阅读说明：本技术 一种β-胡萝卜素的制备方法 (Preparation method of beta-carotene ) 是由 接鲸瑞 王嘉辉 张弈宇 潘亚男 张涛 于 2021-08-30 设计创作，主要内容包括：本发明公开了一种β-胡萝卜素的制备方法,该方法包括：将维生素A有机膦盐加入水中,同时加入过硼酸盐,使维生素A有机膦盐发生氧化偶联反应制得β-胡萝卜素。该方法在过硼酸盐的存在下,催化维生素A有机膦盐氧化偶联生成β-胡萝卜素,其中,过硼酸盐在水相中可同时发挥催化剂和缓慢释放氧化剂的作用,可有效避免生成的β-胡萝卜素被氧化,从而提高产物收率。(The invention discloses a preparation method of beta-carotene, which comprises the following steps: adding the vitamin A organic phosphine salt into water, and simultaneously adding perborate to perform oxidative coupling reaction on the vitamin A organic phosphine salt to prepare the beta-carotene. The method catalyzes vitamin A organic phosphonium salt to carry out oxidative coupling to generate the beta-carotene in the presence of perborate, wherein the perborate can play the roles of a catalyst and a slow release oxidizer in a water phase, and can effectively prevent the generated beta-carotene from being oxidized, thereby improving the yield of the product.)

1. A method for preparing beta-carotene, which is characterized by comprising the following steps:

adding the vitamin A organic phosphine salt shown in the formula I into water, and simultaneously adding perborate to perform oxidative coupling reaction on the vitamin A organic phosphine salt to prepare beta-carotene;

in the formula I, R₁、R₂And R₃Each independently is C₁～C₁₀Substituted or unsubstituted alkyl, C₃～C₁₀Substituted or unsubstituted cycloalkane group of (A) or (C)₆～C₁₀Substituted or unsubstituted aryl of (a); x is halogen, sulfate radical, hydrogen sulfate radical, phosphate radical, tetrafluoroborate radical, acetate radical, toluene sulfonate radical or benzene sulfonate radical.

2. The method for preparing beta-carotene according to claim 1, wherein said perborate is one or more of sodium perborate, potassium perborate, and lithium perborate, preferably sodium perborate.

3. The method for producing β -carotene according to claim 2, wherein said perborate is added in an amount of 1.5 to 2.5 times, preferably 1.8 to 2.0 times, the molar amount of the vitamin a organophosphine salt.

4. The process for the preparation of β -carotene according to any one of claims 1 to 3, wherein said oxidative coupling reaction is carried out at a reaction temperature of 5 to 15 ℃, preferably 5 to 10 ℃; the reaction time is 10-18h, preferably 12-15 h.

5. The method of claim 4, further comprising filtering, washing with alcohol, and drying the product of the oxidative coupling reaction to obtain the beta-carotene product.

6. The process for producing β -carotene according to any one of claims 1 to 3, wherein said vitamin A organophosphine salt is produced by reacting vitamin A, an organophosphine and a strong acid in an alcoholic solvent.

7. The method for producing β -carotene according to claim 6, wherein said vitamin A is at least one of vitamin A alcohol, vitamin A acetate, or a crystallization mother liquor containing any one or more of them.

8. The method of claim 7, wherein the strong acid is one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, xylenesulfonic acid, and benzenesulfonic acid.

9. The process for the preparation of β -carotene according to claim 6, characterized in that said organophosphine is used in an amount of 1 to 1.5 times, preferably 1.05 to 1.2 times, the molar amount of vitamin A;

preferably, the amount of the strong acid is 1.1 to 1.5 times, preferably 1.1 to 1.3 times, the mass of the vitamin A.

10. The method for preparing beta-carotene according to claim 6, wherein in the reaction for preparing the vitamin A organophosphine salt, firstly, vitamin A and organophosphine are mixed in an alcohol solvent, the temperature of the system is controlled to be-10-5 ℃, then strong acid is added into the reaction system within 0.5-1h, and the reaction is continued for 5-12h at room temperature.

Technical Field

The invention relates to a preparation method, in particular to a preparation method of beta-carotene, belonging to the technical field of organic synthesis.

Background

The beta-carotene is an important component of carotenoid, can be used in the fields of medicines, foods, cosmetics, feed additives, dyes and the like, and has very wide development prospect.

At present, the synthesis method of beta-carotene mainly comprises routes of C15+ C10+ C15 and C20+ C20, and due to the symmetrical structure of the beta-carotene, after the vitamin A triphenylphosphine salt is obtained by the reaction of the vitamin A and triphenylphosphine, the process route of carrying out oxidative coupling reaction on two molecules of organic phosphine salt to generate the beta-carotene is more concise, and the reaction expression is as follows:

patents CN101041631A and CN108047112A adopt the above method to prepare β -carotene, but the reaction is performed by using strong oxidants such as nitrate, persulfate, hypochlorite, etc., and the generated β -carotene is easily oxidized, so the reaction yield is low.

Patent CN101081829A adopts the above scheme to prepare beta-carotene by two-phase reaction, but in the two-phase reaction, alkali and oxidant are in water phase, organic phosphonium salt and active intermediate are in organic phase, and the beta-carotene can not be generated in time, and the reaction yield is low.

Patents CN108822015A and CN110452147A adopt molecular oxygen as an oxidant to perform a two-phase reaction to prepare β -carotene, and in the patents, a noble metal catalyst and a phase transfer catalyst are used, so the process is complex, the cost is high, and the method is not suitable for industrial production.

Patent CN112262126A adopts nano silver colloid as catalyst and hydrogen peroxide stabilizer, and the catalytic reaction simultaneously inhibits the decomposition of hydrogen peroxide and the occurrence of oxidation side reaction, but the method has high cost and is not beneficial to industrial production.

Disclosure of Invention

The technical problem to be solved by the invention is how to prepare the beta-carotene with high purity and high yield under the condition of ensuring that the beta-carotene is not oxidized.

In order to solve the technical problems, the invention provides a preparation method of beta-carotene. The method catalyzes vitamin A organic phosphonium salt to carry out oxidative coupling to generate the beta-carotene in the presence of perborate, wherein the perborate can play the roles of a catalyst and a slow release oxidizer in a water phase, and can effectively prevent the generated beta-carotene from being oxidized, thereby improving the yield of the product.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a method for preparing beta-carotene, comprising:

adding the vitamin A organic phosphine salt shown in the formula I into water, and simultaneously adding perborate to perform oxidative coupling reaction on the vitamin A organic phosphine salt to prepare beta-carotene;

in the formula I, R₁、R₂And R₃Each independently is C₁～C₁₀Substituted or unsubstituted alkyl, C₃～C₁₀Substituted or unsubstituted cycloalkane group of (A) or (C)₆～C₁₀More preferably each independently is C₁～C₅Substituted or unsubstituted alkyl, C₃～C₈Substituted or unsubstituted cycloalkane group of (A) or (C)₆～C₁₀Substituted or unsubstituted aryl of (a); x is halogen, sulfate radical, hydrogen sulfate radical, phosphate radical, tetrafluoroborate radical, acetate radical, toluene sulfonate radical or benzene sulfonate radical.

Said C is₁～C₅Specific examples of the substituted or unsubstituted alkyl group of (a) include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl and the like. Said C is₃～C₈Specific examples of the substituted or unsubstituted cycloalkane group include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like. Said C is₆～C₁₀Specific examples of substituted or unsubstituted aryl groups include, but are not limited to: phenyl, o-tolyl, m-tolyl, p-tolyl, o-ethylphenyl, m-ethylphenyl, p-ethylphenyl, naphthyl and the like.

The vitamin A organophosphine salt may be obtained commercially or may be prepared by various methods known in the art, for example, by reacting vitamin A alcohol and/or vitamin A acetate with an organophosphine. In an industrial continuous preparation process, it is preferred that the reaction solution containing the vitamin a organophosphine salt is first prepared by reacting vitamin a alcohol and/or vitamin a acetate with an organophosphine, and then the β -carotene is further prepared by an oxidative coupling reaction.

Perborate is slightly soluble in water and the aqueous solution is alkaline and releases hydrogen peroxide continuously during its slow reaction with water. The invention utilizes the property that perborate reacts with water to be alkaline and slowly release hydrogen peroxide, and is used for a reaction system for generating beta-carotene by oxidative coupling of vitamin A organic phosphine salt, on one hand, the perborate can play the role of an alkaline catalyst in a water phase, other alkaline catalysts are not required to be additionally added, the production cost is reduced, the production process is simplified, on the other hand, the released hydrogen peroxide can be used as a reaction oxidant to oxidize the organic phosphine salt into an active intermediate for condensation reaction, and simultaneously, the content of the hydrogen peroxide in the system can be controlled to be maintained in a lower range, so that the generated beta-carotene is effectively prevented from being oxidized, and the product yield is improved.

In a preferred embodiment of the invention, the perborate is one or more of sodium perborate, potassium perborate, lithium perborate, preferably sodium perborate.

In a preferred embodiment of the invention, the perborate is added in an amount of 1.5 to 2.5 times, preferably 1.8 to 2.0 times, the molar amount of the vitamin A organophosphine salt.

In a preferred embodiment of the invention, the reaction temperature of the oxidative coupling reaction is 5 to 15 ℃, preferably 5 to 10 ℃; the reaction time is 10-18h, preferably 12-15 h.

In a preferred embodiment of the present invention, the process further comprises sequentially filtering, washing with alcohol, and drying the product of the oxidative coupling reaction to obtain the β -carotene product. After the oxidative coupling reaction is finished, the solid is mainly a mixture of organic phosphine oxide and beta-carotene and contains a small amount of organic impurities, and inorganic salt and most of impurities exist in a mobile phase; after the reaction, the solid is obtained by simple filtration, organic phosphine oxides and organic impurities are removed by adding methanol for reflux, and the beta-carotene solid can be obtained by filtration and drying.

In a preferred embodiment of the present invention, the vitamin A organophosphine salt is prepared by reacting vitamin A, an organophosphine and a strong acid in an alcoholic solvent.

In a preferred embodiment of the present invention, the vitamin a is at least one of vitamin a alcohol, vitamin a acetate or a crystallization mother liquor comprising any one or more of them.

In a preferred embodiment of the invention, the organophosphine is a phosphine molecule wherein all hydrogen atoms are optionally C₁～C₁₀Substituted or unsubstituted alkyl, C₃～C₁₀Substituted or unsubstituted cycloalkane group, C₆～C₁₀Substituted or unsubstituted aryl substituted trivalent organophosphorus compounds, preferably one or more of triphenylphosphine, triethylphosphine, tributylphosphine, tri-tert-butylphosphine and tricyclohexylphosphine, more preferably triphenylphosphine.

In a preferred embodiment of the invention, the strong acid is one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, xylenesulfonic acid, benzenesulfonic acid.

Preferably, the alcoholic solvent is one or more of methanol, ethanol, propanol and isopropanol, preferably methanol; the amount of the alcohol solvent is 4-10 times, preferably 5-6 times of the weight of vitamin A.

In a preferred embodiment of the invention, the organophosphine is used in an amount of 1 to 1.5 times, preferably 1.05 to 1.2 times, the molar amount of vitamin A;

preferably, the amount of the strong acid is 1.1 to 1.5 times, preferably 1.1 to 1.3 times, the mass of the vitamin A.

In a preferred embodiment of the invention, in the preparation reaction of the vitamin A organophosphine salt, firstly, vitamin A and organophosphine are mixed in an alcohol solvent, the temperature of the system is controlled to be-10-5 ℃, then strong acid is added into the reaction system within 0.5-1h, and the reaction is continued for 5-12h at room temperature.

Compared with the prior art, the invention has the following beneficial effects:

1. the perborate reacts with water to slowly release hydrogen peroxide as a reaction oxidant, so that strong oxidants such as hypochlorite, nitrate, organic peroxide and the like are avoided, and the safety is good; and the hydrogen peroxide is always kept at a lower concentration in the reaction, so that the generation of oxidation side reaction and the oxidation of the generated beta-carotene are effectively inhibited, and the reaction yield is high.

2. The perborate can play the role of an oxidant and an alkaline catalyst simultaneously in a water phase, an additional alkaline catalyst is not required to be added, the process is simple, and the production cost is reduced.

3. The reaction is carried out under normal pressure, the whole reaction process can be completed in one device, the reaction process is simple, the requirement on a reactor is low, the safety is good, and the method is more favorable for industrial production.

Detailed Description

The present invention is further illustrated by the following specific examples, which are intended to be illustrative of the invention and are not to be construed as limiting the scope of the invention.

First, main material information in the embodiment:

vitamin A acetate (280 ten thousand IU) purity of 98%, VA crystallization mother liquor (comprising 42 wt% all-trans VA acetate, 38 wt% 13-cis VA acetate, and 14 wt% trans VA alcohol) was purchased from Xinjiang and GmbH; vitamin A alcohol with purity not less than 96% is purchased from Xiamen Jindawei vitamin Co Ltd;

triphenylphosphine, purity > 99%, purchased from Beijing YinuoKai science and technology Limited;

NaBO₃·4H₂o and NaBO₃·H₂O was purchased from Shanghai Aladdin Biotechnology GmbH;

other starting materials and reagents are all general commercially available chemically pure reagents or can be prepared from commercially available chemically pure reagents.

II, a main analysis method and an apparatus:

and (3) liquid chromatography characterization: an Agilent 1260 type liquid chromatograph, a chromatographic column Sphersorb C18 column (phi 4.6 multiplied by 250mm), an ultraviolet visible light splitting detector Hitachi L7420, a chromatographic workstation data processing system ChomatoPd C-RIA and a stationary phase Zorbax-SIL. Chromatographic conditions are as follows: the mobile phase was a methanol/acetonitrile 9/1(v/v) mixture, the detection temperature was 40 ℃, the flow rate was 1mL/min, and the wavelength was 455 nm. And carrying out qualitative and quantitative analysis on the product.

[ preparative example 1 ] preparation of KBO₃·4H₂O solid

Weighing 8.1g KBO₂Dissolving the solid in 100mL of distilled water, adding 5g of magnesium silicate into the solution, and stirring at constant temperature of 15 ℃ for 30 min; keeping the temperature for 30min, and adding 11.34g of 30% aqueous hydrogen peroxide solution into the reaction system; after the dropwise addition is finished, the reaction is carried out for 5 hours under the condition of heat preservation, the temperature is reduced to be below 0 ℃, and KBO is obtained by filtering and drying₃·4H₂And (4) O solid.

[ preparative example 2 ] preparation of LiBO₃·4H₂O solid

5g of LiBO are weighed out₂Dissolving the solid in 100mL of distilled water, adding 6g of magnesium silicate into the solution, and stirring at constant temperature of 15 ℃ for 30 min; keeping the temperature for 30min, and adding 11.34g of 30% aqueous hydrogen peroxide solution into the reaction system; after the dropwise adding is finished, the reaction is carried out for 5 hours under the condition of heat preservation, the temperature is reduced to be below 0 ℃, and LiBO is obtained by filtering and drying₃·4H₂And (4) O solid.

[ example 1 ]

Adding 134.0g of vitamin A acetate (0.4mol, 98%), 125.8g of triphenylphosphine (0.48mol) and 670.0g of methanol into a 2L reaction kettle, cooling to 0 ℃ under stirring, maintaining the temperature at 0-5 ℃, slowly adding 44g of concentrated sulfuric acid (0.44mol, 98%) into the system, and finishing dropping within 1 h; then reacting for 8 hours at 25 ℃ to obtain organic phosphonium salt reaction liquid.

After the obtained organic phosphonium salt reaction solution is desolventized, 1206.0g of water is added, the temperature is reduced to 5 ℃, 126.9g of NaBO is added into the reaction system₃·4H₂O (0.8mol, 97%) for 12 h; and filtering the reaction solution, adding 300g of methanol into the obtained filter cake, refluxing for 2 hours, filtering and drying to obtain 100.3g of beta-carotene, wherein the purity is 97.5 percent by HPLC detection, and the total yield is 91.2 percent.

[ example 2 ]

The vitamin A acetate in example 1 was replaced with 139.8g of VA mother liquor for crystallization under the same conditions as above to prepare an organic phosphonium salt reaction solution.

After the obtained organic phosphonium salt reaction solution is desolventized, 1206.0g of water is added, the temperature is reduced to 5 ℃, 126.9g of NaBO is added into the reaction system₃·4H₂O (0.8mol, 97%) for 12 h; filtering the reaction solution, adding 300g of methanol into the obtained filter cake, refluxing for 2h, and filteringFiltering and drying to obtain 99.0g of beta-carotene, the purity is 96.9 percent by HPLC detection, and the total yield is 89.5 percent.

[ example 3 ]

The vitamin A acetate in example 1 was replaced with 119.4g of vitamin A alcohol under the same conditions as above to prepare an organic phosphine salt reaction solution.

After the obtained organic phosphonium salt reaction solution is desolventized, 1206.0g of water is added, the temperature is reduced to 5 ℃, 126.9g of NaBO is added into the reaction system₃·4H₂O (0.8mol, 97%) for 12 h; and filtering the reaction solution, adding 300g of methanol into the obtained filter cake, refluxing for 2 hours, filtering and drying to obtain 99.5g of beta-carotene, wherein the purity is 98.0% by HPLC (high performance liquid chromatography) detection, and the total yield is 91.0%.

[ example 4 ]

Adding 134.0g of vitamin A acetate (0.4mol, 98%), 104.9g of triphenylphosphine (0.4mol) and 536.0g of ethanol into a 2L reaction kettle, cooling to 0 ℃ under stirring, maintaining the temperature at 0-5 ℃, slowly adding 59.2g of concentrated hydrochloric acid (0.6mol, 37%) into the system, and finishing dropwise adding within 1 h; then reacting for 7h at 25 ℃ to obtain organic phosphonium salt reaction liquid.

After the obtained organic phosphonium salt reaction solution was desolventized, 670.0g of water was added, the temperature was lowered to 5 ℃ and 175.1g of KBO was added to the reaction system₃·4H₂O (1.0mol, 97%) for 10 h; and filtering the reaction solution, adding 300g of methanol into the obtained filter cake, refluxing for 2 hours, filtering and drying to obtain 97.3g of beta-carotene, wherein the purity is 97.3 percent according to HPLC detection, and the total yield is 88.3 percent.

[ example 5 ]

134.0g of vitamin A acetate (0.4mol, 98%), 157.4g of triphenylphosphine (0.6mol) and 1340.0g of isopropanol were added to a 2L reaction vessel, and then the mixture was cooled to 0 ℃ with stirring, and 61.2g of hydrobromic acid (0.52mol, 68.8%) was slowly added to the system while maintaining the temperature at 0 to 5 ℃ until the dropwise addition was completed within 1 hour; then reacting for 12h at 25 ℃ to obtain organic phosphonium salt reaction liquid.

After the obtained organic phosphonium salt reaction solution was desolventized, 1340.0g of water was added, the temperature was reduced to 15 ℃ and 85.3g of LiBO was added to the reaction system₃·4H₂O (0.6mol, 97%) for 18 h; filtering the reaction solution, adding 300g of methanol into the obtained filter cake, refluxing for 2h, filtering and drying to obtain the beta-carotene98.5g, purity of 97.0% by HPLC, total yield 89.1%.

[ example 6 ]

Adding 134.0g of vitamin A acetate (0.4mol, 98%), 110.1g of triphenylphosphine (0.42mol) and 804.0g of methanol into a 2L reaction kettle, cooling to 0 ℃ under stirring, maintaining the temperature at 0-5 ℃, slowly adding 44g of concentrated sulfuric acid (0.44mol, 98%) into the system, and finishing dropping within 1 h; then reacting for 10 hours at 25 ℃ to obtain organic phosphonium salt reaction liquid.

After the obtained organic phosphonium salt reaction solution was desolventized, 938.0g of water was added, the temperature was lowered to 10 ℃, 114.2g of NaBO was added to the reaction system₃·4H₂O (0.72mol, 97%) for 15 h; and filtering the reaction solution, adding 300g of methanol into the obtained filter cake, refluxing for 2 hours, filtering and drying to obtain 99.0g of beta-carotene, wherein the purity is 98.0% by HPLC detection, and the total yield is 90.5%.

[ example 7 ]

Adding 134.0g of vitamin A acetate (0.4mol, 98%), 115.3g of triphenylphosphine (0.44mol) and 804.0g of methanol into a 2L reaction kettle, cooling to 0 ℃ under stirring, maintaining the temperature at 0-5 ℃, slowly adding 44g of concentrated sulfuric acid (0.44mol, 98%) into the system, and finishing dropping within 1 h; then reacting for 9 hours at 25 ℃ to obtain organic phosphonium salt reaction liquid.

After the obtained organic phosphonium salt reaction solution is desolventized, 1072.0g of water is added, the temperature is reduced to 8 ℃, 78.2g of NaBO is added into the reaction system₃·H₂O (0.76mol, 97%) for 13 h; and filtering the reaction solution, adding 300g of methanol into the obtained filter cake, refluxing for 2 hours, filtering and drying to obtain 100.8g of beta-carotene, wherein the purity is 97.8 percent according to HPLC detection, and the total yield is 92.0 percent.

Comparative example 1

Adding 134.0g of vitamin A acetate (0.4mol, 98%), 125.8g of triphenylphosphine (0.48mol) and 670.0g of methanol into a 2L reaction kettle, cooling to 0 ℃ under stirring, maintaining the temperature at 0-5 ℃, slowly adding 44g of concentrated sulfuric acid (0.44mol, 98%) into the system, and finishing dropping within 1 h; then reacting for 8 hours at 25 ℃ to obtain organic phosphonium salt reaction liquid.

After the obtained organic phosphonium salt reaction solution is desolventized, 1206.0g of water is added, the temperature is reduced to 5 ℃, 90.69g of hydrogen peroxide (0.8mol, 30%) and 84.8g N are added into the reaction systema₂CO₃(0.8mol) reacting for 12 h; and filtering the reaction solution, adding 300g of methanol into the obtained filter cake, refluxing for 2 hours, filtering and drying to obtain 58.6g of beta-carotene, wherein the purity is 97% by HPLC detection, and the total yield is 53%.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the method of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.