Method for preparing 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one

Abstract

Disclosed in the present invention is a method for preparing a compound of formula 1. The method is shown in the following reaction process. In the method of the present invention, in the presence of a catalyst C1, anhydrous acetaldehyde and diphenyl carbonate are subjected to a one-pot method at a temperature T1 under the condition of an alkali B1 to generate a compound of formula 2, and the compound of formula 2 reacts with tert-butyl hydroperoxide at a temperature T2 by using a catalyst C2 to generate the compound of formula 1. The preparation method of the present invention is simple, has mild reaction conditions and a high reaction yield, and is convenient for industrial production.

Description

Preparation method of 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a method for synthesizing 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one. Background Art

[0002] Azilsartan medoxomil (Formula 6, Azilsartanmedoxomil, trade name: Edarbi), an angiotensin II receptor blocker developed by Japan's Takeda Pharmaceutical Company, has been approved by the U.S. FDA for the treatment of hypertension in adults.

[0003] Patent application WO2005080384 (A2) discloses a synthesis process for azilsartan medoxomil (Formula 6), using azilsartan and the side chain Formula 1 (4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one) as raw materials. Formula 1 is a key side chain of azilsartan medoxomil, making the development of a low-cost, high-purity, and high-yield synthesis process crucial.

[0004] Patent document WO2015046403A1 reports a synthesis method of Formula 1. This method uses 4-(chloromethyl)-1,3-dioxol-2-one and formic acid as raw materials for reaction. After a series of operations and column chromatography, the target product is obtained in a 43% yield. The synthesis of 4-(chloromethyl)-1,3-dioxol-2-one in this method requires the reaction of acetoin with toxic phosgene / diphosgene / triphosgene to form DMDO (Formula 2), which is then chlorinated. The entire synthetic route is complex and tedious, and the yield and quality are unsatisfactory.

[0005] Therefore, there is an urgent need in the art for a synthesis method of 4-hydroxymethyl-5-methyl-[1,3]dioxole-2-one that is simple to operate, has mild reaction conditions, and is conducive to large-scale industrial production.

[0006] Summary of the Invention

[0007] The object of the present invention is to provide a method for synthesizing 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one, which should have the advantages of simple operation, mild reaction conditions and high yield.

[0008] The present invention provides a method for preparing the compound represented by Formula 1, as shown in the following reaction scheme:

[0009] The method described in Formula 1 comprises the following steps:

[0010] 1) Anhydrous acetaldehyde reacts with diphenyl carbonate to produce a compound of formula 2;

[0011] 2) The compound of formula 2 reacts with tert-butyl peroxide to generate the compound of formula 1.

[0012] In a specific embodiment, in step 1), anhydrous acetaldehyde and diphenyl carbonate are reacted in a one-pot process to produce the compound of formula 2.

[0013] In a specific embodiment, in step 1), anhydrous acetaldehyde and diphenyl carbonate are reacted in the presence of a catalyst, and the catalyst is selected from the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 5, or a mixture thereof; preferably, the compound represented by formula 3 (vitamin B1)

[0014] In a specific embodiment, the molar ratio of the catalyst to anhydrous acetaldehyde is 0.005:1 to 0.025:1; preferably 0.01:1.0.

[0015] In a specific embodiment, anhydrous acetaldehyde is reacted with diphenyl carbonate in the presence of a base, and the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide or a mixture thereof; preferably potassium carbonate.

[0016] In a specific embodiment, in step 1), anhydrous acetaldehyde and diphenyl carbonate react at a temperature of 60°C to 120°C, preferably 95°C to 100°C.

[0017] In a specific embodiment, in step 2), the compound of formula 2 reacts with tert-butyl peroxide in the presence of a catalyst, and the catalyst is selected from silicon dioxide, selenium dioxide, copper alumina or a mixture thereof; preferably copper alumina.

[0018] In a specific embodiment, in step 2), the compound of formula 2 reacts with tert-butyl peroxide at a temperature of 0°C to 80°C, preferably 10°C to 15°C.

[0019] In a specific embodiment, the yield of the compound of formula 1 is above 98%, preferably above 99%.

[0020] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG1 shows the HPLC purity profile of the compound of Formula 1;

[0022] FIG2 shows the HPLC detection method of the compound of formula 1. DETAILED DESCRIPTION

[0023] After extensive and in-depth research, the inventors unexpectedly discovered a method for synthesizing 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one. This method utilizes a short synthetic route and uses inexpensive and readily available anhydrous acetaldehyde as a starting material to synthesize the compound of Formula 2 in a one-pot process. The compound of Formula 1 is then produced using a catalytic synthesis method. In addition to innovating the synthetic route, the present invention also optimizes the reaction process conditions, improving the reaction yield and product quality. The mild reaction conditions of the present method facilitate industrial production. This is the basis for the completion of the present invention.

[0024] definition

[0025] The scientific and technical terms used herein are consistent with those commonly understood by those skilled in the art to which the present invention belongs. For the purpose of a clear understanding of the present invention, the following definitions are made for the present invention:

[0026] One-pot method

[0027] The term "one-pot method" as used herein refers to what is commonly understood in the art as a "one-pot synthesis." This method of synthesizing a compound involves combining all raw materials and reagents in a single container and then converting them into the desired compound through a chemical reaction. However, one-pot synthesis often requires rigorous experimental conditions and control due to the complex chemical reactions involved.

[0028] Method of the present invention

[0029] The reaction scheme of the method of the present invention is as follows:

[0030] In the method of the present invention, anhydrous acetaldehyde, a cheap and readily available raw material for large-scale industrial chemical production, is first reacted with diphenyl carbonate under alkaline conditions B1 using catalyst C1 at temperature T1 to produce 4,5-dimethyl-1,3-dioxol-2-one (Formula 2). This one-pot reaction avoids the use of phosgene, resulting in simple operation and high yield. The resulting compound of Formula 2 then reacts with tert-butyl peroxide at temperature T2 in the presence of catalyst C2 to produce the compound of Formula 1.

[0031] The preparation method of the compound represented by Formula 1 provided by the present invention may comprise the following steps:

[0032] 1) Anhydrous acetaldehyde reacts with diphenyl carbonate to produce a compound of formula 2;

[0033] 2) The compound of formula 2 reacts with tert-butyl peroxide to generate the compound of formula 1.

[0034] In a specific embodiment, in step 1), anhydrous acetaldehyde and diphenyl carbonate are reacted in a one-pot process to produce the compound of formula 2.

[0035] In a specific embodiment, in step 1), anhydrous acetaldehyde and diphenyl carbonate are reacted in the presence of a catalyst, and the catalyst is selected from the compound represented by Formula 3, the compound represented by Formula 4, the compound represented by Formula 5, or a mixture thereof; preferably, the compound represented by Formula 3 (vitamin B1)

[0036] In the method of the present invention, the molar ratio of the catalyst to anhydrous acetaldehyde may be 0.005:1 to 0.025:1, preferably 0.01:1.0.

[0037] In the method of the present invention, in step 1), anhydrous acetaldehyde reacts with diphenyl carbonate in the presence of a base. In a specific embodiment, the base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, or a mixture thereof; preferably potassium carbonate.

[0038] In the method of the present invention, in step 1), anhydrous acetaldehyde and diphenyl carbonate may react at a temperature of 60°C to 120°C, preferably 95°C to 100°C.

[0039] In the method of the present invention, the compound of formula 2 in step 2) can react with tert-butyl peroxide in the presence of a catalyst. In a specific embodiment, the catalyst is selected from silicon dioxide, selenium dioxide, copper alumina, or a mixture thereof; preferably copper alumina.

[0040] In the method of the present invention, the compound of formula 2 in step 2) reacts with tert-butyl peroxide at a temperature of 0°C to 80°C, preferably 10°C to 15°C.

[0041] The method of the present invention can produce 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one in high yield. In a specific embodiment, the yield of 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one produced by the method of the present invention is greater than 98%, preferably greater than 99%.

[0042] Advantages of the present invention:

[0043] 1. The synthetic method of the present invention has a short route and is easy to operate;

[0044] 2. The method of the present invention utilizes inexpensive and readily available anhydrous acetaldehyde as a starting material, thereby saving costs;

[0045] 3. The method of the present invention avoids the use of phosgene reaction, thereby being safe to operate and environmentally friendly;

[0046] 4. The reaction yield of the final product obtained by the method of the present invention; and

[0047] 5. The reaction conditions of the method of the present invention are mild, which is conducive to large-scale industrial production.

[0048] The technical solutions of the present invention are further described below with reference to specific implementation examples. However, the following examples do not constitute a limitation of the present invention. All various application methods adopted in accordance with the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following examples, where specific conditions are not specified, generally follow conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0049] Example 1: Synthesis of Compound 2 (Study of Different Catalysts C1)

[0050] To each of the three autoclaves, add 44.05g (1 mol) of anhydrous acetaldehyde, 2g of anhydrous sodium carbonate, and 108.20g (0.505 mol) of diphenyl carbonate. Reactor No. 1 adds 1.69g (0.005 mol) of vitamin B1 (Formula 3), Reactor No. 2 adds 1.64g (0.005 mol) of a thiazole derivative nitrate (Formula 4), and Reactor No. 3 adds 1.36g (0.005 mol) of thiazolyl benzyl hydrochloride (Formula 5). After these additions, replace the atmosphere with nitrogen 2-3 times. All three reactors are heated simultaneously to 80-85°C and then controlled to react for 3 hours. Heating is stopped and cooled, followed by the addition of 200ml of dichloroethane and 100ml of 10% sodium hydroxide solution. Stir and separate the layers, and the organic layer is dried over anhydrous sodium sulfate. Filter, distill the filtrate to a residual solution of 130ml, and subcool to 0-5°C to precipitate a solid. After filtration and drying, the compound of formula 2 was obtained. The yields of the three reactions were calculated as shown in the following table.

[0051] Table 1

[0052] Example 2: Synthesis of the compound of formula 2 (Study of different base B1 types)

[0053] To three autoclaves, add 44.05 g (1 mol) of anhydrous acetaldehyde, 1.69 g (0.005 mol) of vitamin B1 (Formula 3), and 108.20 g (0.505 mol) of diphenyl carbonate. Reactor No. 1 adds 2.12 g (0.02 mol) of sodium carbonate, reactor No. 2 adds 2.8 g (0.02 mol) of potassium carbonate, and reactor No. 3 adds 0.8 g (0.02 mol) of sodium hydroxide. After these additions, replace the atmosphere with nitrogen 2-3 times. All three reactors are heated simultaneously to 80-85°C and then temperature-controlled to react for 3 hours. Heating is stopped and cooled. 200 ml of dichloroethane and 100 ml of 10% sodium hydroxide solution are added separately. Stir and separate, and the organic layer is dried over anhydrous sodium sulfate. Filter, distill the filtrate to a residual solution of 130 ml, and subcool to 0-5°C to precipitate a solid. Filter and dry to obtain the compound of Formula 2. The yields of the three reactions are calculated as shown in the following table.

[0054] Table 2

[0055] Example 3: Synthesis of Compound 2 (Catalyst C1 Molar Ratio Study)

[0056] 44.05g (1 mole) of anhydrous acetaldehyde, 2g of potassium carbonate, and 108.2g (0.505 mole) of diphenyl carbonate were added to three autoclaves, and the atmosphere was purged with nitrogen three times after addition. Reactor No. 1 added 1.69g (0.005 mole) of vitamin B1 (Formula 3) as catalyst, reactor No. 2 added 3.37g (0.01 mole) of vitamin B1 (Formula 3) as catalyst, and reactor No. 3 added 8.45g (0.025 mole) of vitamin B1 (Formula 3) as catalyst. All three reactors were heated simultaneously to 80-85°C and then temperature-controlled to react for 3 hours. Heating was stopped and cooled. 200ml of dichloroethane and 100ml of 10% sodium hydroxide solution were added separately. Stirring allowed the layers to separate, and the organic layer was dried over anhydrous sodium sulfate. Filtered, the filtrate was distilled to a residual solution of 130ml, and subcooled to 0-5°C to precipitate a solid. Filtered and dried to obtain the compound of Formula 2. The yields of the three reactions are calculated as shown in the following table.

[0057] Table 3

[0058] Example 4: Synthesis of the compound of formula 2 (study at different temperatures T1)

[0059] 44.05g (1 mole) of anhydrous acetaldehyde, 3.383g (0.01 mole) of vitamin B1 (Formula 3), 2g of potassium carbonate, and 108.2g (0.505 mole) of diphenyl carbonate were added to three autoclaves respectively. After addition, the atmosphere was purged with nitrogen three times. Reactor No. 1 was temperature-controlled at 80-85°C, Reactor No. 2 at 95-100°C, and Reactor No. 3 at 110-115°C. The three reactions were temperature-controlled for 3 hours. Heating was stopped and cooled, and 200ml of dichloroethane and 100ml of 10% sodium hydroxide solution were added respectively. The layers were stirred and separated, and the organic layer was dried over anhydrous sodium sulfate. Filtered, the filtrate was distilled to a residual solution of 130ml, and subcooled to 0-5°C to precipitate a solid. After filtration, the solution was dried to obtain the compound of Formula 2. The yields of the three reactions are calculated as shown in the following table.

[0060] Table 4

[0061] Example 5: Synthesis of Compound 2 (Optimal Reaction Conditions)

[0062] In the 5L autoclave, add 440.5g (10 moles) of anhydrous acetaldehyde, 33.7g (0.1 mole) of vitamin B1 catalyst, 20g of anhydrous potassium carbonate, and 1082g (5.05 moles) of diphenyl carbonate, and add the following: nitrogen replacement 3 times. The reaction solution is warming up to an interior temperature of 95-100°C, and the temperature control reaction is 3 hours (GC sampling and detection of raw material reaction is complete). Stop heating and cooling, add 2L of dichloroethane and 1L 10% sodium hydroxide solution to stir and layer. Separate the liquid, and the organic layer is dried over anhydrous sodium sulfate. Filter, distill the filtrate to 1300ml of residual solution, and subcool to 0-5°C to separate out a solid. Drying after filtration gives 535.8 grams of formula 2 compound, with a yield of 93.9%.

[0063] Example 6: Synthesis of the compound of formula 1 (Study of different catalysts C2)

[0064] To three reaction flasks, 28.5 g (0.25 mol) of the compound of Formula 2, 75 ml of tetrahydrofuran, and 64.37 g (0.5 mol) of 70% tert-butyl peroxide were added. Experimental group 1 added 2.5 g of silica catalyst; experimental group 2 added 2.5 g of selenium dioxide catalyst; and experimental group 3 added 2.5 g of alumina-copper catalyst. After these additions, all three groups were simultaneously controlled at 10-15°C and reacted for 5 hours. The catalyst was recovered by filtration, extracted with dichloromethane, and the organic layer dried, filtered, and concentrated to yield the compound of Formula 1. The yields and purities of the three reactions were calculated as shown in the following table.

[0065] Table 5

[0066] Example 7: Synthesis of the compound of formula 1 (temperature T2 study)

[0067] To three reaction flasks, add 28.5 g (0.25 mol) of the compound of Formula 2, 75 ml of tetrahydrofuran, 2.5 g of copper alumina, and 64.37 g (0.5 mol) of 70% tert-butyl peroxide. Experimental group 1 was reacted at 0-5°C for 5 hours, experimental group 2 at 10-15°C for 5 hours, and experimental group 3 at 50-55°C for 5 hours. The catalyst was recovered by filtration, extracted with dichloromethane, and the organic layer was dried, filtered, and concentrated to obtain the compound of Formula 1. The yields and HPLC purities of the three reactions were calculated as shown in the following table.

[0068] Table 6

[0069] Example 8: Synthesis of the compound of formula 1 (optimum reaction conditions)

[0070] To a reaction flask, add 114.1 g (1 mol) of the compound of Formula 2, 300 ml of tetrahydrofuran, 10 g of copper alumina, and 257.5 g (2 mol) of 70% tert-butyl peroxide. After complete addition, react at 10-15°C for 5 hours. Filter and recover the catalyst, extract with dichloromethane, dry the organic layer, filter, and concentrate to obtain 121 g of the compound of Formula 1, with a yield of 93.0% and an HPLC purity of 99.001%.

[0071] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing the compound shown in Formula 1, wherein the method is as shown in the following reaction scheme: The method comprises the following steps: 1) Diethyl carbonate reacts with diphenyl carbonate to form a compound of formula 2; 2) The compound of formula 2 reacts with tert-butyl hydroperoxide to form a compound of formula 1.

2. The method according to claim 1, characterized in that, In step 1), diethyl carbonate reacts with diphenyl carbonate by a "one-pot method" to form a compound of formula 2.

3. The method according to claim 2, wherein In step 1), absolute acetaldehyde reacts with diphenyl carbonate in the presence of a catalyst, and the catalyst is selected from the compounds shown in formula 3, the compounds shown in formula 4, the compounds shown in formula 5, or a mixture thereof; preferably the compounds shown in formula 3 (vitamin B1).

4. The method according to claim 3, characterized in that The molar ratio of the catalyst to diethyl carbonate is 0.005:1 to 0.025:1; preferably 0.01:1.

0.

5. The method according to any one of claims 1 to 4, characterized in that, Diethyl carbonate reacts with diphenyl carbonate in the presence of a base selected from sodium carbonate, potassium carbonate, sodium hydroxide or a mixture thereof; preferably potassium carbonate.

6. The method according to any one of claims 1-4, characterized in that In step 1), diethyl carbonate reacts with diphenyl carbonate at a temperature of 60 °C to 120 °C, preferably 95 to 100 °C.

7. The method according to any one of claims 1-4, characterized in that, In step 2), the compound of formula 2 reacts with tert-butyl hydroperoxide in the presence of a catalyst selected from silica, selenium dioxide, alumina copper or a mixture thereof; preferably alumina copper.

8. The method according to any one of claims 1 to 4, characterized in that, In step 2), the compound of formula 2 reacts with tert-butyl hydroperoxide at a temperature of 0 °C to 80 °C, preferably 10 °C to 15 °C.

9. The method according to any one of claims 1 to 4, characterized in that The yield of the compound of formula 1 is above 98%, preferably above 99%.

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