A method for the large scale preparation of eduvan sweet

Abstract

The application discloses an amplification preparation method of idvantsweet, and belongs to the field of organic synthesis. Two methods are adopted: A, propenal and bis(pinacolato)diboron are used as raw materials, and a reaction is carried out in an aqueous solution under the catalysis of copper salt and an organic base to obtain 3-boronic acid pinacol propionaldehyde; then, 5-bromo-2-methoxyphenol is reacted in the presence of a palladium catalyst and an alkali to generate 3-hydroxy-4-methoxybenzene propionaldehyde; B, Grignard exchange is carried out on 5-bromo-2-methoxyphenol, and then, a reaction is carried out with borate to obtain 3-hydroxy-4-methoxybenzene boronic acid; then, propenal is reacted in the presence of a rhodium catalyst and an alkali to generate 3-hydroxy-4-methoxybenzene propionaldehyde; and finally, idvantsweet is obtained by reducing an amine ring. The method reduces the generation amount of isomers, improves the reaction yield, is simple and reliable, is easy for industrial production, and provides a new reaction path for the synthesis of idvantsweet.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a large-scale preparation method of Advantame. BACKGROUND

[0002] Advantame is a new non-nutritive super high-intensity sweetener, its chemical name is N-{N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-alpha-aspartyl}-L-phenylalanine-1-methyl ester. It usually exists in the form of its monohydrate, the molecular formula is C24H30N2O7·H2O, and the chemical structural formula is as follows:

[0003]

[0004] The sweetness of Advantame is 20000 times that of sucrose, and it has a pure sweet taste similar to sucrose, high cost performance, and can replace sucrose and other sweeteners for use in food, beverages and medicine, providing a way to reduce calories and reduce production costs. Advantame also has the property of flavor enhancement, which can effectively reduce the amount of flavor and citric acid used in food. As a non-nutritive sweetener, Advantame is suitable for all people including obese, cardiovascular disease and diabetes patients, and also suitable for patients with phenylketonuria who cannot eat aspartame. At present, Advantame has been approved for use in the United States, Japan, Australia and other countries. China has also approved its use in October 2017.

[0005] Advantame can be synthesized by hydrogenation of 3-hydroxy-4-methoxy cinnamaldehyde or 3-(3-hydroxy-4-methoxyphenyl) propyl aldehyde with aspartame under the catalysis of palladium or platinum supported on activated carbon (see US2003 / 0118710A1; US6,965,055B2), but the use of noble metal catalysts has high cost, complex process operation, and requires a hydrogen source, and the use of hydrogen has safety hazards. SUMMARY

[0006] In order to overcome the above technical defects, the present application provides a large-scale preparation method of Advantame. 5-halogen-2-methoxy phenol is used as a raw material, a Grignard reagent is prepared, and then coupled with propyl aldehyde to form 3-hydroxy-4-methoxy phenyl propyl alcohol, and the 3-hydroxy-4-methoxy phenyl propyl alcohol is subjected to reductive amination with aspartame to obtain the product. This method greatly shortens the reaction steps, reduces the cost of raw materials, and is simple and reliable in process, easy to industrialize, and provides a new reaction path for the synthesis of Advantame.

[0007] The large-scale preparation method of Advantame described in the present application uses propyl aldehyde and 2-methoxy-5-bromophenol as raw materials, and two methods are used, which are represented by the following reaction equations, respectively:

[0008] Method A:

[0009]

[0010] The technical solution A preparation method of the application comprises the following steps:

[0011] First step: taking propenal and pinacol diboronic acid as raw materials, reacting in aqueous solution under the catalysis of copper salt and organic base to obtain 3-pinacol boronic acid propionaldehyde;

[0012] Further, in the above technical solution, the copper salt is selected from copper chloride, copper bromide or copper acetate.

[0013] Further, in the above technical solution, the organic base is selected from DBU, Et3N, TMEDA, i-Pr2NEt, DMAP or DABCO.

[0014] Further, in the above technical solution, the molar ratio of 5-bromo-2-methoxyphenol, pinacol diboronic acid, copper salt and organic base is 1:1-1.2:0.01-0.02:0.02-0.04.

[0015] Second step: 3-pinacol boronic acid propionaldehyde and 5-bromo-2-methoxyphenol are reacted in the presence of a palladium catalyst and a base to generate 3-hydroxy-4-methoxyphenyl propionaldehyde.

[0016] Further, in the above technical solution, the base is selected from sodium acetate, potassium carbonate or potassium phosphate.

[0017] Further, in the above technical solution, the palladium catalyst is selected from PdCl2dppf or Pd(PPh4)3.

[0018] Further, in the above technical solution, the molar ratio of 3-hydroxy-4-methoxyphenyl boronic acid, propenal and palladium catalyst is 1:1-2.5:0.005-0.02.

[0019] Third step: after 3-hydroxy-4-methoxyphenyl propionaldehyde and aspartame are reacted in an organic solvent, a reducing agent and glacial acetic acid are added, and after reduction and amination, edulvan sweetener is obtained.

[0020] Further, in the above technical solution, the organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dichloroethane, methanol, ethanol and isopropanol.

[0021] Further, in the above technical solution, the reaction temperature is selected from 0-40℃.

[0022] Further, in the above technical solution, the reducing agent is selected from sodium borohydride acetate or sodium cyanoborohydride.

[0023] Method B:

[0024]

[0025] The technical solution B of the present application comprises the following steps:

[0026] Step 1: after Grignard exchange of 5-bromo-2-methoxyphenol, then react with borate ester, 3-hydroxy-4-methoxyphenyl boronic acid is obtained;

[0027] Further, in the above technical solution, Grignard exchange uses isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride. The molar ratio of the Grignard reagent to 5-bromo-2-methoxyphenol is 2-2.5:1.

[0028] Further, in the above technical solution, the borate ester is selected from triethyl borate, trimethyl borate, triisopropyl borate or triphenyl borate.

[0029] Further, in the above technical solution, the molar ratio of 5-bromo-2-methoxyphenol to borate ester is 1:2-2.5; the reaction temperature is-78℃ to 0℃.

[0030] Further, in the above technical solution, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.

[0031] Step 2: 3-hydroxy-4-methoxyphenyl boronic acid and acrolein generate 3-hydroxy-4-methoxyphenyl propenal in the presence of rhodium catalyst and base;

[0032] Further, in the above technical solution, the base is selected from sodium acetate, potassium carbonate or potassium phosphate.

[0033] Further, in the above technical solution, the rhodium catalyst is selected from Rh(acac)(C2H4)2.

[0034] Further, in the above technical solution, the molar ratio of 3-hydroxy-4-methoxyphenyl boronic acid, acrolein and rhodium catalyst is 1:1-2.5:0.01-0.05.

[0035] Step 3: after 3-hydroxy-4-methoxyphenyl propenal and aspartame react in an organic solvent, a reducing agent and glacial acetic acid are added, and after reduction and amination, edulvan sweetener is obtained.

[0036] Further, in the above technical solution, the organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dichloroethane, methanol, ethanol and isopropanol.

[0037] Further, in the above technical solution, the reaction temperature is selected from 0-40℃.

[0038] Further, in the above technical solution, the reducing agent is selected from sodium borohydride acetate and sodium cyanoborohydride.

[0039] The method of the present application is simple and reliable, easy to be industrialized, reduces the generation amount of isomers, improves the reaction yield, and greatly reduces the comprehensive production cost compared with the production process in the prior art or patent, and the product has more market competitiveness. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 HNMR spectrum of the product of Example 1, i.e. Evangeline sweetener;

[0041] Figure 2 HPLC spectrum of the product of Example 1, i.e. Evangeline sweetener. DETAILED DESCRIPTION

[0042] The present application will be further described in conjunction with specific examples. These examples should be understood as merely illustrative of the present application and not used to limit the protection scope of the present application. After reading the content described in the present application, those skilled in the art can make various changes or modifications to the present application, and these equivalent changes and modifications also fall within the scope defined by the claims of the present application.

[0043] Example 1

[0044]

[0045] Under nitrogen protection, 2M isopropyl magnesium chloride-tetrahydrofuran solution (110 mL, 0.22 mol) was dropped into 5-bromo-2-methoxyphenol (22.3 g, 0.11 mol) in tetrahydrofuran solution at a temperature of -10 to 0°C, and after the dropping was completed, the reaction was stirred for 2 hours. After the reaction was completed, it was dropped into trimethyl borate (25.7 g, 0.25 mol) and 20 mL tetrahydrofuran cooled to -78°C, and the reaction was stirred for 12 hours. The temperature was increased to room temperature, 1M hydrochloric acid aqueous solution was added dropwise for hydrolysis. After the acid hydrolysis was completed, 100 mL ethyl acetate was added, the organic layer was extracted and separated, the water layer was extracted with 100 mL ethyl acetate twice. The organic layers were combined, dried with anhydrous sodium sulfate, concentrated, and 3-hydroxy-4-methoxyphenyl boronic acid 16.81 g was obtained, with a yield of 91%.

[0046] A mixture of 3-hydroxy-4-methoxybenzeneboronic acid (16.80 g, 0.1 mol), propenal (11.21 g, 0.2 mol), aqueous potassium carbonate (34.55 g, 0.25 mol), Rh(acac)(C2H4)2 (0.002 mol) and dioxane (150 mL) was stirred at 60-65 °C for 12 hours under nitrogen. After the reaction was completed, the solvent dioxane was evaporated, water and dichloromethane were added, and the organic layer was separated. The aqueous layer was extracted with 80 mL of dichloromethane twice. The combined organic layers were washed with 100 mL of aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. All the oily materials were separated by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate 50:1, volume ratio) to give 3-hydroxy-4-methoxybenzene propionaldehyde 16.03 g, yield 89%.

[0047] A mixture of 3-hydroxy-4-methoxybenzene propionaldehyde (16.3 g, 0.091 mol) and aspartame (25.31 g, 0.086 mol) was stirred in tetrahydrofuran (200 mL) at room temperature for half an hour, and then sodium borohydride acetic acid (4.16 g, 0.11 mol) and acetic acid (5.16 g, 0.086 mol) were slowly added. After the reaction was quenched with water, dichloromethane was added for extraction, and toluene was added for recrystallization to give aspartame 35.46 g, yield 90%.

[0048] Example 2

[0049]

[0050] A 1 M isopropylmagnesium bromide-tetrahydrofuran solution (220 mL, 0.22 mol) was added dropwise to a solution of 5-chloro-2-methoxyphenol (17.44 g, 0.11 mol) in 2-methyltetrahydrofuran at a temperature of -10 °C to 0 °C under nitrogen. After the dropwise addition was completed, the reaction was stirred for 2 hours. After the reaction was completed, it was added dropwise to a solution of triethyl borate (36.50 g, 0.25 mol) and 20 mL of tetrahydrofuran cooled to -78 °C, and the reaction was stirred for 12 hours. The temperature was raised to room temperature, and 1 M aqueous hydrochloric acid was added dropwise for hydrolysis. After the aqueous hydrolysis was completed, 100 mL of ethyl acetate was added, and the organic layer was separated by extraction. The aqueous layer was extracted with 100 mL of ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 3-hydroxy-4-methoxybenzeneboronic acid 16.63 g, yield 90%.

[0051] To a solution of 3-hydroxy-4-methoxybenzene boronic acid (16.6 g, 0.099 mol), acrolein (11.21 g, 0.2 mol), aqueous potassium carbonate (34.55 g, 0.25 mol), Rh(acac)(C2H4)2 (0.003 mol) and dioxane (150 mL) was stirred at 60-65 °C for 12 hours under nitrogen. After the reaction was completed, the solvent dioxane was evaporated, water and dichloromethane were added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane twice. The organic layers were combined and washed with 100 mL of aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. All the oily materials were separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 50:1, volume ratio) to give 3-hydroxy-4-methoxybenzene propionaldehyde 16.04 g, yield 90%.

[0052] To a solution of 3-hydroxy-4-methoxybenzene propionaldehyde (16.3 g, 0.091 mol) and aspartame (25.31 g, 0.086 mol) in acetonitrile (200 mL) was stirred at room temperature for half an hour, then sodium cyanoborohydride (6.91 g, 0.11 mol) and acetic acid (5.16 g, 0.086 mol) were slowly added at 10-20 °C. The reaction was stirred for 12 hours, then quenched with water, extracted with dichloromethane, and recrystallized from toluene to give aspartame 35.86 g, yield 91%.

[0053] Example 3

[0054]

[0055] To a solution of copper sulfate pentahydrate (24.97 g, 0.1 mol), pinacol diboronic acid (2793 g, 11 mol), 4-methylpyridine (46.56 g, 0.5 mol) and acrolein (560 g, 10 mol) in tetrahydrofuran (16 L) was stirred at 60-65 °C for 12 hours under nitrogen. After the reaction was completed, water and dichloromethane were added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane twice. The organic layers were combined and washed with 100 mL of aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. All the oily materials were separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 50:1, volume ratio) to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propionaldehyde 1694.0 g, yield 92%.

[0056] Bis(triphenylphosphine)palladium dichloride (105 g, 0.15 mol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanal (1.69 kg, 9.2 mol), cesium carbonate (3 kg, 9.2 mol) and 5-bromo-2-methoxyphenol (1.30 kg, 6.39 mol) were added into toluene (14 L) and the reaction was stirred at 60-65 °C for 12 hours under nitrogen protection. After the reaction was completed, water and methanol were added and stirred at room temperature for 6 hours. Water and dichloromethane were added, and the organic layer was separated. The water layer was extracted twice with dichloromethane. The organic layers were combined and washed with 1 sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. All the oil was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 50:1, by volume) to obtain 3-hydroxy-4-methoxybenzaldehyde 1 kg, with a yield of 87%.

[0057] Aspartame (1.54 kg, 5.25 mol) and 3-hydroxy-4-methoxybenzaldehyde (1 kg, 5.55 mol) were added into dichloroethane (12 L) and stirred at room temperature for half an hour. Sodium borohydride acetate (1.67 kg, 7.88 mol) and acetic acid (315 g, 5.25 mol) were slowly added at 10-20 °C. The reaction was stirred for 12 hours. After the reaction was quenched with water, dichloromethane was extracted, and eduvan sweet was recrystallized from toluene to obtain 2.21 kg, with a yield of 92%.

[0058] The above examples describe the basic principles, main features and advantages of the present application. It should be understood by those skilled in the art that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the scope of the principles of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application.

Claims

1. A method for preparing 3-hydroxy-4-methoxyphenylpropanal, characterized in that, Includes the following steps: Method A Step 1: Using acrolein and pinacol 3-boronic acid as raw materials, react in aqueous solution under the catalysis of copper salt and organic base to obtain pinacol 3-boronic acid propionaldehyde; Step 2: 3-Borate pinacol ester propionaldehyde and 5-bromo-2-methoxyphenol are reacted in the presence of a palladium catalyst and a base to generate 3-hydroxy-4-methoxyphenylpropionaldehyde; Method B Step 1: After Grignard exchange of 5-bromo-2-methoxyphenol, it is then reacted with borate ester to obtain 3-hydroxy-4-methoxyphenylboronic acid; Step 2: 3-Hydroxy-4-methoxyphenylboronic acid and acrolein are reacted with a rhodium catalyst and a base to produce 3-hydroxy-4-methoxyphenylpropanal.

2. The method for preparing 3-hydroxy-4-methoxyphenylpropanal according to claim 1, characterized in that: In the first step of Method A, the copper salt is selected from copper chloride, copper bromide, or copper acetate; the organic base is selected from DBU, Et3N, TMEDA, i-Pr2NEt, DMAP, or DABCO.

3. The method for preparing 3-hydroxy-4-methoxyphenylpropanal according to claim 1, characterized in that: In the first step of Method A, the molar ratio of 5-bromo-2-methoxyphenol, pinacol diboronic acid ester, copper salt and organic base is 1:1-1.2:0.01-0.02:0.02-0.

04.

4. The method for preparing 3-hydroxy-4-methoxyphenylpropanal according to claim 1, characterized in that: In the second step of method A, the base is selected from sodium acetate, potassium carbonate or potassium phosphate; the palladium catalyst is selected from PdCl2dppf or Pd(PPh4)3.

5. The method for preparing 3-hydroxy-4-methoxyphenylpropanal according to claim 1, characterized in that: In the second step of method A, the molar ratio of 3-hydroxy-4-methoxyphenylboronic acid, acrolein and palladium catalyst is 1:1-2.5:0.005-0.

02.

6. The method for preparing 3-hydroxy-4-methoxyphenylpropanal according to claim 1, characterized in that: In the first step of Method B, the Grignard exchange uses isopropyl magnesium chloride, isopropyl magnesium bromide, or isopropyl magnesium chloride-lithium chloride; the borate ester is selected from triethyl borate, trimethyl borate, triisopropyl borate, or triphenyl borate; the reaction temperature is -78°C to 0°C.

7. The method for preparing 3-hydroxy-4-methoxyphenylpropanal according to claim 1, characterized in that: In the first step of method B, the molar ratio of the Grignard reagent to 5-bromo-2-methoxyphenol is 2-2.5:1; the molar ratio of 5-bromo-2-methoxyphenol to borate ester is 1:2-2.

5.

8. The method for preparing 3-hydroxy-4-methoxyphenylpropanal according to claim 1, characterized in that: In the second step of method B, The alkali is selected from sodium acetate, potassium carbonate, or potassium phosphate; the rhodium catalyst is selected from Rh(acac)(C2H4)2; the molar ratio of 3-hydroxy-4-methoxyphenylboronic acid, acrolein, and rhodium catalyst is 1:1-2.5:0.01-0.

05.

9. A method for preparing Advil, characterized in that, Includes the following steps: 3-hydroxy-4-methoxyphenylpropanal is obtained by the method described in any one of claims 1-8. Then, 3-hydroxy-4-methoxyphenylpropanal and aspartame are reacted in an organic solvent, and a reducing agent and glacial acetic acid are added. After reduction amination, Advantest is obtained.

10. The method for preparing Advilt according to claim 9, characterized in that: The organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dichloroethane, methanol, ethanol, and isopropanol; the reaction temperature is selected from 0-40℃; and the reducing agent is selected from sodium borohydride acetate or sodium cyanoborohydride.

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