CN114057642A - Synthetic method of mikui ammonium chloride intermediate - Google Patents
Synthetic method of mikui ammonium chloride intermediate Download PDFInfo
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- CN114057642A CN114057642A CN202111513745.4A CN202111513745A CN114057642A CN 114057642 A CN114057642 A CN 114057642A CN 202111513745 A CN202111513745 A CN 202111513745A CN 114057642 A CN114057642 A CN 114057642A
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- dimethoxyphenethylamine
- dimethoxyphenylethyl
- trimethoxyphenyl
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- 238000010189 synthetic method Methods 0.000 title claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 title abstract description 26
- 235000019270 ammonium chloride Nutrition 0.000 title abstract description 13
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 claims abstract description 62
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000001308 synthesis method Methods 0.000 claims abstract description 38
- DDSJXCGGOXKGSJ-UHFFFAOYSA-N 2-(3,4,5-trimethoxyphenyl)acetic acid Chemical compound COC1=CC(CC(O)=O)=CC(OC)=C1OC DDSJXCGGOXKGSJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 claims abstract description 26
- MMQNZPHFAPHRDA-UHFFFAOYSA-N 6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-3,4-dihydroisoquinoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN=C1CC1=CC(OC)=C(OC)C(OC)=C1 MMQNZPHFAPHRDA-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- -1 3-dimethylaminopropyl Chemical group 0.000 claims description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 45
- 238000000034 method Methods 0.000 abstract description 12
- 150000001408 amides Chemical class 0.000 abstract description 11
- 239000002994 raw material Substances 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000008901 benefit Effects 0.000 abstract description 9
- 238000010992 reflux Methods 0.000 abstract description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000006378 damage Effects 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- 239000005457 ice water Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000005516 benzylisoquinolines Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a method for synthesizing a mikui ammonium chloride intermediate 6, 7-dimethoxy-1- (3,4, 5-trimethoxy benzyl) -3, 4-dihydroisoquinoline, belonging to the technical field of organic synthesis; the technical scheme of the invention uses EDCI as a dehydrating agent to efficiently dehydrate 3,4, 5-trimethoxyphenylacetic acid and 3, 4-dimethoxyphenethylamine at 0-30 ℃, and then efficiently cyclize the prepared amide by trifluoromethanesulfonic anhydride and 2-fluoropyridine at 0-30 ℃ to obtain a product; the technical scheme provided by the invention reacts at 0-30 ℃, so that the damage of high-temperature reflux reaction to an unstable raw material 3, 4-dimethoxyphenethylamine can be avoided, and the high energy consumption and the threat to production safety of high-temperature reflux can also be avoided; meanwhile, the synthesis method has the advantages of few steps, simple operation, no need of complex equipment, high reaction yield, yield of each step of more than 90 percent, total yield of two steps of 91.2 percent, high purity of the prepared product, and high purity of 99.88 percent; therefore, it can be applied to actual industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a mikul ammonium chloride intermediate, wherein the mikul ammonium chloride intermediate is 6, 7-dimethoxy-1- (3,4, 5-trimethoxy benzyl) -3, 4-dihydroisoquinoline.
Background
Mickommonia belongs to benzylisoquinoline compounds, is a non-depolarizing muscle relaxant approved by the U.S. FDA to be marketed in 1992, is used for tracheal intubation and muscle relaxation maintenance due to the characteristics of short action time, no accumulation, quick recovery, no influence on cardiovascular system, intracranial pressure and intraocular pressure in clinical use and small histamine release effect, can be used for carrying out flexible blocking relaxation control on neuromuscular in an intravenous administration mode in operation, is very suitable for being used for carrying out anesthesia operation on children, and is subjected to more and more applications and attention, and the molecular formula of the mickommonia is shown as the following formula:
the key intermediate 5' -methoxy labdanine (I) for preparing mikui ammonium chloride is introduced in Chinese patent CN1203061C applied by original manufacturer of mikui ammonium chloride, Everra drug company, and is prepared by four-step reaction shown in the following formula, wherein the preparation of 6, 7-dimethoxy-1- (3,4, 5-trimethylbenzyl) -3, 4-dihydroisoquinoline (II) is the key step for synthesizing (I), and therefore, the synthesis method of 6, 7-dimethoxy-1- (3,4, 5-trimethylbenzyl) -3, 4-dihydroisoquinoline (II) is concerned.
The method of reflux dehydration of phosphorus oxychloride in toluene in patent CN107778233A is the same as the method described in patent CN1203061C, and the method of one pot boiling in patent CN103880744 is adopted, firstly, 3,4, 5-trimethoxyphenylacetic acid and 3, 4-dimethoxyphenethylamine are refluxed in xylene to prepare amide, then the amide is cooled to 80-85 ℃ and phosphorus oxychloride is dropped in, and then 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline is prepared by dehydration cyclization for the next step, and the preparation process is substantially the same as the method described in patent CN 1203061C; synthesis of 5 '-methoxylawsan element published in chemical reagents [ 2013,35(1),94-96 ] of shinxin, schumamine et al in the same manner as described in the text for the preparation of 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline and then for the preparation of 5' -methoxylawsan element; li xing of Zhejiang university of science and technology also uses the same method to prepare 6, 7-dimethoxy-1- (3,4, 5-trimethoxy benzyl) -3, 4-dihydroisoquinoline in the academic paper of 5' -methoxy labdane synthetic research of key intermediate of myotonin micu ammonium chloride.
The method for preparing 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline described in the above patents, papers and publications has certain advantages, but the defect is obvious, 3, 4-dimethoxyphenethylamine is an unstable compound, the unstable compound and 3,4, 5-trimethoxyphenylacetic acid are refluxed and dehydrated in dimethylbenzene to prepare amide, the amide is easily degraded and destroyed at the high temperature of 140 ℃ to generate impurities, phosphorus oxychloride is refluxed, dehydrated and cyclized in methylbenzene to prepare 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline, the reaction temperature is high, side reactions are likely to generate side products, the energy consumption of both steps is high, and phosphorus oxychloride can release hydrogen chloride gas in the reaction, the equipment is corroded, the environment is polluted, the used methylbenzene and dimethylbenzene belong to toxic and harmful flammable and explosive chemical raw materials, the methylbenzene belongs to an easily-prepared toxic solvent for limiting use, and the methylbenzene and the solvent are subjected to reflux reaction at high temperature, so that the requirements on explosion prevention and fire prevention are high, and safety production and environmental protection are not facilitated.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthetic method of mikui ammonium chloride intermediate 6, 7-dimethoxy-1- (3,4, 5-trimethoxy benzyl) -3, 4-dihydroisoquinoline, which is efficient, mild and environment-friendly.
In order to achieve the purpose, the invention adopts the technical scheme that: a synthetic method of mikaonium chloride intermediate, wherein the mikaonium chloride intermediate is 6, 7-dimethoxy-1- (3,4, 5-trimethoxy benzyl) -3, 4-dihydroisoquinoline, and the synthetic method comprises the following steps:
(1) dissolving 3,4, 5-trimethoxyphenylacetic acid and 3, 4-dimethoxyphenethylamine in an organic solvent, adding 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) as a dehydrating agent at 0-30 ℃, and carrying out dehydration reaction to obtain N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide;
(2) dissolving N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide in an organic solvent, adding trifluoromethanesulfonic anhydride and 2-fluoropyridine at 0-30 ℃, and carrying out cyclization reaction to obtain 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline.
According to the technical scheme, 1- (3-dimethylaminopropyl) -3- (ethyl carbodiimide hydrochloride) is used as a dehydrating agent, so that 3,4, 5-trimethoxyphenylacetic acid and 3, 4-dimethoxyphenethylamine can be efficiently dehydrated at 0-30 ℃, and the 3, 4-dimethoxyphenethylamine is prevented from being damaged and degraded at high temperature; then, the prepared amide is subjected to cyclization reaction by using trifluoromethanesulfonic anhydride and 2-fluoropyridine at 0-30 ℃, so that high-temperature reflux of toxic and harmful solvents is avoided; the two steps of the synthesis method provided by the technical scheme of the invention are reacted at 0-30 ℃, the operation is simple, the energy consumption is low, toxic and harmful solvents are avoided, and complex equipment is not needed.
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is 3,4, 5-trimethoxyphenylacetic acid: 3, 4-dimethoxyphenethylamine: 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) ═ 1 (1.0-1.2): (1.1-1.3).
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is 3,4, 5-trimethoxyphenylacetic acid: 3, 4-dimethoxyphenethylamine: 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) 1:1.05: 1.2.
when the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is within the above range, the yield of the reaction can be made high, especially when the molar ratio of the three is 1:1.05:1.2, the obtained yield is the best and the economic benefit is the best; if the amount of the 3, 4-dimethoxyphenethylamine and the 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is too small, the yield of the reaction is reduced, so that the reaction of the 3,4, 5-trimethoxyphenylacetic acid is incomplete, and if the amount of the 3, 4-dimethoxyphenethylamine and the 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is too large, on the one hand, economic benefits are reduced, and on the other hand, too many unreacted raw materials exist in the reaction, so that the difficulty of post-treatment is increased and the purity of the prepared product is possibly reduced.
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the organic solvent includes any one of ethyl acetate, N-dimethylformamide, dichloromethane, tetrahydrofuran, and acetone.
As a preferable embodiment of the synthesis method of the present invention, in the step (1), the organic solvent is N, N-dimethylformamide or dichloromethane.
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the dehydration reaction is carried out at 0 to 5 ℃ and then at 24 to 30 ℃.
As a preferred embodiment of the synthesis method of the invention, the reaction time is 25-35min at 0-5 ℃ and 1.5-2.5h at 24-30 ℃.
As a preferred embodiment of the synthesis method of the present invention, in the step (2), the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide: trifluoromethanesulfonic anhydride: 2-fluoropyridine ═ 1: (1.0-1.2): (1.0-1.2).
As a preferred embodiment of the synthesis method of the present invention, in the step (2), the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide: trifluoromethanesulfonic anhydride: 2-fluoropyridine ═ 1: 1.1: 1.1.
when the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is within the above range, the yield of the reaction can be made high, especially when the molar ratio of the three is 1: 1.1: 1.1, the obtained yield is the best and the economic benefit is the best; if the addition amounts of the trifluoromethanesulfonic anhydride and the 2-fluoropyridine are too small, the yield of the reaction is reduced, so that the reaction of the N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide is incomplete, and if the addition amounts of the trifluoromethanesulfonic anhydride and the 2-fluoropyridine are too large, on one hand, economic benefits are reduced, and on the other hand, too many unreacted raw materials exist in the reaction, so that the difficulty of aftertreatment is increased, and the purity of the prepared product can be reduced.
As a preferred embodiment of the synthesis method of the present invention, in the step (2), the organic solvent includes any one of ethyl acetate, N-dimethylformamide, dichloromethane, tetrahydrofuran, and acetone.
As a preferable embodiment of the synthesis method of the present invention, in the step (2), the organic solvent is N, N-dimethylformamide or dichloromethane.
As a preferred embodiment of the synthesis method of the present invention, in the step (2), the cyclization reaction is carried out at 0 to 5 ℃ and then at 24 to 30 ℃ at elevated temperature.
As a preferable embodiment of the synthesis method of the present invention, the reaction time at 0-5 ℃ is 1.5-2.5h, and the reaction time at 24-30 ℃ is 1.5-2.5 h.
In a preferred embodiment of the synthesis method of the present invention, in the step (2), purification is further performed after the end of the ring-closure reaction.
As a preferred embodiment of the synthesis method of the present invention, the purification is column chromatography, and the volume ratio of the eluent used for column chromatography is 2:98 of methanol/dichloromethane mixed solvent.
Compared with the prior art, the invention has the beneficial effects that:
firstly, the method comprises the following steps: the invention adopts 1- (3-dimethylaminopropyl) -3- (ethyl carbodiimide hydrochloride) as a dehydrating agent, so that 3,4, 5-trimethoxyphenylacetic acid and 3, 4-dimethoxyphenethylamine can be efficiently dehydrated within 1.5 to 3.0 hours at the temperature of between 0 and 30 ℃, and then the prepared amide is subjected to cyclization reaction by using trifluoromethanesulfonic anhydride and 2-fluoropyridine at the temperature of between 0 and 30 ℃ and can be efficiently cyclized within 3.0 to 4.5 hours;
secondly, the method comprises the following steps: the two steps of the synthesis method provided by the technical scheme of the invention are reacted at 0-30 ℃, so that on one hand, the damage of the high-temperature reflux reaction to the unstable raw material 3, 4-dimethoxyphenethylamine is avoided, and on the other hand, the high consumption of the high-temperature reflux to the energy source and the threat to the production safety are also avoided; meanwhile, the conventional phosphorus oxychloride and xylene or toluene are not adopted in the synthesis method, so that on one hand, the corrosion of hydrogen chloride gas released by decomposing the phosphorus oxychloride to equipment, the pollution to the environment and the harm to production personnel in the high-temperature reflux process are avoided, and on the other hand, the threats of toluene and xylene to safety production and environmental protection due to toxic and harmful, flammable and explosive solvents are also avoided;
thirdly, the method comprises the following steps: the synthesis method provided by the technical scheme of the invention has the advantages of few steps, simple operation and no need of complex equipment, and the synthesis method provided by the invention has high reaction yield, the yield of each step is more than 91%, the total yield of two steps can reach 91.2%, and the purity of the prepared product is high and can reach 99.88%; therefore, it can be applied to actual industrial production.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
The synthetic route for the micraconium chloride intermediate is shown in the above reaction scheme, and the compounds in the reaction are obtained by conventional purchase routes, except as otherwise indicated. Wherein, a compound shown as a formula IV, namely N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, is synthesized by taking a compound shown as a formula II, namely 3, 4-dimethoxyphenethylamine and a compound shown as a formula III, namely 3,4, 5-trimethoxyphenylacetic acid as raw materials under the condition of taking 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) (EDCI) as a dehydrating agent, and then the compound shown as the formula IV reacts with trifluoromethanesulfonic anhydride and 2-fluoropyridine to generate a compound shown as a formula I, namely mikulammonium chloride intermediate 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline.
Example 1
The synthesis method of mikui ammonium chloride intermediate 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline of the embodiment of the invention comprises the first step of reaction, wherein dichloromethane is used as a solvent, and the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is 1:1.05: 1.2; in the second step, dichloromethane is used as a solvent, and the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is 1: 1.1: 1.1; the total reaction yield is 91.20%; the specific synthesis method comprises the following steps:
(1) synthesis of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide:
weighing 3,4, 5-trimethoxyphenylacetic acid (2.26g, 10.00mmol) and 3, 4-dimethoxyphenethylamine (1.90g, 10.49mmol) in a 100-mL round-bottom flask with a stirrer, adding 50mL of dichloromethane, stirring and dissolving under cooling of an ice-water bath, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.30g, 12.00mmol), stirring in the ice-water bath for 30min, returning to room temperature, and continuing to react for 2 h; after completion of the TLC detection reaction of the starting material 3,4, 5-trimethoxyphenylacetic acid, the reaction solvent was removed by concentration under reduced pressure, and 100mL of ethyl acetate was added again to dissolve the reaction solvent, and the mixture was transferred to a 250 mL separating funnel and washed with 20mL of 1.0M dilute hydrochloric acid and 10mL of saturated brine in this order. The organic phase was dried over 5g of anhydrous sodium sulfate, filtered and spin-dried to obtain 3.74g of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide as a pale yellow solid target product in 96% yield;
nuclear magnetic characterization:1H NMR(500MHz,CDCl3):2.72-2.66(2H,m),3.50-3.42(m,4H),3.87-3.78(m,15H),5.65-5.45(m,1H),6.38(s,2H),6.53-6.49(d,J＝6.4Hz,1H),6.65(s,1H),6.76-6.70(m,1H)；13C NMR(100MHz,CDCl3):34.9,40.7,44.12,44.15,55.8(2C),56.1(2C),60.8,106.4(2C),111.2,111.7,120.6(2C),130.4,131.0,137.2,147.7,149.1,153.5,170.8；
(2) synthesis of 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline:
weighing the target product N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide (1.95g, 5mmol) in the step (1) and placing the target product in a 50mL dry round-bottom flask, adding 25mL of dry dichloromethane under the protection of nitrogen, stirring and dissolving the target product under the cooling of an ice-water bath, sequentially adding 2-fluoropyridine (0.47mL, 5.5mmol) and trifluoromethanesulfonic anhydride (0.93mL, 5.5mmol), reacting for 2h in the ice-water bath, recovering the temperature, continuing to react for 2h, detecting the reaction completion of a raw material amide by TLC, adding 5mL of saturated sodium bicarbonate to quench the reaction, extracting dichloromethane (30mL × 3), combining organic phases, adding 5mL of saturated common salt water to wash, adding 10g of anhydrous sodium sulfate to dry, filtering, concentrating the obtained filtrate under reduced pressure, and purifying the obtained filtrate by a column (eluent: methanol/dichloromethane ═ 2:98, V/V) to obtain 1.77g of a light yellow solid target product 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline, the yield is 95 percent, and the purity is 99.88 percent;
nuclear magnetic characterization:1H NMR(400MHz,CDCl3):2.71(2H,m),3.75(s,3H),3.78(m,2H),3.85(s,6H),3.88(s,3H),3.94(s,3H),6.78(s,1H),6.84(s,1H),6.86(s,1H)；13C NMR(100MHz,CDCl3):26.3,47.6,56.2,60.9,106.0,126.5,127.4,127.8,128.5,134.5,130.7,138.9,139.0,152.9,166.9。
example 2
The synthesis method of mikui ammonium chloride intermediate 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline of the embodiment of the invention comprises the first step of reaction, wherein N, N-dimethylformamide is used as a solvent, and the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is 1:1.05: 1.2; in the second step, dichloromethane is used as a solvent, and the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is 1: 1.1: 1.1; the total reaction yield is 88.35%; the specific synthesis method comprises the following steps:
(1) synthesis of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide:
weighing 3,4, 5-trimethoxyphenylacetic acid (226g, 1mol) and 3, 4-dimethoxyphenethylamine (190g, 1.05mol) in a 1L round-bottom flask with a stirrer, adding 500mL of N, N-dimethylformamide, stirring and dissolving under cooling of an ice-water bath, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (230g, 1.2mol), stirring in the ice-water bath for 30min, and returning to room temperature for continuous reaction; reacting for about 2-2.5h, detecting the reaction of the raw material 3,4, 5-trimethoxyphenylacetic acid by TLC (thin layer chromatography), cooling in an ice water bath, slowly dropwise adding the reaction solution into a plastic measuring cup containing prepared 2.5L1.0M diluted hydrochloric acid while stirring, separating out a large amount of solid in the stirring and dropwise adding process, performing vacuum filtration after dropwise adding, washing a filter cake with 200mL of water, and drying in a vacuum drying box at 60 ℃ for 12h to obtain 369.59g of a faint yellow solid target product N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, wherein the yield is 95%;
(2) synthesis of 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline:
weighing the target product N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide (195g, 0.50mol) in the step (1) and placing the target product in a 3-liter dry round-bottom flask, adding 2.5L of dry dichloromethane under the protection of nitrogen, stirring and dissolving the mixture under cooling of an ice water bath, sequentially adding 2-fluoropyridine (47mL, 0.55mol) and trifluoromethanesulfonic anhydride (93mL, 0.55mmol), reacting the mixture for 2h in the ice water bath, recovering the reaction temperature, continuing the reaction for 2-2.5h, detecting the reaction completion of a raw material amide by TLC, adding 200mL of saturated sodium bicarbonate to quench the reaction, extracting dichloromethane (1L × 3), combining organic phases, adding 500mL of saturated saline water to wash, adding 100g of anhydrous sodium sulfate to dry, filtering, concentrating the obtained filtrate under reduced pressure, and purifying the obtained filtrate by a column (eluent: methanol/dichloromethane ═ 2:98, V/V) to obtain 173g of a light yellow solid target product 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline, the yield is 93 percent, and the purity is 99.82 percent.
Example 3
The synthesis method of mikui ammonium chloride intermediate 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline of the embodiment of the invention comprises the first step of reaction, wherein dichloromethane is used as a solvent, and the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is 1: 1.0: 1.1; in the second step, dichloromethane is used as a solvent, and the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is 1: 1.2: 1.2; the total reaction yield is 84.63%; the specific synthesis method comprises the following steps:
(1) synthesis of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide:
weighing 3,4, 5-trimethoxyphenylacetic acid (2.26g, 10.00mmol) and 3, 4-dimethoxyphenethylamine (1.81g, 10.00mmol) in a 100-mL round-bottom flask with a stirrer, adding 50mL of dichloromethane, stirring and dissolving under cooling of an ice-water bath, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.11g, 11.00mmol), stirring in the ice-water bath for 30min, returning to room temperature, and continuing to react for 2 h; after completion of the TLC detection reaction of the starting material 3,4, 5-trimethoxyphenylacetic acid, the reaction solvent was removed by concentration under reduced pressure, and 100mL of ethyl acetate was added again to dissolve the reaction solvent, and the mixture was transferred to a 250 mL separating funnel and washed with 20mL of 1.0M dilute hydrochloric acid and 10mL of saturated brine in this order. The organic phase was dried over 5g of anhydrous sodium sulfate, filtered and spin-dried to obtain 3.54g of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide as a pale yellow solid target product in 91% yield;
(2) synthesis of 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline:
weighing the target product N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide (1.95g, 5mmol) in the step (1) and placing the target product in a 50mL dry round-bottom flask, adding 25mL of dry dichloromethane under the protection of nitrogen, stirring and dissolving the mixture under cooling of an ice-water bath, sequentially adding 2-fluoropyridine (0.52mL, 6.0mmol) and trifluoromethanesulfonic anhydride (1.02mL, 6.0mmol), reacting the mixture for 2 hours in the ice-water bath, recovering the mixture to room temperature, continuing to react for 2 hours, detecting the reaction completion of a raw material amide by TLC, adding 5mL of saturated sodium bicarbonate to quench the reaction, extracting dichloromethane (30mL × 3), combining organic phases, adding 5mL of saturated common salt water to wash, adding 10g of anhydrous sodium sulfate to dry, filtering, concentrating the obtained filtrate under reduced pressure, and purifying the obtained filtrate by a column (eluent: methanol/dichloromethane ═ 2:98, V/V) to obtain 1.73g of a light yellow solid target product 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline, the yield is 93 percent, and the purity is 99.79 percent.
Example 4
The synthesis method of mikui ammonium chloride intermediate 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline of the embodiment of the invention comprises the first step of reaction, wherein N, N-dimethylformamide is used as a solvent, and the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is 1: 1.2: 1.3; in the second step, dichloromethane is used as a solvent, and the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is 1: 1.0: 1.0; the total reaction yield is 84.60%; the specific synthesis method comprises the following steps:
(1) synthesis of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide:
weighing 3,4, 5-trimethoxyphenylacetic acid (2.26g, 10.00mmol) and 3, 4-dimethoxyphenethylamine (2.17g, 12.00mmol) in a 100-mL round-bottom flask with a stirrer, adding 50mL of dichloromethane, stirring and dissolving under cooling of an ice-water bath, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.49g, 13.00mmol), stirring in the ice-water bath for 30min, returning to room temperature, and continuing to react for 2 h; after completion of the TLC detection reaction of the starting material 3,4, 5-trimethoxyphenylacetic acid, the reaction solvent was removed by concentration under reduced pressure, and 100mL of ethyl acetate was added again to dissolve the reaction solvent, and the mixture was transferred to a 250 mL separating funnel and washed with 20mL of 1.0M dilute hydrochloric acid and 10mL of saturated brine in this order. The organic phase was dried over 5g of anhydrous sodium sulfate, filtered and spin-dried to obtain 3.66g of a pale yellow solid target product, N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, in 94% yield;
(2) synthesis of 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline:
weighing the target product N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide (1.95g, 5mmol) in the step (1) and placing the target product in a 50mL dry round-bottom flask, adding 25mL of dry dichloromethane under the protection of nitrogen, stirring and dissolving the target product under the cooling of an ice-water bath, sequentially adding 2-fluoropyridine (0.43mL, 5.0mmol) and trifluoromethanesulfonic anhydride (0.85mL, 5.0mmol), reacting for 2h in the ice-water bath, recovering the temperature, continuing to react for 2h, detecting the reaction completion of a raw material amide by TLC, adding 5mL of saturated sodium bicarbonate to quench the reaction, extracting dichloromethane (30mL × 3), combining organic phases, adding 5mL of saturated common salt water to wash, adding 10g of anhydrous sodium sulfate to dry, filtering, concentrating the obtained filtrate under reduced pressure, and purifying the obtained filtrate by a column (eluent: methanol/dichloromethane ═ 2:98, V/V) to obtain 1.67g of a light yellow solid target product 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline, the yield is 90 percent, and the purity is 99.84 percent.
It can be seen from the data of example 1 and example 2 that the technical scheme of the invention has good effect no matter on gram-grade or hectogram-grade products, the obtained yield is above 88%, and the purity is above 99.79%, further, the scheme provided by the invention can be used for scale-up production and is used in industry; as can be seen from the data of example 1 and examples 3 and 4, the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) in the first reaction step is optimized at 1:1.05:1.2, and the amounts of 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) added are increased, the yield of the reaction is not greatly influenced, but the economic benefit is reduced, the difficulty of the post-treatment is increased, the addition amount of the 3, 4-dimethoxyphenethylamine and the 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is reduced, and the yield is slightly reduced; in the second reaction step, the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is 1: 1.1: 1.1 is optimum, and similarly, increasing the amounts of trifluoromethanesulfonic anhydride and 2-fluoropyridine does not greatly affect the yield, but decreases the economic efficiency and increases the difficulty of the post-treatment, and decreasing the amounts of trifluoromethanesulfonic anhydride and 2-fluoropyridine also shows a tendency to slightly decrease the yield.
Finally, it should be noted that the above embodiments are intended to illustrate the technical solutions of the present invention and not to limit the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. A synthetic method of miichonium chloride intermediate, wherein the miichonium chloride intermediate is 6, 7-dimethoxy-1- (3,4, 5-trimethoxy benzyl) -3, 4-dihydroisoquinoline, and is characterized by comprising the following steps:
(1) dissolving 3,4, 5-trimethoxyphenylacetic acid and 3, 4-dimethoxyphenethylamine in an organic solvent, adding 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) as a dehydrating agent at 0-30 ℃, and carrying out dehydration reaction to obtain N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide;
(2) dissolving N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide in an organic solvent, adding trifluoromethanesulfonic anhydride and 2-fluoropyridine at 0-30 ℃, and carrying out cyclization reaction to obtain 6, 7-dimethoxy-1- (3,4, 5-trimethoxybenzyl) -3, 4-dihydroisoquinoline.
2. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of 3,4, 5-trimethoxyphenylacetic acid, 3, 4-dimethoxyphenethylamine and 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) is 3,4, 5-trimethoxyphenylacetic acid: 3, 4-dimethoxyphenethylamine: 1- (3-dimethylaminopropyl) -3- (ethylcarbodiimide hydrochloride) ═ 1 (1.0-1.2): (1.1-1.3).
3. The synthesis method according to claim 1, wherein in the step (1), the organic solvent comprises any one of ethyl acetate, N-dimethylformamide, dichloromethane, tetrahydrofuran and acetone.
4. The synthesis method according to claim 1, wherein in the step (1), the dehydration reaction is carried out at 0-5 ℃ and then at 24-30 ℃.
5. The synthesis method according to claim 4, wherein the reaction time at 0-5 ℃ is 25-35min, and the reaction time at 24-30 ℃ is 1.5-2.5 h.
6. The synthesis method according to claim 1, wherein in the step (2), the molar ratio of N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide, trifluoromethanesulfonic anhydride and 2-fluoropyridine is N- (3, 4-dimethoxyphenylethyl) -2- (3,4, 5-trimethoxyphenyl) acetamide: trifluoromethanesulfonic anhydride: 2-fluoropyridine ═ 1: (1.0-1.2): (1.0-1.2).
7. The synthesis method according to claim 1, wherein in the step (2), the organic solvent comprises any one of ethyl acetate, N-dimethylformamide, dichloromethane, tetrahydrofuran and acetone.
8. The synthesis method according to claim 1, wherein in the step (2), the cyclization reaction is carried out at 0-5 ℃ and then at 24-30 ℃ at a high temperature.
9. The synthesis method according to claim 8, wherein the reaction time at 0-5 ℃ is 1.5-2.5h, and the reaction time at 24-30 ℃ is 1.5-2.5 h.
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Denomination of invention: A synthetic method for intermediate of micuronium chloride Effective date of registration: 20231130 Granted publication date: 20230328 Pledgee: Industrial and Commercial Bank of China Co.,Ltd. Qingyuan Economic Development Zone Sub branch Pledgor: GUANGDONG JIABO PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980068637 |
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