CN105418392A - Method for preparing veratryl acetone - Google Patents
Method for preparing veratryl acetone Download PDFInfo
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- CN105418392A CN105418392A CN201510849292.0A CN201510849292A CN105418392A CN 105418392 A CN105418392 A CN 105418392A CN 201510849292 A CN201510849292 A CN 201510849292A CN 105418392 A CN105418392 A CN 105418392A
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- benzene
- methacrylic
- veratryl
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- acetone
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- 0 C*c(ccc(C=O)c1)c1O Chemical compound C*c(ccc(C=O)c1)c1O 0.000 description 4
- JGFBGRHDJMANRR-VURMDHGXSA-N C/C(/[N+]([O-])=O)=C/c(cc1)cc(OC)c1OC Chemical compound C/C(/[N+]([O-])=O)=C/c(cc1)cc(OC)c1OC JGFBGRHDJMANRR-VURMDHGXSA-N 0.000 description 1
- JLEJCNOTNLZCHQ-UHFFFAOYSA-N CC(C(OC)=O)Cl Chemical compound CC(C(OC)=O)Cl JLEJCNOTNLZCHQ-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N COc(cc(C=O)cc1)c1O Chemical compound COc(cc(C=O)cc1)c1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/40—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with ozone; by ozonolysis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method for veratryl acetone. The method comprises the steps that an etherification reaction is performed under the conditions of solvent water, a phase transfer catalyst and high pressure by taking a by-product 4-(2-methyl allyl)-1,2-benzenediol and methane chloride as raw materials and taking strong base as an acid-binding agent to obtain an intermediate 1,2-dimethoxy-4-(2-methyl allyl)benzene; the 1,2-dimethoxy-4-(2-methyl allyl)benzene is subjected to an oxidation reaction with ozone in solvent acetic acid, reduction is performed through zinc powder, and then the product veratryl acetone is prepared, wherein the reaction formula is as followed (please see the reaction formula in the specification). According to the preparation method, waste utilization is achieved, and the requirements for environmental protection and circular economy development are met; the obtained intermediate 4-(2-methyl allyl)-1,2-benzenediol is high in quality, and a good base is laid for preparation of the high-quality product veratryl acetone; the technology is simple, operation is convenient, the raw materials are easy to obtain, the production cost is low, and industrialized production is facilitated; the product yield is higher, the total yield is larger than 70%, the product quality is high, and the mass content is 98% or above.
Description
Technical field
The present invention relates to a kind of method preparing veratryl acetone, particularly with benzofuranol by product for the method for veratryl acetone prepared by raw material.
Background technology
Veratryl acetone is also known as veratone, and chemistry 3,4-dimethoxy Propiophenone by name, is the important intermediate of the medicine such as synthesis tetrahydropalmatine, ipoveratril hydrochloride, nordihydroguaiaretic acid, depressor methyldopa, is widely used at medicine industry.Molecular structural formula:
The method of report is had to mainly contain by raw material at present following: veratryl benzyl chlorine method, vanillin food grade,1000.000000ine mesh method, veratrum aldehyde method.
Zhao Jinzhao etc. [CN103864590A, 2014-06-18] have invented a kind of preparation method of veratryl acetone: with veratryl benzyl chlorine for raw material, first prepare grignard reagent with metal magnesium powder; Then grignard reagent and acetonitrile reaction, be hydrolyzed to obtain product, yield 75% ~ 80%, after aftertreatment, product purity is not less than 98.5% (HPLC).This invention special character is that route is short, yield is higher, is easy to purifying, and this invention route raw material veratryl benzyl chlorine cost is higher, grignard reagent is dangerous higher, and industrialization difficulty is large.
[the CN1193980C such as Bian Xiuwu, 2005-03-23] in the process patent of a kind of synthesizing stereoselectively and efficiently diphenyl butane lignan compound of invention, relate to the synthesis of veratryl acetone: take vanillin food grade,1000.000000ine mesh as raw material, obtain veratryl aldehyde with dimethyl sulfate methylation of ester; Then veratryl aldehyde and nitroethane condensation obtain 1-(3,4-Dimethoxyphenyl)-2-nitro-1-propylene; Veratryl acetone is reduced to obtain finally by iron powder/hydrochloric acid.This route respectively walks that reaction yield is higher, and total recovery reaches 78.6% ~ 91.2%, but step is long, material cost is high, the three wastes are many, and comprehensive cost is too high.
[the CN102320945B such as Li Lanhua, 2014-07-23] disclose a kind of preparation technology of Li Lu ketone: take veratrum aldehyde as body material, first condensation under the catalysis of 2-methyl chloropropionate at sodium methylate, then be hydrolyzed in the basic conditions, salt acid decarboxylation, finally carries out distillation and obtains product, molar yield 98%, through the main content more than 98.5% of efficient vapor detection, under product room temperature, place also nondiscoloration for a long time.This patent route constant product quality, yield is high, content is high, but material cost is higher, and the three wastes are more, and industrialization cost is high.
In addition, [the JournaloftheAmericanChemicalSociety such as KevinDH, 2011,133 (14): 5194-5197] report with 4-bromo-1,2-dimethoxy benzene is raw material, with acetone Reactive Synthesis veratryl acetone under palladium chtalyst, yield 88%, content 94% (GC); AnZ-W etc. [Synthesis, 1992, (12): 1229-1231] report 2-(3,4-dimethoxy-benzyl) oxyethane and Manganese diiodide Reactive Synthesis veratryl acetone, yield 100%; [the OrganicLetters such as GerritzSW, 2000,2 (25): 4099-4102] 2-(3,4-Dimethoxyphenyl)-N-methoxy N-methylacetamide and methyl-magnesium-bromide Reactive Synthesis veratryl acetone is reported, yield 93%; [the TetrahedronLetters such as KulkarniMG, 2013,54 (19): 2293-2295] 4-allyl group-1 is reported, 2-dimethoxy benzene is obtained veratryl acetone by Potassium Bromate under palladium chtalyst, yield 73%, these routes or raw material is not easy to obtain, or expensive catalyst, synthesis cost is high, can only be applied to laboratory synthesis.
Current domestic employing pyrocatechol is raw material production benzofuranol, and annual output is about 6000 tons, and its Main By product 4-(2-methacrylic)-1,2-dihydroxy-benzene remains in rectifying still raffinate, about has 700 tons every year.Owing to not having the derived product be suitable for, and it can be used as astatki process, not only added value is low, returns environmental protection build-up of pressure.
Summary of the invention
The preparation method of veratryl acetone provided by the invention, with the by product 4-of benzofuranol (2-methacrylic)-1,2-dihydroxy-benzene and monochloro methane are raw material, take highly basic as acid binding agent, under aqueous solvent, phase-transfer catalyst and condition of high voltage, carry out etherification reaction obtain intermediate 1,2-dimethoxy-4 '-(2-methacrylic) benzene.Then 1,2-dimethoxy-4 '-(2-methacrylic) benzene carries out oxidizing reaction with ozone in solvent acetic acid, then through zinc powder reduction, prepares product veratryl acetone.
Reaction formula is as follows:
Described highly basic is the one in lithium hydroxide or sodium hydroxide, potassium hydroxide; Phase-transfer catalyst is the one in Tetrabutyl amonium bromide or DMAP, benzyltriethylammoinium chloride.
Concrete technology operation steps of the present invention is:
1. intermediate 1,2-dimethoxy-4 '-(2-methacrylic) benzene step is prepared;
2. preparing product veratryl acetone step.
Step 1. in, first by benzofuranol rectifying still raffinate adopt high vacuum rectification reclaim obtain 4-(2-methacrylic)-1,2-dihydroxy-benzene.Again with 4-(2-methacrylic)-1,2-dihydroxy-benzene and monochloro methane for raw material, be solvent with water, be acid binding agent with highly basic, add phase-transfer catalyst, in autoclave, carry out etherification reaction.Acid binding agent and 4-(2-methacrylic)-1, the molar ratio of 2-dihydroxy-benzene is 2 ~ 3 ︰ 1, phase-transfer catalyst and 4-(2-methacrylic)-1, the molar ratio of 2-dihydroxy-benzene is 0.005 ~ 0.05 ︰ 1, the mass ratio that feeds intake of water and 4-(2-methacrylic)-1,2-dihydroxy-benzene is 4 ~ 8 ︰ 1; Temperature of reaction is 60 ~ 120 DEG C, and reaction pressure is 0.3 ~ 0.7MPa, and the reaction times is 4 ~ 10h.React complete, separatory, after organic phase distillation, obtain 1,2-dimethoxy-4 '-(2-methacrylic) benzene.
Step 2. in, 1,2-dimethoxy-4 '-(2-methacrylic) benzene, in solvent acetic acid, carries out oxidizing reaction with ozone, then through zinc powder reduction, then after extraction, washing, dry aftertreatment and rectifying obtained product veratryl acetone.The mass ratio that feeds intake of solvent acetic acid and 1,2-dimethoxy-4 '-(2-methacrylic) benzene is 2 ~ 4 ︰ 1; The molar ratio of ozone and 1,2-dimethoxy-4 '-(2-methacrylic) benzene is 1 ~ 3 ︰ 1, passes into ozone 0.5h ~ 1.5h at-5 ~ 5 DEG C; Logical N again
2after 1h, divide 3 ~ 5 batches and add zinc powder, insulation reaction 1h ~ 3h at-5 ~ 5 DEG C.The molar ratio of zinc powder and 1,2-dimethoxy-4 '-(2-methacrylic) benzene is 1 ︰ 1.
The present invention utilizes by product 4-(2-methacrylic)-1, the 2-dihydroxy-benzene in benzofuranol distillation residual liquid to be the basic material preparing veratryl acetone, achieves utilization of waste material, meets the requirement of environment protection, recycling economy development.The mass percentage about 90% of gained intermediate 4-(2-methacrylic)-1,2-dihydroxy-benzene, for preparation high-quality product veratryl acetone lays good basis.Present invention process is simple, and easy to operate, raw material is easy to get, and low production cost is conducive to suitability for industrialized production.Product yield is higher, and total recovery is greater than 70% (with 4-(2-methacrylic)-1,2-dihydroxy-benzene meter), and product quality is high, mass content more than 98% (HPLC, external standard).
Embodiment
First high vacuum rectification is adopted to reclaim benzofuranol by product 4-(2-methacrylic)-1, the 2-dihydroxy-benzene obtaining mass percentage about 90% benzofuranol rectifying still raffinate.
Embodiment 1
1. intermediate 1,2-dimethoxy-4 '-(2-methacrylic) benzene is prepared
In 1000mL autoclave, add 36.5g (0.2mol successively, content 90%) 4-(2-methacrylic)-1, 2-dihydroxy-benzene, 14.5g (0.6mol, content 99%) lithium hydroxide, 0.65g (0.002mol, content 99%) Tetrabutyl amonium bromide and 146g water, nitrogen replacement 3 times, pass into monochloro methane, be heated to 120 DEG C, pressure is kept to react 7h under 0.3MPa, separatory, organic phase is distilled, get the cut that boiling range is 110-112 DEG C/5mmHg, obtain 33.8g colorless clear liquid 1, 2-dimethoxy-4 '-(2-methacrylic) benzene, content 97.3%, yield 85.6%.
1HNMR(CDCl
3，400MHz)δ:1.67(s，3H，CH
3)，3.26(s，2H，ArCH
2)，3.85(s，6H，2×OCH
3)，4.73(s，1H，C＝CH)，4.80(s，1H，C＝CH)，6.71(s，1H，C
6H
33-H)，6.72(d，J＝8.0Hz，1H，C
6H
35-H)，6.79(d，J＝8.0Hz，1H，C
6H
36-H)。
2. veratryl acetone is prepared
In 250mL four-hole boiling flask, add 40.5g (0.2mol, 95%) 1,2-dimethoxy-4 '-(2-methacrylic) benzene and 121.5g acetic acid, after cryosel bath is cooled to-5 DEG C, pass into 28.8g (0.6mol) O
3(source of oxygen, O
3content is about 6.2%), pass into time 1.5h, confirm raw material complete reaction with liquid chromatography monitoring, pass into N
21.0h; Divide 5 batches and add 13.0g (0.2mol) Zn powder, control reacting liquid temperature at about-5 DEG C, stir 3h, filter, 50mL extraction into ethyl acetate, washing, anhydrous sodium sulfate drying.Adopt ceramic random packing tower rectification under vacuum (reflux ratio is 5: 1) after organic phase precipitation, get the cut that boiling range is 122-124 DEG C/5mmHg, obtain 33.4g pale yellowish oil liquid veratryl acetone, content 99.0%, yield 85.0%.LC-MS(m/z)：195(M+1)，
1HNMR(CDCl
3，300MHz)δ：2.14(s，3H，CH
3)，3.61(s，2H，CH
2)，3.86(s，6H，CH
3×2)，6.62–6.77(m，3H，Ar-H)。
Embodiment 2
1. intermediate 1,2-dimethoxy-4 '-(2-methacrylic) benzene is prepared
In 1000mL autoclave, add 36.5g (0.2mol successively, content 90%) 4-(2-methacrylic)-1, 2-dihydroxy-benzene, 20.2g (0.5mol, content 99%) sodium hydroxide, 0.12g (0.001mol, content 99%) DMAP and 219g water, nitrogen replacement 3 times, pass into monochloro methane, be heated to 90 DEG C, pressure is kept to react 4h under 0.5MPa, separatory, organic phase is distilled, get the cut that boiling range is 110-112 DEG C/5mmHg, obtain 35.8g colorless clear liquid 1, 2-dimethoxy-4 '-(2-methacrylic) benzene, content 95.0%, yield 88.5%.
2. veratryl acetone is prepared
In 250mL four-hole boiling flask, add 40.5g (0.2mol, 95%) 1,2-dimethoxy-4 '-(2-methacrylic) benzene and 91g acetic acid, after cryosel bath is cooled to 0 DEG C, pass into 19.2g (0.4mol) O
3(source of oxygen, O
3content is about 6.2%), pass into time 1.0h, confirm raw material complete reaction with liquid chromatography monitoring, pass into N
21.0h; Divide 4 batches and add 13.0g (0.2mol) Zn powder, control reacting liquid temperature at about 0 DEG C, stir 2h, filter, 50mL extraction into ethyl acetate, washing, anhydrous sodium sulfate drying.Adopt ceramic random packing tower rectification under vacuum (reflux ratio is 5: 1) after organic phase precipitation, get the cut that boiling range is 122-124 DEG C/5mmHg, obtain 32.7g pale yellowish oil liquid veratryl acetone, content 99.2%, yield 83.6%.
Embodiment 3
1. intermediate 1,2-dimethoxy-4 '-(2-methacrylic) benzene is prepared
In 1000mL autoclave, add 36.5g (0.2mol successively, content 90%) 4-(2-methacrylic)-1, 2-dihydroxy-benzene, 22.7g (0.4mol, content 99%) potassium hydroxide, 0.023g (0.0001mol, content 99%) benzyltriethylammoinium chloride and 292g water, nitrogen replacement 3 times, pass into monochloro methane, be heated to 60 DEG C, pressure is kept to react 10h under 0.7MPa, separatory, organic phase is distilled, get the cut that boiling range is 110-112 DEG C/5mmHg, obtain 34.8g colorless clear liquid 1, 2-dimethoxy-4 '-(2-methacrylic) benzene, content 96.5%, yield 87.3%.
2. veratryl acetone is prepared
In 250mL four-hole boiling flask, add 40.5g (0.2mol, 95%) 1,2-dimethoxy-4 '-(2-methacrylic) benzene and 182g acetic acid, after cryosel bath is cooled to 5 DEG C, pass into 9.6g (0.2mol) O
3(source of oxygen, O
3content is about 6.2%), pass into time 0.5h, confirm raw material complete reaction with liquid chromatography monitoring, pass into N
21.0h; Divide 3 batches and add 13.0g (0.2mol) Zn powder, control reacting liquid temperature at about 5 DEG C, stir 1h, filter, 50mL extraction into ethyl acetate, washing, anhydrous sodium sulfate drying.Adopt ceramic random packing tower rectification under vacuum (reflux ratio is 5: 1) after organic phase precipitation, get the cut that boiling range is 122-124 DEG C/5mmHg, obtain 325g pale yellowish oil liquid veratryl acetone, content 98.7%, yield 82.5%.
Claims (2)
1. the preparation method of a veratryl acetone, it is characterized in that with the by product 4-of benzofuranol (2-methacrylic)-1,2-dihydroxy-benzene and monochloro methane are raw material, take highly basic as acid binding agent, under aqueous solvent, phase-transfer catalyst and condition of high voltage, carry out etherification reaction obtain intermediate 1,2-dimethoxy-4 '-(2-methacrylic) benzene, then 1,2-dimethoxy-4 '-(2-methacrylic) benzene carries out oxidizing reaction with ozone in solvent acetic acid, then through zinc powder reduction, product veratryl acetone is prepared;
Reaction formula is as follows:
Described highly basic is the one in lithium hydroxide or sodium hydroxide, potassium hydroxide; Phase-transfer catalyst is the one in Tetrabutyl amonium bromide or DMAP, benzyltriethylammoinium chloride.
2. the preparation method of veratryl acetone according to claim 1, it is characterized in that acid binding agent and 4-(2-methacrylic)-1 in etherification reaction, the molar ratio of 2-dihydroxy-benzene is 2 ~ 3 ︰ 1, phase-transfer catalyst and 4-(2-methacrylic)-1, the molar ratio of 2-dihydroxy-benzene is 0.005 ~ 0.05 ︰ 1, the mass ratio that feeds intake of water and 4-(2-methacrylic)-1,2-dihydroxy-benzene is 4 ~ 8 ︰ 1; Temperature of reaction is 60 ~ 120 DEG C, and reaction pressure is 0.3 ~ 0.7MPa, and the reaction times is 4 ~ 10h; Solvent acetic acid and 1 in the oxidation reaction, the mass ratio that feeds intake of 2-dimethoxy-4 '-(2-methacrylic) benzene is 2 ~ 4 ︰ 1, ozone and 1, the molar ratio of 2-dimethoxy-4 '-(2-methacrylic) benzene is 1 ~ 3 ︰ 1, ozone 0.5h ~ 1.5h is passed at-5 ~ 5 DEG C, more logical N
2divide 3 ~ 5 batches after 1h and add zinc powder, insulation reaction 1h ~ 3h at-5 ~ 5 DEG C, the molar ratio of zinc powder and 1,2-dimethoxy-4 '-(2-methacrylic) benzene is 1 ︰ 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117486695A (en) * | 2023-11-27 | 2024-02-02 | 山东泓瑞医药科技股份公司 | Veratone synthesis method based on claisen rearrangement and etherification reaction |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503788A (en) * | 2011-11-21 | 2012-06-20 | 湖南大学 | Application of 4-(2-methylallyl)-1,2-dihydroxybenzene in preparation of perfume |
-
2015
- 2015-11-30 CN CN201510849292.0A patent/CN105418392A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503788A (en) * | 2011-11-21 | 2012-06-20 | 湖南大学 | Application of 4-(2-methylallyl)-1,2-dihydroxybenzene in preparation of perfume |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117486695A (en) * | 2023-11-27 | 2024-02-02 | 山东泓瑞医药科技股份公司 | Veratone synthesis method based on claisen rearrangement and etherification reaction |
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Application publication date: 20160323 |