Synthetic method of intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propionaldehyde of Advantame

Abstract

The invention provides a synthetic method of an Advantame intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propionaldehyde, which comprises the following steps: step 1, carrying out Wittig reaction on isovanillin and cyano methylene triphenylphosphine to generate 3-(3-hydroxy-4-methoxyphenyl) acrylonitrile; step 2, carrying out hydrogenation reaction on the 3-(3-hydroxy-4-methoxyphenyl) acrylonitrile under the catalysis of Pd / C, so as to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile; and step 3, reducing the 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile by using diisobutylaluminium hydride, so as to obtain the 3-(3-hydroxy-4-methoxyphenyl)-1-propionaldehyde. The synthesis method is mild in reaction condition, high in overall yield and high in product purity.

Description

Technical Field

[0001] The invention relates to the technical field of food additive synthesis, and in particular to a method for synthesizing an Advantamine intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propanal. Background Art

[0002] Advantame (English name: Advantame), the molecular formula is N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl-La-aspartyl]]-L-phenylalanine-1-methyl ester (C 24 H 30 N2O7), with a molecular weight of 458.5.

[0003]

[0004] Advantame is a new type of non-nutritive, low-calorie, high-intensity sweetener with very weak perceived bitterness and sourness. It can be added to a variety of foods, and its sweetness can be up to 20,000 times that of sucrose, so the dosage can be much lower than sucrose and other high-intensity sweeteners on the current market. It has good water solubility and high heat resistance, and is suitable for high-temperature processing products. Advantame is a derivative of aspartame, and its chemical structure is similar to neotame.

[0005] Aspartame contains phenylalanine, but because Advantame can achieve the sweetening effect with a very small dose, it will not cause phenylketonuria or amino acid metabolic diseases. In 2014, the US FDA approved Advantame as a non-nutritive sweetener and flavor enhancer for use in foods other than meat and poultry. In the same year, the European Union issued regulations allowing Advantame to be used as a sweetener. In addition to being a food additive, Advantame is also used in daily cosmetics.

[0006] The synthetic route disclosed in WO2001087813 is as follows:

[0007]

[0008] The first step is to synthesize (2E)-(3-hydroxy-4-methoxy)cinnamaldehyde. Isovanillin (3-hydroxy-4-methoxybenzaldehyde) and 28% acetaldehyde aqueous solution react in sodium hydroxide solution at -10°C for about 46 hours to generate products with a yield of 57%. The second step is to hydrogenate (2E)-(3-hydroxy-4-methoxy)cinnamaldehyde under the catalysis of 5% Pd / Al2O3 to obtain 3-(3-hydroxy-4-methoxyphenyl)propanal with a yield of 87%. In this synthetic route, the first step reaction itself is highly exothermic, the reaction conditions are relatively harsh, the reaction time is long, and the starting material isovanillin cannot be completely converted, resulting in a low reaction yield. Since the raw material isovanillin and the product are phenolic compounds, side reactions such as oxidation and polymerization will occur under strong alkaline conditions for a long time, producing darker impurities. The researchers of the present invention have found that as the scale of the reaction is enlarged, the color of the product obtained by this reaction will gradually deepen, from light yellow to orange-yellow, and even to brown. Colored impurities are difficult to be completely removed in subsequent steps, which ultimately affects the appearance quality of the target product Advantite. Summary of the invention

[0009] In view of the defects in the prior art, the purpose of the present invention is to provide a method for synthesizing 3-(3-hydroxy-4-methoxyphenyl)-1-propanal, an intermediate of Advantamine.

[0010] The object of the present invention is achieved through the following solutions:

[0011] The present invention provides a method for synthesizing 3-(3-hydroxy-4-methoxyphenyl)-1-propanal, an intermediate of Advantamine, comprising the following steps:

[0012] Step 1: Isovanillin and cyanomethylenetriphenylphosphine Wittig reaction occurs to generate 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile

[0013] Step 2: 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile is subjected to hydrogenation reaction under the catalysis of a hydrogenation catalyst to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile The hydrogenation catalyst is selected from Pd / C, Pt / C, etc., preferably Pd / C;

[0014] Step 3: Reducing 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile with a reducing agent to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionaldehyde The reducing agent is preferably diisobutylaluminum hydride.

[0015] Furthermore, in step 1, the molar ratio of isovanillin to cyanomethylenetriphenylphosphine is 1:(1-1.5), preferably 1:(1-1.2).

[0016] Furthermore, in step 1, the reaction solvent is selected from any one of tetrahydrofuran, ethanol, and dichloromethane, preferably tetrahydrofuran; and the reaction temperature is 20-70°C, preferably 40-60°C.

[0017] Furthermore, in step 2, the amount of catalyst Pd / C used is 1% to 5% by weight of 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile, preferably 1% to 3%.

[0018] Furthermore, in step 2, the reaction solvent is selected from any one of methanol, ethanol, and ethyl acetate, preferably methanol and ethanol; the reaction temperature is 10 to 60°C, preferably 20 to 30°C.

[0019] Furthermore, in the step 2, the reaction solution obtained by the hydrogenation reaction is filtered to remove Pd / C, the filtrate is concentrated to dryness under reduced pressure and then recrystallized with ethyl acetate / petroleum ether to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile.

[0020] Furthermore, in step 3, the molar ratio of diisobutylaluminum hydride to 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile is (2 to 2.2):1.

[0021] Furthermore, in step 3, the reaction solvent is selected from tetrahydrofuran or dichloromethane, preferably tetrahydrofuran; and the reaction temperature is -20 to 0°C, preferably -10 to 0°C.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The synthesis method of the present invention has mild reaction conditions and high step-by-step reaction yield, thereby greatly improving the overall yield.

[0024] 2. The synthesis method of the present invention avoids the reaction conditions of two phenolic compounds, isovanillin and 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile, producing dark impurities under strong alkaline conditions, reduces the difficulty of subsequent purification, and greatly improves the quality of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0026] Figure 1 3-(3-hydroxy-4-methoxyphenyl)-1-propanal 1 HNMR spectrum. DETAILED DESCRIPTION

[0027] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several changes and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0028] The present invention provides a method for synthesizing 3-(3-hydroxy-4-methoxyphenyl)-1-propanal, an intermediate of Advantamine. The synthetic route is as follows:

[0029]

[0030] (1) Isovanillin and cyanomethylenetriphenylphosphine undergo Wittig reaction to generate 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile with a yield of up to 94%. The solvent can be tetrahydrofuran, ethanol, dichloromethane, etc. Tetrahydrofuran is preferred. The reaction temperature is 20-70°C, preferably 40-60°C. Isovanillin / cyanomethylenetriphenylphosphine is 1.0 / 1.0-1.5 (molar ratio), preferably 1.0 / 1.1-1.2. Cyanomethylenetriphenylphosphine is a stable ylide and does not need to be generated in situ during the reaction. Isovanillin and the product 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile are not very soluble in general organic solvents. Solvent screening first examines the solubility of the raw materials and the reaction conditions, and then the solubility of the product. The reaction temperature mainly affects the reaction rate and the ratio of the cis-trans isomers of the carbon-carbon double bond in the product. Since the cis-trans isomers of the carbon-carbon double bond produce the same product in the next step of hydrogenation, the effect of the reaction temperature on the yield and reaction rate is mainly investigated. Through research, it was found that solvents such as tetrahydrofuran, ethanol, and dichloromethane showed good solubility for the substrate isovanillin, and the best yield was obtained in tetrahydrofuran.

[0031] Table 1. Screening experiment of reaction conditions in step (1)

[0032] Solvents Isovanillin / cyanomethylenetriphenylphosphine (molar ratio) Reaction temperature (℃) Yield Tetrahydrofuran 1 / 1.2 50 94％ Tetrahydrofuran 1 / 1.5 50 91％ Tetrahydrofuran 1 / 1.2 60 88％ Tetrahydrofuran 1 / 1.2 40 87％ Anhydrous ethanol 1 / 1.2 50 80％ Anhydrous ethanol 1 / 1.2 60 82％ Anhydrous ethanol 1 / 1.5 60 85％ Dichloromethane 1 / 1.2 40(Reflux) 84％ Dichloromethane 1 / 1.5 40(Reflux) 87％

[0033] General reaction conditions: 10.0 g of isovanillin was dissolved in 120 mL of solvent, and then cyanomethylenetriphenylphosphine was added; after the reaction was completed under HPLC monitoring, the reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent as the eluent.

[0034] (2) 3-(3-hydroxy-4-methoxyphenyl) acrylonitrile is hydrogenated under 5% Pd / C catalysis to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile with a yield of up to 90%. The solvent can be methanol, ethanol or ethyl acetate, preferably methanol or ethanol. The reaction temperature is 10-60°C, preferably 20-30°C. The amount of catalyst used is 1%-5% of the weight of the substrate, preferably 1%-3%. Taking 5% Pd / C catalyst as an example, under more severe reaction conditions (for example, 50°C / 1atm.H2 or 25°C / 3atm.H2), over-hydrogenated products (highly polar byproducts produced by hydrogenation of cyano groups) can be observed; under milder conditions (for example, 25°C / 1atm.H2), no over-hydrogenated products are observed. Pd / C and Pt / C are commonly used hydrogenation catalysts. Compared with 5% Pt / C, 5% Pd / C shows better catalytic performance and faster reaction rate, so 5% Pd / C is selected as the hydrogenation catalyst.

[0035] Table 2. Screening experiment of reaction conditions in step (2)

[0036] Solvents catalyst Catalyst dosage <![CDATA[H2 pressure]]> Reaction temperature (℃) Yield Methanol 5%Pd / C 0.10g 1atm. 25 90％ Methanol 5%Pd / C 0.10g <![CDATA[3atm. a ]]> 25 <![CDATA[72% b ]]> Methanol 5%Pd / C 0.10g 1atm. 50 <![CDATA[55% b ]]> Methanol 5%Pd / C 0.30g 1atm. 25 88％ Methanol 5%Pt / C 0.10g 1atm. 25 91％ Ethanol 5%Pd / C 0.10g 1atm. 25 87％ Ethyl acetate 5%Pd / C 0.10g 1atm. 25 82％

[0037] General reaction conditions: 10.0g 3-(3-hydroxy-4-methoxyphenyl) acrylonitrile is dissolved in 100mL solvent, and after adding catalyst (calculated as catalyst without water), the air is replaced with nitrogen first, and then the nitrogen is replaced with hydrogen; after the reaction is completed, the reaction liquid is filtered to remove the catalyst, and the catalyst is washed with a small amount of solvent, and the filtrate is combined and concentrated to dryness under reduced pressure, and the residue is recrystallized with ethyl acetate / petroleum ether, and the precipitated solid is collected by filtration and vacuum dried. (a, the reaction is carried out in a stainless steel autoclave; b, the product is purified by silica gel column chromatography).

[0038] (3) DIBALH (diisobutylaluminum hydride) reduces 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionaldehyde, with a yield of up to 83%. The solvent can be tetrahydrofuran or dichloromethane, preferably tetrahydrofuran. The reaction temperature is -20 to 0°C, preferably -10 to 0°C. DIBALH / 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile (molar ratio) is 2.0 to 2.2 / 1. DIBALH is used as a reducing agent to reduce the cyano group to the aldehyde group. When the reaction temperature is too high or DIBALH is excessive, an over-reduced product (cyano group is reduced to amino group) will appear. In this reaction, due to the presence of free hydroxyl groups, 1 equivalent of DIBALH will be consumed, so the optimal equivalent is 2.0 to 2.2 equivalents of reducing agent.

[0039] Table 3. Screening experiment of reaction conditions in step (3)

[0040] Solvents DIBALH equivalent Dropping temperature (℃) Yield Tetrahydrofuran 2.1 -10 85％ Tetrahydrofuran 2.1 0 83％ Tetrahydrofuran 2.1 10 57％ Tetrahydrofuran 2.0 0 80％ Tetrahydrofuran 2.2 0 77％ Tetrahydrofuran 2.5 0 65％ Dichloromethane 2.1 0 66％

[0041] General reaction conditions: 5.0g 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile is dissolved in 60mL solvent, cooled to -10°C and then 1M DIBALH / toluene solution is added dropwise thereto. After the addition, the reaction is continued at low temperature for 3 hours, and then the reaction is continued at room temperature for 8 hours. After the reaction is completed, the reaction solution is added dropwise to a 5% sulfuric acid aqueous solution at ≤5°C for quenching. After the addition is completed, the mixture is stirred at 0-5°C for 1 hour, and the reaction solution is extracted with ethyl acetate. The extract is washed with water, 5% NaHCO3 aqueous solution, and 5% brine, respectively, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to dryness under reduced pressure, and the residue is purified by silica gel column chromatography, with ethyl acetate / petroleum ether mixed solvent as the eluent.

[0042] The technical solution of the present invention will be further described below in conjunction with specific embodiments.

[0043] Example 1

[0044] Step 1, preparation of 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile:

[0045] Under nitrogen protection, in a 250mL three-necked reaction bottle, isovanillin (10.0g, 65.7mmol, 1eq.) was dissolved in anhydrous tetrahydrofuran (120mL), and then cyanomethylenetriphenylphosphine (23.8g, 78.8mmol, 1.2eq.) was added, and the reaction was carried out at 50°C for 5 hours. HPLC monitoring showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a petroleum ether / ethyl acetate mixed solvent as an eluent to obtain 10.8g of a light yellow solid with a yield of 94%.

[0046] 1 H NMR showed that the product was a mixture of carbon-carbon double bond cis-trans isomers, with a ratio of about 1 / 1, and the two could not be separated under this purification condition. The cis-trans isomers produced the same product in the next step of hydrogenation, so there was no need to separate the two isomers in this step. 1H NMR (400MHz, CDCl3) δ: 7.41 (dd, J1=2.0Hz, J2=8.4Hz, 1H), 7.39 (d, J=2.0Hz, 1H), 7 .29(d,J=16.4Hz,1H),7.05(d,J=2.4Hz,1H),6.98(d,J=12.4Hz,1H),6.95(dd,J1= 2.0Hz,J2=8.4Hz,1H),6.89(d,J=8.4Hz,1H),6.85(d,J=8.4,1H),5.70(d,J=16.4H z,1H),5.67(s,1H),5.66(s,1H),5.30(d,J=12.4Hz,1H),3.95(s,3H),3.94(s,3H).

[0047] Step 2, preparation of 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile:

[0048] In a 250mL glass reaction bottle, 3-(3-hydroxy-4-methoxyphenyl) acrylonitrile (10.0g, 57mmol) was dissolved in methanol (100mL), and then 5% Pd / C (0.20g) containing 50% water was added. The reaction solution was vigorously stirred for 6 hours at 25°C and 1atm.H2. HPLC monitoring showed that the reaction was complete. The reaction solution was filtered to remove Pd / C, and the solid was washed with a small amount of methanol. The filtrate was combined and concentrated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate / petroleum ether to obtain 9.1g of white solid with a yield of 90%. Melting point: 83.6-84.0°C. 1 H NMR (400MHz, CDCl3) δ: 6.81 (d, J = 8.4Hz, 1H), 6.78 (d, J = 2.0Hz, 1H), 6.72 (dd, J1 = 2.0Hz ,J2=8.4Hz,1H),5.61(s,1H),3.88(s,3H),2.87(t,J=7.6Hz,2H),2.58(t,J=7.6Hz,2H).

[0049] Step 3, preparation of 3-(3-hydroxy-4-methoxyphenyl)-1-propanal:

[0050] Under nitrogen protection, in a 250mL three-necked reaction bottle, 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile (5.0g, 28.2mmol, 1eq.) was dissolved in anhydrous tetrahydrofuran (60mL) and cooled to -10°C. 1M DIBALH / toluene solution (59.3mL, 59.3mmol, 2.1eq.) was added dropwise to the reaction solution, and the reaction temperature was controlled to be ≤0°C during the addition process. After the addition was completed, it was stirred at 0°C for 3 hours, and then the temperature was raised to room temperature and the reaction was continued for 8 hours. After the reaction was completed, the reaction solution was slowly added dropwise to a cold 5% aqueous sulfuric acid solution (100mL) to quench, and the internal temperature was controlled to be ≤5°C during the addition process. After the addition was completed, it was continued to stir at 0-5°C for 1 hour. The reaction solution was extracted 3 times with 50mL of ethyl acetate. The combined extracts were washed with 50 mL of water, 50 mL of 5% sodium bicarbonate aqueous solution and 50 mL of 5% brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate / petroleum ether as the eluent to obtain 4.2 g of a white solid with a yield of 83%. Figure 1 As shown: 1 H NMR(400MHz, CDCl3)δ:9.81(t,J=1.2Hz,1H),6.79-6.76(m,2H),6.67(dd,J1=2.0Hz,J 2=8.0Hz,1H),5.57(s,1H),3.87(s,3H),2.87(t,J=7.6Hz,2H),2.74(t,J=7.6Hz,2H).

[0051] Embodiment 2:

[0052] Step 1, preparation of 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile

[0053] Under nitrogen protection, in a 250mL three-necked reaction bottle, isovanillin (10.0g, 65.7mmol, 1eq.) was dissolved in anhydrous ethanol (120mL), and then cyanomethylenetriphenylphosphine (29.7g, 98.6mmol, 1.5eq.) was added, and the reaction was carried out at 60°C for 4 hours. HPLC monitoring showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography, using a petroleum ether / ethyl acetate mixed solvent as an eluent to obtain 9.8g of a light yellow solid with a yield of 85%. The product is a mixture of cis-trans isomers of carbon-carbon double bonds.

[0054] The remaining steps are the same as those in Example 1.

[0055] Embodiment 3:

[0056] The difference from Example 1 is that the reaction solvent methanol in step 2 is replaced by ethanol, the reaction yield of step 2 is 87%, and the remaining steps are the same as Example 1.

[0057] Example 4

[0058] The difference from Example 1 is that the reaction solvent tetrahydrofuran in step 3 is replaced by dichloromethane, the reaction yield of step 3 is 66%, and the remaining steps are the same as Example 1.

[0059] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various changes or modifications within the scope of the claims, which does not affect the essence of the present invention. In the absence of conflict, the embodiments of the present application and the features in the embodiments can be combined with each other arbitrarily.

Claims

1. A method for synthesizing 3-(3-hydroxy-4-methoxyphenyl)-1-propanal, an intermediate of Advantamine, characterized in that: The steps include: Step 1: Isovanillin and cyanomethylenetriphenylphosphine Wittig reaction occurs to generate 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile Step 2: 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile is subjected to hydrogenation reaction under the catalysis of a hydrogenation catalyst to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile Step 3: Reducing 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile with a reducing agent to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionaldehyde 2. The method for synthesizing the adventitious intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propanal according to claim 1, characterized in that: In the step 1, the molar ratio of isovanillin to cyanomethylenetriphenylphosphine is 1:(1-1.5).

3. The method for synthesizing the adventitious intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propanal according to claim 1, characterized in that: In the step 1, the reaction solvent is selected from any one of tetrahydrofuran, ethanol and dichloromethane, and the reaction temperature is 20-70°C.

4. The method for synthesizing the adventitious intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propanal according to claim 1, characterized in that: In the step 2, the amount of catalyst Pd / C used is 1% to 5% of the weight of 3-(3-hydroxy-4-methoxyphenyl)acrylonitrile.

5. The method for synthesizing the adventitious intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propanal according to claim 1, characterized in that: In step 2, the reaction solvent is selected from any one of methanol, ethanol and ethyl acetate, and the reaction temperature is 10 to 60°C.

6. The method for synthesizing the adventitious intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propanal according to claim 1, characterized in that: In the step 2, the reaction solution obtained by the hydrogenation reaction is filtered to remove Pd / C, the filtrate is concentrated to dryness under reduced pressure and then recrystallized with ethyl acetate / petroleum ether to obtain 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile.

7. The method for synthesizing the adventitious intermediate 3-(3-hydroxy-4-methoxyphenyl)-1-propanal according to claim 1, characterized in that: In the step 3, the molar ratio of diisobutylaluminum hydride to 3-(3-hydroxy-4-methoxyphenyl)-1-propionitrile is (2-2.2):

1.

8. The method for synthesizing 3-(3-hydroxy-4-methoxyphenyl)-1-propanal, an intermediate of Advantamine according to claim 1, characterized in that: In the step 3, the reaction solvent is selected from tetrahydrofuran or dichloromethane, and the reaction temperature is -20 to 0°C.

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