CN102924249B - Preparation method of lycopene intermediate 2-methyl-3,3-dimethoxy-1-propionaldehyde - Google Patents
Preparation method of lycopene intermediate 2-methyl-3,3-dimethoxy-1-propionaldehyde Download PDFInfo
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Abstract
The invention provides a preparation method of a lycopene intermediate 2-methyl-3,3-dimethoxy-1-propionaldehyde. The method comprises the following steps: 1, carrying out an epoxidation reaction of 3,3-dimethoxy-1-propylene having a structure represented by formula (2) in the presence of an organic solvent and an epoxidation reagent at 0-30DEG C to obtain 2,3-epoxy-2-methyl-1-aldehyde dimethyl acetal having a structure represented by formula (3); and 2, carrying out a rearrangement reaction of the 2,3-epoxy-2-methyl-1-aldehyde dimethyl acetal of the formula (3) in the organic solvent under the catalysis of a Lewis acid at -30-0DEG C to obtain the 2-methyl-3,3-dimethoxy-1-propionaldehyde having a structure represented by formula (1). The preparation method has the advantages of simple technological route, low cost, and great industrial values.
Description
Technical field
The present invention relates to pharmaceutical-chemical intermediate, particularly a kind of 2-methyl-3 as lycopene intermediate, the preparation method of 3-dimethoxy-1-propionic aldehyde.
Background technology
2-methyl-3,3-dimethoxy-1-propionic aldehyde, as pharmaceutical-chemical intermediate, has good application prospect, and there are two kinds of groups of aldehyde and acetal in its molecular structure uniqueness, is particularly suitable for building double bond systems.Shen Run is broad in the recent period waits people in CN201110157489.X, to report that one is with 2-methyl-3,3-dimethoxy-1-propionic aldehyde is the novel method that raw material is prepared Lyeopene, the representative instance of this compounds as medicine intermediate application, this operational path is simple and direct, simple to operate, cost is low, has industrial value.
2-methyl-3,3-dimethoxy-1-propionic aldehyde yet there are no its synthetic method of bibliographical information; Ojima etc. report with 3,3-diethoxy-1-propylene (3) is raw material, under rhodium complex catalyst catalysis, prepare 2-methyl-3 with CO and H2 condensation, 3-diethoxy-1-propionic aldehyde (1B) (DE3403427, Verfahren zur Herstellung von 1,4-Butandial, 1985-01-08).Reaction equation is as follows:
This operational path is simpler and more direct, but needs to use hydrogen and carbon monoxide to carry out under high pressure catalysis, and device fabrication difficulty synthetic used is large, dangerous high, and will use expensive complicated catalyzer, and yield is lower, more difficult industrialization.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defect that above-mentioned prior art exists, and provides the 2-that a kind of operational path is simple and direct, raw material is easy to get methyl-3, the preparation method of 3-dimethoxy-1-propionic aldehyde.
For this reason, the technical solution used in the present invention is: lycopene intermediate 2-methyl-3, and the preparation method of 3-dimethoxy-1-propionic aldehyde, comprises the following steps:
(1) under organic solvent and epoxidation reagent exist to 3 shown in formula (2), 3-dimethoxy-1-propylene carries out epoxidation under 0～30 DEG C of temperature condition;
(2) under organic solvent and Louis acid catalysis to 2 shown in formula (3), 3-epoxy group(ing)-2-methyl isophthalic acid-methylal is reset the formula of obtaining (1) 2-methyl-3 under-30～0 DEG C of temperature condition, 3-dimethoxy-1-propionic aldehyde, reaction equation is as follows:
Described reaction raw materials 3,3-dimethoxy-1-propylene (2) is provided by Zhejiang Medicine Co;
Above-mentioned the first step reaction, described epoxidation reagent comprises metachloroperbenzoic acid, Peracetic Acid, clorox etc., other epoxidation reagents there is no particular restriction.
Preferably, 3 shown in formula (2), the consumption mol ratio of 3-dimethoxy-1-propylene and epoxidation reagent is 0.8～1.5.
More preferably, 3 shown in formula (2), the consumption mol ratio of 3-dimethoxy-1-propylene and epoxidation reagent is 1.0～1.3.
Preferably, described solvent is methylene dichloride, ethylene dichloride, chloroform, toluene, ether.
Preferably, described epoxidation reaction is carried out under 10～20 DEG C of conditions.
Above-mentioned second step reaction is carried out under Louis acid catalysis, and described lewis acid catalyst comprises boron trifluoride diethyl etherate, magnesium bromide.
Preferably, 2 shown in formula (3), the consumption mol ratio of 3-epoxy group(ing)-2-methyl isophthalic acid-methylal and lewis acid catalyst is 0.5～1.2.
More preferably, the consumption mol ratio of 2,3-epoxy group(ing)-2-methyl isophthalic acid methylal and lewis acid catalyst is 0.8～1.1.
Preferably, described solvent is methylene dichloride, ethylene dichloride, chloroform, toluene, ether.
Preferably, described epoxidation reaction is carried out under-30～0 DEG C of condition.
Operational path of the present invention is simple and direct, and raw material is easy to get, and cost is low, has industrial value.
Embodiment
Now be described in detail as follows in conjunction with appended preferred embodiment, illustrated preferred embodiment is only for technical scheme of the present invention is described, and non-limiting the present invention.
The analytical instrument and the equipment that in each embodiment of the present invention, use are: gas chromatograph-mass spectrometer, MS5973N-GC6890N (Agilent company of the U.S.); Nuclear magnetic resonance analyser, AVANCEDMX II I 400M (mark in TMS, Bruker company); Infrared spectrometer, NICOLET360FT-IR; Gas-chromatography, GC1690 dawn of section.
Embodiment 1:2, the preparation of 3-epoxy group(ing)-2-methyl isophthalic acid-methylal (3)
By 58g (0.5mol) 3, 3-dimethoxy-1-propylene (2) and 50ml ethylene dichloride join 1000 milliliters and are equipped with in churned mechanically four-hole bottle, at 20 DEG C, drip the dichloroethane solution 600ml of 103g (0.6mol) metachloroperbenzoic acid containing, about 1.5 hours, drip off, gas-chromatography is followed the tracks of reaction, reaction in approximately 3 hours finishes, reacting liquid filtering, filtrate 50ml washs 2 times with 5% sodium bisulfite, again with 30ml saturated sodium bicarbonate aqueous solution washing 2 times, finally with the washing of 50ml saturated sodium-chloride water solution, anhydrous sodium sulfate drying, after reclaiming ethylene dichloride, obtain 2, 3-epoxy group(ing)-2-methyl isophthalic acid-methylal crude product 58.2g, for light yellow liquid, gas phase content 90.8%, yield 80.1%.Product structure is confirmed:
1HNMR(δ，ppm，400MHz，CDCl
3)：1.356(s，3H，CH
3)；2.714(dd，J＝5.2Hz，J＝96.8Hz，2H，CH
2)；3.422，3.437(s，6H，OCH
3)；4.079(s，1H，CH
*(OCH
3)
2)
13CNMR(δ，ppm，100MHz，CDCl
3)：16.066，50.099，55.144，55.436，56.623，105.831
Embodiment 2:2-methyl-3, the preparation of 3-dimethoxy-1-propionic aldehyde (1)
Under nitrogen protection, by the 30g of above-mentioned preparation (0.2mol) 2, 3-epoxy group(ing)-2-methyl isophthalic acid methylal and 50ml ethylene dichloride join 500 milliliters and are equipped with in churned mechanically four-hole bottle,-30 DEG C of left and right of cryostat insulation add 13.2g (0.1mol) boron trifluoride diethyl etherate liquid stirring reaction 10 minutes, then add 20 grams of sodium carbonate, continue to stir 30 minutes, reacting liquid filtering, filtrate is washed 2 times with 50ml saturated sodium carbonate solution, again with 10% sodium chloride aqueous solution 30ml washing, dried over mgso, reclaim ethylene dichloride and obtain 2-methyl-3, 3-dimethoxy-1-propionic aldehyde crude product 28.2g, it is colourless liquid that 55-58 DEG C/3mmHg cut 18.5g is collected in decompression, gas phase content 95.2%, yield 66.7%.
Product structure is confirmed:
1HNMR(δ，ppm，400MHz，CDCl
3)：1.106(d，J＝7.2Hz，3H，CH
3)；2.723-2.761(m，1H，CH
*CH
3)；3.339，3.419(s，6H，OCH
3)；4.469(d，J＝6.4Hz，1H，CH
*(OCH
3)
2)；9.734(d，J＝1.6Hz，1H，CHO)；
13CNMR(δ，ppm，100MHz，CDCl
3)：9.127，49.303，53.556，55.158，105.243，202.587
GC-MS：31，39，41，45，73，75(100％)，87，103
Embodiment 3～5:2, the preparation of 3-epoxy group(ing)-2-methyl isophthalic acid-methylal (3)
By 11.6g (0.1mol) 3, 3-dimethoxy-1-propylene (2) and 10ml solvent join 250 milliliters and are equipped with in churned mechanically four-hole bottle, a certain amount of epoxidation reagent adding under certain temperature, gas-chromatography is followed the tracks of reaction, after reaction finishes, add 20ml 5% sodium bisulfite to wash 2 times, again with 10ml saturated sodium bicarbonate aqueous solution washing 2 times, finally with the washing of 10ml saturated sodium-chloride water solution, anhydrous sodium sulfate drying, after reclaiming solvent, obtain 2, 3-epoxy group(ing)-2-methyl isophthalic acid-methylal crude product, measure gas phase content, calculate productive rate, result is as shown in table 1.
Product structure is confirmed:
1HNMR(δ，ppm，400MHz，CDCl
3)：1.356(s，3H，CH
3)；2.714(dd，J＝5.2Hz，J＝96.8Hz，2H，CH
2)；3.422，3.437(s，6H，OCH
3)；4.079(s，1H，CH
*(OCH
3)
2)
13CNMR(δ，ppm，100MHz，CDCl
3)：16.066，50.099，55.144，55.436，56.623，105.831
Reactant, temperature of reaction and the result of condensation reaction in table 1 embodiment 3-6
Embodiment 6-9:2-methyl-3, the preparation of 3-dimethoxy-1-propionic aldehyde (1)
Under nitrogen protection, by the 14.5g of above-mentioned preparation (0.1mol) 2, 3-epoxy group(ing)-2-methyl isophthalic acid-methylal (content 90.8%) and 20ml solvent join 250 milliliters and are equipped with in churned mechanically four-hole bottle, under cryostat insulation, add a certain amount of lewis acid catalyst stirring reaction, after gas-chromatography tracking reaction finishes, add 10 grams of sodium carbonate, continue to stir, reacting liquid filtering, filtrate is washed 2 times with 10ml saturated sodium carbonate solution, again with 10% sodium chloride aqueous solution 30ml washing, dried over mgso, reclaim solvent and obtain 2-methyl-3, 3-dimethoxy-1-propionic aldehyde crude product, 55-58 DEG C/3mmHg cut is collected in decompression, measure gas phase content, calculate productive rate, result is as shown in table 2.
Product structure is confirmed:
1HNMR(δ，ppm，400MHz，CDCl
3)：1.106(d，J＝7.2Hz，3H，CH
3)；2.723-2.761(m，1H，CH
*CH
3)；3.339，3.419(s，6H，OCH
3)；4.469(d，J＝6.4Hz，1H，CH
*(OCH
3)
2)；9.734(d，J＝1.6Hz，1H，CHO)；
13CNMR(δ，ppm，100MHz，CDCl
3)：9.127，49.303，53.556，55.158，105.243，202.587
GC-MS：31，39，41，45，73，75(100％)，87，103
Reactant, temperature of reaction and the result of condensation reaction in table 2 embodiment 7-10
Need statement, foregoing invention content and embodiment are intended to prove the practical application of technical scheme provided by the present invention, should not be construed as limiting the scope of the present invention.Those skilled in the art are in spirit of the present invention and principle, when doing various amendments, be equal to and replace or improve.
Claims (6)
1. lycopene intermediate 2-methyl-3, the preparation method of 3-dimethoxy-1-propionic aldehyde, described preparation method comprises the steps:
Step 1): 2-methyl-3 shown in formula (2), 3-dimethoxy-1-propylene carries out epoxidation reaction and obtains 2 shown in formula (3), 3-epoxy group(ing)-2-methyl isophthalic acid-methylal under organic solvent and epoxidation reagent existence at 0～30 DEG C of temperature;
Step 2): 2 shown in formula (3), 3-epoxy group(ing)-2-methyl isophthalic acid-methylal carries out rearrangement reaction and obtains 2-methyl-3 shown in formula (1), 3-dimethoxy-1-propionic aldehyde under organic solvent and Louis acid catalysis under-30～0 DEG C of temperature condition;
Reaction equation is as follows:
Wherein: described epoxidation reagent is Peracetic Acid or clorox; Described Lewis acid is magnesium bromide; Described organic solvent is ethylene dichloride, chloroform, toluene or ether.
2. preparation method according to claim 1, is characterized in that, 2-methyl-3 shown in formula (2), and the consumption mol ratio of 3-dimethoxy-1-propylene and epoxidation reagent is 0.8～1.5.
3. preparation method according to claim 2, is characterized in that, 2-methyl-3 shown in formula (2), and the consumption mol ratio of 3-dimethoxy-1-propylene and epoxidation reagent is 1.0～1.3.
4. preparation method according to claim 1, is characterized in that, described epoxidation reaction is carried out under 10～20 DEG C of conditions.
5. preparation method according to claim 1, is characterized in that, 2 shown in formula (3), and the consumption mol ratio of 3-epoxy group(ing)-2-methyl isophthalic acid-methylal and lewis acid catalyst is 0.5～1.2.
6. preparation method according to claim 5, is characterized in that, 2 shown in formula (3), and the consumption mol ratio of 3-epoxy group(ing)-2-methyl isophthalic acid-methylal and lewis acid catalyst is 0.8～1.1.
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|---|---|---|---|---|
| US4608443A (en) * | 1984-02-01 | 1986-08-26 | Degussa Aktiengesellschaft | Method for the preparation of 1,4-butandial |
| CN101041646A (en) * | 2007-04-30 | 2007-09-26 | 浙江大学 | Preparation method and usage for nitrogen-containing chalcone derivatives |
| CN101456808A (en) * | 2009-01-06 | 2009-06-17 | 长沙理工大学 | Method for preparing ibuprofen |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4608443A (en) * | 1984-02-01 | 1986-08-26 | Degussa Aktiengesellschaft | Method for the preparation of 1,4-butandial |
| CN101041646A (en) * | 2007-04-30 | 2007-09-26 | 浙江大学 | Preparation method and usage for nitrogen-containing chalcone derivatives |
| CN101456808A (en) * | 2009-01-06 | 2009-06-17 | 长沙理工大学 | Method for preparing ibuprofen |
Non-Patent Citations (5)
| Title |
|---|
| Alkaline fluoride-m-chloroperoxybenzoic acid systems as modulated oxidation reagents: epoxidation of a,b-unsaturated acetals;Francisco CAMPS等;《CHEMISTRY LETTERS》;19830731(第7期);971-974 * |
| FranciscoCAMPS等.Alkalinefluoride-m-chloroperoxybenzoicacidsystemsasmodulatedoxidationreagents:epoxidationofa b-unsaturated acetals.《CHEMISTRY LETTERS》.1983 |
| 万新民等.乙酸（α－烷基－3，3－二甲基－2－降冰片烷甲基）酯的合成.《北京大学学报(自然科学版)》.1995,第31卷(第06期),644-648. * |
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