CN101293863A - Zeaxanthin synthesizing method - Google Patents

Abstract

The invention discloses a synthetic method of zeaxanthin, comprising the following steps of: (1) adding magnesium, ethyl bromide, iodine and tetrahydrofuran into a reactor, heating, dripping ethyl bromide, reacting under constant temperature until magnesium disappears, adding C22 conjugate diine polyenic compounds, reacting under constant temperature until uniform viscous solution is formed, increasing temperature, dripping nonanone, reacting under constant temperature, decreasing temperature, dripping dilute sulfuric acid, performing liquid extraction with CH2Cl2, washing with water, and removing CH2Cl2 under reduced pressure to obtain isoflavin; and (2) adding isoflavin and organic solvent into the reactor, stirring to dissolve, cooling, adding zinc powder under stirring, dripping glacial acetic acid, keeping the temperature, filtering to obtain filtrate, neutralizing with Na2CO3, separating to obtain organic layer, washing with water, drying with anhydrous MgSO4, concentrating under reduced pressure, adding anhydrous ethyl ether, cooling, filtering, and drying to obtain zeaxanthin. The inventive method has the advantages of high total yield, good reaction selectivity, less byproducts, simple process, and convenient operation.

Description

A kind of synthetic method of zeaxanthin

Technical field

The present invention relates to the synthetic method of compound, relate in particular to a kind of synthetic method of zeaxanthin.

Background technology

Carotenoid extensively exists at nature, and the carotenoid of finding in human body mainly comprises alpha-carotene, β-Hu Luobusu, xenthophylls, zeaxanthin, kryptoxanthin and Lyeopene.Wherein β-Hu Luobusu etc. is the precursor of VA, because they can change into VA in human body, so be subjected to people's attention for a long time.Along with to the going deep into of carotenoid research, can not be converted into VA but have xenthophylls, the zeaxanthin of important physiological function to be it is found that gradually and cognitive human body.

Aspect chronic disease prevented and treated, zeaxanthin had the special role that is different from other carotenoid, has special physiological properties aspect vision protection, preventing cardiovascular disease and cancer and the strengthening immunity.Studies show that human eye retina's macular pigment is that xenthophylls (lutein) and zeaxanthin (zeaxanthin) are formed by the two kinds of xenthophylls (xanthophylls) that exist in the diet.Two kinds of pigments have the function of absorption to the blue light wave of retina injury maximum.Active oxygen radical (reactive oxygen species in the human body, be called for short ROS) be the important factor of infringement HUMAN HEALTH, and xenthophylls and maize mass-energy stop the biomembranous infringement of radical pair, and cancellation singlet oxygen and catch active oxygen radical has specific antioxygenation.

1.Isler [Helv.Chim.Acta 39 (1956) 2041 Deng having proposed a stage reduction method; Justus Liebigs Ann.Chem.603 (1957) 129] synthetic zeaxanthin, this route obtains zeaxanthin by the dehydrogenation zeaxanthin by reduction reaction.Reaction formula is as follows:

In addition, Helv.Chim.Acta 65 (7) 1982,2198-2211 also have report to prepare the method for zeaxanthin by epoxy compounds, and reaction formula is as follows:

Though these two kinds of method reactions steps are short, processing ease; But shortcoming is because raw material is difficult to obtain.

2.Widmer in the C15+C10+C15 route [Helv.Chim.Acta 73 (4) 1990,861-867.] that proposes, this route obtains zeaxanthin by two molecule C15 phosphonium salts and a part C10 through the Wittig reaction, reaction formula is as follows:

The C25+C15 route [Helv.Chim.Acta 64 (4) 1981,1092-1097.] that Ellis etc. propose, this route obtains zeaxanthin by a part C15 phosphonium salt and a part C25 aldehyde through the Wittig reaction, and reaction formula is as follows:

Many, the complicated operation of the used C15 phosphonium salt of above-mentioned two lines intermediate reactions steps, yield is low.

3.Karrer Deng what propose is the synthetic route [Helv.Chim.Acta 18 (1935), 477-479.] of raw material with the canthaxanthin, canthaxanthin is solvent with benzene, and under the situation that aluminium salt exists, reduction obtains zeaxanthin, and reaction formula is as follows:

The preparation feedback step of raw materials used canthaxanthin is many in this route, complicated operation.

Summary of the invention

The objective of the invention is the problem that exists in the above-mentioned route, a kind of synthetic method of zeaxanthin is provided.

The synthetic method of zeaxanthin comprises the steps:

1) 0.11mol Mg, 0.02～0.03mol monobromethane, 0.001～0.002mol iodine, tetrahydrofuran (THF) are added in the reactor, be heated to 30～35 ℃, drip the 0.11mol monobromethane, drip and finish, insulation reaction adds 0.05mol C until the Mg completely dissolve in batches ₂₂Conjugation diine polyenic compounds, insulation reaction until forming uniform viscous soln, is warming up to 50～60 ℃, drip 0.1～0.5moL C9 ketone, drip and finish insulation reaction 6～10 hours, be cooled to below 10～20 ℃, drip 10～20% dilute sulphuric acids, 100～300ml, use CH ₂Cl ₂Extract 2～3 times, wash 2～3 times, CH is removed in decompression ₂Cl ₂, get different flavine;

2) the different flavine of 0.04～0.05mol, organic solvent are added in the reactor, add in the reactor, stirring and dissolving, be cooled to 10～20 ℃, stir adding 0.15～0.45mol zinc powder down, drip 1～5mol Glacial acetic acid, 1～3 hour dropping time, dripped Bi Baowen 1～2 hour, and filtered, filtrate adds 10～20%Na ₂CO ₃Organic layer is told in neutralization, washes anhydrous MgSO 2～3 times ₄Drying, concentrating under reduced pressure adds anhydrous diethyl ether, is cooled to 10～20 ℃, filters, and drying gets zeaxanthin.

Described organic solvent is CH ₂Cl ₂Or CHCl ₃Organic solvent is preferably CH ₂Cl ₂

Advantage of the present invention is: 1) adopt C ₂₂The two Grignard reagents of eneyne are starting raw material, through the synthetic zeaxanthin of two-step reaction, total recovery height.2) in zeaxanthin synthetic, good reaction selectivity, by product is few.3) this method technology is simpler, easy to operate.

Embodiment

The present invention adopts following method to synthesize target product zeaxanthin (D): be raw material with two grignard compounds (B) promptly, obtain different flavine (C) with compound (A) reaction, obtain zeaxanthin (D) through reduction.Reaction formula is as follows:

Below in conjunction with embodiment the present invention is described in detail.

Embodiment 1

1) 0.11mol Mg, 0.02mol monobromethane, 0.001mol iodine, tetrahydrofuran (THF) are added in the reactor, be heated to 30 ℃, drip the 0.11mol monobromethane, drip and finish, insulation reaction is until the Mg completely dissolve, the conjugation diine polyenic compounds that in batches add 0.05mol C22, insulation reaction until forming uniform viscous soln, is warming up to 50 ℃, drip 0.1moL C9 ketone, drip and finish, insulation reaction 6 hours is cooled to below 10 ℃, drip 10% dilute sulphuric acid 100ml, with CH2Cl2 extraction 2 times, to wash 2 times, CH2Cl2 is removed in decompression, get different flavine 22.6g, yield 80.0%; M.p.:188-190 ℃.

2) the different flavine of 0.04mol, CH2Cl2 are added in the reactor, add in the reactor, stirring and dissolving is cooled to 10 ℃, stir and add the 0.15mol zinc powder down, dropping 1mol Glacial acetic acid, 1 hour dropping time, a Bi Baowen 1 hour, filter, filtrate adds the 10%Na2CO3 neutralization, tells organic layer, wash anhydrous MgSO4 drying, concentrating under reduced pressure 2 times, add anhydrous diethyl ether, be cooled to 10 ℃, filter, drying gets zeaxanthin 20.5g, yield 90.2%.m.p.：206-208℃。

Embodiment 2

1) 0.11mol Mg, 0.03mol monobromethane, 0.002mol iodine, tetrahydrofuran (THF) are added in the reactor, be heated to 35 ℃, drip the 0.11mol monobromethane, drip and finish, insulation reaction is until the Mg completely dissolve, the conjugation diine polyenic compounds that in batches add 0.05mol C22, insulation reaction until forming uniform viscous soln, is warming up to 60 ℃, drip 0.5moL C9 ketone, drip and finish, insulation reaction 10 hours is cooled to below 20 ℃, drip 20% dilute sulphuric acid 300ml, with CH2Cl2 extraction 3 times, to wash 3 times, CH2Cl2 is removed in decompression, get different flavine 26.1g, yield 92.4%; M.p.:188-190 ℃.

2) the different flavine of 0.05mol, CHCl3 are added in the reactor, add in the reactor, stirring and dissolving is cooled to 20 ℃, stir and add the 0.45mol zinc powder down, Dropwise 5 mol Glacial acetic acid, 3 hours dropping time, a Bi Baowen 2 hours, filter, filtrate adds the 20%Na2CO3 neutralization, tells organic layer, wash anhydrous MgSO4 drying, concentrating under reduced pressure 3 times, add anhydrous diethyl ether, be cooled to 20 ℃, filter, drying gets zeaxanthin 25.8g, yield 90.9%.m.p.：206-208℃。

Embodiment 3

1) in the 1000ml flask, add THF300ml, Mg 2.6g, the 2g monobromethane, 0.1g iodine, heating makes it to cause, and control reaction temperature is 30～35 ℃ then, drips remaining 12g monobromethane, drips to finish, and insulation reaction is until the Mg completely dissolve.In above-mentioned reaction solution, add 14.4g (0.05mol) C then in batches ₂₂Conjugation diine polyenic compounds (E), insulation reaction is until forming uniform viscous soln.Be warming up to 50 ℃, drip the 200ml THF solution that contains 22.8g (0.10moL) compound (A), drip and finish, insulation reaction 8 hours is cooled to below 20 ℃, drips 10% dilute sulphuric acid 100ml, 3 * 400ml CH then in reaction solution ₂Cl ₂Extraction, CH ₂Cl ₂Layer reduces pressure and removes CH with 3 * 400 washings ₂Cl ₂, get different flavine (C) 22.6g, yield 80.0%; M.p.:188-190 ℃.

2) in the 1000ml flask, add different flavine (C) 22.6g, CH ₂Cl ₂400ml, stirring and dissolving is cooled to below 20 ℃, adds the 12g zinc powder under the violent stirring, drips the 60ml Glacial acetic acid, about 1 hour dropping time, drips Bi Baowen 1 hour.The solids removed by filtration thing, filtrate adds 20%Na ₂CO ₃Be neutralized to neutrality, tell organic layer, 2 * 300ml washing, the anhydrous MgSO of 13g ₄Drying is evaporated to 60ml, adds anhydrous diethyl ether 100ml, is cooled to below 20 ℃, filters, and drying gets zeaxanthin (D) 21.0g, yield 92.5%.m.p.：206-208℃。

Embodiment 4

1) in the 1000ml flask, add THF300ml, Mg 2.6g, the 2g monobromethane, 0.1g iodine, heating makes it to cause, and control reaction temperature is 30～35 ℃ then, drips remaining 12g monobromethane, drips to finish, and insulation reaction is until the Mg completely dissolve.In above-mentioned reaction solution, add 14.4g (0.05mol) C then in batches ₂₂Conjugation diine polyenic compounds (E), insulation reaction is until forming uniform viscous soln.Be warming up to 50 ℃, drip the 300ml THF solution that contains 45.6g (0.2mol) compound (A), drip and finish, insulation reaction 8 hours is cooled to below 20 ℃, drips 10% dilute sulphuric acid 100ml, 3 * 400ml CH then in reaction solution ₂Cl ₂Extraction, CH ₂Cl ₂Layer reduces pressure and removes CH with 3 * 400 washings ₂Cl ₂, get different flavine (C) 24.3g, yield 86.3%; M.p.:188-190 ℃.

2) in the 1000ml flask, add different flavine (C) 24.3g, CHCl ₃850ml, stirring and dissolving is cooled to below 20 ℃, adds the 13g zinc powder under the violent stirring, drips the 65ml Glacial acetic acid, about 1 hour dropping time, drips Bi Baowen 1 hour.The solids removed by filtration thing, filtrate adds 20%Na ₂CO ₃Be neutralized to neutrality, tell organic layer, 2 * 300ml washing, the anhydrous MgSO of 13g ₄Drying is evaporated to 90ml, adds anhydrous diethyl ether 100ml, is cooled to below 20 ℃, filters, and drying gets zeaxanthin (D) 22.7g, yield 92.8%.m.p.：206-208℃。

Embodiment 5

1) in the 1000ml flask, add THF300ml, Mg 2.6g, the 2g monobromethane, 0.1g iodine, heating makes it to cause, and control reaction temperature is 30～35 ℃ then, drips remaining 12g monobromethane, drips to finish, and insulation reaction is until the Mg completely dissolve.In above-mentioned reaction solution, add 14.4g (0.05mol) C then in batches ₂₂Conjugation diine polyenic compounds (E), insulation reaction is until forming uniform viscous soln.Be warming up to 50 ℃, drip the 500ml THF solution that contains 91.2g (0.4mol) compound (A), drip and finish, insulation reaction 8 hours is cooled to below 20 ℃, drips 10% dilute sulphuric acid 100ml, 3 * 400ml CH then in reaction solution ₂Cl ₂Extraction, CH ₂Cl ₂Layer reduces pressure and removes CH with 3 * 400 washings ₂Cl ₂, get different flavine (C) 25.5g, yield 90.4%; M.p.:188-190 ℃.

2) in the 1000ml flask, add different flavine (C) 25.5g, CH ₂Cl ₂450ml, stirring and dissolving is cooled to below 20 ℃, adds the 14g zinc powder under the violent stirring, drips the 70ml Glacial acetic acid, about 1 hour dropping time, drips Bi Baowen 1 hour.The solids removed by filtration thing, filtrate adds 20%Na ₂CO ₃Be neutralized to neutrality, tell organic layer, 2 * 300ml washing, the anhydrous MgSO of 13g ₄Drying is evaporated to 90ml, adds anhydrous diethyl ether 100ml, is cooled to below 20 ℃, filters, and drying gets zeaxanthin (D) 23.5g, yield 91.5%.m.p.：206-208℃。

Claims (3)

1. the synthetic method of a zeaxanthin is characterized in that comprising the steps:

1) 0.11mol Mg, 0.02～0.03mol monobromethane, 0.001～0.002mol iodine, tetrahydrofuran (THF) are added in the reactor, be heated to 30～35 ℃, drip the 0.11mol monobromethane, drip and finish, insulation reaction adds 0.05mol C until the Mg completely dissolve in batches ₂₂Conjugation diine polyenic compounds, insulation reaction until forming uniform viscous soln, is warming up to 50～60 ℃, drip 0.1～0.5moL C9 ketone, drip and finish insulation reaction 6～10 hours, be cooled to below 10～20 ℃, drip 10～20% dilute sulphuric acids, 100～300ml, use CH ₂Cl ₂Extract 2～3 times, wash 2～3 times, CH is removed in decompression ₂Cl ₂, get different flavine;

2) the different flavine of 0.04～0.05mol, organic solvent are added in the reactor, add in the reactor, stirring and dissolving, be cooled to 10～20 ℃, stir adding 0.15～0.45mol zinc powder down, drip 1～5mol Glacial acetic acid, 1～3 hour dropping time, dripped Bi Baowen 1～2 hour, and filtered, filtrate adds 10～20%Na ₂CO ₃Organic layer is told in neutralization, washes anhydrous MgSO 2～3 times ₄Drying, concentrating under reduced pressure adds anhydrous diethyl ether, is cooled to 10～20 ℃, filters, and drying gets zeaxanthin.

2. the synthetic method of a kind of zeaxanthin according to claim 1 is characterized in that described organic solvent is CH ₂Cl ₂Or CHCl ₃

3. the synthetic method of a kind of zeaxanthin according to claim 1 and 2 is characterized in that described organic solvent is CH ₂Cl ₂