CN115160200A - Preparation method of vitamin A palmitate - Google Patents
Preparation method of vitamin A palmitate Download PDFInfo
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- CN115160200A CN115160200A CN202210984683.3A CN202210984683A CN115160200A CN 115160200 A CN115160200 A CN 115160200A CN 202210984683 A CN202210984683 A CN 202210984683A CN 115160200 A CN115160200 A CN 115160200A
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- Prior art keywords
- vitamin
- palmitate
- reaction
- steps
- acetate
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- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 title claims abstract description 38
- VYGQUTWHTHXGQB-UHFFFAOYSA-N Retinol hexadecanoate Natural products CCCCCCCCCCCCCCCC(=O)OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229940108325 retinyl palmitate Drugs 0.000 title claims abstract description 19
- 235000019172 retinyl palmitate Nutrition 0.000 title claims abstract description 19
- 239000011769 retinyl palmitate Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims abstract description 28
- FLIACVVOZYBSBS-UHFFFAOYSA-N Methyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC FLIACVVOZYBSBS-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 21
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 229960000342 retinol acetate Drugs 0.000 claims abstract description 15
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 claims abstract description 15
- 235000019173 retinyl acetate Nutrition 0.000 claims abstract description 15
- 239000011770 retinyl acetate Substances 0.000 claims abstract description 15
- 235000021314 Palmitic acid Nutrition 0.000 claims abstract description 14
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims abstract description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910004373 HOAc Inorganic materials 0.000 claims abstract description 13
- 238000010791 quenching Methods 0.000 claims abstract description 11
- 230000000171 quenching effect Effects 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 238000003760 magnetic stirring Methods 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 claims 1
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 25
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 235000019169 all-trans-retinol Nutrition 0.000 description 8
- 239000011717 all-trans-retinol Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- 239000002274 desiccant Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229960003471 retinol Drugs 0.000 description 4
- 235000020944 retinol Nutrition 0.000 description 4
- 239000011607 retinol Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 150000004370 vitamin A ester derivatives Chemical class 0.000 description 2
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of vitamin A palmitate, belonging to the technical field of medicines and comprising the following steps: the method comprises the following steps: using vitamin A acetate as a raw material to react with methyl palmitate under the catalysis of NaOMe or KOMe, wherein the reaction formula is as follows:
(ii) a Step two: quenching the product of step one using HOAc, palmitic acid, or a mixture of both. The invention has the advantages of reducing cost and avoiding environmental pollution; the operation is simplified, and the product quality is improved.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of vitamin A palmitate.
Background
Retinol is a vitamin essential to the human body. However, retinol is unstable and is easily subjected to degradation, isomerization, and other reactions under conditions such as light irradiation and oxidation. The form of vitamin a ester is somewhat more stable than retinol, which can be hydrolyzed to retinol in vivo. Vitamin a esters have two common forms: vitamin A acetate and vitamin A palmitate, wherein the vitamin A palmitate is generally synthesized by using the vitamin A acetate as a raw material. The currently used more ways are: the vitamin A acetate is hydrolyzed into vitamin A alcohol, and then the vitamin A alcohol reacts with palmitic acid under the enzyme catalysis to prepare the vitamin A palmitate. However, vitamin A alcohol is unstable, and the vitamin A alcohol is easy to deteriorate under the conditions of heat, light, oxidation and the like in the operation process, so that the product quality is influenced.
The patent numbers are: WO2014023772A1 discloses a method of synthesizing vitamin a palmitate: at least one hydroxide and/or at least one alkaline earth metal hydroxide (e.g., naOH, KOH, ca (OH)) dissolved in at least one alcohol 2 Etc.) and reacting the vitamin A acetic ester with methyl palmitate under the conditions of vacuum and 50-55 ℃ to obtain the vitamin A palmitate. After the reaction is finished, adding water and CO into the reaction system 2 Extracting the gas by using normal hexane, drying the organic phase by using a drying agent, and performing rotary evaporation and drying to remove the normal hexane to obtain the product. The method has the following defects:
firstly, solid NaOH and the like need to be dissolved in alcohol, a large amount of alcohol is needed, the cost is high, and the environment is polluted;
secondly, water is introduced into the reaction system, a drying agent is needed for drying, the operation is complex, and the post-treatment cost is increased;
thirdly, as the vitamin A alcohol and the methyl palmitate are dissolved in normal hexane, the method has certain residue of the vitamin A alcohol and the methyl palmitate, and the quality of the obtained product is often poor.
Disclosure of Invention
In order to solve the serious defects of the prior art, the invention aims to provide a preparation method of vitamin A palmitate, which adopts a commercially available NaOMe solid or NaOMe/MeOH solution to catalyze the reaction, can save the process of dissolving NaOH and other solids in alcohol, reduce the dosage of alcohol, reduce the cost and avoid environmental pollution; meanwhile, the method uses HOAc, palmitic acid or a mixture of the HOAc and the palmitic acid to quench the reaction, so that water is prevented from being generated in the system, and a drying agent is not required to be used for drying the product, thereby simplifying the operation and reducing the post-treatment cost; finally, the method adopts one solvent or a mixture of two or more solvents of methanol, ethanol, acetonitrile and the like to wash and remove main impurities in the reactions of vitamin A alcohol, methyl palmitate, naOAc and the like. The product quality is improved.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of vitamin A palmitate comprises the following steps: the method comprises the following steps: using vitamin A acetate as a raw material to react with methyl palmitate under the catalysis of NaOMe or KOMe, wherein the reaction formula is as follows:
step two: quenching the product of step one using HOAc, palmitic acid, or a mixture of both.
Preferably, the main impurities in the reaction are removed by washing with one or more solvents selected from methanol, ethanol or acetonitrile.
Preferably, in the first step, after the vitamin A acetate and the methyl palmitate are mixed, a methanol solution of NaOMe is dripped under magnetic stirring, after the addition, the mixture is vacuumized by an oil pump, the vacuum degree is kept at 100 to 2000 Pa, the mixture is stirred for 3 to 5 h at the temperature of between 50 and 55 ℃, and after the reaction is finished, the reaction system is cooled to between 20 and 30 ℃ by water.
Preferably, HPLC shows vitamin a acetate < 1% indicates the end of the reaction.
Preferably, the quenching reaction in step two comprises the steps of:
step three: dripping HOAc, palmitic acid or a mixture of the HOAc and the palmitic acid into the system after the reaction in the step one is finished for quenching, and stirring for 5-10 min;
step four: the system was washed with MeOH and dried by rotary evaporation to give the product.
The invention has the technical effects and advantages that:
(1) The reaction can be catalyzed by commercial NaOMe solid or NaOMe/MeOH solution. The method can save the process of dissolving solids such as NaOH and the like in alcohol, reduce the using amount of the alcohol, reduce the cost and avoid environmental pollution;
(2) The method uses HOAc, palmitic acid or a mixture of the HOAc and the palmitic acid to quench the reaction, and can avoid water generation in the system, so that a drying agent is not needed to dry the product, the operation is simplified, and the post-treatment cost is reduced.
(3) Because the vitamin A palmitate is not mutually soluble with methanol and the like. Therefore, the invention adopts one solvent or a mixture solvent of two or more than two of methanol, ethanol, acetonitrile and the like to wash and remove main impurities in reactions such as vitamin A alcohol, methyl palmitate, naOAc and the like, thereby improving the product quality.
Drawings
FIG. 1 is a reaction mechanism diagram for preparing vitamin A palmitate according to the invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
As shown in fig. 1, a method for preparing vitamin a palmitate comprises the following steps:
the method comprises the following steps: the vitamin A acetate is taken as a raw material and reacts with methyl palmitate under the catalysis of NaOMe or KOMe, and the reaction mechanism is as follows:
step two: quenching the product of step one using HOAc, palmitic acid, or a mixture of both. The specific implementation procedure is shown in example 1 and example 2.
Example 1
Vitamin A acetate (10 g, 30.44 mmol, 1.0 eq) and methyl palmitate (10.7 g, 39.572 mmol, 1.3 eq) were placed in a three-necked flask and a solution of NaOMe in methanol (0.5 g, 2.8 mmol, 0.09 eq) was added dropwise with magnetic stirring. When the dripping is carried out, the system is obviously changed into brown from light yellow, after the addition is finished, the oil pump is used for vacuumizing, the vacuum degree is kept between 100 and 2000 Pa, the temperature is kept between 50 and 55 ℃, and the stirring is carried out for 3 to 5 h. HPLC showed that vitamin A acetate < 1% indicated the end of the reaction and the reaction was cooled to 20-30 ℃ with water.
HOAc (0.5 g, 0.27 eq) is added into the system to quench, and the mixture is stirred for 5-10 min. The system was washed with MeOH (50 mL x 3) and rotary evaporation dried to give 12 g. The product purity is 97.8 percent, and the yield is 75 percent.
Example 2
Vitamin A acetate (10 g, 30.44 mmol, 1.0 eq) and methyl palmitate (10.7 g, 39.572 mmol, 1.3 eq) were placed in a three-necked flask. Solid KOMe (0.196 g, 2.8 mmol, 0.09 eq) was added with magnetic stirring. After the addition, the mixture is vacuumized by an oil pump, the vacuum degree is kept at 100 to 2000 Pa, and the mixture is stirred at 50 to 55 ℃ for 3 to 5 h. HPLC showed that vitamin A acetate < 1% indicated the end of the reaction and the reaction was cooled to 20-30 ℃ with water.
The system is quenched by adding palmitic acid (2.107 g, 0.27 eq) and stirred for 5-10 min. The system was washed with methanol-acetonitrile mixture (1:1) (50 mL x 3) and rotary evaporated to dryness to give 12.2 g product. The purity of the product is 98.2 percent, and the yield is 76.3 percent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that are within the spirit and principle of the present invention are intended to be included in the scope of the present invention.
Claims (5)
1. A preparation method of vitamin A palmitate is characterized by comprising the following steps: the method comprises the following steps:
the method comprises the following steps: using vitamin A acetate as a raw material to react with methyl palmitate under the catalysis of NaOMe or KOMe, wherein the reaction formula is as follows:
step two: quenching the product of step one using HOAc, palmitic acid, or a mixture of both.
2. The process for producing vitamin a palmitate as claimed in claim 1, wherein: the main impurities in the reaction are removed by washing with one or more solvents selected from methanol, ethanol or acetonitrile.
3. The process for producing vitamin a palmitate as claimed in claim 1 or 2, wherein: in the first step, after mixing vitamin A acetate and methyl palmitate, dropwise adding a NaOMe methanol solution under magnetic stirring, vacuumizing by using an oil pump after adding, keeping the vacuum degree at 100-2000 Pa, stirring at 50-55 ℃ for 3-5 h, and after the reaction is finished, cooling the reaction system to 20-30 ℃ by using water.
4. The process for producing vitamin a palmitate as claimed in claim 3, wherein: HPLC showed vitamin a acetate < 1% indicating the end of the reaction.
5. The process for producing vitamin a palmitate as claimed in claim 3, wherein: the quenching reaction in the second step comprises the following steps:
step three: dripping HOAc, palmitic acid or a mixture of the HOAc and the palmitic acid into the system after the reaction in the step one is finished for quenching, and stirring for 5-10 min;
step four: the system was washed with MeOH and dried by rotary evaporation to give the product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210984683.3A CN115160200A (en) | 2022-08-17 | 2022-08-17 | Preparation method of vitamin A palmitate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210984683.3A CN115160200A (en) | 2022-08-17 | 2022-08-17 | Preparation method of vitamin A palmitate |
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| CN115160200A true CN115160200A (en) | 2022-10-11 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202210984683.3A Pending CN115160200A (en) | 2022-08-17 | 2022-08-17 | Preparation method of vitamin A palmitate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363606A (en) * | 2011-11-03 | 2012-02-29 | 厦门金达威集团股份有限公司 | Method for synthesizing vitamin A palmitate |
| CN108623507A (en) * | 2017-03-15 | 2018-10-09 | 四川海思科制药有限公司 | The preparation method of Retinol Palmitate |
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- 2022-08-17 CN CN202210984683.3A patent/CN115160200A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363606A (en) * | 2011-11-03 | 2012-02-29 | 厦门金达威集团股份有限公司 | Method for synthesizing vitamin A palmitate |
| CN108623507A (en) * | 2017-03-15 | 2018-10-09 | 四川海思科制药有限公司 | The preparation method of Retinol Palmitate |
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Application publication date: 20221011 |