CN105601496A - Preparation method of 3,4-dimethoxy phenylpropionic acid - Google Patents
Preparation method of 3,4-dimethoxy phenylpropionic acid Download PDFInfo
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- cinnamic acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- KWOMNGWHOBWKBP-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)propanoic acid Chemical compound COC1=CC=C(C(C)C(O)=O)C=C1OC KWOMNGWHOBWKBP-UHFFFAOYSA-N 0.000 title abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 42
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 68
- 239000000243 solution Substances 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 26
- 229910052708 sodium Inorganic materials 0.000 claims description 23
- 239000011734 sodium Substances 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 22
- SUFLQJBENWTBOL-UHFFFAOYSA-N ethyl 3-(3,4-dimethoxyphenyl)prop-2-enoate Chemical compound CCOC(=O)C=CC1=CC=C(OC)C(OC)=C1 SUFLQJBENWTBOL-UHFFFAOYSA-N 0.000 claims description 19
- LHHKQWQTBCTDQM-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)propanoic acid Chemical compound COC1=CC=C(CCC(O)=O)C=C1OC LHHKQWQTBCTDQM-UHFFFAOYSA-N 0.000 claims description 18
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- -1 sodium alkoxide Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- HJBWJAPEBGSQPR-GQCTYLIASA-N 3,4-dimethoxycinnamic acid Chemical compound COC1=CC=C(\C=C\C(O)=O)C=C1OC HJBWJAPEBGSQPR-GQCTYLIASA-N 0.000 claims description 7
- HJBWJAPEBGSQPR-UHFFFAOYSA-N DMCA Natural products COC1=CC=C(C=CC(O)=O)C=C1OC HJBWJAPEBGSQPR-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000012545 processing Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 238000012805 post-processing Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 3
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 abstract description 2
- 229960003135 donepezil hydrochloride Drugs 0.000 abstract description 2
- KBEBGUQPQBELIU-UHFFFAOYSA-N cinnamic acid ethyl ester Natural products CCOC(=O)C=CC1=CC=CC=C1 KBEBGUQPQBELIU-UHFFFAOYSA-N 0.000 abstract 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000010446 mirabilite Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis and in particular relates to a preparation method of a donepezil hydrochloride key intermediate 3,4-dimethoxy phenylpropionic acid. The method comprises the following steps: taking 3,4-dimethoxybenzaldehyde as a raw material to react with ethyl acetate under the action of sodium ethoxide to obtain an intermediate 3,4-dimethoxy ethyl cinnamate; hydrolyzing the 3,4-dimethoxy ethyl cinnamate under an alkaline condition, and carrying out hydrogenation reduction to obtain the 3,4-dimethoxy phenylpropionic acid. The preparation method provided by the invention has the advantages of environmental friendliness, high product purity, high yield and low raw material cost and the like.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of donepezil hydrochloride key intermediate 3, the preparation method of 4-dimethoxy benzenpropanoic acid.
Background technology
Doneppezil Hydrochloride is simultaneously by the medicine for light, moderate AD (Alzheimer disease) symptomatic treatment of U.S. FDA and Britain MCA approval listing, chemical name is 2, two hydroxyl-5 of 3-, 6-bi-methoxy-2-{1-(benzyl)-4-piperidino methyl }-1H-1-Indanone hydrochloride. AD is a kind of taking hypomnesia as main manifestations, with the acquired hypophrenia of other Cognitive function damages. Doneppezil Hydrochloride is second generation anticholinesterase, and its therapeutic action is that the acetyl courage acyl that reversibly acetylcholine esterase inhibition causes is hydrolyzed and the acetyl choline content of increase receptor site.
The key intermediate that 3,4-dimethoxy benzenpropanoic acid is Doneppezil Hydrochloride, document has several synthetic methods: all with 3,4-dimethoxy benzaldehyde is raw material, carry out condensation with malonic acid or diethyl malonate, dehydration is reset and is obtained 3,4-dimethoxy-cinnamic acid ethyl ester; 3,4-dimethoxy-cinnamic acid ethyl ester is hydrolyzed and obtains 3,4-dimethoxy-cinnamic acid under alkali condition, and hydrogenating reduction obtains 3,4-dimethoxy benzenpropanoic acid. Wherein, can use pyridine and piperidines as catalyst in course of reaction a, reaction and last handling process all can have very smelly smell, are unfavorable for producing and post processing. Huaqiao University once celebrated friend wait deliver 3, the synthetic method of 4-dimethoxy-cinnamic acid ethyl ester, taking L-PROLINE/potassium phosphate as catalyst, obtain 3,4-dimethoxy benzenpropanoic acid yield 70% left and right is on the low side. The reaction equation of general preparation 3,4-dimethoxy benzenpropanoic acid is as follows:
。
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides a kind of preparation method of 3,4-dimethoxy benzenpropanoic acid. The method has adopted ethyl acetate to replace malonic acid or diethyl malonate, reacts taking alcohol sodium solution as alkali, obtains new intermediate 3,4-dimethoxy-cinnamic acid ethyl ester; Under 3,4-dimethoxy-cinnamic acid ethyl ester alkali condition, hydrolysis obtains 3,4-dimethoxy-cinnamic acid, obtains target product 3,4-dimethoxy benzenpropanoic acid by hydrogenating reduction. This synthetic method has been removed the catalyst of the foul smelling smell such as pyridine and piperidines in reaction in the past, greatly reduces the pollution level to environment, simple to operate, do not need special production equipment, is easy to suitability for industrialized production.
The present invention is achieved through the following technical solutions:
A kind of preparation method of 3,4-dimethoxy benzenpropanoic acid, comprises the steps: taking Veratraldehyde as raw material, under caustic alcohol effect and acetic acid ethyl reaction, obtains intermediate 3,4-dimethoxy-cinnamic acid ethyl ester; Under 3,4-dimethoxy-cinnamic acid ethyl ester alkali condition, hydrolysis obtains 3,4-dimethoxy-cinnamic acid, and repeated hydrogenation reduction obtains 3,4-dimethoxy benzenpropanoic acid. Synthetic route is as follows:
。
Above-mentioned 3, in the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, described sodium alkoxide/alcohol sodium solution is the one in sodium methoxide solid, caustic alcohol solid, the methanol solution of sodium methoxide or the ethanolic solution of caustic alcohol.
Preferably, above-mentioned 3, in the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, described sodium alkoxide/alcohol sodium solution is alcohol sodium alcohol solution, described 3, the weight ratio of 4-dimethoxy benzaldehyde and alcohol sodium alcohol solution is 1:2.4-3.7, and the mass percent concentration of described alcohol sodium alcohol solution is 15 ~ 25%.
Above-mentioned 3, in the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, described Veratraldehyde and the weight ratio of ethyl acetate are 1:5-10.
Above-mentioned 3, in the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, described Veratraldehyde and acetic acid ethyl reaction temperature are 50-75 DEG C, and the reaction time is 2-5 hour.
Above-mentioned 3, in the preparation method of 4-dimethoxy benzenpropanoic acid, described 3, after the hydrolysis of 4-dimethoxy-cinnamic acid ethyl ester, repeated hydrogenation reduction reaction, step comprises: 3,4-dimethoxy-cinnamic acid ethyl ester first and sodium hydroxide solution is hydrolyzed after mixing; Be solvent catalysis hydrogenating reduction with alcohol again, be heated to pressurize reaction 10-18 hour under 30-45 DEG C of condition, react complete processing and obtain 3,4-dimethoxy benzenpropanoic acid.
Above-mentioned 3, in the preparation method of 4-dimethoxy benzenpropanoic acid, described alkali condition is one or both of NaOH, its aqueous solution of potassium hydroxide; Described alkali is 20% sodium hydrate aqueous solution.
Above-mentioned 3, in the preparation method of 4-dimethoxy benzenpropanoic acid, described alcohol is one or both in methyl alcohol, ethanol; Described catalyst is palladium charcoal, and described palladium charcoal palladium content is 5% or 10%.
Preferably, above-mentioned 3, in the preparation method of 4-dimethoxy benzenpropanoic acid, described alcohol is ethanol, described 3, and the weight ratio of 4-dimethoxy-cinnamic acid ethyl ester and ethanol is 1:3-8.
Preferably, above-mentioned 3, in the preparation method of 4-dimethoxy benzenpropanoic acid, described palladium charcoal is 5% palladium charcoal, described 3, and the weight ratio of 4-dimethoxy-cinnamic acid ethyl ester and 5% palladium charcoal is 1:0.008-0.012, described catalyst 5% palladium charcoal is finished using, and filtration treatment, can apply mechanically more than 10 times.
Above-mentioned 3, in the preparation method of 4-dimethoxy benzenpropanoic acid, use acetic acid ethyl dissolution Veratraldehyde, add alcohol sodium alcohol solution insulation reaction, post processing obtains 3,4-dimethoxy-cinnamic acid ethyl ester. 3,4-dimethoxy-cinnamic acid ethyl ester is with after 20% sodium hydrate aqueous solution hydrolysis, taking ethanol as solvent by 5% palladium charcoal catalytic reaction; React complete filtration; Filtrate processing obtains 3,4-dimethoxy benzenpropanoic acid. The palladium charcoal that filtration obtains washs with ethanol, can apply mechanically more than 10 times.
Preferably, of the present invention 3, the preparation method of 4-dimethoxy benzenpropanoic acid, comprises the steps:
(1) in reaction bulb, add ethyl acetate and Veratraldehyde stirring and dissolving, drip 20% alcohol sodium alcohol solution in 15 ~ 35 DEG C. Mixture slowly heats up in 50 ~ 75 DEG C of reactions 2 ~ 5 hours, and thin layer monitoring raw material reaction is complete, solution be cooled to 10 ~ 30 DEG C with hydrochloric acid adjust pH to neutral. Separatory, dry with glauber salt after the water washing of organic layer use saturated common salt, filtration, concentrated 3, the 4-dimethoxy-cinnamic acid ethyl ester that obtains.
(2) sodium hydroxide solution is added in reaction bulb, add 3,4-dimethoxy-cinnamic acid ethyl ester to react; After hydrolysis, obtain 3,4-dimethoxy-cinnamic acid, adds in autoclave after dissolving with ethanol, then adds palladium catalyst charcoal, after nitrogen replacement, 10 ~ 20 kilograms of logical hydrogen, in 30 ~ 45 DEG C of pressurizes 10 ~ 18 hours, are inhaled and are removed by filter palladium charcoal after hydrogen and wait to apply mechanically; After filtrate decompression is concentrated, use deionized water crystallization, filtering drying to obtain 3,4-dimethoxy benzenpropanoic acid.
Beneficial effect of the present invention is:
(1) of the present invention 3, in the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, adopt ethyl acetate to replace malonic acid or diethyl malonate, react taking alcohol sodium solution as alkali, obtain 3,4-dimethoxy-cinnamic acid ethyl ester, has avoided the use of the catalyst of the foul smelling smell such as pyridine and piperidines in reaction, has reduced the pollution of environment.
(2) of the present invention 3, in the preparation method of 4-dimethoxy benzenpropanoic acid, after adopting the hydrolysis of 3,4-dimethoxy-cinnamic acid ethyl ester, then be that solvent obtains 3,4-dimethoxy benzenpropanoic acid by hydrogenating reduction with ethanol; Solvent for use is that ethanol is conducive to the recovery of solvent and applies mechanically; Environmentally friendly, reduce the use of solvent and saved cost of material, be conducive to suitability for industrialized production.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further described, so that those skilled in the art more understands the present invention, but does not therefore limit the present invention.
In the present invention, the concentration of concentrated hydrochloric acid used is 35 ~ 37%.
Embodiment 1
In 3L reaction bulb, add ethyl acetate 1200g, under stirring, add Veratraldehyde 166g; After dissolving, drip 15% alcohol sodium alcohol solution 640g in 15 ~ 20 DEG C. After dropwising, solution slowly heats up in 50 ~ 55 DEG C of reactions 5 hours, and thin layer monitoring raw material reaction is complete, solution be cooled to 15 ~ 20 DEG C with concentrated hydrochloric acid 150g adjust pH to neutral. Separatory, water layer extracts once with 100g ethyl acetate again, merges organic layer saturated aqueous common salt 300g and washs once; Organic phase is dry with glauber salt, filters, concentrates crystallization and obtain 212g off-white color 3,4-dimethoxy-cinnamic acid ethyl ester. Molar yield 89.8%, liquid phase purity is more than 98.5%.
20% sodium hydrate aqueous solution 150g is added in reaction bulb, then add 118g3, after 4-dimethoxy-cinnamic acid ethyl ester is uniformly mixed, heat up in 60 DEG C of reaction hydrolysis 2 hours; Reacting complete is down to 20 ~ 25 DEG C and is adjusted to neutrality with 90g concentrated hydrochloric acid; Ethyl acetate 100g*2 extraction for solution, dry after merging organic layer. Filtration, concentrated 3, the 4-dimethoxy-cinnamic acid that obtains, by 450g ethanol stirring and dissolving. Ethanolic solution is added in 1L autoclave, then add in 5% palladium charcoal 1.2g to 20g ethanol, nitrogen replacement 3 times, 10 ~ 15 kilograms of logical hydrogen were in 30 ~ 35 DEG C of pressurizes 16 hours. Nitrogen replacement after suction hydrogen, removes by filter palladium charcoal and waits to apply mechanically; Solution decompression is concentrated, the concentrated complete 360g deionized water that adds, and stirring is cooled to 0 ~ 5 DEG C and filters to obtain wet product 108g. Dry 20 ~ 24 hours to obtain off-white color 3,4-dimethoxy benzenpropanoic acid 96.6g for 60 ~ 70 DEG C; Molar yield 92.0%, liquid phase purity 99.62%.
Embodiment 2
In 3L reaction bulb, add ethyl acetate 1200g, under stirring, add Veratraldehyde 166g; After dissolving, drip 20% alcohol sodium alcohol solution 510g in 25 ~ 30 DEG C. After dropwising, solution slowly heats up in 70 ~ 75 DEG C of reactions 2 hours, and thin layer monitoring raw material reaction is complete, solution be cooled to 20 ~ 25 DEG C with concentrated hydrochloric acid 150g adjust pH to neutral. Separatory, water layer extracts once with 100g ethyl acetate again, merges organic layer saturated aqueous common salt 300g and washs once; Organic phase is dry with glauber salt, filters, concentrates crystallization and obtain 215g off-white color 3,4-dimethoxy-cinnamic acid ethyl ester. Molar yield 91.1%, liquid phase purity is more than 98.5%.
20% sodium hydrate aqueous solution 150g is added in reaction bulb, then add 118g3, after 4-dimethoxy-cinnamic acid ethyl ester is uniformly mixed, heat up in 60 DEG C of reaction hydrolysis 2 hours; Reacting complete is down to 20 ~ 25 DEG C and is adjusted to neutrality with 90g concentrated hydrochloric acid; Ethyl acetate 100g*2 extraction for solution, dry after merging organic layer. Filtration, concentrated 3, the 4-dimethoxy-cinnamic acid that obtains, by 450g ethanol stirring and dissolving. Ethanolic solution is added in 1L autoclave, then add in 5% palladium charcoal 1.2g to 20g ethanol, nitrogen replacement 3 times, 15 ~ 20 kilograms of logical hydrogen were in 35 ~ 40 DEG C of pressurizes 12 hours. Nitrogen replacement after suction hydrogen, removes by filter palladium charcoal and waits to apply mechanically; Solution decompression is concentrated, the concentrated complete 360g deionized water that adds, and stirring is cooled to 0 ~ 5 DEG C and filters to obtain wet product 106g. Dry 20 ~ 24 hours to obtain off-white color 3,4-dimethoxy benzenpropanoic acid 96.8g for 60 ~ 70 DEG C; Molar yield 92.2%, liquid phase purity 99.65%.
Claims (11)
1. one kind 3, the preparation method of 4-dimethoxy benzenpropanoic acid, comprises the steps:
Taking Veratraldehyde as raw material, under sodium alkoxide/sodium alkoxide solution effects and acetic acid ethyl reaction, obtain intermediate 3,4-dimethoxy-cinnamic acid ethyl ester; 3,4-dimethoxy-cinnamic acid ethyl ester obtains 3,4-dimethoxy-cinnamic acid after being hydrolyzed under alkali condition, and repeated hydrogenation reduction obtains 3,4-dimethoxy benzenpropanoic acid.
2. according to claim 13, the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, is characterized in that, described sodium alkoxide/alcohol sodium solution is the one in sodium methoxide solid, caustic alcohol solid, the methanol solution of sodium methoxide or the ethanolic solution of caustic alcohol.
3. according to claim 23, the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, it is characterized in that, described sodium alkoxide/alcohol sodium solution is alcohol sodium alcohol solution, described 3, the weight ratio of 4-dimethoxy benzaldehyde and alcohol sodium alcohol solution is 1:2.4-3.7, and the mass percent concentration of described alcohol sodium alcohol solution is 15 ~ 25%.
4. according to claim 13, the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, is characterized in that, described Veratraldehyde and the weight ratio of ethyl acetate are 1:5-10.
5. according to claim 13, the preparation method of 4-dimethoxy-cinnamic acid ethyl ester, is characterized in that, described Veratraldehyde and acetic acid ethyl reaction temperature are 50-75 DEG C, and the reaction time is 2-5 hour.
6. according to claim 13, the preparation method of 4-dimethoxy benzenpropanoic acid, is characterized in that, described 3, after the hydrolysis of 4-dimethoxy-cinnamic acid ethyl ester, repeated hydrogenation reduction reaction step comprises: 3,4-dimethoxy-cinnamic acid ethyl ester is hydrolyzed to 3,4-dimethoxy-cinnamic acid under alkali condition; Reduce with catalyst hydrogenation taking alcohol as solvent again, be heated to pressurize reaction 10-18 hour under 30-45 DEG C of condition, react complete processing and obtain 3,4-dimethoxy benzenpropanoic acid.
7. according to claim 63, the preparation method of 4-dimethoxy benzenpropanoic acid, described alkali condition is one or both of NaOH, its aqueous solution of potassium hydroxide; Described alkali is 20% sodium hydrate aqueous solution.
8. according to claim 63, the preparation method of 4-dimethoxy benzenpropanoic acid, described alcohol is one or both in methyl alcohol, ethanol; Described catalyst is palladium charcoal, and described palladium content is 5% or 10%.
9. according to claim 63, the preparation method of 4-dimethoxy benzenpropanoic acid, described alcohol is ethanol, described 3, the weight ratio of 4-dimethoxy-cinnamic acid ethyl ester and ethanol is 1:3-8.
10. according to claim 63, the preparation method of 4-dimethoxy benzenpropanoic acid, described palladium charcoal is 5% palladium charcoal, described 3, the weight ratio of 4-dimethoxy-cinnamic acid ethyl ester and 5% palladium charcoal is 1:0.008-0.012, described catalyst 5% palladium charcoal is finished using, and filtration treatment, can apply mechanically more than 10 times.
11. is according to claim 13, and the preparation method of 4-dimethoxy benzenpropanoic acid, is characterized in that, uses acetic acid ethyl dissolution Veratraldehyde, adds alcohol sodium alcohol solution insulation reaction, and post processing obtains 3,4-dimethoxy-cinnamic acid ethyl ester. Under 3,4-dimethoxy-cinnamic acid ethyl ester alkali condition, hydrolysis obtains 3,4-dimethoxy-cinnamic acid; Be that solvent is with 5% palladium charcoal catalytic reaction with ethanol again; React complete filtration; Filtrate processing obtains 3,4-dimethoxy benzenpropanoic acid, filters after the palladium charcoal ethanol obtaining washs and recycles, and can apply mechanically more than 10 times.
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