CN104341345B - A kind of synthetic method of 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline - Google Patents
A kind of synthetic method of 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline Download PDFInfo
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- CN104341345B CN104341345B CN201410579839.5A CN201410579839A CN104341345B CN 104341345 B CN104341345 B CN 104341345B CN 201410579839 A CN201410579839 A CN 201410579839A CN 104341345 B CN104341345 B CN 104341345B
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- tetrahydroquinoline
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- methoxyl group
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- 0 C*1[C@@](C)C(CCC2(C3)OCCO2)C3[C@@](C)C(*)C1O Chemical compound C*1[C@@](C)C(CCC2(C3)OCCO2)C3[C@@](C)C(*)C1O 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Abstract
The invention discloses a kind of synthetic method of pharmaceutical intermediate 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline.The present invention for raw material, through 5 step reactions, generates important intermediate 2-methoxyl group-6-ketone-5,6,7, the 8-tetrahydroquinoline of Huperzine A with Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal.In present method building-up process, operational condition is gentle, can carry out iodine, be applied to suitability for industrialized production.
Description
Technical field
The present invention relates to the chemical synthesis process of tetrahydroquinoline derivative, be specifically related to a kind of synthetic method of 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline.
Background technology
Huperzine A is by a kind of alkaloid extracted in Huperziaceae plant Herba Lycopodii serrati Huperzinaserrata (Thumb.) Trev, is a potent Pseudocholinesterase reversible inhibitor.Have multi-medicament purposes, comprise anti-inflammatory, reducing blood-fat etc. are medicinal.
Recently, provide protection is had at clinical middle discovery selagine to cranial nerve degeneration.In the pathology of alzheimer's disease, acetylcholinesterase plays a part very important.The medicine of known alzheimer's disease, such as tacrine, lycoremine, donepezil hydrochloride tablet etc. are all acetylcholinesterase depressant.Clinical trial certificate, Huperzine A has more good therapeutic action and less side effect.A kind of method developing good this compound of synthesis has market future widely.
Summary of the invention
The object of the invention is to, a kind of synthetic method of 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline is provided.
The present invention is as follows for solving the problems of the technologies described above adopted technical scheme:
The invention discloses a kind of synthetic method of 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline, this synthetic method is:
Concrete synthesis step is:
Step 1, compound 1 and DMF dimethylacetal add in DMF solution, reacting generating compound 2;
Step 2, aforesaid compound 2 and benzene sulfonyl acetonitrile add in ethanolic soln, heating reflux reaction, obtained compound 3;
Step 3, aforesaid compound 3 and V-Brite B add in the mixed solution of DMF and water, reacting generating compound 4;
Step 4, aforesaid compound 4 in the basic conditions, utilizes benzyltriethylammoinium chloride and silver carbonate, generates compound 5 with iodomethane reaction;
Step 5, aforesaid compound 5 sloughs ethylene glycol protection in acid condition, obtains target product compound 6.
Further, after reacting completely in described step 1, removal of solvent under reduced pressure and remaining DMF dimethylacetal obtain compound 2, and this compound can directly apply to the reaction of step 2 without purifying.
Further, in described step 1, the mol ratio of DMF dimethylacetal and compound 1 is 1.5:1 ~ 3:1, and temperature of reaction is 60 ~ 80 DEG C.
Further, in described step 2, the mol ratio of benzene sulfonyl acetonitrile and compound 2 is 1:1 ~ 1.2:1.
Further, in described step 3 DMF and water mixed solution in, the mass ratio of DMF and water is 2:1 ~ 4:1.
Further, in described step 3, the mol ratio of V-Brite B and compound 3 is 1.5:1 ~ 3:1, and temperature of reaction is 70 ~ 85 DEG C.
Further, in described step 3, V-Brite B divides 2 ~ 4 times to add in reaction solution.
Further, the process of described step 4 is: the sodium hydroxide solution of compound 4,1mol/L, benzyltriethylammoinium chloride are added respectively in dichloromethane solution, then under condition of ice bath, silver carbonate is added, slowly drip methyl iodide again, in dropping process, solution temperature is no more than 20 DEG C, and the mol ratio of described compound 4, sodium hydroxide, benzyltriethylammoinium chloride, silver carbonate, methyl iodide is 1:1:0.5:1:2.Described benzyltriethylammoinium chloride is phase-transfer catalyst.
Further, the process of described step 5 is: be added to the water by the phosphoric acid of compound 5 and 85%, 70 ~ 85 DEG C of reactions, having reacted rear adjust ph is 3.5 ~ 4.5, and dichloromethane extraction, concentrate drying obtains compound 6.
Compared with prior art, beneficial effect of the present invention is as follows:
1, invention herein provides a kind of easy synthetic method of important intermediate 2-methoxyl group-6-ketone-5,6,7, the 8-tetrahydroquinoline of Huperzine A.
2, in the present invention, with Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal for raw material, through 5 step reactions, synthesize important intermediate 2-methoxyl group-6-ketone-5,6,7, the 8-tetrahydroquinoline of Huperzine A.In present method building-up process, operational condition is gentle, can carry out iodine, be applied to suitability for industrialized production.
Embodiment
Below by way of specific embodiment, technical scheme of the present invention is described.Raw material used in the present invention and reagent are all commercially.
One, the synthesis of compound 2
In the present invention, the chemical name of compound 2 is: 2-(2-dimethylin vinyl)-4-ethylene ketal pentylcyclohexanone; The chemical name of the starting compound 1 of synthetic compound 2 is: Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal, and the reaction formula of synthetic compound 2 is as follows:
The concrete preparation process of compound 2 is: be furnished with in the 3L there-necked flask of prolong at one, add Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal (250g, 1.6mol) respectively, DMF (the N of 1L, dinethylformamide) and DMADMF (DMF dimethylacetal) (360g, 3.0mol), be warmed up to 70 DEG C of stirring reactions, TLC detection reaction process, reacts completely for 2 hours, stops heating.Removal of solvent under reduced pressure and remaining DMADMF, the liquid obtained is 2-(2-dimethylin vinyl)-4-ethylene ketal pentylcyclohexanone (compound 2).The compound 2 obtained without further purifying, can be directly used in next step reaction.
Two, the synthesis of compound 3
In the present invention, the chemical name of compound 3 is: 2-ketone-3-benzenesulfonyl-6-ethylene ketal-5,6,7,8-tetrahydroquinoline, and its chemical equation is as follows:
The concrete preparation process of compound 3 is: in the there-necked flask of a 2L, adds compound 2 (211g, 1mol) obtained in the previous step, benzene sulfonyl acetonitrile (181g, 1mol) respectively, and the chemical structural formula of this benzene sulfonyl acetonitrile is: C
6h
5sO
2cH
2cN.And then add ethanol 500L, mix reflux condensing tube heating reflux reaction.TLC detection reaction process, reacts and reacts completely after 1 hour, stops heating, naturally cooling, now has a large amount of solids to separate out.Filter this solid, use a small amount of washing with alcohol, dry, white solid 2-ketone-3-benzenesulfonyl-6-ethylene ketal-5,6,7,8-tetrahydroquinoline (compound 3) 185g (productive rate 53.3%) can be obtained.
Three, the synthesis of compound 4
In the present invention, the chemical name of compound 4 is: 2-ketone-6-ethylene ketal-5,6,7,8-tetrahydroquinoline, and its chemical equation is as follows:
The concrete preparation process of compound 4 is: in the there-necked flask of a 2L, adds the water of DMF and 200ml of 600g, turn on agitator, then adds compound 3 (173.5g, 0.5mol), adds V-Brite B Na
2s
2o
4(261g, 1.5mol), this V-Brite B can add in reaction process in batches, and reaction solution is heated to 80 DEG C of reactions, TLC detection reaction process, reacts after 5 hours and terminates.Stop heating, naturally cooling.Filter, collect filter cake, use toluene respectively, water washing is dry, obtains gray solid 2-ketone-6-ethylene ketal-5,6,7,8-tetrahydroquinoline (compound 4) 65g (productive rate 63%).1H-NMR (the CDCl of compound 4
3) δ 1.90 (2H, t), δ 2.67 (2H, s), δ 2.90 (2H, t), δ 3.98 (4H, s), δ 6.35 (1H, d), δ 7.12 (1H, d).
Four, the synthesis of compound 5
In the present invention, the chemical name of compound 5 is: 2-methoxyl group-6-ethylene ketal-5,6,7,8-tetrahydroquinoline, and its chemical equation is as follows:
The concrete preparation process of compound 5 is: in the flask of a 1L, add compound 4 (41.4g, 0.2mol) respectively, 1N sodium hydroxide solution 200mL, phase-transfer catalyst benzyltriethylammoinium chloride (22.8g, 0.1mol) and 200mL methylene dichloride.Ice bath cooling and stirring, then adds silver carbonate (55.4g, 0.2mol).Slow dropping methyl iodide (56.8g, 0.4mol), dropping temperature is no more than 20 DEG C.Dropwise rear continuation to react at 20 DEG C, TLC detection reaction process, react end in 6 hours.Filter, by the dichloromethane extraction of filtrate 1L, extract 3 times, add anhydrous sodium sulfate drying.Concentrating under reduced pressure, except desolventizing, obtains gray solid 2-methoxyl group-6-ethylene ketal-5,6,7,8-tetrahydroquinoline (compound 5) 38g productive rate 85.9%).1H-NMR (the CDCl of compound 5
3) δ 2.01 (2H, t), δ 2.90 (2H, s), δ 3.00 (2H, t), δ 3.89 (3H, s), δ 4.04 (4H, s), δ 6.52 (1H, d), δ 7.25 (1H, d).
Five, the synthesis of compound 6
In the present invention, the chemical name of compound 6 is: 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline, and its chemical equation is as follows:
The concrete preparation process of compound 6 is: in the flask of a 1L, add the water of 400ml, the phosphoric acid of 200g85%, with the 2-methoxyl group-6-ethylene ketal-5,6,7 of 30g, 8-tetrahydroquinoline (compound 5), be stirred and heated to 80 DEG C of reactions, TLC detection reaction process, react after 1 hour and stop heating.Reaction solution adopts sodium carbonate solution adjust pH to 4, then uses the dichloromethane extraction of 1L, extracts 3 times.Extraction liquid is through anhydrous sodium sulfate drying, and removal of solvent under reduced pressure, obtains 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline (compound 6) 22g, (productive rate 91.5%).1H-NMR (the CDCl of compound 6
3) δ 2.65 (2H, t), δ 3.15 (2H, t), δ 3.51 (2H, s), δ 3.93 (3H, s), δ 6.61 (1H, d), δ 7.31 (1H, d).
Above are only part preferred embodiment of the present invention, the present invention is not limited in the content of embodiment.To those skilled in the art, can have various change and change in the concept of technical solution of the present invention, any change done and change, all within scope.
Claims (9)
1. the synthetic method of 2-methoxyl group-6-ketone-5,6,7, a 8-tetrahydroquinoline, this synthetic method is:
Concrete synthesis step is:
Step 1, compound 1 and DMF dimethylacetal add in DMF solution, reacting generating compound 2;
Step 2, aforesaid compound 2 and benzene sulfonyl acetonitrile add in ethanolic soln, heating reflux reaction, obtained compound 3;
Step 3, aforesaid compound 3 and V-Brite B add in the mixed solution of DMF and water, reacting generating compound 4;
Step 4, aforesaid compound 4 in the basic conditions, utilizes benzyltriethylammoinium chloride and silver carbonate, generates compound 5 with iodomethane reaction;
Step 5, aforesaid compound 5 sloughs ethylene glycol protection in acid condition, obtains target product compound 6.
2. 2-methoxyl group-6-ketone-5 as claimed in claim 1,6,7, the synthetic method of 8-tetrahydroquinoline, it is characterized in that: after reacting completely in described step 1, removal of solvent under reduced pressure and remaining DMF dimethylacetal obtain compound 2, directly apply to the reaction of step 2 without purifying.
3. 2-methoxyl group-6-ketone-5,6,7 as claimed in claim 1 or 2, the synthetic method of 8-tetrahydroquinoline, is characterized in that: in described step 1, N, the mol ratio of dinethylformamide dimethylacetal and compound 1 is 1.5:1 ~ 3:1, and temperature of reaction is 60 ~ 80 DEG C.
4. the synthetic method of 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline as claimed in claim 1, it is characterized in that: in described step 2, the mol ratio of benzene sulfonyl acetonitrile and compound 2 is 1:1 ~ 1.2:1.
5. the synthetic method of 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline as claimed in claim 1, is characterized in that: in described step 3 DMF and water mixed solution in, the mass ratio of DMF and water is 2:1 ~ 4:1.
6. the synthetic method of 2-methoxyl group-6-ketone-5,6,7, the 8-tetrahydroquinoline as described in claim 1 or 5, is characterized in that: in described step 3, the mol ratio of V-Brite B and compound 3 is 1.5:1 ~ 3:1, and temperature of reaction is 70 ~ 85 DEG C.
7. the synthetic method of 2-methoxyl group-6-ketone-5,6,7,8-tetrahydroquinoline as claimed in claim 1, is characterized in that: in described step 3, V-Brite B divides 2 ~ 4 times to add in reaction solution.
8. 2-methoxyl group-6-ketone-5 as claimed in claim 1,6,7, the synthetic method of 8-tetrahydroquinoline, it is characterized in that, the process of described step 4 is: the sodium hydroxide solution of compound 4,1mol/L, benzyltriethylammoinium chloride are added respectively in methylene dichloride, then under condition of ice bath, silver carbonate is added, slowly drip methyl iodide again, in dropping process, solution temperature is no more than 20 DEG C, and the mol ratio of described compound 4, sodium hydroxide, benzyltriethylammoinium chloride, silver carbonate, methyl iodide is 1:1:0.5:1:2.
9. 2-methoxyl group-6-ketone-5 as claimed in claim 1,6,7, the synthetic method of 8-tetrahydroquinoline, is characterized in that, the process of described step 5 is: be added to the water by the phosphoric acid of compound 5 and 85%, 70 ~ 85 DEG C of reactions, having reacted rear adjust ph is 3.5 ~ 4.5, and dichloromethane extraction, concentrate drying obtains compound 6.
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| CN114213327A (en) * | 2021-12-06 | 2022-03-22 | 杭州易合生物医药科技有限公司 | Synthesis method of (-) -huperzine A |
| CN114716449B (en) * | 2022-04-12 | 2023-09-29 | 浙江工业大学 | Preparation method of 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline |
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