Preparation method of DL-panthenol

Abstract

The invention relates to a preparation method of DL-panthenol. The preparation method comprises the following steps: S1, providing a mixed solution containing L-pantoic acid lactone, D-pantoic acid lactone, D-pantoic acid and a first solvent; s2, carrying out water phase and organic phase separation on the mixed solution, and recovering the first solvent in the organic phase to obtain crude lactone; s3, the crude lactone and 3-aminopropanol are subjected to a first reaction, and crude panthenol is obtained; and S4, carrying out a second reaction on the crude product panthenol and an alkaline substance to obtain a DL-panthenol reaction solution. According to the preparation method provided by the invention, the problem of waste of L-pantoic acid lactone during preparation of D-pantoic acid lactone through resolution of DL-pantoic acid lactone is solved, waste of raw materials is avoided, and DL-panthenol can be obtained at low cost. Meanwhile, the DL-panthenol particles prepared by the invention are uniform and high in purity, good in crystal form and fluidity, and convenient to transport, store and use.

Description

Technical Field

[0001] The present application relates to a method for preparing DL-panthenol. Background Art

[0002] D-panthenol and D-panthenol ethyl ether are liquid, and DL-panthenol is a racemic mixture of L-panthenol and D-panthenol. It can exist in solid form, is convenient to use and transport, and can be widely used in the pharmaceutical, food, and cosmetic industries. Especially in the pharmaceutical industry, it is used as a vitamin B drug and can be directly added to cosmetics.

[0003] At present, the industrial production method of DL-panthenol is usually to use DL-pantolactone and 3-aminopropanol as raw materials, carry out acylation reaction in alcohol solvents such as methanol and ethanol, and then crystallize and purify to obtain DL-panthenol. For example, CN110835309A discloses a DL-panthenol crystallization method, which uses DL-pantolactone and 3-aminopropanol to react in anhydrous ethanol at 65-85°C to synthesize DL-panthenol, and then optimizes the crystallization conditions to prepare a high-purity DL-panthenol solid product, but the maximum DL-panthenol yield is only 77%.

[0004] Therefore, it is necessary to study the preparation method of DL-panthenol with higher yield and greener properties. Summary of the invention

[0005] In order to solve the above technical problems existing in the prior art, the present application provides a method for preparing DL-panthenol. The preparation method provided by the present application solves the waste of L-pantoic acid lactone when DL-pantoic acid lactone is split to prepare D-pantoic acid lactone, avoids the waste of raw materials, and can obtain DL-panthenol at a low cost. At the same time, the DL-panthenol particles prepared by the present application are uniform, high in purity, good in crystal form and good in fluidity, and are also easy to transport, store and use.

[0006] The preparation method of DL-panthenol provided in the present application comprises the following steps:

[0007] S1: providing a mixed solution comprising L-pantoic acid lactone, D-pantoic acid lactone, D-pantoic acid and a first solvent;

[0008] S2: separating the mixed solution into an aqueous phase and an organic phase, recovering the first solvent in the organic phase to obtain a crude lactone, and optionally preparing D-pantoic acid lactone in the aqueous phase;

[0009] S3: subjecting the crude lactone and 3-aminopropanol to a first reaction to obtain crude panthenol;

[0010] S4: subjecting the crude panthenol to a second reaction with an alkaline substance to obtain a DL-panthenol reaction solution.

[0011] In some embodiments, the preparation method further comprises step S5: subjecting the DL-panthenol reaction solution to crystallization, solid-liquid separation, and drying to obtain DL-panthenol solid.

[0012] In some embodiments, in step S1, providing a mixed solution comprising L-pantoic acid lactone, D-pantoic acid lactone, D-pantoic acid and a first solvent includes: splitting DL-pantoic acid lactone in the first solvent under the influence of D-pantoic acid lactone-directed hydrolase to obtain a mixed solution comprising L-pantoic acid lactone, D-pantoic acid, D-pantoic acid and the first solvent after the splitting.

[0013] L-pantoic acid lactone is an organic chemical obtained by chiral splitting of DL-pantoic acid lactone. The split D-pantoic acid lactone can be used to synthesize D-pantothenic acid alcohol, D-calcium pantothenate and other widely used additives. There are various methods for splitting DL-pantothenic acid lactone reported in the prior art, including splitting by biological enzymes and splitting by chemical methods. However, the existing splitting methods inevitably encounter the problem of how to treat L-pantothenic acid lactone. The present application solves the waste of L-pantothenic acid lactone when splitting DL-pantothenic acid lactone to prepare D-pantothenic acid lactone by using the split L-pantothenic acid lactone and D-pantothenic acid lactone solution as raw materials, avoids the waste of raw materials, and can obtain DL-pantothenic acid alcohol at a low cost. At the same time, the DL-pantothenic acid alcohol particles prepared by the present application are uniform and have high purity, good crystal form and good fluidity, and are also easy to transport, store and use.

[0014] In some embodiments, the molar ratio of L-pantoic acid lactone, D-pantoic acid lactone and D-pantoic acid is 1: (0.01-0.05): (0.95-0.99), for example, 1: 0.01: 0.99, 1: 0.02: 0.98, 1: 0.03: 0.97, 1: 0.04: 0.96, 1: 0.05: 0.95 or any value therebetween. In some embodiments, the molar ratio of L-pantoic acid lactone, D-pantoic acid lactone and D-pantoic acid is 1: (0.01-0.03): (0.97-0.99). In some embodiments, in the mixed solution, the molar ratio of L-pantoic acid lactone, D-pantoic acid lactone and D-pantoic acid is 1: (0.02-0.05): (0.95-0.98). In some embodiments, the molar ratio of L-pantolactone, D-pantolactone and D-pantoic acid is 1:0.02:0.98.

[0015] In some embodiments, the first solvent is selected from ethyl acetate.

[0016] In some embodiments, the first solvent in the organic phase is recovered by concentration.

[0017] In some embodiments, in step S2, the concentration treatment temperature is 50°C-90°C, for example, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C or 85°C. In some embodiments, in step S2, the concentration treatment temperature is 60°C-85°C.

[0018] In some embodiments, in step S2, the concentration process is performed under negative pressure conditions.

[0019] In some embodiments, in step S2, the optical rotation of the crude lactone is +35° to +50°, for example, +38°, 40°, 43°, 45° or 47°.

[0020] In some embodiments, in step S3, the molar ratio of the crude lactone to 3-aminopropanol is 1:(0.8-1.2), for example, 1:0.9, 1:1.0 or 1:1.1.

[0021] In some embodiments, in step S3, the temperature of the first reaction is 50° C.-90° C., for example, 55° C., 60° C., 65° C., 70° C., 75° C., 80° C. or 85° C. In some embodiments, in step S3, the temperature of the first reaction is 60° C.-80° C.

[0022] In some embodiments, in step S4, the mass ratio of crude lactone to alkaline substance is 1:(0.005-0.025), for example, 1:0.007, 1:0.009, 1:0.01, 1:0.012, 1:0.013, 1:0.014, 1:0.015, 1:0.016, 1:0.017, 1:0.018, 1:0.019, 1:0.02, 1:0.021, 1:0.023 or any value therebetween. In some embodiments, in step S4, the mass ratio of crude lactone to alkaline substance is 1:(0.01-0.02). If the mass ratio of crude lactone to alkaline substance is too little, racemization is incomplete, affecting product quality, and if the mass ratio of crude lactone to alkaline substance is too little, panthenol is partially hydrolyzed, affecting product yield.

[0023] In some embodiments, in step S4, the alkaline substance is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydroxide.

[0024] In some embodiments, in step S4, the temperature of the second reaction is 70° C.-120° C., for example, 75° C., 80° C., 85° C., 90° C., 95° C., 100° C., 105° C., 110° C. or 115° C. In some embodiments, in step S4, the temperature of the second reaction is 80° C.-100° C.

[0025] In some embodiments, in step S4, the optical rotation of the DL-panthenol reaction solution is -0.5° to +0.5°, for example, -0.4°, -0.3°, -0.2°, -0.1°, 0°, 0.1°, 0.2°, 0.3° or 0.4°.

[0026] In some embodiments, the crystallization in step S5 comprises the following steps:

[0027] Step a: mixing the DL-panthenol reaction solution with a C1-C6 monohydric alcohol, filtering, and obtaining a DL-panthenol alcohol solution;

[0028] Step b: After mixing the alcohol solution of DL-panthenol with the second solvent, performing crystallization treatment to obtain a wet product of DL-panthenol.

[0029] In some embodiments, in step a, the C1-C6 monohydric alcohol is selected from one or more of methanol, ethanol and propanol. In some embodiments, in step a, the C1-C6 monohydric alcohol is anhydrous methanol.

[0030] In some embodiments, the mass ratio of the DL-panthenol reaction solution to the C1-C6 monohydric alcohol is 1:(0.05-0.3), preferably 1:(0.1-0.15).

[0031] In some embodiments, in step b, the second solvent is selected from ethyl acetate and / or dichloromethane.

[0032] In some embodiments, the mass ratio of the alcohol solution of DL-panthenol to the second solvent is 1:(1-5), such as 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4 or 1:4.5. In some embodiments, the mass ratio of the alcohol solution of DL-panthenol to the second solvent is 1:(2-3).

[0033] In some embodiments, seed crystals of DL-panthenol are added during the crystallization process.

[0034] In some embodiments, the temperature of the crystallization process is -10°C to 10°C, for example, -9°C, -7°C, -5°C, -3°C, -1°C, 0°C, 1°C, 3°C, 5°C, 7°C or 9°C. In some embodiments, the temperature of the crystallization process is -5°C to 5°C.

[0035] In some embodiments, the method for preparing DL-panthenol comprises the following specific steps:

[0036] (1) Separating the aqueous phase and the organic phase of the resolved L-pantoic acid lactone ethyl acetate, D-pantoic acid lactone and D-pantoic acid ethyl acetate solution, recovering the ethyl acetate in the organic phase at a negative pressure of 60-85° C. to obtain a crude lactone with an optical rotation of +35° to +50°.

[0037] (2) Add 3-aminopropanol to the material described in step (1) at a molar ratio of 1:1, raise the temperature to 60-80°C for reaction after adding aminopropanol, start stirring the reaction for 1.5-2 hours, and obtain crude panthenol with an optical rotation of -10° to -25°.

[0038] (3) Add anhydrous sodium carbonate to the material described in step (2), and continue to heat to 80-100° C. and stir to react for 2 h according to the material mass ratio (crude lactone: anhydrous sodium carbonate = 100:1-100:2). Then take a sample and measure the optical rotation to ±0.5° to obtain a DL-panthenol reaction solution.

[0039] (4) Weigh the material described in step (3) and add anhydrous methanol according to (mass ratio of DL-panthenol: anhydrous methanol = 1:0.1-0.15), stir evenly, filter to remove solid residue, and obtain DL-panthenol methanol solution, and transfer the material into a crystallization kettle.

[0040] (5) After the material of step (4) is transferred into a crystallization kettle, ethyl acetate is added according to (mass ratio of DL-panthenol methanol solution: ethyl acetate = 1:2-3), and then the temperature is further lowered to -5-5°C, and the mixture is kept warm for 6-8 hours under stirring conditions for crystallization, filtered to obtain DL-panthenol wet product, and vacuum dried to obtain DL-panthenol solid.

[0041] The beneficial effects of this application are:

[0042] (1) The method for preparing DL-panthenol provided in the present application solves the problem of the waste of L-pantolactone when DL-pantolactone is split to prepare D-pantolactone, avoids the waste of raw materials, and can obtain DL-pantolactone at a relatively low cost.

[0043] (2) The DL-panthenol particles prepared in the present application are uniform, high in purity, good in crystal form and fluidity, and are also easy to transport, store and use. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical solution and advantages of the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. The specific embodiments described here are only used to explain the present application and are not intended to constitute any limitation to the present application.

[0045] Unless otherwise specified, in the following examples and comparative examples, % represents mass percentage.

[0046] In the following examples and comparative examples, DL-pantoic acid lactone was split under the D-pantoic acid lactone directed hydrolase to obtain ethyl acetate solutions of L-pantoic acid lactone, D-pantoic acid lactone and D-pantoic acid after the splitting.

[0047] Example 1

[0048] (1) 1000 mL of ethyl acetate solution of L-pantoic acid lactone, D-pantoic acid lactone and D-pantoic acid after separation was placed in a reaction kettle, and the aqueous phase and the organic phase were separated, wherein the molar ratio of L-pantoic acid lactone, D-pantoic acid lactone and D-pantoic acid was 1:0.02:0.98. The aqueous phase was used to prepare D-pantoic acid lactone. The organic phase was recovered with ethyl acetate under negative pressure and 60°C-85°C to obtain 195 g of crude lactone with an optical rotation of +38°.

[0049] (2) 112.5 g of 3-aminopropanol was added to the reactor in a molar ratio of 1:1 between the crude lactone and 3-aminopropanol, and the temperature was raised to 60°C-80°C to start the reaction. After 2 hours of reaction, 3.1 g of anhydrous sodium carbonate was added to the reactor, and the temperature was raised to 90°C after addition and the timing was started. After 2 hours of reaction, sampling and testing were started, and the optical rotation of the material was measured to be -0.3°.

[0050] (3) Then, 37 g of anhydrous methanol was added to the reaction kettle, stirred evenly, and filtered to obtain 336 g of DL-panthenol methanol solution and 6.2 g of residue.

[0051] (4) The obtained DL-panthenol methanol solution is placed in a crystallization kettle, 700 g of ethyl acetate is added and stirred evenly, then the temperature is lowered to 20° C., 3 g of DL-panthenol is added, and then the temperature is further lowered to 5° C. After crystals appear, the mixture is kept warm for 6 h under stirring conditions for crystallization, and the DL-panthenol wet product is obtained by centrifugation.

[0052] (5) The wet DL-panthenol product was vacuum dried to obtain 292.5 g of DL-panthenol solid. After testing, the DL-panthenol content in the DL-panthenol solid was 99.6% and the optical rotation was 0°.

[0053] Example 2

[0054] The only difference from Example 1 is that 1 g of anhydrous sodium carbonate is added to the reaction kettle in (2). The DL-panthenol content of the finally obtained DL-panthenol solid is 63.5%, and the optical rotation is +13°.

[0055] Example 3

[0056] The only difference from Example 1 is that 2.3 g of anhydrous sodium carbonate is added to the reaction kettle in (2). The DL-panthenol content of the finally obtained DL-panthenol solid is 96.8%, and the optical rotation is +3.9°.

[0057] Example 4

[0058] The only difference from Example 1 is that 4 g of anhydrous sodium carbonate is added to the reaction kettle in (2). The DL-panthenol content of the finally obtained DL-panthenol solid is 98.8% and the optical rotation is +1.6°.

[0059] Example 5

[0060] The only difference from Example 1 is that 10 g of anhydrous sodium carbonate is added to the reaction kettle in (2). The DL-panthenol content of the finally obtained DL-panthenol solid is 96.3% and the optical rotation is +3.3°.

[0061] Example 6

[0062] The only difference from Example 1 is that 3.1 g of anhydrous sodium bicarbonate is added to the reaction kettle in (2). The DL-panthenol content of the finally obtained DL-panthenol solid is 99.1% and the optical rotation is +0.2°.

[0063] Example 7

[0064] The only difference from Example 1 is that 3.1 g of anhydrous potassium carbonate is added to the reaction kettle in (2). The DL-panthenol content of the finally obtained DL-panthenol solid is 99.2% and the optical rotation is 0°.

[0065] Example 8

[0066] The only difference from Example 1 is that 3.1 g of sodium hydroxide is added to the reaction kettle in (2). The DL-panthenol content of the finally obtained DL-panthenol solid is 99.3% and the optical rotation is +0.1°.

[0067] The technical solution of the present application is not limited to the above-mentioned specific embodiments, and all technical variations made according to the technical solution of the present application fall within the protection scope of the present application.

Claims

1. A method for preparing DL-panthenol, comprising the following steps: S1: providing a mixed solution comprising L-pantoic acid lactone, D-pantoic acid lactone, D-pantoic acid and a first solvent; S2: separating the mixed solution into an aqueous phase and an organic phase, recovering the first solvent in the organic phase to obtain a crude lactone, and optionally preparing D-pantoic acid lactone in the aqueous phase; S3: subjecting the crude lactone and 3-aminopropanol to a first reaction to obtain crude panthenol; S4: subjecting the crude panthenol to a second reaction with an alkaline substance to obtain a DL-panthenol reaction solution.

2. The preparation method according to claim 1, characterized in that: The preparation method further comprises step S5: subjecting the DL-panthenol reaction solution to crystallization, solid-liquid separation, and drying to obtain DL-panthenol solid.

3. The preparation method according to claim 1 or 2, characterized in that: In step S1, providing a mixed solution comprising L-pantoic acid lactone, D-pantoic acid lactone, D-pantoic acid and a first solvent includes: splitting DL-pantoic acid lactone in the first solvent under the presence of a D-pantoic acid lactone-directed hydrolase to obtain a mixed solution comprising L-pantoic acid lactone, D-pantoic acid lactone, D-pantoic acid and the first solvent after the splitting.

4. The preparation method according to any one of claims 1 to 3, characterized in that In the mixed solution, the molar ratio of L-pantolactone, D-pantolactone and D-pantoic acid is 1:(0.01-0.05):(0.95-0.99), preferably 1:(0.01-0.03):(0.97-0.99); and / or The first solvent is selected from ethyl acetate.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In step S2, the first solvent in the organic phase is recovered by concentration treatment. Preferably, the temperature of the concentration treatment is 50°C-90°C, preferably 60°C-85°C; and / or The concentration process is carried out under negative pressure; and / or The optical rotation of the crude lactone is +35° to +50°.

6. The preparation method according to any one of claims 1 to 5, characterized in that: In step S3, the molar ratio of the crude lactone to 3-aminopropanol is 1:(0.8-1.2); and / or The temperature of the first reaction is 50°C-90°C, preferably 60°C-80°C.

7. The preparation method according to any one of claims 1 to 6, characterized in that In step S4, the mass ratio of the crude lactone to the alkaline substance is 1:(0.005-0.025), preferably 1:(0.01-0.02); and / or The alkaline substance is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydroxide.

8. The preparation method according to any one of claims 1 to 7, characterized in that: In step S4, the temperature of the second reaction is 70°C-120°C, preferably 80°C-100°C; and / or The optical rotation of the DL-panthenol reaction solution is -0.5° to +0.5°.

9. The preparation method according to any one of claims 2 to 8, characterized in that: The crystallization in step S5 comprises the following steps: Step a: mixing the DL-panthenol reaction solution with a C1-C6 monohydric alcohol, filtering, and obtaining a DL-panthenol alcohol solution; Step b: After mixing the alcohol solution of DL-panthenol with the second solvent, performing crystallization treatment to obtain a wet product of DL-panthenol.

10. The preparation method according to claim 9, characterized in that: In step a, the C1-C6 monohydric alcohol is selected from one or more of methanol, ethanol and propanol, preferably anhydrous methanol; and / or The mass ratio of DL-panthenol reaction solution to C1-C6 monohydric alcohol is 1:(0.05-0.3), preferably 1:(0.1-0.15); and / or In step b, the second solvent is selected from ethyl acetate and / or dichloromethane; and / or The mass ratio of the alcohol solution of DL-panthenol to the second solvent is 1:(1-5), preferably 1:(2-3); and / or Adding seed DL-panthenol during the crystallization process; and / or The temperature of the crystallization treatment is -10°C to 10°C, preferably -5°C to 5°C.