CN111995555A - Preparation method of vitamin A acetate - Google Patents
Preparation method of vitamin A acetate Download PDFInfo
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- CN111995555A CN111995555A CN202011005157.5A CN202011005157A CN111995555A CN 111995555 A CN111995555 A CN 111995555A CN 202011005157 A CN202011005157 A CN 202011005157A CN 111995555 A CN111995555 A CN 111995555A
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- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
- C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups
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Abstract
The invention relates to the field of organic synthesis, and discloses a method for preparing vitamin A acetate. The method comprises the following steps: in a nonpolar aprotic solvent, in the presence of crown ether, carrying out a first Wittig reaction on C14 aldehyde trans-2-methyl-4- (2,6, 6-trimethyl-1-cyclohexene) -2-butenal and C1 phosphate (tetraethyl methylenediphosphate or tetramethyl methylenediphosphate) in the presence of organic alkali to obtain a material containing C15 phosphate; wherein R is selected from C1-C3 alkyl, preferably ethyl; (2) and (2) carrying out a second Wittig reaction on the material containing the C15 phosphate ester obtained in the step (1) and the C5 aldehyde 2-methyl-4-acetoxyl-2-butenal to obtain a reaction liquid containing the vitamin A acetate. The method has the advantages of environmental friendliness and high yield, and provides convenience for large-scale production of vitamin A acetate.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a method for preparing vitamin A acetate.
Background
Vitamin a acetate is an important pharmaceutical and nutraceutical, with the following structure:
at present, two synthesis routes are commonly used in the field of vitamin A production, one is a C14 and C6 method:
the other method is C15 plus C5:
the method of adding C14 and C6 relates to more materials, long route, complex equipment and large fixed investment, and the method of adding C15 and C5 is gradually favored in recent years, however, the method of adding C15 and C5 uses triphenyl phosphorus at present, and the byproduct of triphenyl phosphorus oxide is difficult to recycle and has great influence on the environment, so people are continuously searching the process route.
CN103044302A discloses a method for preparing vitamin A acetate by a one-pot method, which utilizes C14 aldehyde and an intermediate C1 (tetraethyl methylenediphosphonate or tetramethyl methylenediphosphonate) to react under alkaline conditions to generate C15 phosphonate; the C15 phosphonate directly reacts with C5 aldehyde in a one-pot method to prepare vitamin A acetate without separation. The method adopts polar aprotic solvents such as N, N-dimethylformamide and the like, has the technical problem of complex product separation and has low yield.
In summary, the prior art methods for preparing vitamin a acetate have the following problems: triphenylphosphine is used in the reaction, the byproduct triphenylphosphine oxide is difficult to recycle and has great influence on the environment, and meanwhile, the adopted solvent system is difficult to separate, so that the yield is low and the like, therefore, a method for preparing vitamin A acetate with environmental friendliness and high yield is required to be found.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a method for preparing vitamin A acetate, which has the advantages of environmental friendliness and high yield and provides convenience for large-scale production of vitamin A acetate.
In order to achieve the above object, the present invention provides a process for preparing vitamin a acetate represented by formula (I), comprising the steps of:
(1) in a nonpolar aprotic solvent, in the presence of crown ether, carrying out a first Wittig reaction on C14 aldehyde shown in a formula (II) and C1 phosphate shown in a formula (III) in the presence of organic base to obtain a material containing C15 phosphate; wherein R is selected from C1-C3 alkyl, preferably ethyl;
(2) carrying out a second Wittig reaction on the material containing the C15 phosphate ester obtained in the step (1) and C5 aldehyde shown in a formula (IV) to obtain a reaction liquid containing vitamin A acetate
The method provided by the invention has the advantages that the two-step Wittig reaction is carried out in the nonpolar aprotic solvent in the presence of the crown ether, so that the post-reaction treatment can be realized by extraction and crystallization, on one hand, the technical problem of product damage caused by the fact that a large amount of polar aprotic solvents such as N, N-dimethylformamide and the like need to be evaporated at high temperature is avoided, and on the other hand, the process steps are simplified. The method provided by the invention has the advantages of ensuring higher product yield and simple process steps, and in addition, triphenyl phosphine is not used in the reaction of the invention, thereby avoiding the generation of byproduct triphenyl phosphine oxide and having the advantage of environmental friendliness.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The invention provides a method for preparing vitamin A acetate shown as a formula (I), which comprises the following steps:
(1) in a nonpolar aprotic solvent, in the presence of crown ether, carrying out a first Wittig reaction on C14 aldehyde shown in a formula (II) and C1 phosphate shown in a formula (III) in the presence of organic base to obtain a material containing C15 phosphate; wherein R is selected from C1-C3 alkyl, preferably ethyl;
(2) carrying out a second Wittig reaction on the material containing the C15 phosphate ester obtained in the step (1) and C5 aldehyde shown in a formula (IV) to obtain a reaction liquid containing vitamin A acetate
According to the method of the present invention, in the step (1), the nonpolar aprotic solvent may be selected from at least one of hexane, heptane, octane, toluene, and xylene, preferably toluene.
According to the method of the present invention, the amount of the non-polar aprotic solvent is not particularly limited as long as the requirement of the first Wittig reaction in the present invention can be satisfied, and preferably, the amount of the non-polar aprotic solvent may be 0.5 to 10mL, and more preferably 1 to 5mL, per gram of C14 aldehyde.
According to the process of the present invention, generally, the first Wittig reaction is carried out in the presence of a catalyst, preferably a crown ether (carbon number is preferably 8 to 24), more preferably at least one of 18-crown-6, 15-crown-5, 12-crown-4, dibenzo-18-crown-6, benzo 15-crown-5, and even more preferably 18-crown-6 or 15-crown-5.
According to the process of the present invention, there is no particular requirement for the amount of the crown ether used, as long as it can satisfy the requirements of the first Wittig reaction in the present invention, and preferably, the amount of the crown ether used may be 0.05 to 5 moles, more preferably 0.1 to 1 mole, per 100 moles of the C14 aldehyde.
According to the method of the invention, in the step (1), the temperature of the first Wittig reaction can be-50 ℃ to 100 ℃, preferably-10 ℃ to 5 ℃; the time of the first Wittig reaction is 1-10h, preferably 2-5 h.
According to the method of the present invention, in step (1), in order to obtain a more excellent reaction effect of the first Wittig reaction, the first Wittig reaction may be performed in an inert atmosphere, which is preferably provided by nitrogen.
According to the process of the present invention, in step (1), the molar ratio of the organic base to the C14 aldehyde may be (1-5): 1, preferably (2-3.5): 1.
According to the process of the present invention, the organic base may be selected from at least one of sodium tert-butoxide, potassium tert-butoxide, and sodium salt of dimethyl sulfoxide.
Among them, sodium salt of dimethyl sulfoxide can be obtained commercially, and can also be prepared by various methods commonly used in the art, for example, by the following steps: under the protection of inert gas, sodium hydride (with the content of 60 percent) is added into dimethyl sulfoxide to react for 1 to 2 hours at the temperature of between 55 and 65 ℃. The sodium salt of dimethyl sulfoxide can be prepared as it is or stored for later use, and the storage conditions can include: and (3) keeping away from light at the temperature of between 2 and 8 ℃, and protecting in a nitrogen atmosphere.
According to one embodiment of the present invention, in step (1), when the organic base is dimethylsulfoxide sodium salt, the dimethylsulfoxide sodium salt can be prepared as it is, for example, sodium hydride is added into a nonpolar aprotic solvent, stirred at 20 to 30 ℃ for 5 to 15min, left standing for 20 to 50min, the nonpolar aprotic solvent in the upper layer portion is removed, dimethylsulfoxide is added, and the reaction is carried out at 55 to 65 ℃ for 1 to 2 hours, and then cooled to 25 to 35 ℃.
According to the method, in the step (2), the temperature of the second Wittig reaction is-50 ℃ to 100 ℃, and preferably-40 ℃ to 20 ℃; the time of the second Wittig reaction is 1-10h, preferably 0.5-5 h.
According to the process of the invention, the molar ratio of the C14 aldehyde, C1 phosphate ester and C5 aldehyde may be 1: (1-5): (1-5), preferably 1: (1-1.5): (1-1.5).
According to the method of the invention, preferably, in the step (2), during the second Wittig reaction, the C5 aldehyde can be dissolved in the dissolving solvent to obtain a mixed solution of the C5 aldehyde and the dissolving solvent, and the mixed solution is added to the material containing the C15 phosphate ester obtained in the step (1) at the temperature of between 50 ℃ below zero and 30 ℃. The dissolution solvent may be the same as or different from the nonpolar aprotic solvent in step (1).
According to the method of the present invention, the method may further comprise step (3): and (3) extracting and crystallizing the reaction liquid obtained in the step (2) to obtain the vitamin A acetate shown in the formula (I).
In the present invention, preferably, the extraction treatment is carried out in the presence of an extractant selected from at least one of hexane, heptane, octane, toluene, and xylene.
In the present invention, it is preferable that the crystallization treatment is performed in the presence of a crystallization solvent selected from at least one of methanol, ethanol, and isopropanol. Preferably, the crystallization conditions may include: treatment with a crystallization solvent and extraction gives a residue of (0.5-5): 1, stirring at 20-40 ℃ for 0.5-1 hour, keeping the temperature at-25-0 ℃ for 1-5 hours, and filtering.
According to the method of the present invention, preferably, the method further comprises, before performing step (3): introducing CO into the reaction solution containing vitamin A acetate obtained in the step (2) in the presence of water2Neutralizing the gas until the pH value of the reaction liquid is 6-7, and standing and layering at 0-20 ℃.
According to a preferred embodiment of the present invention, there is provided a process for preparing vitamin A acetate represented by formula (I), comprising the steps of:
(1) first Wittig reaction: in an inert atmosphere, in the presence of 18-crown-6 or 15-crown-5, in toluene or heptane, carrying out heat preservation reaction on C14 aldehyde shown in a formula (II) and C1 phosphate shown in a formula (III) in the presence of organic base at-10 ℃ to 5 ℃ for 2-5h to obtain a material containing C15 phosphate; wherein R is ethyl; the amount of 18-crown-6 or 15-crown-5 is 0.1 to 1 mole per 100 moles of C14 aldehyde; the organic base is selected from at least one of sodium tert-butoxide, potassium tert-butoxide and the sodium salt of dimethyl sulfoxide;
(2) and (3) carrying out a second Wittig reaction: reacting the material containing C15 phosphate in the step (1) with C5 aldehyde shown in a formula (IV) at the temperature of between 40 ℃ below zero and 20 ℃ for 0.5 to 5 hours to obtain a reaction solution containing vitamin A acetate;
(3) separation: introducing CO into the reaction solution containing vitamin A acetate obtained in the step (2) in the presence of water2Neutralizing the gas until the pH of the reaction solution is 6-7, and neutralizing the reaction solution with toluene or heptaneExtracting, concentrating organic phase under reduced pressure to obtain concentrated solution, and crystallizing the concentrated solution with C1-C3 alkyl alcohol at-25 deg.C to 40 deg.C to obtain vitamin A acetate;
wherein the molar ratio of the C14 aldehyde, the organic base, the C1 phosphate ester and the C5 aldehyde is 1: (2-3.5): (1-1.5): (1-1.5).
According to a more preferred embodiment of the present invention, there is provided a process for preparing vitamin A acetate represented by formula (I), comprising the steps of:
(1) first Wittig reaction: adding a toluene or heptane solution of C1 phosphate shown in formula (III) into a mixed solution of toluene or heptane containing 18-crown-6 or 15-crown-5 and organic base at 25-35 deg.C under nitrogen atmosphere; cooling to-10 deg.C to 0 deg.C, adding C14 aldehyde represented by formula (II); then reacting for 2-5h at the temperature of-10 ℃ to 5 ℃ to obtain a material containing C15 phosphate; wherein R is ethyl; the amount of 18-crown-6 or 15-crown-5 is 0.1 to 1 mole per 100 moles of C14 aldehyde; the organic base is selected from at least one of sodium tert-butoxide, potassium tert-butoxide and the sodium salt of dimethyl sulfoxide;
(2) and (3) carrying out a second Wittig reaction: reacting the material containing C15 phosphate in the step (1) with C5 aldehyde shown in a formula (IV) at the temperature of between 40 ℃ below zero and 30 ℃ below zero for 0.5 to 5 hours to obtain a reaction solution containing vitamin A acetate;
(3) separation: introducing CO into the reaction solution containing vitamin A acetate obtained in the step (2) in the presence of water2Neutralizing the gas until the pH of the mixture is 6-7, and the temperature is 0-20 deg.CStirring for 20-30min, layering, extracting with toluene or heptane, concentrating organic phase under reduced pressure to obtain concentrated solution, decolorizing with C1-C3 alkyl alcohol at-25 deg.C to 40 deg.C with activated carbon, and crystallizing to obtain vitamin A acetate;
wherein the molar ratio of the C14 aldehyde, the organic base, the C1 phosphate ester and the C5 aldehyde is 1: (2-3.5): (1-1.5): (1-1.5).
In the present invention, the C14 aldehyde can be obtained commercially or prepared by various methods commonly used in the art, for example, citral can be used as a starting material to prepare pseudo-ionone and beta-ionone, and further obtain C14 aldehyde.
In the present invention, the C1 phosphate is commercially available or can be obtained by various methods conventionally used in the art, and can be prepared, for example, by the method disclosed in WO/97/33893.
In the present invention, the C5 aldehyde can be obtained commercially.
The present invention will be described in detail below by way of examples.
The following examples used starting materials, bases, solvents, etc. were all obtained commercially. The activated carbon is medicinal activated carbon purchased from national medicine group. Reaction monitoring by GC (gas chromatography); HPLC (liquid chromatography) is used for detecting the content of the product, and the yield is calculated by using actual yield/theoretical yield multiplied by 100%.
GC (gas chromatography): shimadzu GC-2014 (instrument model), a chromatographic column SE-30, a column length of 30m, a column diameter of 0.32mm, a particle size of 0.33um, a sample inlet temperature of 300 ℃, a split ratio of 10: 1, column pressure: 128.9kPa, DET 10-2, detector temperature 300 ℃, column temperature 160 ℃;
HPLC (liquid chromatography): shimadzu LC-20AT (instrument model), chromatography column ODS-34.6 × 250mm, particle size 5um, column temperature 30 ℃, mobile phase methanol: water 98: 2.
example 1
Under the protection of nitrogen, 70g of toluene, 117g of potassium tert-butoxide and 0.5g of 18-crown-6 are added into a dry 1000mL three-neck flask, after uniform stirring, a mixed solution of 123g of tetraethyl methylenediphosphonate and 123g of toluene is added dropwise into the system from a constant pressure dropping funnel 1 at 30 ℃ and then cooled to-5 ℃ after 30 minutes, a mixed solution of 80g of tetradecanal represented by the formula (II) and 80g of toluene is added dropwise from a constant pressure dropping funnel 2 and then kept at-5 ℃ for 2 hours, after the reaction is monitored by GC and without separation, the reaction solution is cooled to-40 ℃ and a mixed solution of 75g of pentanal represented by the formula (IV) and 75g of toluene is added dropwise into the reaction solution from a constant pressure dropping funnel 3 and then added dropwise within 30 minutes, then continuing the heat preservation reaction at-40 ℃ for 30 minutes, then pouring the mixed material into 400g of water, introducing carbon dioxide gas to neutralize the mixed material until the pH value of the system reaches 7, stirring the mixed material for 30 minutes at 15 ℃, then layering the mixed material, washing an organic layer twice by 50g of water, recovering toluene at the temperature of below 45 ℃ under reduced pressure, adding 90g of methanol and 2g of activated carbon into the residue, stirring the mixture for 30 minutes at the temperature of 30 ℃, filtering the mixture while the mixture is hot, cooling the filtrate to-18 ℃, preserving the heat for 5 hours, and filtering the mixture to obtain 124.7g of vitamin A acetate with the content of 95 weight percent and the yield of 93 percent.
Example 2
Under the protection of nitrogen, adding 90g of toluene and 42g of sodium hydride (content of 60%) into a dry 1000mL three-neck flask, stirring for 10 minutes at 25 ℃, standing for 30 minutes, extracting 45g of upper toluene clear liquid, adding 90g of dimethyl sulfoxide into the flask, heating to 60 ℃, keeping the temperature, reacting for 1 hour, reducing the temperature to 25 ℃, adding 0.5g of 15-crown-5, uniformly stirring, dropwise adding a mixed solution of 123g of tetraethyl methylenediphosphonate and 123g of toluene into the system at 30 ℃ from a constant-pressure dropping funnel 1, reducing the temperature to-5 ℃ after the dropwise addition is finished for 30 minutes, continuously dropwise adding a mixed solution of 80g of tetradecanal represented by formula (II) and 80g of toluene from a constant-pressure dropping funnel 2, keeping the temperature, reacting for 3 hours at 0 ℃, monitoring the reaction by GC, without separation, continuously reducing the temperature of the reaction solution to-40 ℃ after the dropwise addition is finished for 30 minutes, dropwise adding a mixed solution of 75g of pentanal shown in the formula (IV) and 75g of toluene into the reaction solution through a constant-pressure dropping funnel 3, finishing dropwise adding within 30 minutes, then continuing to perform heat preservation reaction at-40 ℃ for 1 hour, then pouring the materials into 400g of water, simultaneously introducing carbon dioxide gas to neutralize until the pH value of the system is 7, stirring for 30 minutes at 20 ℃, then layering, washing an organic layer twice with 50g of water, recovering toluene at 45 ℃ below under reduced pressure, adding 90g of methanol and 2g of activated carbon into the residue, stirring for 30 minutes at 30 ℃, filtering while hot, cooling the filtrate to-18 ℃, preserving heat for 5 hours, and filtering to obtain 123.5g of vitamin A acetate, wherein the content is 94.4 percent by weight, and the yield is 91.5 percent.
Example 3
Under the protection of nitrogen, 90g of heptane and 42g of sodium hydride (content: 60%) are added into a dry 1000mL three-neck flask, the mixture is stirred for 10 minutes at 25 ℃ and then kept stand for 30 minutes, 45g of supernatant heptane clear liquid is extracted, 90g of dimethyl sulfoxide is added into the flask, the mixture is heated to 65 ℃ for heat preservation reaction for 1 hour, then the temperature is reduced to 25 ℃, 0.5g of 15-crown-5 is added, a mixed solution of 123g of tetraethyl methylenediphosphonate and 123g of heptane is dropwise added into the system from an constant pressure funnel 1 at 25 ℃, the temperature is reduced to-10 ℃ after the dropwise addition is completed in 30 minutes, a mixed solution of 80g of tetradecanal represented by formula (II) and 80g of heptane is continuously dropwise added from an constant pressure funnel 2, the heat preservation reaction is carried out for 5 hours at-10 ℃, GC monitoring reaction is completed, separation is not needed, the reaction solution is continuously reduced to-40 ℃, and 75g of pentanal represented by formula (IV) and 75g of heptane are dropwise added into the reaction solution from an And (3) after dropwise adding the mixed solution of the heptane within 30 minutes, carrying out heat preservation reaction at-40 ℃ for 5 hours, then pouring the materials into 400g of water, introducing carbon dioxide to neutralize the materials until the pH value of the system is 6.5, stirring the materials at 0 ℃ for 30 minutes, then layering the materials, washing an organic layer twice by using 50g of water, recovering the heptane at the temperature of below 45 ℃, adding 90g of methanol and 2g of activated carbon into the residue, stirring the materials for 30 minutes at the temperature of 30 ℃, filtering the mixture while the mixture is hot, cooling the filtrate to-18 ℃, preserving the temperature for 5 hours, and filtering the mixture to obtain 124g of vitamin A acetate, wherein the content of the vitamin A acetate is 92 weight percent, and the yield of the vitamin.
Example 4
Under the protection of nitrogen, adding 90g of toluene and 42g of sodium hydride (with the content of 60%) into a dry 1000mL three-neck flask, stirring for 10 minutes at 25 ℃, standing for 30 minutes, extracting 45g of upper toluene clear liquid, adding 90g of dimethyl sulfoxide into the flask, heating to 60 ℃, preserving heat, reacting for 1 hour, reducing the temperature to 25 ℃, adding 0.5g of 15-crown-5, uniformly stirring, dropwise adding a mixed solution of 123g of tetraethyl methylenediphosphonate and 123g of toluene into the system at 30 ℃ from a constant-pressure dropping funnel 1, reducing the temperature to-5 ℃ after the dropwise addition is finished for 30 minutes, continuously dropwise adding a mixed solution of 80g of tetradecanal represented by formula (II) and 80g of toluene from a constant-pressure dropping funnel 2, preserving heat, reacting for 4 hours at 2 ℃, monitoring the reaction by GC, without separation, continuously reducing the temperature of the reaction solution to-30 ℃, dropwise adding a mixed solution of 75g of pentanal shown in the formula (IV) and 75g of toluene into the reaction solution through a constant-pressure dropping funnel 3, continuously cooling to-40 ℃ within 30 minutes, continuously preserving heat at-40 ℃ for reaction for 1 hour, then pouring the materials into 400g of water, simultaneously introducing carbon dioxide for neutralization until the pH value of the system is 6.5, stirring for 30 minutes at 10 ℃, then layering, washing an organic layer twice with 50g of water, recovering toluene at the temperature of below 45 ℃, adding 78g of methanol and 2g of activated carbon into the residue, stirring for 30 minutes at 30 ℃, filtering while hot, cooling the filtrate to-18 ℃, preserving heat for 5 hours, and filtering to obtain 122.2g of vitamin A acetate with the content of 94.4 weight percent and the yield of 90.6 percent.
Example 5
Under the protection of nitrogen, 70g of toluene, 75g of sodium tert-butoxide and 0.1g of 18-crown-6 are added into a dry 1000mL three-neck flask, after uniform stirring, a mixed solution of 111.7g of tetraethyl methylenediphosphonate and 123g of toluene is added dropwise into the system from a constant pressure dropping funnel 1 at 25 ℃, after the completion of dropping for 30 minutes, the temperature is reduced to-5 ℃, a mixed solution of 80g of tetradecanal represented by the formula (II) and 80g of toluene is continuously dropped from a constant pressure dropping funnel 2, after the completion of dropping for 2 hours, the temperature is kept at-2 ℃ for 4 hours, after the completion of the reaction monitored by GC, separation is not required, the reaction solution is continuously reduced to-40 ℃, a mixed solution of 82.67g of pentanal represented by the formula (IV) and 75g of toluene is dropped into the reaction solution from a constant pressure dropping funnel 3, after the completion of dropping within 30 minutes, the temperature is continuously kept at-40 ℃ for 2 hours, then the materials are poured into 400g of water, carbon dioxide gas is introduced to neutralize until the pH value of the system is 6.5, the materials are stirred for 30 minutes at 20 ℃ and then layered, an organic layer is washed twice by 50g of water, toluene is recovered under reduced pressure at the temperature of below 45 ℃, 90g of methanol and 2g of activated carbon are added into the residue, the mixture is stirred for 30 minutes at the temperature of 30 ℃, the mixture is filtered while the mixture is hot, the temperature of the filtrate is reduced to-18 ℃, the temperature is kept for 5 hours, and the vitamin A acetate 112.4g is obtained by filtering, the content is 92 weight percent, and the yield is 81.2 percent.
Example 6
Under the protection of nitrogen, 70g of heptane, 152g of potassium tert-butoxide and 1g of 18-crown-6 are added into a dry 1000mL three-neck flask, after uniform stirring, a mixed solution of 167.6g of tetraethyl methylenediphosphonate and 123g of heptane is added dropwise into the system from an isopiestic dropping funnel 1 at 30 ℃ and is cooled to-5 ℃ after 30 minutes, a mixed solution of 80g of tetradecanal represented by the formula (II) and 80g of heptane is added dropwise from an isopiestic dropping funnel 2 and is kept warm for reaction at-5 ℃ for 2.5 hours after 2 hours, after the reaction is monitored by GC and is finished, the reaction solution is cooled to-40 ℃ continuously without separation, a mixed solution of 55.1g of pentanal represented by the formula (IV) and 75g of heptane is added dropwise into the reaction solution from an isopiestic dropping funnel 3 and is kept warm for reaction for 30 minutes after 30 minutes, then the materials are poured into 400g of water, carbon dioxide gas is introduced to neutralize until the pH value of the system is 6, the materials are stirred for 30 minutes at 15 ℃ and then layered, an organic layer is washed twice by 50g of water, heptane is recovered under reduced pressure at 45 ℃, 90g of methanol and 2g of activated carbon are added into the residue, the mixture is stirred for 30 minutes at 30 ℃, the mixture is filtered while the mixture is hot, the temperature of the filtrate is reduced to-18 ℃, the temperature is kept for 5 hours, and the mixture is filtered to obtain 123.8g of vitamin A acetate, the content of the vitamin A acetate is 93 weight percent, and the yield of the vitamin A acetate is 90.4 percent.
Example 7
The procedure of example 1 was followed, except that 70g of toluene, 117g of potassium t-butoxide, 0.5g of a mixed solution of 18-crown-6, 123g of tetraethyl methylenediphosphonate and 123g of toluene, and 80g of a mixed solution of tetradecanal represented by the formula (II) and 80g of toluene were sequentially charged into a dry 1000mL three-necked flask at-5 ℃ and the reaction was maintained at-5 ℃ for 2.5 hours, followed by monitoring by GC to complete the reaction, to obtain a C15 phosphate-containing material.
103.7g of vitamin A acetate was finally obtained, the content was 91% by weight, and the yield was 74.1%.
Example 8
The procedure is as in example 1, except that 18-crown-6 is replaced by the same molar amount of 12-crown-4.
98g of vitamin A acetate was finally obtained, with a content of 91% by weight and a yield of 70.1%.
Comparative example 1
The method is carried out in a mode that crown ether is not added and the alkali is mixed alkali of sodium hydride and sodium tert-butoxide.
70g of toluene and 16.1g of sodium hydrogen (content: 60%) were added to a dry 1000mL three-necked flask under nitrogen protection, the mixture was stirred at 25 ℃ for 10 minutes and allowed to stand for 30 minutes, 50g of the supernatant toluene was extracted, a mixed solution of 80g of tetradecanal, 123g of tetraethyl methylenediphosphonate and 200g of toluene was added dropwise to the above system from a dropping funnel 1 at 35 ℃, after completion of the addition, the reaction was kept at 25 ℃ for 4 hours, the reaction mixture was poured into 240g of ice water, carbon dioxide was simultaneously introduced to adjust the pH of the aqueous phase to 7 to 7.5, the mixture was allowed to stand for separation, the organic layer was washed twice with 50g of water, and the reaction mixture was concentrated under reduced pressure at 70 ℃ to give 129g of C15 phosphate as a yellow oil with an HPLC content of 94%.
Adding 70g of toluene and 60g of sodium tert-butoxide into a dry 1000mL three-neck flask under the protection of nitrogen, stirring uniformly, continuously cooling the reaction solution to-10 ℃, dropwise adding a mixed solution of 129g of C15 phosphate and 300g of toluene solution into the reaction solution by a dropping funnel 2, keeping the temperature at-10 ℃ for 2 hours after the dropwise adding is finished for 30 minutes, cooling the reaction temperature to-45 ℃, continuously dropwise adding a mixed solution of 75g of pentanal and 75g of toluene by a dropping funnel 3, keeping the temperature at-30 ℃ for reaction for 15 minutes after the dropwise adding is finished, then pouring the materials into 400g of water, simultaneously introducing carbon dioxide to neutralize the pH of the system to 7, stirring at 15 ℃ for 30 minutes, demixing, washing the organic layer twice by 50g of water, recovering toluene at 45 ℃ below, adding 90g of methanol and 2g of activated carbon into the remainder under reduced pressure, stirring for 30 minutes at 30 ℃, filtering while hot, cooling the filtrate to-18 ℃, preserving the heat for 5 hours, and filtering to obtain 91.6g of vitamin A acetate with the content of 94.5 weight percent and the yield of 68 percent.
Comparative example 2
The method is carried out in a mode that crown ether is not added and a solvent is N, N-dimethylformamide.
Under the protection of nitrogen, 388g of N, N-dimethylformamide and 79.1g of solid sodium ethoxide are added into a 2000 ml three-neck flask, the mixture is cooled, the temperature is kept between minus 5 ℃ and 5 ℃, a mixed solution prepared by 80g of tetradecanal, 134.2g of tetraethyl methylenediphosphonate and 388g of N, N-dimethylformamide is dripped in 2 hours, the temperature is kept between minus 5 ℃ and 5 ℃ for reaction for 2.5 hours after the dripping is finished, the obtained intermediate C15 phosphonate is directly cooled to minus 20 ℃ without separation, a mixed solution of 66g of pentanal and 194g of N, N-dimethylformamide is dripped in 1 hour, the temperature is kept at minus 5 ℃ for 2-3 hours, the N, N-dimethylformamide is recovered by reduced pressure distillation at the temperature of 75 ℃ under the condition of 5 mm Hg until no fraction is distilled, cooling to room temperature, adding 776g of saturated aqueous ammonium chloride solution and 776g of ethyl acetate, stirring at 0-20 ℃ for 1 hour, then layering, extracting the water layer twice with 194g of ethyl acetate, combining the organic phases, adding 39g of anhydrous sodium sulfate, drying for 4 hours, filtering, recovering ethyl acetate, adding 350g of 95% ethanol into the residue, stirring and dissolving at 30 ℃, adding 7.7g of activated carbon, stirring at 30 ℃ for 30 minutes, filtering while hot, cooling the filtrate to-5 ℃, preserving the heat for 5 hours, and filtering to obtain 97.6g of vitamin A acetate with the content of 93 weight percent and the yield of 71.2 percent.
Comparative example 3
The procedure is as in example 1, except that 18-crown-6 is not added during the first Witting reaction.
95.7g of vitamin A acetate was finally obtained, the content being 90.5% by weight, the yield being 68%.
Comparative example 4
The procedure of example 1 was followed except that toluene was replaced with an equal amount of N, N-dimethylformamide.
Vitamin A acetate 65.9g, 85% by weight content, 44% yield was obtained.
Comparative example 5
The procedure is as in example 1, except that potassium tert-butoxide is replaced by the same molar amount of sodium hydride.
105.2g of vitamin A acetate was finally obtained, with a content of 92% by weight and a yield of 76%.
Comparative example 6
The procedure of example 1 was followed, except that 18-crown-6 was replaced with the same molar amount of benzyltriethylammonium chloride.
94.5g of vitamin A acetate was finally obtained, with a content of 93% by weight and a yield of 69%.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A process for preparing vitamin a acetate of formula (I), comprising the steps of:
(1) in a nonpolar aprotic solvent, in the presence of crown ether, carrying out a first Wittig reaction on C14 aldehyde shown in a formula (II) and C1 phosphate shown in a formula (III) in the presence of organic base to obtain a material containing C15 phosphate; wherein R is selected from C1-C3 alkyl, preferably ethyl;
(2) carrying out a second Wittig reaction on the material containing the C15 phosphate ester obtained in the step (1) and C5 aldehyde shown in a formula (IV) to obtain a reaction liquid containing vitamin A acetate
2. The process according to claim 1, wherein in step (1), the non-polar aprotic solvent is selected from at least one of hexane, heptane, octane, toluene and xylene, preferably toluene;
and/or the amount of the apolar aprotic solvent is from 0.5 to 10mL, preferably from 1 to 5mL, per gram of C14 aldehyde.
3. The method according to claim 1 or 2, wherein in step (1), the crown ether is selected from at least one of 18-crown-6, 15-crown-5, 12-crown-4, dibenzo-18-crown-6, benzo 15-crown-5, preferably 18-crown-6 or 15-crown-5.
4. The process according to any one of claims 1 to 3, wherein the crown ether is used in an amount of 0.05 to 5 moles, preferably 0.1 to 1 mole, per 100 moles of C14 aldehyde.
5. The process according to any one of claims 1 to 4, wherein in step (1), the temperature of the first Wittig reaction is between-50 ℃ and 100 ℃, preferably between-10 ℃ and 5 ℃;
and/or the time of the first Wittig reaction is 1-10h, preferably 2-5 h;
and/or, the first Wittig reaction is carried out in an inert atmosphere, preferably provided by nitrogen.
6. The process according to any one of claims 1 to 5, wherein in step (1), the organic base is selected from at least one of sodium tert-butoxide, potassium tert-butoxide and sodium salt of dimethyl sulfoxide.
7. The process according to any one of claims 1 to 6, wherein in step (2), the temperature of the second Wittig reaction is between-50 ℃ and 100 ℃, preferably between-40 ℃ and 20 ℃;
and/or the time of the second Wittig reaction is 0.1-10h, preferably 0.5-5 h.
8. The process of any one of claims 1 to 7, wherein the molar ratio of C14 aldehyde, C1 phosphate ester and C5 aldehyde is 1: (1-5): (1-5), preferably 1: (1-1.5): (1-1.5).
9. The method according to any one of claims 1-8, wherein the method further comprises step (3): extracting and crystallizing the reaction liquid obtained in the step (2) to obtain vitamin A acetate shown in a formula (I);
preferably, the extraction treatment is carried out in the presence of an extractant selected from at least one of hexane, heptane, octane, toluene and xylene;
preferably, the crystallization treatment is performed in the presence of a crystallization solvent selected from at least one of methanol, ethanol, and isopropanol.
10. A process for preparing vitamin a acetate of formula (I), comprising the steps of:
(1) first Wittig reaction: in an inert atmosphere, in the presence of 18-crown-6 or 15-crown-5, in toluene or heptane, carrying out heat preservation reaction on C14 aldehyde shown in a formula (II) and C1 phosphate shown in a formula (III) in the presence of organic base at-10 ℃ to 5 ℃ for 2-5h to obtain a material containing C15 phosphate; wherein R is ethyl; the amount of 18-crown-6 or 15-crown-5 is 0.1 to 1 mole per 100 moles of C14 aldehyde; the organic base is selected from at least one of sodium tert-butoxide, potassium tert-butoxide and dimethyl sulfoxide sodium salt;
(2) and (3) carrying out a second Wittig reaction: reacting the material containing C15 phosphate in the step (1) with C5 aldehyde shown in a formula (IV) at the temperature of between 40 ℃ below zero and 20 ℃ for 0.5 to 5 hours to obtain a reaction solution containing vitamin A acetate;
(3) separation: introducing CO into the reaction solution containing vitamin A acetate obtained in the step (2) in the presence of water2Neutralizing the gas until the pH of the reaction solution is 6-7, extracting with toluene or heptane, concentrating the organic phase under reduced pressure to obtain concentrated solution, and crystallizing the concentrated solution with C1-C3 alkyl alcohol at-25 deg.C to 40 deg.C to obtain vitamin A acetate;
wherein the molar ratio of the C14 aldehyde, the organic base, the C1 phosphate ester and the C5 aldehyde is 1: (2-3.5): (1-1.5): (1-1.5).
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| CN114031534A (en) * | 2021-11-19 | 2022-02-11 | 万华化学集团股份有限公司 | High-stability vitamin A and preparation method thereof |
| WO2023108327A1 (en) * | 2021-12-13 | 2023-06-22 | 万华化学集团股份有限公司 | Preparation method for light-colored vitamin a |
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