A preparation method of 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal

Abstract

The invention discloses a method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-hepttrienal, comprising the following steps: (1) in the presence of a dual catalyst, (E)-3-methylpent-2-ene-4-yn-1-ol and methacrylate undergo a hydroalkenylation coupling reaction to obtain a C10 alcohol ester; the dual catalyst is composed of a copper catalyst and an acid; (2) the C10 alcohol ester undergoes an oxidation reaction in a TEMPO catalytic oxidation system, and after the reaction is completed, the 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-hepttrienal is obtained by post-treatment. The preparation method has a short reaction route, a high reaction yield, and good atom economy; and the production process has no phosphorus-containing wastewater, and is environmentally friendly.

Description

Technical Field

[0001] The invention relates to the technical field of fine chemical synthesis, and in particular to a method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal. Background Art

[0002] 7-Alkoxycarbonyl-3,7-dimethyl-2,4,6-hepttrienal (hereinafter referred to as C10 aldehyde ester) is a key intermediate in the synthesis of 8'-apo-β-carotene ethyl ester (hereinafter referred to as "apo ester") via the C20+C10 route. The synthesis route of apo ester is shown in Formula 1. After vitamin A acetate reacts with triphenylphosphine and hydrochloric acid to generate a C20 intermediate, it continues to react with C10 aldehyde ester to undergo a Wittig reaction to obtain the apo ester product.

[0003]

[0004] Formula 1, C20+C10 synthetic route of apoester

[0005] According to reports in literature and patents, there are two main methods for synthesizing C10 aldehyde esters:

[0006] (1) Using the byproduct trans-C6 of Roche vitamin A acetate C14+C6 route as raw material, through Grignard, partial hydrogenation, hydrolysis, Wittig-Horner and oxidation reactions, a total of five steps of reaction to obtain C10 aldehyde ester (US3989758A, US3687990). Its synthesis route is shown in Formula 2.

[0007]

[0008] Formula 2, trans-C6 synthesis route of C10 aldehyde ester

[0009] This method uses trans-C6, a byproduct of vitamin A acetate, as a raw material, which is relatively economical. However, the reaction route is relatively long, with a total of five steps, and the atom economy is relatively poor. The process involves Grignard reaction, partial hydrogenation reaction, and Wittig-Horner reaction, which is relatively complicated. Since trans-C6 is very unstable, it is easy to polymerize in the Grignard reaction, which is difficult to control and has a very low reaction yield. Therefore, the overall yield of the route is also relatively low. In addition, the Wittig-Horner reaction produces a large amount of phosphorus-containing wastewater, which has a high treatment cost.

[0010] (2) Using C5 of the C15+C5 route of BASF vitamin A acetate as raw material, a total of six steps of reaction were performed to obtain C10 aldehyde ester (CN201210364500.4) through oxidation, esterification hydrolysis, chlorination, phosphination, Wittig-Horner, and oxidation reactions. The synthesis route is shown in Formula 3.

[0011]

[0012] Formula 3, C5 synthetic route of C10 aldehyde ester

[0013] This method uses the same raw material C5 as the BASF vitamin A acetate route, which is relatively easy to obtain. However, the reaction route is relatively long, with a total of six steps, poor atom economy, and low overall reaction yield. The process involves oxidation, chlorination, phosphinositization, and Wittig-Horner reaction, which is relatively complicated. Moreover, the oxidation step and the Wittig-Horner reaction will produce a large amount of phosphorus-containing wastewater, and the treatment cost is relatively high.

[0014] As described in the review, the existing synthetic routes of C10 aldehyde esters all have the following disadvantages:

[0015] (1) Long reaction route and poor atom economy;

[0016] (2) The process is complicated and the overall reaction yield is low;

[0017] (3) A large amount of phosphorus-containing wastewater needs to be treated, and the treatment cost is high.

[0018] Therefore, the present invention aims to develop a green and environmentally friendly C10 aldehyde ester synthesis process with a short route, simple process, high yield and no phosphorus-containing wastewater. Summary of the invention

[0019] The technical problem to be solved by the present invention is as follows: the present invention provides a method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-hepttrienal, the raw materials of the preparation method are cheap and easily available, the reaction route is short, only two steps of reaction are required, the yield is high, and the atom economy is high; and no phosphorus-containing wastewater is generated, thus greatly reducing the production cost, and the shortcomings of the existing synthesis route of C10 aldehyde ester can be well solved, thus bringing greater environmental and economic benefits, and industrial production can be realized.

[0020] The technical solution of the present invention is as follows:

[0021] A method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal comprises the following steps:

[0022] (1) in the presence of dual catalysts, (E)-3-methylpent-2-en-4-yn-1-ol and methacrylate undergo a hydroalkenylation coupling reaction to obtain a C10 alcohol ester;

[0023] The dual catalyst is composed of a copper catalyst and an acid;

[0024] (2) the C10 alcohol ester is subjected to an oxidation reaction in a TEMPO catalytic oxidation system, and after the reaction, the 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal is obtained by post-treatment;

[0025] The TEMPO catalytic oxidation system is composed of TEMPO and an auxiliary agent;

[0026] The reaction formula is as follows:

[0027]

[0028] Preferably, in step (1), the copper catalyst is a cuprous salt, selected from one or more of Cu2SO4, CuCl, CuBr, CuNO3, and CuAc, and further preferably one or two of Cu2SO4 and CuNO3. Cu2SO4 and CuNO3 have ideal effects, have fewer side reactions than cuprous halides, and have a higher total reaction yield.

[0029] Increasing the acidity of the reaction system is beneficial to the synthesis of the intermediate C10 alcohol ester. Preferably, in step (1), the acid is selected from one or more of HCl, HBr, sulfuric acid, nitric acid, phosphoric acid, and trifluoroacetic acid, and more preferably one or more of sulfuric acid, phosphoric acid, and trifluoroacetic acid. Compared with hydrochloric acid and hydrobromic acid, sulfuric acid, phosphoric acid, and trifluoroacetic acid have fewer side reactions, and trifluoroacetic acid has the most ideal effect.

[0030] Preferably, in step (1), the hydroolefination coupling reaction is carried out in one or more of the following solvents:

[0031] Inert solvents such as benzene, toluene, xylene, trimethylbenzene, heptane, hexane, octane, dichloromethane, chloroform, chloroform or dichloroethane are used, among which toluene and dichloromethane have good economic benefits and experimental verification results, and toluene or dichloromethane is further preferred.

[0032] In step (1), after the reaction is completed, the post-treatment process is as follows:

[0033] The reaction solution is washed with deionized water to remove the catalyst, and the organic layer is dried with anhydrous sodium sulfate to obtain an intermediate C10 alcohol ester solution which is directly introduced into step (2) for oxidation reaction.

[0034] Preferably, in step (2), the auxiliary agent is a cuprous salt, a ferric salt or I2; wherein the TEMPO / cuprous salt system has an ideal oxidation effect, and thus the TEMPO / cuprous salt system is further preferred, wherein the cuprous salt is Cu2SO4, CuCl, CuBr, CuNO3 or CuAc.

[0035] Preferably, in step (2), the solvent of the oxidation reaction is one or more of an inert solvent such as benzene, toluene, xylene, trimethylbenzene, heptane, hexane, octane, dichloromethane, chloroform, chloroform, and dichloroethane, among which toluene and dichloromethane have good economic benefits and experimental verification results, and toluene or dichloromethane is further preferred. Furthermore, the solvent of the oxidation reaction in step (2) is the same as that of the hydroolefination coupling reaction in step (1), and the reaction solvent may not be removed after the reaction in step (1) is completed.

[0036] Preferably, the post-treatment is recrystallization, and the solvent for recrystallization is an ether solvent. C10 aldehyde ester has a certain solubility in ether solvents and is sensitive to temperature. As a further preference, the solvent for recrystallization can be selected from: methyl ether, ethyl ether, isopropyl ether, tert-butyl ether, isobutyl ether, methyl tert-butyl ether, etc., and further isopropyl ether and methyl tert-butyl ether have better economic benefits and experimental verification results.

[0037] Furthermore, the specific preparation method of 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal of the present invention is as follows:

[0038] (1) A 500ml four-necked flask reaction device with a stirring and cooling reflux device is placed in a low-temperature circulation tank. First, add 100g of solvent, 60g of ethyl methacrylate, 0.1-0.5g of catalyst M (copper catalyst), and 0.05-0.5g of catalyst L (acid catalyst). Under room temperature conditions (25±2°C), slowly drop 50g of trans-C6 + 50g of solvent mixture precooled to 0-5°C. During the dropwise addition, the temperature of the reaction system rises. The temperature of the reaction system is controlled to 35-40°C. After the dropwise addition, keep warm for 30 minutes. GC detection shows that the residual ethyl methacrylate is ≤0.2%, which is considered qualified. The reaction solution is washed with deionized water 3 times, 100ml / time, to remove catalysts M+L. The organic layer is dried over anhydrous sodium sulfate to obtain an intermediate C10 alcohol ester solution;

[0039] (2) Add C10 alcohol ester solution and 0.1g TEMPO / 0.1g auxiliary system catalyst to the autoclave, control the temperature at 30-80°C, introduce oxygen / compressed air under stirring, control the pressure at 0.01-0.5MPa, and react for 10h. Take a sample for HPLC detection, and stop the reaction if the intermediate C10 alcohol ester residue is qualified. Wash the oxidation reaction liquid with deionized water for 3 times, 100ml / time, and remove the catalyst. Concentrate the organic layer C10 aldehyde ester solution under reduced pressure, the concentration temperature is ≤80°C, and recover the solvent. Add 300g crystallization solvent for crystallization, cool to -10±1°C, and precipitate C10 aldehyde ester crude product. Add 1.5-2 times the mass ratio of crystallization solvent to the C10 aldehyde ester crude product, heat to reflux for 30min, slowly cool to -5±1°C, crystallize for 2-4h, filter, -0.1MPa, 45-60°C, and dry to obtain C10 aldehyde ester fine product.

[0040] Compared with the prior art, the present invention has the following advantages:

[0041] (1) The reaction route of the present invention is short, the target product can be obtained in two steps, and the yield is high and the atom economy is good;

[0042] (2) The process of the present invention is simple, the reaction conditions are mild, and the equipment investment is small;

[0043] (3) The raw materials of the present invention are easily available, and the waste material of vitamin A acetate production, trans-C6, is effectively utilized; the production process does not contain phosphorus-containing wastewater, and is environmentally friendly. DETAILED DESCRIPTION

[0044] The general preparation process of C10 aldehyde ester is as follows:

[0045] (1) A 500ml four-necked flask reaction device with a stirring and cooling reflux device is placed in a low-temperature circulation tank. First, 100g of solvent, 60g of ethyl methacrylate, 0.1g of catalyst M, and 0.05g of catalyst L are added. Under room temperature conditions (25±2°C), 50g of trans-C6+50g of toluene mixed solution precooled to 0-5°C is slowly added dropwise. During the addition, the temperature of the reaction system rises. The temperature of the reaction system is controlled to 35-40°C. After the addition is completed, the temperature is kept for 30 minutes. After GC detection is qualified. The reaction solution is washed with deionized water 3 times, 100ml / time, to remove catalysts M+L. The organic layer is dried with anhydrous sodium sulfate, and the water content is detected to be ≤100ppm to obtain the intermediate C10 alcohol ester solution.

[0046] (2) Add C10 alcohol ester solution and 0.1g TEMPO / 0.1g catalyst of auxiliary system to the autoclave, control the temperature at 30-40°C, introduce compressed air under stirring, control the pressure at 0.1-0.5MPa, and react for 8-10h. Take a sample for HPLC detection, and the residual intermediate 1C10 alcohol ester is ≤0.5%, which is considered qualified. Stop the reaction. Wash the reaction solution with deionized water for 3 times, 100ml / time, and remove the catalyst. Concentrate the organic layer C10 aldehyde ester solution under reduced pressure, the concentration temperature is ≤80°C, and recover the solvent. Add 300g crystallization solvent for crystallization, cool to -10±1°C, and precipitate the crude C10 aldehyde ester. Add 1.5-2 times the mass ratio of isopropyl ether to the crude C10 aldehyde ester, raise the temperature to reflux for 30 minutes, slowly cool to -5±1°C, crystallize for 2-4 hours, filter, -0.1MPa, 45-60°C, and dry to obtain the C10 aldehyde ester product. The purity is detected by HPLC, and the molar yield is calculated based on trans-C6.

[0047] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0048] Examples 1-30

[0049] Experimental design: orthogonal experimental table of catalyst M+L (as shown in the table below), catalyst M+L feed amount 0.1g+0.05g, C10 alcohol ester oxidation catalytic system 0.1g TEMPO / 0.1g auxiliary M (the selection of M in the oxidation reaction in the embodiment is the same as that in the hydroolefination coupling reaction), experimental results: HPLC detection purity, molar yield of C10 aldehyde ester calculated as trans-C6.

[0050]

[0051] The experimental results are statistically as follows:

[0052]

[0053]

[0054] Examples 31-41

[0055] Different reaction solvents, catalyst Cu2SO4+trifluoroacetic acid: feed amount 0.1g+0.05g, C10 alcohol ester oxidation catalytic system 0.1g TEMPO / 0.1g Cu2SO4, crystallization solvent isopropyl ether, experimental results HPLC detection purity, molar yield of C10 aldehyde ester based on trans-C6. The experimental results are as follows:

[0056] Experiment No. Experimental protocol (reaction solvent) Crystallization solvent Product purity (%) Molar yield (%) Example 31 benzene Isopropyl ether 99.21 93.98 Example 32 Toluene Isopropyl ether 99.60 95.77 Example 33 Xylene Isopropyl ether 99.33 94.75 Example 34 Trimethylbenzene Isopropyl ether 99.29 93.28 Example 35 Heptane Isopropyl ether 99.31 92.79 Example 36 Hexane Isopropyl ether 98.78 92.57 Example 37 Octane Isopropyl ether 98.56 93.22 Example 38 Dichloromethane Isopropyl ether 99.04 92.35 Example 39 Chloroform Isopropyl ether 98.56 91.89 Example 40 Chloroform Isopropyl ether 99.02 92.37 Example 41 Ethylene dichloride Isopropyl ether 99.23 93.26

[0057] Examples 42-44

[0058] The reaction solvent is toluene, the catalyst is Cu2SO4+trifluoroacetic acid: the feed amount is 0.1g+0.05g, different C10 alcohol ester oxidation catalytic systems, C10 alcohol ester oxidation catalytic system 0.1g TEMPO / 0.1g auxiliary agent; the crystallization solvent is isopropyl ether, the experimental results are HPLC detection purity, and the molar yield of C10 aldehyde ester is calculated based on trans-C6. The experimental results are as follows:

[0059]

[0060] Examples 45-50

[0061] The reaction solvent is toluene, the catalyst is Cu2SO4+trifluoroacetic acid: the feed amount is 0.1g+0.05g, the C10 alcohol ester oxidation catalytic system is 0.1g TEMPO / 0.1g Cu2SO4, different crystallization solvents, the experimental results are HPLC detection purity, and the molar yield of C10 aldehyde ester is calculated based on trans-C6. The experimental results are as follows:

[0062] Experiment No. Experimental protocol (crystallization solvent) Reaction solvent Product purity (%) Molar yield (%) Example 45 Methyl ether Toluene 98.97 94.57 Example 46 Ether Toluene 99.23 94.50 Example 47 Isopropyl ether Toluene 99.67 95.82 Example 48 Tert-butyl ether Toluene 98.26 93.29 Example 49 Isobutyl ether Toluene 98.57 90.37 Example 50 Methyl tert-butyl ether Toluene 97.52 90.41

Claims

1. A method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal, characterized in that: The following steps are involved: (1) In the presence of dual catalysts, (E)-3-methylpent-2-en-4-yn-1-ol and methacrylate undergo a hydroolefination coupling reaction to obtain a C10 alcohol ester; The dual catalyst is composed of a copper catalyst and an acid; (2) the C10 alcohol ester is subjected to an oxidation reaction in a TEMPO catalytic oxidation system, and after the reaction is completed, the 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-hepttrienal is obtained by post-treatment; The TEMPO catalytic oxidation system is composed of TEMPO and an auxiliary agent; The reaction formula is as follows: ； In step (1), the copper catalyst is selected from one or more of Cu2SO4, CuCl, CuBr and CuNO3; In step (1), the acid is selected from one or more of HCl, HBr, sulfuric acid, nitric acid, phosphoric acid, and trifluoroacetic acid; In step (2), the auxiliary agent is a cuprous salt, and the cuprous salt is selected from one or more of Cu2SO4, CuCl, CuBr and CuNO3, or the auxiliary agent is Fe2(SO4)3 or I2; In step (2), the oxidation reaction is carried out in the presence of oxygen or compressed air.

2. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: In step (1), the hydroolefination coupling reaction is carried out in a solvent, and the solvent is selected from one or more of benzene, toluene, xylene, trimethylbenzene, heptane, hexane, octane, dichloromethane, chloroform, chloroform and dichloroethane.

3. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: By mass, (E)-3-methylpent-2-en-4-yn-1-ol: copper catalyst: acid = 1: 0.002~0.01: 0.001~0.

01.

4. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: By weight, (E)-3-methylpent-2-en-4-yn-1-ol: methacrylate = 1: 1.1-1.

3.

5. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: In step (1), the temperature of the hydroolefination coupling reaction is 20-60°C.

6. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 5, characterized in that: In step (1), the temperature of the hydroolefination coupling reaction is 35-50°C.

7. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, 5 or 6, characterized in that: By mass, (E)-3-methylpent-2-en-4-yn-1-ol:TEMPO:auxiliary agent=1:0.002~0.01:0.002~0.

01.

8. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: In step (2), the oxidation temperature is 25-100°C.

9. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: In step (2), the oxidation temperature is 30-80°C.

10. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: In step (2), the pressure is controlled at 0.01-5.0 MPa.

11. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 10, characterized in that: In step (2), the pressure is controlled to be 0.1-0.5 MPa.

12. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: In step (2), the post-treatment is recrystallization, and the solvent for recrystallization is one or more of methyl ether, ethyl ether, isopropyl ether, tert-butyl ether, isobutyl ether, and methyl tert-butyl ether.

13. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 12, characterized in that: In step (2), the solvent for recrystallization is one or both of isopropyl ether and methyl tert-butyl ether.

14. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 1, characterized in that: In step (2), the post-treatment is recrystallization, and the recrystallization temperature is -10~5°C.

15. The method for preparing 7-alkoxycarbonyl-3,7-dimethyl-2,4,6-heptatrienal according to claim 14, characterized in that: In step (2), the post-treatment is recrystallization, and the recrystallization temperature is -5~1°C.

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