A process for the preparation of 2,4-dibond pentadecaphosphonic acid ester

Abstract

The application discloses a preparation method of 2,4-dibond fifteen carbon phosphonate, which uses methylenediphosphonic acid tetraethyl ester and 2-methyl-4-(2,6,6-trimethyl-3-hydroxycyclohexene-1-yl)-2-butene aldehyde (referred to as fourteen carbon aldehyde) as raw materials, and generates Wittig-Horner reaction, and then is hydrolyzed to obtain 2,4-dibond fifteen carbon phosphonate. In the process that the methylenediphosphonic acid tetraethyl ester and the fourteen carbon aldehyde generate Wittig-Horner reaction, a transposition catalyst is introduced, and then the hydrolysis is carried out to obtain 2,4-dibond fifteen carbon phosphonate with a content of more than 98%, which avoids the 2,4-dibond fifteen carbon phosphonate generated by the Wittig-Horner reaction in the prior art, and improves the product quality due to the influence of by-products in a subsequent vitamin A acetate or beta-carotene synthesis process caused by the residual fifteen carbon aldehyde isomer at other positions, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of vitamin A acetate and β-carotene synthesis technology, and particularly to a method for preparing a 2,4-didouble-bonded pentadecylphosphonate. Background Technology

[0002] C5-phosphate, chemically named 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-1,3-pentadiene phosphate dialkyl ester or 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2,4-pentadiene phosphate dialkyl ester, are isomers. Among them, 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2,4-pentadiene phosphate dialkyl ester is an important intermediate in the synthesis of vitamin A acetate and β-carotene. Existing technology indicates that, under alkaline conditions, the Wittig-Horner reaction between tetraethyl methylene bisphosphonate and tetradecaldehyde yields a 1,3-didouble-bonded pentadecphosphonate. Under strong base catalysis, this 1,3-didouble-bonded pentadecphosphonate dissociates into a carbanion, which then rearranges through an intermediate transition state to form a more stable 2,4-didouble-bonded pentadecphosphonate carbanion at position 1. This carbanion then reacts with hydrogen ions to become the target product, 2,4-didouble-bonded pentadecphosphonate. The reaction process is shown in the following equation:

[0003]

[0004] There are two main methods:

[0005] (1) Using 4-(2,6,6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-buten-2-one as a starting material, methyl chloroacetate undergoes a Darzens reaction in the presence of a base to give 2-methyl-4-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2-butenal (abbreviated as tetradecanoal); the latter reacts with methylene diphosphate in the presence of a base to undergo a Wittig-Horner reaction to give 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-1,3-pentadienphosphonic acid dialkyl ester, which is rearranged to give 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2,4-pentadienphosphonic acid dialkyl ester. The overall yield of the two steps is approximately 83%.

[0006] (2) In the presence of sodium methoxide and cyclohexane as solvent, tetraethyl methylene diphosphonate (tetraethyl methylene diphosphonate) is activated into a carbanion. Tetradecanoic aldehyde (2-methyl-4-(2,2,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-aldehyde) is added dropwise to induce a Wittig-Horner reaction. After hydrolysis, 2,4-didouble bond pentadecylphosphonate with a content of over 93% is obtained.

[0007] In the subsequent synthesis of vitamin A acetate or β-carotene, 2,4-didouble-bonded pentadecylphosphonate reacts with pentaldehyde to form vitamin A acetate, and with decadecaldehyde to form all-trans β-carotene. Other pentadecylphosphonate isomers react with pentaldehyde to form vitamin A acetate with other configurations, and with decadecaldehyde to form cis β-carotene. These other different configurations of vitamin A acetate and different cis β-carotene exist as byproducts and require purification or transposition to remove them. Therefore, residual pentadecylphosphonate isomers will significantly affect the subsequent synthesis of vitamin A acetate or β-carotene. The effects of different contents of 2,4-didouble-bonded pentadecylphosphonate on the synthesized vitamin A acetate and β-carotene products are shown in Tables 1 and 2.

[0008] Table 1. Effects of different contents of 2,4-didouble-bonded pentadecylphosphonate on the synthesis of vitamin A acetate.

[0009]

[0010] Table 2. Effects of different contents of 2,4-didouble-bonded pentadecylphosphonate on the synthesis of β-carotene.

[0011]

[0012] Both of the above-mentioned methods for synthesizing 2,4-didouble-bonded pentadecyl phosphonates use tetradecyl aldehydes and methylene bisphosphonates as raw materials. Their shortcomings are as follows:

[0013] 1. Method (1) The method involves first synthesizing 1,3-didouble-bonded pentadecylphosphonate, and then rearranging it to obtain 2,4-didouble-bonded pentadecylphosphonate. The two-step reaction is adopted, and the overall yield is only about 83%, which is low. Moreover, the residual by-products will be converted into oily substances or other cis-position β-carotene in the subsequent synthesis process of vitamin A acetate or β-carotene, which affects the quality of the product.

[0014] 2. Although method (2) uses a one-step method to synthesize 2,4-didouble bond pentadecylphosphonate, the content of 2,4-didouble bond pentadecylphosphonate obtained in the one-step method is only 93%. The remaining 7% of other isomers will introduce about 7% of byproducts at different positions into the subsequent process of synthesizing β-carotene, thus affecting the content of the target product. It is necessary to add a product transposition or purification process to purify the β-carotene product to the range of ≥96% required by the national standard. Summary of the Invention

[0015] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing 2,4-didouble-bonded pentadecylphosphonate. In the process of reacting tetraethyl methylene bisphosphonate with tetradecyl aldehyde in a Wittig-Horner reaction, a transposition catalyst is introduced. After hydrolysis, 2,4-didouble-bonded pentadecylphosphonate with a content of more than 98% is obtained. This reduces the impact on the product content in the subsequent synthesis of vitamin A acetate or β-carotene, effectively improves the process level, and is therefore suitable for industrial production.

[0016] The objective of this invention is achieved through the following technical solution:

[0017] This invention provides a method for preparing a 2,4-didouble-bonded pentadecylphosphonate, comprising the following steps:

[0018] (1) Wittig-Horner reaction

[0019] (1-1) According to the mass ratio of tetraethyl methylene diphosphonate: solvent: sodium methoxide = 1:1~1.5:0.5~0.6, after mixing tetraethyl methylene diphosphonate and solvent evenly, sodium methoxide is added and dissolved completely, and then the mixture is cooled to -10℃ to obtain mixture A.

[0020] (1-2) According to the mass ratio of tetradecaldehyde: solvent: transposition catalyst = 1:1~1.5:0.1~0.5, tetradecaldehyde and solvent are mixed evenly, and then the transposition catalyst is added and completely dissolved. After cooling to -10℃, a mixture B is obtained; wherein, the transposition catalyst is a quaternary ammonium salt, crown ether, or metal catalyst.

[0021] (1-3) Add the mixture B dropwise into the mixture A at a rate of 35-40 L / h. After the addition is complete, keep the mixture at -10°C for 2-6 hours to obtain the reaction solution.

[0022] (2) Hydrolysis reaction

[0023] The reaction solution was subjected to a hydrolysis reaction with water added to the reaction solution at a mass ratio of 1:0.5-1. The reaction endpoint was determined by gas chromatography, which showed that the content of 2,4-didouble-bonded pentadecylphosphonate was greater than or equal to 98%. After the hydrolysis reaction was completed, the layers were separated to obtain an upper extract phase and a lower raffinate phase. The lower raffinate phase was added to a solvent for a second extraction to obtain a secondary extract phase and a raffinate. The upper extract phase and the secondary extract phase were mixed, and the solvent was recovered by distillation to obtain 2,4-didouble-bonded pentadecylphosphonate. The raffinate was sent to the wastewater recovery system.

[0024] Furthermore, the solvents used in this invention are chloroform, trichloroethane, ethyl acetate, butyl acetate, toluene, and cyclohexane. The quaternary ammonium salts are benzyltriethylammonium bromide and tetrabutylammonium bromide, the crown ethers are 15-crown ether-5 and 18-crown ether-6, and the metal catalysts are cuprous iodide, copper acetate, ferric chloride, and titanium tetrachloride.

[0025] The present invention has the following beneficial effects:

[0026] This invention introduces a transposition catalyst during the Wittig-Horner reaction of tetraethyl methylene diphosphonate and tetradecyl aldehyde. After hydrolysis, a 2,4-didouble-bonded pentadecyl phosphonate with a content ≥98% is obtained, while the levels of other pentadecyl phosphonate isomers are reduced to below 2%. The obtained 2,4-didouble-bonded pentadecyl phosphonate can be reacted with pentadecyl or decadecyl aldehydes to directly obtain qualified vitamin A acetate (content >280 M IU / g) or β-carotene (content >98%). This improves product quality, reduces subsequent product synthesis and purification steps, simplifies the process, effectively enhances the technological level, and is suitable for industrial production.

[0027] The present invention will now be described in further detail with reference to embodiments. Detailed Implementation

[0028] Example 1:

[0029] This embodiment describes a method for preparing a 2,4-didouble-bonded pentadecylphosphonate, the steps of which are as follows:

[0030] (1) Wittig-Horner reaction

[0031] (1-1) After mixing 102g of tetraethyl methylene diphosphonate with 102g of chloroform, add 51g of sodium methoxide and dissolve completely, then cool to -10℃ to obtain mixture A;

[0032] (1-2) After mixing 72g tetradecaldehyde and 72g chloroform evenly, add 14.4g of the transposition catalyst benzyltriethylammonium bromide and dissolve completely, then cool to -10℃ to obtain mixture B;

[0033] (1-3) Slowly add the above mixture B dropwise into mixture A over a period of 4 hours. After the addition is complete, keep the mixture at -10°C for 4 hours to obtain the reaction solution.

[0034] (2) Hydrolysis reaction

[0035] 248g of water was added to the above reaction solution for hydrolysis. The reaction endpoint was defined as a content of 2,4-didouble-bonded pentadecylphosphonate greater than or equal to 98% as detected by gas chromatography. After the hydrolysis reaction, the layers separated into an upper extract phase and a lower raffinate phase. The lower raffinate phase was subjected to a second extraction with chloroform to obtain a secondary extract phase and a raffinate. The upper extract phase and the secondary extract phase were mixed, and the solvent was recovered by distillation to obtain a solution with a content of [missing information]. 98.2% 2,4-Didouble-bonded pentadecyl phosphonate; the raffinate enters the wastewater recovery system.

[0036] Example 2:

[0037] This embodiment describes a method for preparing a 2,4-didouble-bonded pentadecylphosphonate, the steps of which are as follows:

[0038] (1) Wittig-Horner reaction

[0039] (1-1) After mixing 102g of tetraethyl methylene diphosphonate and 102g of butyl acetate evenly, add 51g of sodium methoxide and dissolve completely, then cool to -10℃ to obtain mixture A;

[0040] (1-2) After mixing 72g tetradecaldehyde and 72g butyl acetate evenly, add 14.4g of the transposition catalyst 15-crown ether-5 and dissolve it completely, then cool to -10℃ to obtain mixture B;

[0041] (1-3) Slowly add the above mixture B dropwise into mixture A over a period of 4 hours. After the addition is complete, keep the mixture at -10°C for 5 hours to obtain the reaction solution.

[0042] (2) Hydrolysis reaction

[0043] 248g of water was added to the above reaction solution for hydrolysis. The reaction endpoint was determined by gas chromatography, which showed that the content of 2,4-didouble-bonded pentadecylphosphonate was greater than or equal to 98%. After the hydrolysis reaction, the layers were separated to obtain an upper extract phase and a lower raffinate phase. Butyl acetate was added to the lower raffinate phase for a second extraction to obtain a secondary extract phase and a raffinate. The upper extract phase and the secondary extract phase were mixed and distilled to recover the solvent, resulting in 2,4-didouble-bonded pentadecylphosphonate with a content of 98.5%. The raffinate was then sent to the wastewater recovery system.

[0044] Example 3:

[0045] This embodiment describes a method for preparing a 2,4-didouble-bonded pentadecylphosphonate, the steps of which are as follows:

[0046] (1) Wittig-Horner reaction

[0047] (1-1) After mixing 102g of tetraethyl methylene diphosphonate with 102g of toluene evenly, add 51g of sodium methoxide and dissolve completely, then cool to -10℃ to obtain mixture A;

[0048] (1-2) After mixing 72g tetradecaldehyde and 72g toluene evenly, add 14.4g of the transposition catalyst cuprous iodide and dissolve completely, then cool to -10℃ to obtain mixture B;

[0049] (1-3) Slowly add the above mixture B dropwise into mixture A over a period of 4 hours. After the addition is complete, keep the mixture at -10°C for 3 hours to obtain the reaction solution.

[0050] (2) Hydrolysis reaction

[0051] 248g of water was added to the above reaction solution for hydrolysis. The reaction endpoint was determined by gas chromatography, which showed that the content of 2,4-didouble-bonded pentadecylphosphonate was greater than or equal to 98%. After the hydrolysis reaction, the layers were separated to obtain an upper extract phase and a lower raffinate phase. Toluene was added to the lower raffinate phase for a second extraction to obtain a secondary extract phase and a raffinate. The upper extract phase and the secondary extract phase were mixed and distilled to recover the solvent, resulting in 2,4-didouble-bonded pentadecylphosphonate with a content of 98.0%. The raffinate was then sent to the wastewater recovery system.

[0052] The 2,4-didouble-bonded pentadecylphosphonate obtained in the embodiments of the present invention was reacted with 2,7-dimethyl-2,4,6-octtrien-1,8-dialdehyde and 4-acetoxy-2-methyl-2-butenal, respectively, and the contents of β-carotene and vitamin A acetate obtained are shown in Table 2.

[0053] Table 2. Content of β-carotene and vitamin A acetate

[0054]

Claims

1. A method for preparing a 2,4-didouble-bonded pentadecylphosphonate, characterized in that... Includes the following steps: (1) Wittig-Horner reaction (1-1) According to the mass ratio of tetraethyl methylene diphosphonate: solvent: sodium methoxide = 1:1~1.5:0.5~0.6, after mixing tetraethyl methylene diphosphonate and solvent evenly, sodium methoxide is added and dissolved completely, and then the mixture is cooled to -10℃ to obtain mixture A; (1-2) According to the mass ratio of tetradecaldehyde: solvent: transposition catalyst = 1:1~1.5:0.1~0.5, tetradecaldehyde and solvent are mixed evenly, and then the transposition catalyst is added and completely dissolved. After cooling to -10℃, a mixture B is obtained; wherein the transposition catalyst is a quaternary ammonium salt, crown ether or metal catalyst. (1-3) Add the mixture B dropwise into the mixture A at a rate of 35-40 L / h. After the addition is complete, keep the mixture at -10°C for 2-6 hours to obtain the reaction solution. (2) Hydrolysis reaction The reaction solution was subjected to a hydrolysis reaction with water added to the reaction solution at a mass ratio of 1:0.5-1. The reaction endpoint was determined by gas chromatography, which showed that the content of 2,4-didouble-bonded pentadecylphosphonate was greater than or equal to 98%. After the hydrolysis reaction was completed, the layers were separated into an upper extract phase and a lower raffinate phase. The lower raffinate phase was added to a solvent for a second extraction to obtain a secondary extract phase and a raffinate. The upper extract phase and the secondary extract phase were mixed, and the solvent was recovered by distillation to obtain 2,4-didouble-bonded pentadecylphosphonate. The raffinate was sent to the wastewater recovery system.

2. The method for preparing 2,4-didouble-bonded pentadecylphosphonate according to claim 1, characterized in that: The solvent is chloroform, trichloroethane, ethyl acetate, butyl acetate, toluene, or cyclohexane.

3. The method for preparing 2,4-didouble-bonded pentadecylphosphonate according to claim 1, characterized in that: The quaternary ammonium salt is benzyltriethylammonium bromide or tetrabutylammonium bromide, the crown ether is 15-crown ether-5 or 18-crown ether-6, and the metal catalyst is cuprous iodide, copper acetate, ferric chloride or titanium tetrachloride.

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