CN102924249A - 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, a kind of 2-methyl-3 as lycopene intermediate particularly, the preparation method of 3-dimethoxy-1-propionic aldehyde.
Background technology
2-methyl-3,3-dimethoxy-1-propionic aldehyde has good application prospect as pharmaceutical-chemical intermediate, and its molecular structure is unique, has two kinds of groups of aldehyde and acetal, is particularly suitable for making up double bond systems.Shen Run is broad in the recent period waits the people to report a kind of with 2-methyl-3 in CN201110157489.X, 3-dimethoxy-1-propionic aldehyde is the novel method that raw material prepares Lyeopene, it is the representative instance that this compounds is used as medicine intermediate, 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; The report such as Ojima is 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 synthetic used device fabrication difficulty is large, and is 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 defective that above-mentioned prior art exists, and provides the 2-methyl-3 that a kind of operational path is simple and direct, raw material is easy to get, 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 may further comprise the steps:
(1) in the presence of organic solvent and epoxidation reagent to 3 shown in the formula (2), 3-dimethoxy-1-propylene carries out epoxidation under 0～30 ℃ of temperature condition;
(2) under organic solvent and Louis acid catalysis to 2 shown in the formula (3), 3-epoxy group(ing)-2-methyl isophthalic acid-methylal is reset the formula of obtaining (1) 2-methyl-3 under-30～0 ℃ 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 the formula (2), the consumption mol ratio of 3-dimethoxy-1-propylene and epoxidation reagent is 0.8～1.5.
More preferably, 3 shown in the 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 ℃ 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 the 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 ℃ 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 only is used for technical scheme of the present invention is described, and non-limiting the present invention.
Employed analytical instrument and equipment are among each embodiment of the present invention: gas chromatograph-mass spectrometer, MS5973N-GC6890N (U.S. Agilent company); Nuclear magnetic resonance analyser, AVANCEDMX II I 400M (mark in the 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)
With 58g (0.5mol) 3,3-dimethoxy-1-propylene (2) and 50ml ethylene dichloride join 1000 milliliters and are equipped with in the churned mechanically four-hole bottle, 20 ℃ of lower dichloroethane solution 600ml that drip 103g (0.6mol) metachloroperbenzoic acid that contains, 1.5 drip off about hour, gas-chromatography is followed the tracks of reaction, approximately reaction in 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, with the washing of 50ml saturated sodium-chloride water solution, anhydrous sodium sulfate drying obtains 2 behind the recovery ethylene dichloride at last, 3-epoxy group(ing)-2-methyl isophthalic acid-methylal crude product 58.2g, be 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; 30g (0.2mol) 2 with above-mentioned preparation; 3-epoxy group(ing)-2-methyl isophthalic acid methylal and 50ml ethylene dichloride join 500 milliliters and are equipped with in the churned mechanically four-hole bottle; cryostat is incubated about-30 ℃ and added 13.2g (0.1mol) boron trifluoride diethyl etherate liquid stirring reaction 10 minutes; then add 20 gram yellow soda ash; continue to stir 30 minutes; reacting liquid filtering; filtrate is washed 2 times with the 50ml saturated sodium carbonate solution; wash with 10% sodium chloride aqueous solution 30ml again; 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 ℃/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)
With 11.6g (0.1mol) 3,3-dimethoxy-1-propylene (2) and 10ml solvent join 250 milliliters and are equipped with in the churned mechanically four-hole bottle, a certain amount of epoxidation reagent that under certain temperature, adds, gas-chromatography is followed the tracks of reaction, after reaction finishes, adding 20ml washs 2 times with 5% sodium bisulfite, again with 10ml saturated sodium bicarbonate aqueous solution washing 2 times, with the washing of 10ml saturated sodium-chloride water solution, anhydrous sodium sulfate drying obtains 2 behind the recovery solvent at last, 3-epoxy group(ing)-2-methyl isophthalic acid-methylal crude product, measure gas phase content, calculate productive rate, the 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 among the table 1 embodiment 3-6
Embodiment 6-9:2-methyl-3, the preparation of 3-dimethoxy-1-propionic aldehyde (1)
Under nitrogen protection; 14.5g (0.1mol) 2 with above-mentioned preparation; 3-epoxy group(ing)-2-methyl isophthalic acid-methylal (content 90.8%) and 20ml solvent join 250 milliliters and are equipped with in the churned mechanically four-hole bottle; the a certain amount of lewis acid catalyst stirring reaction of the lower adding of cryostat insulation; after gas-chromatography is followed the tracks of the reaction end; add 10 gram yellow soda ash; continue to stir; reacting liquid filtering; filtrate is with 10ml saturated sodium carbonate solution washing 2 times, 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 ℃/3mmHg cut is collected in decompression, measures gas phase content; calculate productive rate, the 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 among the table 2 embodiment 7-10
What need statement is that 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 the restriction to protection domain of the present invention.Those skilled in the art are in spirit of the present invention and principle, when doing various modifications, being equal to and replacing 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): 3 shown in the formula (2), 3-dimethoxy-1-propylene obtain 2 shown in the formula (3), 3-epoxy group(ing)-2-methyl isophthalic acid-methylal carrying out epoxidation reaction in the presence of organic solvent and the epoxidation reagent under 0～30 ℃ of temperature;
Step 2): 2 shown in the formula (3), 3-epoxy group(ing)-2-methyl isophthalic acid-methylal obtains the 2-methyl-3 shown in the formula (1), 3-dimethoxy-1-propionic aldehyde carrying out rearrangement reaction under organic solvent and the Louis acid catalysis under-30～0 ℃ of temperature condition;
Reaction equation is as follows:
Wherein: described epoxidation reagent comprises metachloroperbenzoic acid, Peracetic Acid, clorox; Described Lewis acid comprises boron trifluoride diethyl etherate, magnesium bromide; Described solvent comprises methylene dichloride, ethylene dichloride, chloroform, toluene, ether.
2. preparation method according to claim 1 is characterized in that, 3 shown in the 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, 3 shown in the 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 ℃ of conditions.
5. preparation method according to claim 1 is characterized in that, 2 shown in the 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 the 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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113203A (en) * | 2013-03-12 | 2013-05-22 | 黑龙江大学 | Synthetic method for 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone |
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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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2011
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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 |
Non-Patent Citations (3)
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|---|
| FRANCISCO CAMPS等: "Alkaline fluoride-m-chloroperoxybenzoic acid systems as modulated oxidation reagents: epoxidation of a,b-unsaturated acetals", 《CHEMISTRY LETTERS》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113203A (en) * | 2013-03-12 | 2013-05-22 | 黑龙江大学 | Synthetic method for 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone |
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