CN105601496B - A kind of preparation method of 3,4 dimethoxy benzenpropanoic acid - Google Patents
A kind of preparation method of 3,4 dimethoxy benzenpropanoic acid Download PDFInfo
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- CN105601496B CN105601496B CN201511013379.0A CN201511013379A CN105601496B CN 105601496 B CN105601496 B CN 105601496B CN 201511013379 A CN201511013379 A CN 201511013379A CN 105601496 B CN105601496 B CN 105601496B
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- benzenpropanoic
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- LHHKQWQTBCTDQM-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)propanoic acid Chemical compound COC1=CC=C(CCC(O)=O)C=C1OC LHHKQWQTBCTDQM-UHFFFAOYSA-N 0.000 title claims abstract description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical class COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 6
- 230000000694 effects Effects 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 70
- 239000000243 solution Substances 0.000 claims description 31
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 19
- 239000011734 sodium Substances 0.000 claims description 19
- 229910052708 sodium Inorganic materials 0.000 claims description 19
- 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 16
- HJBWJAPEBGSQPR-UHFFFAOYSA-N DMCA Natural products COC1=CC=C(C=CC(O)=O)C=C1OC HJBWJAPEBGSQPR-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 6
- -1 sodium alkoxide Chemical class 0.000 claims description 5
- 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 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 241000522254 Cassia Species 0.000 claims description 2
- 150000002118 epoxides Chemical class 0.000 claims description 2
- 238000010931 ester hydrolysis Methods 0.000 claims description 2
- HIJPDTDHFISGDA-UHFFFAOYSA-N ethyl 2,3-dimethoxy-3-phenylprop-2-enoate Chemical compound CCOC(=O)C(OC)=C(OC)C1=CC=CC=C1 HIJPDTDHFISGDA-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims description 2
- 235000013372 meat Nutrition 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims 1
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 claims 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229930016911 cinnamic acid Natural products 0.000 claims 1
- 235000013985 cinnamic acid Nutrition 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims 1
- 238000012545 processing Methods 0.000 claims 1
- 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 abstract description 16
- 238000000034 method Methods 0.000 abstract description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 abstract description 4
- 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
- 239000000463 material Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 235000011167 hydrochloric acid Nutrition 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012544 monitoring process Methods 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
- 238000000926 separation method Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- KBEBGUQPQBELIU-CMDGGOBGSA-N Ethyl cinnamate Chemical compound CCOC(=O)\C=C\C1=CC=CC=C1 KBEBGUQPQBELIU-CMDGGOBGSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- KBEBGUQPQBELIU-UHFFFAOYSA-N cinnamic acid ethyl ester Natural products CCOC(=O)C=CC1=CC=CC=C1 KBEBGUQPQBELIU-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 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
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical class COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- GPESMPPJGWJWNL-UHFFFAOYSA-N azane;lead Chemical compound N.[Pb] GPESMPPJGWJWNL-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 229940048961 cholinesterase Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 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
-
- 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
Landscapes
- 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 chemosynthesis technical field, and in particular to a kind of preparation method of 3,4 dimethoxy benzenpropanoic acid of donepezil hydrochloride key intermediate.This method comprises the following steps：With 3,4 dimethoxy benzaldehydes for raw material, sodium ethoxide effect under and acetic acid ethyl reaction, obtain 3,4 dimethoxy-cinnamic acid ethyl ester of intermediate；After 3,4 dimethoxy-cinnamic acid ethyl esters hydrolyze in alkaline conditions, repeated hydrogenation reduces to obtain 3,4 dimethoxy benzenpropanoic acids.The preparation method of the present invention has environmentally friendly, the advantages such as product purity height, high income, cost of material are low.
Description
Technical field
The invention belongs to chemosynthesis technical field, and in particular to a kind of donepezil hydrochloride key intermediate 3,4- diformazans
The preparation method of epoxide benzenpropanoic acid.
Background technology
Doneppezil Hydrochloride is while is used for light, moderate AD by what U.S. FDA and Britain MCA approvals listed（Alzheimer '
Silent disease）The medicine of symptomatic treatment, chemical name 2, double hydroxyl -5,6- bi-methoxy -2- { 1- (the benzyl) -4- piperidyls of 3-
Methyl } -1H- 1-Indanone hydrochlorides.AD is a kind of using hypomnesia as main performance, with obtaining for other Cognitive function damages
Obtain property hypophrenia.Doneppezil Hydrochloride is second generation anticholinesterase, its therapeutic effect is reversibly to suppress acetyl
Acetyl courage acyl caused by cholinesterase hydrolyzes and increases the acetyl choline content of receptor site.
3,4- dimethoxy benzenpropanoic acids are the key intermediate of Doneppezil Hydrochloride, and document has several synthetic methods：With
Veratraldehyde is raw material, and malonic acid or diethyl malonate are condensed, and dehydrative rearrangement obtains 3,4- bis-
Methoxycinnamate acetoacetic ester；3,4- dimethoxy-cinnamic acids ethyl ester hydrolyzes to obtain 3,4- dimethoxy Chinese cassia trees in alkaline conditions
Acid, hydrogenating reduction obtain 3,4- dimethoxy benzenpropanoic acids.Wherein, pyridine and piperidines can be used in reaction process a as catalyst,
Reaction and last handling process can all have very smelly smell, are unfavorable for producing and post-process.Huaqiao University once celebrated what friend etc. delivered
The synthetic method of 3,4- dimethoxy-cinnamic acid ethyl esters, using L-PROLINE/potassium phosphate as catalyst, obtained 3,4- dimethoxys
Benzenpropanoic acid yield 70% or so is relatively low.The reaction equation for being typically prepared 3,4- dimethoxy benzenpropanoic acids is as follows：
。
The content of the invention
In order to solve above-mentioned technical problem, the present invention provides the preparation method of one kind 3,4- dimethoxy benzenpropanoic acids.
The process employs ethyl acetate to replace malonic acid or diethyl malonate, is reacted, obtained by alkali of alcohol sodium solution
New intermediate 3,4- dimethoxy-cinnamic acid ethyl esters；3,4- dimethoxy-cinnamic acid ethyl ester hydrolyzed under basic conditions obtains 3,4-
Dimethoxy-cinnamic acid, target product 3,4- dimethoxy benzenpropanoic acids are obtained by hydrogenating reduction.This synthetic method eliminate with
Into reaction, the catalyst of the foul smelling smell such as pyridine and piperidines, greatly reduces the pollution level to environment, easy to operate, no
Special production equipment is needed, is easy to industrialized production.
The present invention is achieved through the following technical solutions：
The preparation method of one kind 3,4- dimethoxy benzenpropanoic acids, includes the following steps：Using 3,4- dimethoxy benzaldehydes as
Raw material, sodium ethoxide effect under and acetic acid ethyl reaction, obtain intermediate 3,4- dimethoxy-cinnamic acid ethyl esters；3,4- dimethoxies
Base ethyl cinnamate hydrolyzed under basic conditions obtains 3,4- dimethoxy-cinnamic acids, and repeated hydrogenation reduces to obtain 3,4- dimethoxy benzenes
Propionic acid.Synthetic route is as follows：
。
In the preparation method of above-mentioned 3,4- dimethoxy-cinnamic acid ethyl esters, the sodium alkoxide/alcohol sodium solution is consolidated for sodium methoxide
Body, sodium ethoxide solid, the methanol solution of sodium methoxide or sodium ethoxide ethanol solution in one kind.
Preferably, in the preparation method of above-mentioned 3,4- dimethoxy-cinnamic acid ethyl esters, the sodium alkoxide/alcohol sodium solution is second
The weight ratio of alcohol sodium ethoxide solution, the Veratraldehyde and alcohol sodium alcohol solution is 1:2.4-3.7, it is described
The mass percent concentration of alcohol sodium alcohol solution is 15 ~ 25%.
In the preparation method of above-mentioned 3,4- dimethoxy-cinnamic acid ethyl esters, the Veratraldehyde and second
The weight ratio of acetoacetic ester is 1:5-10.
In the preparation method of above-mentioned 3,4- dimethoxy-cinnamic acid ethyl esters, the Veratraldehyde and acetic acid
Ethyl ester reaction temperature is 50-75 DEG C, when the reaction time is 2-5 small.
In the preparation method of above-mentioned 3,4- dimethoxy benzenpropanoic acids, 3, the 4- dimethoxy-cinnamic acids ethyl ester hydrolysis
Afterwards, repeated hydrogenation reduction reaction, step include：3,4- dimethoxy-cinnamic acids ethyl ester first and after sodium hydroxide solution mixing hydrolyzes；
It is again solvent catalysis hydrogenating reduction with alcohol, when pressurize reaction 10-18 is small under the conditions of being heated to 30-45 DEG C, reaction, which finishes, to be handled
To 3,4- dimethoxy benzenpropanoic acids.
In the preparation method of above-mentioned 3,4- dimethoxy benzenpropanoic acids, the alkaline condition is sodium hydroxide, hydroxide
The one or two of its aqueous solution of potassium；The alkali is 20% sodium hydrate aqueous solution.
In the preparation method of above-mentioned 3,4- dimethoxy benzenpropanoic acids, the alcohol is methanol, one kind in ethanol or two
Kind；The catalyst is palladium charcoal, and the palladium charcoal palladium content is 5% or 10%.
Preferably, in the preparation method of above-mentioned 3,4- dimethoxy benzenpropanoic acids, the alcohol is ethanol, described 3,4-
The weight ratio of dimethoxy-cinnamic acid ethyl ester and ethanol is 1:3-8.
Preferably, in the preparation method of above-mentioned 3,4- dimethoxy benzenpropanoic acids, the palladium charcoal is 5% palladium charcoal, described
The weight ratio of 3,4- dimethoxy-cinnamic acids ethyl ester and 5% palladium charcoal is 1:0.008-0.012, the 5% palladium charcoal of catalyst use
Finish, filtration treatment, can apply mechanically more than 10 times.
In the preparation method of above-mentioned 3,4- dimethoxy benzenpropanoic acids, 3,4- dimethoxy benzene first is dissolved with ethyl acetate
Aldehyde, adds alcohol sodium alcohol solution insulation reaction, and post processing obtains 3,4- dimethoxy-cinnamic acid ethyl esters.3,4- dimethoxy meat
It is solvent with 5% palladium charcoal catalytic reaction using ethanol after ethyl cinnamate is hydrolyzed with 20% sodium hydrate aqueous solution；Reaction finishes filtering；
Filtrate handles to obtain 3,4- dimethoxy benzenpropanoic acids.The palladium charcoal being obtained by filtration is washed with ethanol, can be applied mechanically more than 10 times.
Preferably, the preparation method of 3,4- dimethoxy benzenpropanoic acids of the invention, includes the following steps：
（1）Ethyl acetate and Veratraldehyde stirring and dissolving are added in reaction bulb, 20% is added dropwise in 15 ~ 35 DEG C
Alcohol sodium alcohol solution.Slowly when 50 ~ 75 DEG C of reactions 2 ~ 5 are small, the reaction was complete for thin layer monitoring raw material, solution for heating for mixture
10 ~ 30 DEG C are cooled to hydrochloric acid tune pH value to neutrality.Liquid separation, organic layer are dried with after saturated common salt water washing with anhydrous sodium sulphate, mistake
Filter, be concentrated to give 3,4- dimethoxy-cinnamic acid ethyl esters.
（2）Sodium hydroxide solution is added in reaction bulb, 3,4- dimethoxy-cinnamic acid ethyl esters is added and is reacted；Hydrolysis
After obtained 3,4- dimethoxy-cinnamic acids, added after being dissolved with ethanol in autoclave, add palladium catalyst charcoal, nitrogen
Lead to 10 ~ 20 kilograms of hydrogen after displacement when 30 ~ 45 DEG C of pressurizes 10 ~ 18 are small, being filtered to remove palladium charcoal after suction hydrogen waits to apply mechanically；Filtrate
Deionized water crystallization is used after being concentrated under reduced pressure, filtering drying obtains 3,4- dimethoxy benzenpropanoic acids.
Beneficial effects of the present invention are：
（1）In the preparation method of 3, the 4- dimethoxy-cinnamic acid ethyl esters of the present invention, malonic acid is replaced using ethyl acetate
Or diethyl malonate, reacted by alkali of alcohol sodium solution, obtain 3,4- dimethoxy-cinnamic acid ethyl esters, avoided anti-
The use of the catalyst of the foul smelling smell such as pyridine and piperidines, reduces the pollution of environment in answering.
（2）In the preparation method of 3, the 4- dimethoxy benzenpropanoic acids of the present invention, using 3,4- dimethoxy-cinnamic acid ethyl esters
After hydrolysis, then with ethanol it is that solvent obtains 3,4- dimethoxy benzenpropanoic acids by hydrogenating reduction；Solvent for use has for ethanol
Recycling beneficial to solvent and apply mechanically；Environmentally friendly, cost of material has been saved in the use for reducing solvent, is conducive to industrial metaplasia
Production.
Embodiment
The present invention is further described with reference to specific embodiment, so that those skilled in the art knows more about
The present invention, but be not intended to limit the present invention.
The concentration of concentrated hydrochloric acid used is 35 ~ 37% in the present invention.
Embodiment 1
Ethyl acetate 1200g is added in 3L reaction bulbs, stirs lower addition Veratraldehyde 166g；Dissolving after
15 ~ 20 DEG C of alcohol sodium alcohol solution 640g for being added dropwise 15%.After being added dropwise, solution slowly heats up when 50 ~ 55 DEG C of reactions 5 are small,
The reaction was complete for thin layer monitoring raw material, and solution is cooled to 15 ~ 20 DEG C with concentrated hydrochloric acid 150g tune pH value to neutrality.Liquid separation, water layer are used again
100g ethyl acetate extracts once, merges organic layer and washed once with saturated salt solution 300g；Organic phase is dried with anhydrous sodium sulphate, mistake
Filter, concentration crystallization obtain 212g off-white color 3,4- dimethoxy-cinnamic acid ethyl esters.Molar yield 89.8%, liquid phase purity 98.5% with
On.
20% sodium hydrate aqueous solution 150g is added in reaction bulb, adds 118g3,4- dimethoxy-cinnamic acid ethyl esters
After being stirred, heat up when 60 DEG C of reaction hydrolysis 2 are small；Reaction, which finishes, is down to 20 ~ 25 DEG C and is adjusted to neutrality with 90g concentrated hydrochloric acids；It is molten
Liquid is extracted with ethyl acetate 100g*2, merges drying after organic layer.Filter, be concentrated to give 3,4- dimethoxy-cinnamic acids, use
450g ethanol stirring and dissolvings.Ethanol solution is added in 1L autoclaves, adds 5% palladium charcoal 1.2g into 20g ethanol, nitrogen is put
Change 3 times, lead to 10 ~ 15 kilograms of hydrogen when 30 ~ 35 DEG C of pressurizes 16 are small.Nitrogen displacement after suction hydrogen, is filtered to remove palladium charcoal and waits to cover
With；Solution decompression concentrates, and concentration, which finishes, adds 360g deionized waters, and stirring is cooled to 0 ~ 5 DEG C and filters to obtain wet product 108g.60~70
DEG C drying 20 ~ 24 it is small when obtain off-white color 3,4- dimethoxy benzenpropanoic acids 96.6g；Molar yield 92.0%, liquid phase purity 99.62%.
Embodiment 2
Ethyl acetate 1200g is added in 3L reaction bulbs, stirs lower addition Veratraldehyde 166g；Dissolving after
25 ~ 30 DEG C of alcohol sodium alcohol solution 510g for being added dropwise 20%.After being added dropwise, solution slowly heats up when 70 ~ 75 DEG C of reactions 2 are small,
The reaction was complete for thin layer monitoring raw material, and solution is cooled to 20 ~ 25 DEG C with concentrated hydrochloric acid 150g tune pH value to neutrality.Liquid separation, water layer are used again
100g ethyl acetate extracts once, merges organic layer and washed once with saturated salt solution 300g；Organic phase is dried with anhydrous sodium sulphate, mistake
Filter, concentration crystallization obtain 215g off-white color 3,4- dimethoxy-cinnamic acid ethyl esters.Molar yield 91.1%, liquid phase purity 98.5% with
On.
20% sodium hydrate aqueous solution 150g is added in reaction bulb, adds 118g3,4- dimethoxy-cinnamic acid ethyl esters
After being stirred, heat up when 60 DEG C of reaction hydrolysis 2 are small；Reaction, which finishes, is down to 20 ~ 25 DEG C and is adjusted to neutrality with 90g concentrated hydrochloric acids；It is molten
Liquid is extracted with ethyl acetate 100g*2, merges drying after organic layer.Filter, be concentrated to give 3,4- dimethoxy-cinnamic acids, use
450g ethanol stirring and dissolvings.Ethanol solution is added in 1L autoclaves, adds 5% palladium charcoal 1.2g into 20g ethanol, nitrogen is put
Change 3 times, lead to 15 ~ 20 kilograms of hydrogen when 35 ~ 40 DEG C of pressurizes 12 are small.Nitrogen displacement after suction hydrogen, is filtered to remove palladium charcoal and waits to cover
With；Solution decompression concentrates, and concentration, which finishes, adds 360g deionized waters, and stirring is cooled to 0 ~ 5 DEG C and filters to obtain wet product 106g.60~70
DEG C drying 20 ~ 24 it is small when obtain off-white color 3,4- dimethoxy benzenpropanoic acids 96.8g；Molar yield 92.2%, liquid phase purity 99.65%.
Claims (7)
1. one kind 3, the preparation method of 4- dimethoxy benzenpropanoic acids, include the following steps：
Using Veratraldehyde as raw material, under sodium alkoxide solution effects and acetic acid ethyl reaction, intermediate 3,4- is obtained
Dimethoxy-cinnamic acid ethyl ester；3,4- dimethoxy-cinnamic acid ethyl esters obtain 3,4- dimethoxy meat after hydrolyzing in alkaline conditions
Cinnamic acid, repeated hydrogenation reduce to obtain 3,4- dimethoxy benzenpropanoic acids；
The alcohol sodium solution is the weight of alcohol sodium alcohol solution, the Veratraldehyde and alcohol sodium alcohol solution
Amount is than being 1:2.4-3.7, the mass percent concentration of the alcohol sodium alcohol solution is 15 ~ 25%；
After 3, the 4- dimethoxy-cinnamic acids ethyl ester hydrolysis, repeated hydrogenation reduction reaction step includes：3,4- dimethoxy Chinese cassia trees
Acetoacetic ester is hydrolyzed to 3,4- dimethoxy-cinnamic acids in alkaline conditions；Reduce, heat using alcohol as solvent with catalyst hydrogenation again
When pressurize reaction 10-18 is small under the conditions of to 30-45 DEG C, reaction finishes processing and obtains 3,4- dimethoxy benzenpropanoic acids；
The alcohol is one or both of methanol, ethanol；The catalyst is palladium charcoal, the palladium content for 5% or
10%。
2. the preparation method of 3,4- dimethoxys benzenpropanoic acid according to claim 1, it is characterised in that 3, the 4- bis-
The weight ratio of methoxybenzaldehyde and ethyl acetate is 1:5-10.
3. the preparation method of 3,4- dimethoxys benzenpropanoic acid according to claim 1, it is characterised in that 3, the 4- diformazans
Epoxide benzaldehyde and acetic acid ethyl reaction temperature are 50-75 DEG C, when the reaction time is 2-5 small.
4. the preparation method of 3,4- dimethoxys benzenpropanoic acid according to claim 1, the alkaline condition is hydroxide
The one or two of sodium, potassium hydroxide its aqueous solution；The alkali is 20% sodium hydrate aqueous solution.
5. the preparation method of 3,4- dimethoxys benzenpropanoic acid according to claim 1, the alcohol is ethanol, described 3,
The weight ratio of 4- dimethoxy-cinnamic acids ethyl ester and ethanol is 1:3-8.
6. the preparation method of 3,4- dimethoxys benzenpropanoic acid according to claim 1, the palladium charcoal is 5% palladium charcoal, described
3,4- dimethoxy-cinnamic acids ethyl ester and 5% palladium charcoal weight ratio be 1:0.008-0.012, the 5% palladium charcoal of catalyst make
With finishing, filtration treatment, can apply mechanically more than 10 times.
7. the preparation method of 3,4- dimethoxys benzenpropanoic acid according to claim 1, it is characterised in that molten with ethyl acetate
Veratraldehyde is solved, adds alcohol sodium alcohol solution insulation reaction, post processing obtains 3,4- dimethoxy-cinnamic acids
Ethyl ester；3,4- dimethoxy-cinnamic acid ethyl ester hydrolyzed under basic conditions obtains 3,4- dimethoxy-cinnamic acids；It is again molten with ethanol
Agent is with 5% palladium charcoal catalytic reaction；Reaction finishes filtering；Filtrate handles to obtain 3,4- dimethoxy benzenpropanoic acids, the palladium charcoal being obtained by filtration
Posterior circle is washed with ethanol to use, and can be applied mechanically more than 10 times.
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