL) were sequentially added to a 500mL reaction flask at room temperature, methyl iodide (85.2g,0.6mol) was slowly added thereto, and the mixture was left to react at 20 ℃ in the dark, and the progress of the reaction was checked by TLC plate. After the reaction, the solid was filtered and washed, the filtrate was decompressed to remove the excess solvent, and dried to obtain 26.9g of 2-methoxy-3-methanesulfonyl-6-ethanediol ketal-5, 7, 8-trihydroquinoline (compound 4) with a yield of 90.2%.
The hydrogen spectrum of compound 4 is:1H NMR(CDCl3,600MHz):δ:7.89(1H,s,CH),4.06(3H,s,OCH3),4.03(4H, s,2×OCH2),3.18(3H,s,CH3),3.06(2H,t,J＝6.84Hz,CH2),2.94(2H,s,CH2),2.03(2H,t,J＝6.84Hz, CH2).
synthesis of Compound 5:
at room temperature, adding the obtained compound 4(20.9g,0.0.07mol) and magnesium metal (10.1g,0.42mol) into a reaction bottle, adding anhydrous methanol (150mL) under the protection of nitrogen, slowly heating to 50 ℃, detecting the reaction progress by a TLC plate, cooling to room temperature after the reaction is finished, then slowly dropwise adding 10% dilute hydrochloric acid into the mixture, extracting by ethyl acetate after the solid is completely dissolved, combining organic phases, drying by anhydrous sodium sulfate, and drying to obtain 11.4g of 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline (compound 5), wherein the yield is 73.6%.
The hydrogen spectrum of compound 5 is:1H NMR(CDCl3,600MHz):δ:7.23(1H,d,J＝8.34Hz,CH),6.581(1H,d,J＝ 8.34Hz,CH),4.03(4H,s,2×OCH2),3.88(3H,s,OCH3),3.01(2H,t,J＝6.78Hz,CH2),2.89(2H,s,CH2), 2.01((2H,t,J＝6.84Hz,CH2)。
Claims (8)
1. a preparation method of 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline is characterized by comprising the following steps:
step 1: placing the compound 1 and DMF-DMA in N, N dimethylformamide, stirring for reaction at 70-90 ℃, monitoring by TLC (thin layer chromatography) until the reaction is completed, and then distilling under reduced pressure to remove the residual DMF-DMA and N, N dimethylformamide to obtain a compound 2;
step 2: adding the compound 2 and methylsulfonyl acetonitrile into absolute ethyl alcohol, stirring and reacting at 60-80 ℃, monitoring by TLC (thin layer chromatography) until the reaction is completed, and performing post-treatment to obtain a compound 3;
and 3, step 3: adding the compound 3 and silver carbonate into dichloromethane, then adding methyl iodide, placing at 0-20 ℃ in a dark place for reaction, monitoring by TLC (thin layer chromatography) until the reaction is finished, and then carrying out aftertreatment to obtain a compound 4;
and 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 by TLC (thin layer chromatography) until the reaction is finished, and performing post-treatment to obtain a compound 5;
the synthetic route is as follows:
2. the method for synthesizing 2-methoxy-6-ethanediol ketal-5, 7, 8-trihydroquinoline according to claim 1, wherein in the step 2, the mass ratio of the compound 2 to the methanesulfonylacetonitrile is 1:1.0 to 1: 1.2.
3. The method for synthesizing 2-methoxy-6-ethanediol ketal-5, 7, 8-trihydroquinoline as claimed in claim 1, wherein the post-treatment in step 2 comprises: and after the reaction is finished, naturally cooling to room temperature, separating out a solid, filtering, washing a filter cake with cold ethanol, and drying to obtain the compound 3.
4. The method for synthesizing 2-methoxy-6-ethanediol ketal-5, 7, 8-trihydroquinoline according to claim 1, wherein in the step 3, the ratio of the amount of the compound 3 to the amount of the silver carbonate is 1:0.8 to 1: 1.0.
5. The method for synthesizing 2-methoxy-6-ethanediol ketal-5, 7, 8-trihydroquinoline according to claim 1, wherein in the step 3, the ratio of the amount of the compound 3 to the amount of the methyl iodide is 1:3 to 1: 6.
6. The method for synthesizing 2-methoxy-6-ethanediol ketal-5, 7, 8-trihydroquinoline as claimed in claim 1, wherein in the step 3, the post-treatment method comprises: and after the reaction is finished, filtering, washing a filter cake by using dichloromethane, taking a filtrate, decompressing, distilling to remove the solvent, and drying to obtain a compound 4.
7. The method for synthesizing 2-methoxy-6-ethanediol ketal-5, 7, 8-trihydroquinoline according to claim 1, wherein in the step 4, the ratio of the amount of the compound 4 to the amount of the metallic magnesium is 1:3 to 1: 6.
8. The method for synthesizing 2-methoxy-6-ethanediol ketal-5, 7, 8-trihydroquinoline as claimed in claim 1, wherein in the step 4, the post-treatment method comprises: after the reaction is finished, cooling to room temperature, dropwise adding 10% dilute hydrochloric acid into the reaction solution, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, and then evaporating under reduced pressure to remove the solvent and drying to obtain a compound 5.
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