A process for the preparation of an apogossypol intermediate, C25 aldehyde

Abstract

The application discloses a preparation method of an apophenine intermediate C25 aldehyde, wherein decandial and C15 phosphonium salt are reacted under the action of a solid base catalyst, and the solid base catalyst is a supported catalyst loaded with fluorine, calcium, zirconium and cobalt; compared with the preparation method of a kettle reactor in the prior art, the preparation method significantly improves the conversion rate of raw materials and the selectivity of products, and the yield is 90-95%, and the preparation method has a good application prospect in large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of fine chemicals, specifically relating to a method for preparing C25 aldehyde, an intermediate of apoester. Background Technology

[0002] β-Apo-8'-carotene ethyl ester, also known as apoester, is mainly used industrially in margarine, jams, jellies, and beverages. It is also widely used in poultry, especially for coloring the skin of chicken. As a chemically synthesized carotenoid, the known synthetic methods for apoester (GB 1137429A, US5773635A) use the C15+C10+C5 route. However, this process generates 10-15% β-carotene during the synthesis of C25 aldehydes. This impurity is very similar in properties to C25 aldehydes and is difficult to remove, resulting in a decrease in the quality of the produced apoester products.

[0003]

[0004] Therefore, finding a mild, simple, and easy-to-operate method for preparing the apoester intermediate C25 aldehyde is a pressing problem that needs to be solved in the industry. Summary of the Invention

[0005] To address the aforementioned problems, the present invention aims to provide a method for preparing the apoester intermediate C25 aldehyde. This method can solve the problems of complex reaction operations and difficult impurity purification in the current technology, providing a practical and efficient method for synthesizing C25 aldehyde.

[0006] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0007] A method for preparing an apoester intermediate C25 aldehyde includes the following steps: reacting a decacarbon dialdehyde and a C15 phosphate salt under the action of a solid base catalyst.

[0008] Preferably, the solid base catalyst is a supported catalyst containing fluorine, calcium, zirconium, and cobalt.

[0009] Preferably, the support for the solid base catalyst is activated carbon.

[0010] In this invention, the preparation method of the solid base catalyst is as follows:

[0011] 1) Add calcium salt, cobalt salt, zirconium salt and activated carbon to deionized water and stir to obtain a suspension. Under heating and stirring conditions, add a mixed solution of hydrazine hydrate and sodium fluoride dropwise. After the addition is complete, continue stirring to obtain a mixed solution.

[0012] 2) The mixed solution was transferred to a reaction vessel for reaction, then cooled and filtered. After washing with water, the filter cake was dried and calcined to obtain a solid alkali catalyst supported on fluorine, calcium, zirconium and cobalt.

[0013] Preferably, the calcium salt, cobalt salt, and zirconium salt are soluble salts of calcium, cobalt, and zirconium, respectively.

[0014] Preferably, in step 1), the mixture of hydrazine hydrate and sodium fluoride is added dropwise after heating to 90-120°C, and the dropwise addition time is 2-10 hours.

[0015] Preferably, in step (2), the reaction temperature is 80-120℃, the reaction pressure is 0.3-0.5MPa, and the reaction time is 10-20h.

[0016] Preferably, the roasting temperature in step (2) is 500-600℃ and the roasting time is 10-20h.

[0017] Preferably, the mass ratio of the calcium salt, cobalt salt, zirconium salt, and activated carbon is 1:0.01-0.2:0.5-2.0:2.0-4.0;

[0018] Preferably, the mass ratio of the calcium salt to hydrazine hydrate is 1:0.2-1.0, and the mass ratio of the calcium salt to sodium fluoride is 1:0.1-1.0.

[0019] Preferably, firstly, a decacarbon dialdehyde, a halocarbon solvent, and a solid base catalyst are mixed to obtain material A; then, a C15 phosphate salt and an alcohol are mixed to obtain material B; finally, material A and material B are reacted by mixing to obtain a reaction solution.

[0020] Preferably, the reaction is carried out in a microchannel reactor.

[0021] In this invention, the mass ratio of the decacarbon dialdehyde to the solid base catalyst is 1:0.1-2.0, preferably 1:0.2-0.5;

[0022] In this invention, the halogenated hydrocarbon solvent is one or more selected from dichloromethane, trichloromethane, dichloroethane, and chlorobenzene;

[0023] The mass ratio of the amount of halohydrocarbon solvent to decacarbon dialdehyde is 6-10:1, preferably 7-8:1.

[0024] In this invention, the alcohol is selected from one or more of methanol, ethanol, isopropanol, n-butanol, etc.

[0025] The amount of alcohol added is 2-10 times the mass of C15 phosphate salt, preferably 3-5 times.

[0026] In this invention, the structural formula of the decacarbon dialdehyde is shown in formula (1):

[0027]

[0028] The structural formula of the C15 phosphate salt is shown in formula (2):

[0029]

[0030] Where X is Cl - or Br - .

[0031] Preferably, the molar ratio of the decacarbon dialdehyde and the C15 phosphate salt is 1:1.0-2.0, and more preferably, the molar ratio is 1:1.3-1.8;

[0032] Preferably, the structural formula of the apoester intermediate C25 aldehyde is shown in formula (3):

[0033]

[0034] In this invention, a mixture of decacarbon dialdehyde, halogenated hydrocarbon solvent, and alkaline solution is pumped into the microchannel reactor via metering pump 1; a mixture of C15 phosphate salt and alcohol is pumped into the microchannel reactor via metering pump 2.

[0035] Preferably, the volumetric flow rate ratio of material A to material B is 0.8-1.5:1, and more preferably, the flow rate ratio is 0.9-1.1:1.

[0036] In this invention, the temperature of the microchannel reactor is controlled by circulating heat transfer oil through an integrated refrigeration and heating system.

[0037] Preferably, the reaction temperature of decacarbon dialdehyde and C15 phosphate salt is 0-120℃, more preferably 20-50℃.

[0038] In this invention, the reaction residence time is 10-50s, preferably 20-30s.

[0039] After the reaction is complete, the reaction solution is washed, and then impurities such as β-carotene are crystallized and separated. The resulting liquid phase is a C25 aldehyde solution system.

[0040] The washing solvent is pure water, the washing temperature is 20-45℃, and the mass of pure water is 2-10 times the mass of decacarbon dialdehyde. A poor solvent is added to crystallize the impurities. The preferred poor solvent is n-hexane, the crystallization temperature is 5-25℃, and the amount of poor solvent used is 10-25 times the mass of decacarbon dialdehyde.

[0041] The beneficial effects of this invention are as follows:

[0042] 1. In terms of reaction: Using solid alkali supported on F-Co / CaO-ZrO2 activated carbon can effectively improve reaction selectivity and reduce the formation of β-carotene. The doped fluorine ions effectively enrich the basic catalytic sites Ca, thereby improving the basicity of the catalyst. The doped Co element can effectively increase the proportion of all-trans aldehyde products of C25 aldehydes.

[0043] 2. Process: The microchannel reaction method can not only effectively realize the Wittig reaction, but also control the occurrence of excessive reaction, so that the impurity content of β-carotene in the system is <0.5%.

[0044] 3. Cost: Compared with traditional batch reactors, microchannel reactors can be operated by 1-2 people, the post-reaction processing is simple, and the reaction time is shortened from 3.0h to 20min, which has a great advantage in terms of reaction cost and labor cost. Detailed Implementation

[0045] The following embodiments will further illustrate the method provided by the present invention, but the present invention is not limited to the listed embodiments, and should also include any other known modifications within the scope of the claims of the present invention.

[0046] High-performance liquid chromatography (HPLC) characterization: Agilent 1260 HPLC system, Sphersorb C18 column (4.6*250mm), Hitachi L7420 UV-Vis detector, Chomatopac C-RIA HPLC workstation data processing system, Zorbax-SIL stationary phase. Chromatographic conditions: mobile phase was methanol / acetonitrile = 8 / 2 (v / v) mixed solvent, detection temperature 40℃, flow rate 1 ml / min, wavelength 455 nm. Qualitative and quantitative analysis of the product composition was performed.

[0047] The main raw materials used in the following examples and comparative examples are as follows:

[0048] C15 phosphate salt, prepared in-house, is prepared using the same method as step (1) of Example 1 in patent CN109651150A;

[0049] Decacarbon dialdehyde (99% purity) was purchased externally.

[0050] Sodium hydroxide, potassium hydroxide, triethylamine, sodium tert-butoxide, sodium methoxide, analytical grade, Aladdin;

[0051] The present invention will now be described in detail with reference to specific embodiments.

[0052] Preparation Example 1

[0053] Add 50g calcium chloride, 5g cobalt chloride, 100g zirconium chloride and 200g activated carbon to 500g deionized water and stir to obtain a suspension. Under the conditions of heating in a 100℃ water bath and stirring, add a mixed solution of 30g hydrazine hydrate and 10g sodium fluoride dropwise. After the addition is completed in 2 hours, continue stirring to obtain a mixed solution.

[0054] The mixed solution was transferred to a high-pressure reactor, and the reaction temperature was 110℃ and the reaction pressure was 0.4MPa. After reacting for 20h, the mixture was cooled and filtered. The filter cake was washed with 30g of deionized water and then vacuum dried. The resulting solid was calcined in a muffle furnace at 600℃ for 15h to obtain F-Co / CaO-ZrO2 activated carbon solid base catalyst I.

[0055] Preparation Example 2

[0056] Add 50g calcium chloride, 1.5g cobalt chloride, 50g zirconium chloride and 200g activated carbon to 500g deionized water and stir to obtain a suspension. Under the conditions of heating in a 100℃ water bath and stirring, add a mixed solution of 25g hydrazine hydrate and 10g sodium fluoride dropwise. After the addition is completed in 2 hours, continue stirring to obtain a mixed solution.

[0057] The mixed solution was transferred to a high-pressure reactor, and the reaction temperature was 110℃ and the reaction pressure was 0.4MPa. After reacting for 20h, the mixture was cooled and filtered. The filter cake was washed with 30g of deionized water and then vacuum dried. The resulting solid was calcined in a muffle furnace at 600℃ for 15h to obtain F-Co / CaO-ZrO2 activated carbon solid base catalyst II.

[0058] Preparation Example 3

[0059] Add 100g calcium chloride, 10g cobalt chloride, 80g zirconium chloride and 350g activated carbon to 800g deionized water and stir to obtain a suspension. Under the conditions of heating in a 100℃ water bath and stirring, add a mixed solution of 50g hydrazine hydrate and 25g sodium fluoride dropwise. After the addition is completed in 2 hours, continue stirring to obtain a mixed solution.

[0060] The mixed solution was transferred to a high-pressure reactor, and the reaction temperature was 110℃ and the reaction pressure was 0.4MPa. After reacting for 20h, the mixture was cooled and filtered. The filter cake was washed with 30g of deionized water and then vacuum dried. The resulting solid was calcined in a muffle furnace at 600℃ for 15h to obtain F-Co / CaO-ZrO2 activated carbon solid base catalyst III.

[0061] Example 1

[0062] This embodiment provides a method for preparing a decacarbon dialdehyde intermediate, which specifically includes the following steps:

[0063] 16.4 g of decacarbon dialdehyde, 3.28 g of solid alkali I loaded with F-Co / CaO-ZrO2 activated carbon, and 120 g of dichloromethane solution were mixed and fed into a microchannel reactor via a metering pump. 200 g of 20 wt% C15 phosphate methanol solution was also fed into the microchannel reactor via a metering pump. Metering pumps 1 and 2 were fed into the microchannel reactor at a feed volumetric flow rate ratio of 1.5:1. The Wittig reaction was carried out at 30 °C, with a residence time of 40 s in the microchannel reactor. The resulting reaction solution was stored in storage tank 1. A sample was taken for liquid phase analysis, revealing a 99.3% conversion rate for the decacarbon dialdehyde, a 95.5% selectivity for the C25 aldehyde, a 98.6 wt% all-trans C25 aldehyde content, a 0.3 wt% β-carotene content, and a 94.8% reaction yield.

[0064] Example 2

[0065] 16.4 g of decacarbon dialdehyde, 1.64 g of solid alkali II loaded with F-Co / CaO-ZrO2 activated carbon, and 110 g of dichloromethane solution were mixed and fed into a microchannel reactor via a metering pump. 200 g of 20 wt% C15 phosphate methanol solution was also fed into the microchannel reactor via a metering pump. Metering pumps 1 and 2 were fed into the microchannel reactor at a feed volumetric flow rate ratio of 1.3:1. The Wittig reaction was carried out at 30 °C, with a residence time of 30 s in the microchannel reactor. The resulting reaction solution was stored in storage tank 1. A sample was taken for liquid phase analysis, revealing a 97.8% conversion rate for the decacarbon dialdehyde, a 96.7% selectivity for the C25 aldehyde, a 99.1 wt% all-trans C25 aldehyde content, a 0.1 wt% β-carotene content, and a 94.6% reaction yield.

[0066] Example 3

[0067] 16.4 g of decacarbon dialdehyde, 4.92 g of solid alkali III loaded with F-Co / CaO-ZrO2 activated carbon, and 100 g of dichloromethane solution were mixed and fed into a microchannel reactor via a metering pump. 200 g of 20 wt% C15 phosphate methanol solution was also fed into the microchannel reactor via a metering pump. Metering pumps 1 and 2 were fed into the microchannel reactor at a feed volumetric flow rate ratio of 0.95:1. The Wittig reaction was carried out at 30 °C, with a residence time of 15 s in the microchannel reactor. The resulting reaction solution was stored in storage tank 1. A sample was taken for liquid phase analysis, revealing a 94.6% conversion rate for the decacarbon dialdehyde, a 95.9% selectivity for the C25 aldehyde, a 98.7 wt% all-trans C25 aldehyde content, a 0.15 wt% β-carotene content, and a 90.7% reaction yield.

[0068] Example 4

[0069] 16.4 g of decacarbon dialdehyde, 3.28 g of solid alkali II loaded with F-Co / CaO-ZrO2 activated carbon, and 120 g of dichloromethane solution were mixed and fed into a microchannel reactor via a metering pump. 190 g of 20 wt% C15 phosphate methanol solution was also fed into the microchannel reactor via a metering pump. Metering pumps 1 and 2 were fed into the microchannel reactor at a feed volumetric flow rate ratio of 1.2:1. The Wittig reaction was carried out at 20 °C, with a residence time of 25 s in the microchannel reactor. The resulting reaction solution was stored in storage tank 1. A sample was taken for liquid phase analysis, revealing a 99.0% conversion rate for the decacarbon dialdehyde, a 96.5% selectivity for the C25 aldehyde, a 99.2 wt% all-trans C25 aldehyde content, a 0.1 wt% β-carotene content, and a 95.5% reaction yield.

[0070] Example 5

[0071] 16.4 g of decacarbon dialdehyde, 3.28 g of solid alkali III loaded with F-Co / CaO-ZrO2 activated carbon, and 150 g of dichloromethane solution were mixed and fed into a microchannel reactor via a metering pump. 205 g of 20 wt% C15 phosphate methanol solution was also fed into the microchannel reactor via a metering pump. Metering pumps 1 and 2 were fed into the microchannel reactor at a feed volumetric flow rate ratio of 1.4:1. The Wittig reaction was carried out at 35 °C, with a residence time of 30 s in the microchannel reactor. The resulting reaction solution was stored in storage tank 1. A sample was taken for liquid phase analysis, revealing a 98.3% conversion rate for the decacarbon dialdehyde, a 96.7% selectivity for the C25 aldehyde, a 98.9 wt% all-trans C25 aldehyde content, a 0.2 wt% β-carotene content, and a 95.1% reaction yield.

[0072] Example 6

[0073] 16.4 g of decacarbon dialdehyde, 8.2 g of solid alkali I loaded with F-Co / CaO-ZrO2 activated carbon, and 120 g of dichloromethane solution were mixed and fed into a microchannel reactor via a metering pump. 180 g of 20 wt% C15 phosphate methanol solution was also fed into the microchannel reactor via a metering pump. Metering pumps 1 and 2 were fed into the microchannel reactor at a feed volumetric flow rate ratio of 1.5:1. The Wittig reaction was carried out at 45 °C, with a residence time of 30 s in the microchannel reactor. The resulting reaction solution was stored in storage tank 1. A sample was taken for liquid phase analysis, revealing a 98.9% conversion rate for the decacarbon dialdehyde, a 94.2% selectivity for the C25 aldehyde, a 98.5 wt% all-trans C25 aldehyde content, a 0.4 wt% β-carotene content, and a 93.2% reaction yield.

[0074] Example 7

[0075] 16.4 g of decacarbonyl dialdehyde, 8.2 g of solid alkali I supported on F-Co / CaO-ZrO2 activated carbon, and 120 g of dichloromethane solution were mixed and added to a 1000 mL three-necked flask. 180 g of 20 wt% C15 phosphate salt methanol solution was added dropwise to the reaction system. The Wittig reaction was carried out at 45 °C. Samples were taken for liquid phase analysis, and the conversion rate of the decacarbonyl dialdehyde was 92.6%, the selectivity of the C25 aldehyde product was 89.5%, the all-trans proportion of C25 aldehyde was 98.8 wt%, the β-carotene content was 0.25 wt%, and the reaction yield was 82.9%.

[0076] Comparative Example 1

[0077] 16.4 g of decacarbonyl dialdehyde, 8.2 g of activated carbon solid alkali loaded with potassium carbonate, and 120 g of dichloromethane solution were mixed and fed into a microchannel reactor via a metering pump. 180 g of 20 wt% C15 phosphate methanol solution was also fed into the microchannel reactor via a metering pump. Metering pumps 1 and 2 were fed into the microchannel reactor at a feed volumetric flow rate ratio of 1.5:1. The Wittig reaction was carried out at 45 °C, with a residence time of 30 s in the microchannel reactor. The resulting reaction solution was stored in storage tank 1. A sample was taken for liquid phase analysis, revealing a 95.3% conversion rate for the decacarbonyl dialdehyde, a 78.6% selectivity for the C25 aldehyde, a 90.5 wt% all-trans C25 aldehyde content, a 5.9 wt% β-carotene content, and a 74.9% reaction yield.

Claims

1. A method for preparing aporphyrin intermediate C25 aldehyde, characterized in that, The reaction includes the following steps: reacting a decacarbon dialdehyde and a C15 phosphate salt in the presence of a solid base catalyst; The solid base catalyst is a supported catalyst containing fluorine, calcium, zirconium, and cobalt. The structural formula of the decacarbon dialdehyde is shown in formula (1): The structural formula of the C15 phosphate salt is shown in formula (2): Where X is Cl - or Br - ; The structural formula of the apoester intermediate C25 aldehyde is shown in formula (3):

2. The preparation method according to claim 1, characterized in that, The solid base catalyst is supported on activated carbon.

3. The preparation method according to claim 1, characterized in that, The preparation method of the solid base catalyst is as follows: 1) Add calcium salt, cobalt salt, zirconium salt and activated carbon to deionized water and stir to obtain a suspension. Under heating and stirring conditions, add a mixed solution of hydrazine hydrate and sodium fluoride dropwise. After the addition is complete, continue stirring to obtain a mixed solution. 2) The mixed solution was transferred to a reaction vessel for reaction, then cooled and filtered. After washing with water, the filter cake was dried and calcined to obtain a solid alkali catalyst supported on fluorine, calcium, zirconium and cobalt.

4. The preparation method according to claim 3, characterized in that, The calcium salt, cobalt salt, and zirconium salt are soluble salts of calcium, cobalt, and zirconium, respectively.

5. The preparation method according to claim 3, characterized in that, In step 1), heat the solution to 90-120℃ and then add a mixed solution of hydrazine hydrate and sodium fluoride dropwise over a period of 2-10 hours.

6. The preparation method according to claim 3, characterized in that, In step 2), the reaction temperature is 80-120℃, the reaction pressure is 0.3-0.5MPa, and the reaction time is 10-20h.

7. The preparation method according to claim 3, characterized in that, In step 2), the roasting temperature is 500-600℃ and the roasting time is 10-20h.

8. The preparation method according to claim 3 or 4, characterized in that, The mass ratio of the calcium salt, cobalt salt, zirconium salt and activated carbon is 1:0.01-0.2:0.5-2.0:2.0-4.

0.

9. The preparation method according to claim 3, characterized in that, The mass ratio of the calcium salt to hydrazine hydrate is 1:0.2-1.0, and the mass ratio of the calcium salt to sodium fluoride is 1:0.1-1.

0.

10. The preparation method according to claim 1, characterized in that, A decacarbon dialdehyde, a halocarbon solvent, and a solid base catalyst are mixed to obtain material A; a C15 phosphate salt and an alcohol are mixed to obtain material B; then material A and material B are reacted by mixing to obtain a reaction solution.

11. The preparation method according to claim 3, characterized in that, The reaction takes place in a microchannel reactor.

12. The preparation method according to claim 10, characterized in that, The halogenated hydrocarbon solvent is one or more of dichloromethane, trichloromethane, dichloroethane, and chlorobenzene.

13. The preparation method according to claim 10, characterized in that, The mass ratio of the amount of halohydrocarbon solvent to the decacarbon dialdehyde is 6-10:

1.

14. The preparation method according to claim 13, characterized in that, The mass ratio of the halogenated hydrocarbon solvent to the decacarbon dialdehyde is 7-8:

1.

15. The preparation method according to claim 10, characterized in that, The alcohols are selected from one or more of methanol, ethanol, isopropanol, and n-butanol.

16. The preparation method according to claim 10, characterized in that, The amount of alcohol added is 2-10 times the mass of C15 phosphate salt.

17. The preparation method according to claim 16, characterized in that, The amount of alcohol added is 3-5 times the mass of C15 phosphate salt.

18. The preparation method according to claim 1, characterized in that, The mass ratio of the decacarbon dialdehyde to the solid base catalyst is 1:0.1-2.

0.

19. The preparation method according to claim 18, characterized in that, The mass ratio of the decacarbon dialdehyde to the solid base catalyst is 1:0.2-0.

5.

20. The preparation method according to claim 1, characterized in that, The molar ratio of the decacarbon dialdehyde and C15 phosphate salt is 1:1.0-2.

0.

21. The preparation method according to claim 20, characterized in that, The molar ratio of the decacarbon dialdehyde and C15 phosphate salt is 1:1.3-1.

8.

22. The preparation method according to claim 11, characterized in that, A mixture of decacarbon dialdehyde, halogenated hydrocarbon solvent, and alkaline solution is pumped into the microchannel reactor via metering pump 1; a mixture of C15 phosphate salt and alcohol is pumped into the microchannel reactor via metering pump 2.

23. The preparation method according to claim 10, characterized in that, The volumetric flow rate ratio of material A to material B is 0.8-1.5:

1.

24. The preparation method according to claim 23, characterized in that, The volumetric flow rate ratio of material A to material B is 0.9-1.1:

1.

25. The preparation method according to claim 1, characterized in that, The reaction temperature of decacarbon dialdehyde and C15 phosphate salt is 0-120℃.

26. The preparation method according to claim 25, characterized in that, The reaction temperature of decacarbon dialdehyde and C15 phosphate salt is 20-50℃.

27. The preparation method according to claim 1, characterized in that, The reaction residence time is 10-50 seconds.

28. The preparation method according to claim 27, characterized in that, The reaction residence time is 20-30 seconds.

29. The preparation method according to claim 1, characterized in that, After the reaction is complete, the resulting reaction solution is washed, and then the impurities are crystallized and separated, resulting in a C25 aldehyde solution system.

30. The preparation method according to claim 29, characterized in that, The washing solvent is pure water, and the washing temperature is 20-45℃.

31. The preparation method according to claim 30, characterized in that, The mass of pure water is 2-10 times that of decacarbon dialdehyde.

32. The preparation method according to claim 29, characterized in that, Add a poor solvent to crystallize the impurities. The crystallization temperature is 5-25℃, and the amount of poor solvent used is 10-25 times the mass of decacarbon dialdehyde.

33. The preparation method according to claim 32, characterized in that, The unsuitable solvent is n-hexane.

Images