Scaled-up preparation method for advantame

Abstract

The present invention belongs to the field of organic synthesis, and discloses a scaled-up preparation method for advantame. Two methods are used. Method A: taking acrolein and bis(pinacolato)diboron as raw materials, and reacting same in an aqueous solution under the catalysis of a copper salt and an organic alkali, so as to obtain 3-boric acid pinacol ester propionaldehyde; and then reacting same with 5-bromo-2-methoxyphenol in the presence of a palladium catalyst and an alkali, so as to generate 3-hydroxy-4-methoxybenzene propionaldehyde. Method B: performing a Grignard exchange on 5-bromine-2-methoxyphenol, and then reacting same with boric acid ester, so as to obtain 3-hydroxy-4-methoxyphenylboronic acid; and then reacting same with acrolein in the presence of a rhodium catalyst and an alkali, so as to generate 3-hydroxy-4-methoxybenzene propionaldehyde. Finally, reduction and ammoniation are performed to obtain advantame. The method reduces the amount of isomers produced and improves the reaction yield, the process is simple and reliable, the method is convenient for industrial production, and a new reaction path is provided for the synthesis of advantame.

Description

A scaled-up preparation method for Advantane Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for enlarging the preparation of Advantamine. Background Art

[0002] Advantame is a new, non-nutritive, ultra-high-intensity sweetener. Its chemical name is N-{N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl}-L-phenylalanine-1-methyl ester. It typically exists as a monohydrate with the molecular formula C24H30N2O7·H2O. Its chemical structure is as follows:

[0003]

[0004] Advantame is 20,000 times sweeter than sucrose and offers a pure, sweet taste similar to sucrose. It offers a cost-effective alternative to sucrose and other sweeteners in food, beverages, and pharmaceuticals, providing a calorie-reducing solution and lowering production costs. Advantame also has flavor-enhancing properties, effectively reducing the amount of flavorings and citric acid used in food. As a non-nutritive sweetener, Advantame is suitable for all populations, including those with obesity, cardiovascular disease, and diabetes, as well as for individuals with phenylketonuria who cannot consume aspartame. Advantame has been approved for use in the United States, the European Union, Japan, Australia, New Zealand, South Korea, Brazil, Argentina, Turkey, Malaysia, the Philippines, and Thailand, among other countries. my country approved its use in October 2017.

[0005] Advantame can be synthesized by hydroalkylation of 3-hydroxy-4-methoxycinnamaldehyde or 3-(3-hydroxy-4-methoxyphenyl)propionaldehyde with aspartame in the presence of palladium or platinum supported on activated carbon (see U.S. Patents US2003 / 0118710A1; US6,965,055B2). However, the use of precious metal catalysts is costly, the process is complex, and a hydrogen source is required, which poses safety risks. Summary of the Invention

[0006] To overcome the above technical deficiencies, the present invention provides a scaled-up preparation method for adventitamine. 5-halogenated 2-methoxyphenol is used as a raw material to prepare a Grignard reagent, which is then coupled with propionaldehyde to produce 3-hydroxy-4-methoxyphenylpropanol. The 3-hydroxy-4-methoxyphenylpropanol then undergoes a reductive amination reaction with aspartame to obtain the product. This method significantly shortens the reaction steps and reduces raw material costs. The process is simple, reliable, and amenable to industrial production, providing a new reaction pathway for the synthesis of adventitamine.

[0007] The amplified preparation method of Advantame of the present invention uses acrolein and 2-methoxy-5-bromophenol as raw materials and adopts two methods, respectively represented by the following reaction equations:

[0008] Method A:

[0009]

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

[0011] The first step is to use acrolein and bis(pinacol borate) as raw materials, react in an aqueous solution under the catalysis of copper salt and organic base to obtain 3-bis(pinacol borate) propionaldehyde;

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

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

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

[0015] Step 2: 3-boronic acid pinacol ester propanal and 5-bromo-2-methoxyphenol are reacted in the presence of a palladium catalyst and a base to generate 3-hydroxy-4-methoxyphenylpropanal.

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

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

[0018] Furthermore, in the above technical solution, the molar ratio of 3-hydroxy-4-methoxyphenylboronic acid, acrolein and palladium catalyst is 1:1-2.5:0.005-0.02.

[0019] Step 3: After 3-hydroxy-4-methoxyphenylpropionaldehyde and aspartame react in an organic solvent, a reducing agent and glacial acetic acid are added to obtain Advantame after reductive amination.

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

[0021] Furthermore, in the above technical solution, the reaction temperature is selected from 0-40°C.

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

[0023] Method B:

[0024]

[0025] The preparation method of technical solution B of the present invention comprises the following steps:

[0026] Step 1: 5-bromo-2-methoxyphenol is Grignard exchanged and then reacted with borate ester to obtain 3-hydroxy-4-methoxyphenylboronic acid;

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

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

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

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

[0031] Step 2: 3-hydroxy-4-methoxyphenylboronic acid and acrolein react in the presence of a rhodium catalyst and a base to generate 3-hydroxy-4-methoxyphenylpropionaldehyde;

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

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

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

[0035] Step 3: After 3-hydroxy-4-methoxyphenylpropionaldehyde and aspartame react in an organic solvent, a reducing agent and glacial acetic acid are added to obtain Advantame after reductive amination.

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

[0037] Furthermore, in the above technical solution, the reaction temperature is selected from 0-40°C.

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

[0039] The method of the present invention is simple and reliable, and is easy to industrialize; it reduces the amount of isomers generated, improves the reaction yield, and greatly reduces the overall production cost compared with the production processes in existing literature or patents, making the product more competitive in the market. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIG1 is a HNMR spectrum of Advantine, a product of Example 1;

[0041] FIG2 is an HPLC spectrum of the product Advantine obtained in Example 1. DETAILED DESCRIPTION

[0042] The present invention will be further described below in conjunction with specific examples. These examples should be understood to be merely illustrative of the present invention and not intended to limit the scope of protection of the present invention. After reading the contents described herein, those skilled in the art may make various changes or modifications to the present invention, and these equivalent variations and modifications also fall within the scope defined by the claims of the present invention.

[0043] Example 1

[0044]

[0045] Under nitrogen, a 2M isopropylmagnesium chloride-tetrahydrofuran solution (110 mL, 0.22 mol) was added dropwise to a 5-bromo-2-methoxyphenol (22.3 g, 0.11 mol) / tetrahydrofuran solution at -10°C to 0°C. The reaction was stirred for 2 hours. After the reaction, the mixture was added dropwise to trimethyl borate (25.7 g, 0.25 mol) and 20 mL of tetrahydrofuran cooled to -78°C and stirred for 12 hours. The mixture was warmed to room temperature and hydrolyzed by the addition of 1M aqueous hydrochloric acid. After the acid hydrolysis was complete, 100 mL of ethyl acetate was added, and the organic layer was separated and extracted. The aqueous layer was extracted twice with 100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to yield 16.81 g of 3-hydroxy-4-methoxyphenylboronic acid in a yield of 91%.

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

[0047] 3-Hydroxy-4-methoxyphenylpropionaldehyde (16.3 g, 0.091 mol) and aspartame (25.31 g, 0.086 mol) were added to tetrahydrofuran (200 mL) and stirred at room temperature for half an hour. Sodium acetate borohydride (4.16 g, 0.11 mol) and acetic acid (5.16 g, 0.086 mol) were then slowly added. The reaction was quenched with water, extracted with dichloromethane, and recrystallized from toluene to obtain 35.46 g of Advantame, with a yield of 90%.

[0048] Example 2

[0049]

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

[0051] 3-Hydroxy-4-methoxyphenylboronic acid (16.6 g, 0.099 mol), acrolein (11.21 g, 0.2 mol), potassium carbonate aqueous solution (34.55 g, 0.25 mol), Rh(acac)(C2H4)2 (0.003 mol), and dioxane (150 mL) were stirred at 60-65°C under nitrogen for 12 hours. After the reaction, the dioxane solvent was evaporated, and water and dichloromethane were added. The organic layer was separated, and the aqueous layer was extracted twice with 80 mL of dichloromethane. The organic layers were combined and washed with 100 mL of sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The oily product was separated by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate 50:1, volume ratio) to obtain 16.04 g of 3-hydroxy-4-methoxyphenylpropanal in a 90% yield.

[0052] 3-Hydroxy-4-methoxyphenylpropionaldehyde (16.3 g, 0.091 mol) and aspartame (25.31 g, 0.086 mol) were added to acetonitrile (200 mL) and 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, quenched with water, extracted with dichloromethane, and recrystallized from toluene to obtain 35.86 g of Advantame, with a yield of 91%.

[0053] Example 3

[0054]

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

[0056] Bistriphenylphosphine 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 to toluene (14 L). The reaction system was stirred at 60-65°C under nitrogen for 12 hours. After the reaction, water and methanol were added and stirred at room temperature for 6 hours. Water and dichloromethane were then added, and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined and washed with 1% sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The oily product was separated by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate 50:1, volume ratio) to obtain 1 kg of 3-hydroxy-4-methoxyphenylpropanal in an 87% yield.

[0057] 3-Hydroxy-4-methoxyphenylpropionaldehyde (1 kg, 5.55 mol) and aspartame (1.54 kg, 5.25 mol) were added to dichloroethane (12 L) and stirred at room temperature for half an hour. Then, sodium acetate borohydride (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, quenched with water, extracted with dichloromethane, and recrystallized from toluene to obtain 2.21 kg of Advantame, with a yield of 92%.

[0058] The above embodiments illustrate the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and improvements may be made to the present invention without departing from the scope of the principles of the present invention, and all such changes and improvements fall within the scope of protection of the present invention.

Claims

1. A method for preparing 3-hydroxy-4-methoxycinnamaldehyde, characterized in that, It includes the following steps: Method A 2. The first step: Using acrolein and bis(pinacolato)diboron as raw materials, reacting in an aqueous solution under the catalysis of a copper salt and an organic base to obtain 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanal; The second step: Reacting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanal and 5-bromo-2-methoxyphenol in the presence of a palladium catalyst and a base to generate 3-hydroxy-4-methoxycinnamaldehyde; Method B 3. The first step: After the Grignard exchange of 5-bromo-2-methoxyphenol, then reacting with a borate ester to obtain 3-hydroxy-4-methoxyphenylboronic acid; The second step: Reacting 3-hydroxy-4-methoxyphenylboronic acid and acrolein in the presence of a rhodium catalyst and a base to generate 3-hydroxy-4-methoxycinnamaldehyde.

4. The preparation method of 3-hydroxy-4-methoxycinnamaldehyde 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.

5. The preparation method of 3-hydroxy-4-methoxycinnamaldehyde according to claim 1, characterized in that: In the first step of Method A, the molar ratio of 5-bromo-2-methoxyphenol, bis(pinacolato)diboron, copper salt to organic base is 1:1 - 1.2:0.01 - 0.02:0.02 - 0.

04.

6. The preparation method of 3-hydroxy-4-methoxybenzaldehyde 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.

7. The preparation method of 3-hydroxy-4-methoxycinnamaldehyde according to claim 1, characterized in that: In the second step of Method A, the molar ratio of 3-hydroxy-4-methoxyphenylboronic acid, acrolein to palladium catalyst is 1:1 - 2.5:0.005 - 0.

02.

8. The preparation method of 3-hydroxy-4-methoxycinnamaldehyde according to claim 1, characterized in that: In the first step of Method B, the Grignard exchange uses isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium 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; the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.

9. The preparation method of 3-hydroxy-4-methoxycinnamaldehyde 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.

10. The preparation method of 3-hydroxy-4-methoxycinnamaldehyde according to claim 1, characterized in that: In the second step of Method B, the base 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 to rhodium catalyst is 1:1 - 2.5:0.01 - 0.

05.

11. A preparation method of advantame, characterized in that, It includes the following steps:

12. Using 3-hydroxy-4-methoxycinnamaldehyde obtained by the method described in any one of claims 1 - 8, then reacting 3-hydroxy-4-methoxycinnamaldehyde and aspartame in an organic solvent, adding a reducing agent and glacial acetic acid, and performing reductive amination to obtain advantame.

13. The preparation method of advantame 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°C; the reducing agent is selected from sodium triacetoxyborohydride or sodium cyanoborohydride.

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