Method for preparing calcium beta-aminopropionate

Abstract

The invention relates to the field of organic chemistry, and discloses a method for preparing calcium beta-aminopropionate, which comprises the following steps: (1) in the presence of a solvent, mixing acrylic acid and a calcification agent, and filtering; (2) contacting the filtrate obtained in the step (1) with an ammonia source; and (3) purifying the mixture obtained in the step (2) to obtain the beta-alanine calcium propionate. Preferably, the step (2) is carried out in a microchannel reactor. According to the method provided by the invention, the calcium acrylate is used for replacing acrylic acid to carry out addition reaction with the ammonia source, the generation amount of byproducts, especially iminodipropionic acid (calcium), is lower, the selectivity of a target product is higher, and the utilization rate of raw materials can be improved. Furthermore, by using the micro-channel reactor, the reaction time can be shortened, the generation of byproducts is reduced, the raw material conversion rate and the product yield are improved, continuous reaction can be realized, and industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to the field of organic chemistry, and in particular to a method for preparing calcium beta-alanine. Background Art

[0002] Calcium β-alanine is a key intermediate in the synthesis of vitamin-based drugs, calcium pantothenate, and is formed by the reaction of β-alanine with a calcifying agent. At present, the main method for synthesizing β-alanine is the acrylonitrile production method, in which acrylonitrile and ammonia are synthesized at 100-115°C and 3-4MPa to synthesize β-aminopropionitrile, and then hydrolyzed under certain conditions to generate β-alanine. This method has many reaction steps and side reactions, the content of the obtained product is low, purification is difficult, and impurities are difficult to reach the internal control quality index. In addition, the price of acrylonitrile is much higher than that of acrylic acid, which is not economically reasonable.

[0003] Another synthetic method is to prepare β-alanine by amination of acrylic acid. CN101844992A discloses a method for preparing β-alanine from acrylic acid and ammonia in an autoclave. The reaction lasts for 10 hours, and the yield is only 73%, which is not suitable for large-scale industrial production. CN108892621A prepares β-alanine from acrylic acid through a microchannel reactor. The yield is only 88% after application, and the reaction selectivity is not high and the yield is low. Summary of the invention

[0004] In order to overcome the defect of low yield of β-alanine in the prior art of preparing calcium β-alanine by calcification of β-alanine, a method for preparing calcium β-alanine is provided, and the yield and purity of calcium β-alanine obtained by the method are higher.

[0005] In order to achieve the above object, the present invention provides a method for preparing calcium β-alanine, which comprises:

[0006] (1) mixing acrylic acid and a calcifying agent in the presence of a solvent and filtering;

[0007] (2) contacting the filtrate obtained in step (1) with an ammonia source;

[0008] (3) Purifying the mixture obtained in step (2) to obtain calcium β-alanine.

[0009] Preferably, step (2) is carried out in a microchannel reactor.

[0010] The present invention has the following technical effects:

[0011] Compared with the prior art, the present invention uses calcium acrylate to replace acrylic acid in the addition reaction with an ammonia source, the amount of by-products, especially iminodipropionic acid (calcium) is lower, the selectivity of the target product is higher, and the utilization rate of raw materials can be improved.

[0012] Furthermore, the use of a microchannel reactor in the present invention can shorten the reaction time, reduce the generation of by-products, improve the raw material conversion rate and product yield, and can react continuously, which is beneficial to industrial production. DETAILED DESCRIPTION

[0013] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0014] The present invention provides a method for preparing calcium β-alanine, which comprises:

[0015] (1) mixing acrylic acid and a calcifying agent in the presence of a solvent and filtering;

[0016] (2) contacting the filtrate obtained in step (1) with an ammonia source;

[0017] (3) Purifying the mixture obtained in step (2) to obtain calcium β-alanine.

[0018] Compared with the prior art in which acrylic acid is directly contacted with an ammonia source, in the present invention, acrylic acid is first calcified and then contacted with an ammonia source, which can significantly improve the selectivity of the target product.

[0019] In the present invention, there is no particular limitation on the specific type of the calcifying agent, as long as it can provide calcium ions, and those skilled in the art can routinely select it. According to a preferred embodiment of the present invention, the calcifying agent is selected from at least one of calcium oxide, calcium hydroxide and calcium carbonate, preferably calcium oxide.

[0020] In the present invention, there is no particular limitation on the specific type of the ammonia source, and those skilled in the art can routinely select. According to a preferred embodiment of the present invention, the ammonia source is selected from ammonia and / or ammonium salt.

[0021] The ammonia source may be provided in the form of aqueous ammonia or an aqueous solution of an ammonium salt.

[0022] According to a preferred embodiment of the present invention, the molar ratio of the acrylic acid to the calcifying agent is 1:0.4-0.6.

[0023] In the present invention, when the molar ratio of the acrylic acid to the calcifying agent is within the above range, the purity of calcium β-alanine can be improved.

[0024] According to a preferred embodiment of the present invention, the molar ratio of the acrylic acid to the amino group in the ammonia source is 1:5-30.

[0025] In the present invention, if the ammonia source is too little, too much secondary nucleophilic addition impurity, i.e., iminodipropionic acid (calcium), will be generated, and the reaction selectivity will deteriorate; if the ammonia source is too much, the unreacted ammonia source will enter the product, resulting in increased difficulty in post-processing.

[0026] More preferably, the molar ratio of the acrylic acid to the amino group in the ammonia source is 1:8-20.

[0027] The present invention does not particularly limit the specific type of the solvent, and those skilled in the art can routinely select. According to the present invention, preferably, the solvent is water.

[0028] According to the present invention, preferably, the concentration of calcium acrylate in the filtrate obtained in step (1) is 1.3-1.65 mol / L.

[0029] The present invention has no particular limitation on the contact temperature and pressure in step (2), and those skilled in the art can select the temperature and pressure according to the conventional method of the amination reaction. According to a preferred embodiment of the present invention, the contact temperature is 140-200° C. and the pressure is 1.5-4 MPa.

[0030] In the present invention, when the contact temperature and pressure are within the above ranges, the reaction rate can be further increased, and the rate of the side reaction will not be too fast.

[0031] More preferably, the contacting temperature is 150-170° C. and the contacting pressure is 2-3 MPa.

[0032] According to a preferred embodiment of the present invention, the contact time is 30-90 minutes.

[0033] In the present invention, when the contact time is within the above range, the amination reaction can be carried out more completely and the amount of by-products generated is low.

[0034] More preferably, the contact time is 50-80 min.

[0035] According to a preferred embodiment of the present invention, step (2) is carried out in a microchannel reactor.

[0036] In the present invention, the use of a microchannel reactor can further shorten the reaction time, reduce the generation of by-products, improve the raw material conversion rate and product yield, and enable the reaction to proceed continuously.

[0037] According to the present invention, preferably, the channel cross-sectional area of ​​the microchannel reactor is 0.01-0.1 cm 2 .

[0038] In the present invention, when the channel cross-sectional area of ​​the microchannel reactor is within the above range, the raw materials can be fully mixed while the channel pressure drop of the microchannel reactor is balanced.

[0039] More preferably, the cross-sectional area of ​​the channel of the microchannel reactor is 0.06-0.08 cm 2 .

[0040] According to a preferred embodiment of the present invention, the filtrate obtained in step (1) is premixed with an ammonia source to obtain a reaction solution, and the reaction solution is passed into a microchannel reactor to perform the contact in step (2).

[0041] The present invention has no particular limitation on the specific manner of premixing, and those skilled in the art can make a conventional selection.

[0042] According to a preferred embodiment of the present invention, the flow rate of the reaction liquid at the inlet of the microchannel reactor is 0.6-2 mL / min.

[0043] In the present invention, when the flow rate of the reaction liquid at the inlet of the microchannel reactor is within the above range, the reaction liquid has a preferred residence time in the microchannel.

[0044] More preferably, the flow rate of the reaction solution at the inlet of the microchannel reactor is 0.8-1.2 mL / min.

[0045] According to the present invention, preferably, the concentration method is reduced pressure distillation.

[0046] The present invention does not particularly limit the temperature and pressure of the vacuum distillation, and those skilled in the art can make conventional selections. According to the present invention, preferably, the temperature of the vacuum distillation is 40-70°C and the pressure is 0.085-0.095MPa.

[0047] The present invention does not particularly limit the temperature and time of heating and refluxing in step (3), and those skilled in the art can conventionally select. The purpose of heating and refluxing is to fully dissolve the prepared calcium β-alanine so as to separate and collect it. According to a preferred embodiment of the present invention, the temperature of heating and refluxing in step (3) is 60-70° C. and the time is 1-3h.

[0048] In the present invention, the concentrated material can be dissolved in a lower alcohol solvent such as methanol or ethanol and heated to reflux. The amount of solvent added can be 3-5 times the mass of the acrylic acid feed amount.

[0049] The present invention does not particularly limit the specific method of the crystallization, and those skilled in the art can routinely select. According to the present invention, preferably, the crystallization method is to cool the mother liquor to 5-15° C. and then filter out the crystallized solid using filter paper.

[0050] In the present invention, the mother liquor remaining after crystallization can be mixed with fresh raw materials and recycled.

[0051] The mother liquor contains not only uncrystallized calcium β-alanine but also calcium iminodipropionate. Calcium iminodipropionate can continue to react with aqueous ammonia to generate the target product calcium β-alanine. Therefore, applying the mother liquor can improve the utilization rate of calcium acrylate and the reaction yield.

[0052] The present invention will be described in detail below through examples.

[0053] In the following examples, unless otherwise specified, all raw materials and reagents are commercially available.

[0054] The content of calcium acrylate and the purity of calcium β-alanine product were determined using liquid chromatography.

[0055] Unless otherwise specified, pressure is absolute pressure.

[0056] Example 1

[0057] At room temperature, acrylic acid and calcium oxide in a molar ratio of 1:0.5 were mixed with water 3 times the weight of acrylic acid, stirred for 0.5 h, and filtered to obtain an aqueous solution of calcium acrylate with a concentration of 1.65 mol / L.

[0058] The above calcium acrylate aqueous solution was mixed with an appropriate amount of 25 wt % ammonia water through a microchannel reactor premixer to obtain a reaction solution with a molar ratio of acrylate to ammonia water (calculated as NH 3 ) of 1:10.

[0059] The reaction solution was pumped into a microchannel reactor with a volume of 60 mL and a channel cross-sectional area of ​​0.0724 cm 2 The flow rate of the reaction liquid at the inlet was 1 mL / min, and the contact reaction lasted for 60 min. The temperature in the microchannel reactor was controlled to be 160° C. and the pressure was 2.3 MPa.

[0060] The liquid flowing out of the microchannel reactor was cooled to 20°C, and after the remaining ammonia was recovered by an ammonia recovery pump, it was distilled under reduced pressure at 65°C and 0.09MPa to a syrupy state, and then methanol 3 times the mass of the acrylic acid feed was added to dissolve it, and refluxed at 65°C for 1h, and the content of calcium acrylate in the liquid was determined, and the conversion rate of acrylic acid was calculated to be 96%. Then it was cooled to 10°C for crystallization, and the precipitated crystals were filtered and dried to obtain the calcium β-aminopropionate product.

[0061] The purity of calcium β-alanine in the product is 99.5%. The mass of the product is weighed and the yield of calcium β-alanine is calculated to be 92.5%.

[0062] Example 2

[0063] At room temperature, acrylic acid and calcium oxide in a molar ratio of 1:0.5 were mixed with water 3 times the weight of acrylic acid, stirred for 0.5 h, and filtered to obtain an aqueous solution of calcium acrylate with a concentration of 1.65 mol / L.

[0064] The above calcium acrylate aqueous solution was mixed with an appropriate amount of 25 wt % ammonia water through a microchannel reactor premixer to obtain a reaction solution with a molar ratio of acrylate to ammonia water (calculated as NH 3 ) of 1:8.

[0065] The reaction solution was pumped into a microchannel reactor with a volume of 60 mL and a channel cross-sectional area of ​​0.0724 cm 2 The flow rate of the reaction liquid at the inlet was 0.8 mL / min, and the contact reaction lasted for 75 min. The temperature in the microchannel reactor was controlled to be 150° C. and the pressure was 2 MPa.

[0066] The liquid flowing out of the microchannel reactor was cooled to 20°C, and after the remaining ammonia was recovered by an ammonia recovery pump, it was distilled under reduced pressure at 65°C and 0.09MPa to a syrupy state, and then methanol 3 times the mass of the acrylic acid feed was added to dissolve it, and refluxed at 65°C for 1h, and the content of calcium acrylate in the liquid was measured, and the conversion rate of acrylic acid was calculated to be 95.8%. Then it was cooled to 10°C for crystallization, and the precipitated crystals were filtered and dried to obtain the calcium β-aminopropionate product.

[0067] The purity of calcium beta-alanine in the product is 99.3%, and the yield of calcium beta-alanine is 91.8%.

[0068] Example 3

[0069] At room temperature, acrylic acid and calcium oxide in a molar ratio of 1:0.5 were mixed with water 3 times the weight of acrylic acid, stirred for 0.5 h, and filtered to obtain an aqueous solution of calcium acrylate with a concentration of 1.65 mol / L.

[0070] The above calcium acrylate aqueous solution was mixed with an appropriate amount of 25 wt % ammonia water through a microchannel reactor premixer to obtain a reaction solution with a molar ratio of acrylate to ammonia water (calculated as NH 3 ) of 1:20.

[0071] The reaction solution was pumped into a microchannel reactor with a volume of 60 mL and a channel cross-sectional area of ​​0.0724 cm 2 The flow rate of the reaction liquid at the inlet was 1.2 mL / min, and the contact reaction lasted for 50 min. The temperature in the microchannel reactor was controlled to be 170° C. and the pressure was 3 MPa.

[0072] The liquid flowing out of the microchannel reactor was cooled to 20°C, and after the remaining ammonia was recovered by an ammonia recovery pump, it was distilled under reduced pressure at 65°C and 0.09MPa to a syrupy state, and then methanol 3 times the mass of the acrylic acid feed was added to dissolve it, and refluxed at 65°C for 1h, and the content of calcium acrylate in the liquid was measured, and the conversion rate of acrylic acid was calculated to be 95.3%. Then it was cooled to 10°C for crystallization, and the precipitated crystals were filtered and dried to obtain the calcium β-aminopropionate product.

[0073] The purity of calcium beta-alanine in the product is 99.1%, and the yield of calcium beta-alanine is 90.5%.

[0074] Example 4

[0075] At room temperature, acrylic acid and calcium oxide in a molar ratio of 1:0.5 were mixed with water 3 times the weight of acrylic acid, stirred for 0.5 h, and filtered to obtain an aqueous solution of calcium acrylate with a concentration of 1.65 mol / L.

[0076] The above calcium acrylate aqueous solution was mixed with an appropriate amount of 25 wt % ammonia water through a microchannel reactor premixer to obtain a reaction solution with a molar ratio of acrylate to ammonia water (calculated as NH 3 ) of 1:5.

[0077] The reaction solution was pumped into a microchannel reactor with a volume of 60 mL and a channel cross-sectional area of ​​0.0724 cm 2 The flow rate of the reaction liquid at the inlet was 0.67 mL / min, and the contact reaction lasted for 90 min. The temperature in the microchannel reactor was controlled to be 140° C. and the pressure was 1.5 MPa.

[0078] The liquid flowing out of the microchannel reactor was cooled to 20°C, and after the remaining ammonia was recovered by an ammonia recovery pump, it was distilled under reduced pressure at 65°C and 0.09MPa to a syrupy state, and then methanol 3 times the mass of the acrylic acid feed was added to dissolve it, and refluxed at 65°C for 1h, and the content of calcium acrylate in the liquid was measured, and the conversion rate of acrylic acid was calculated to be 94.9%. Then it was cooled to 10°C for crystallization, and the precipitated crystals were filtered and dried to obtain the calcium β-aminopropionate product.

[0079] The purity of calcium beta-alanine in the product is 99.2%, and the yield of calcium beta-alanine is 90.1%.

[0080] Example 5

[0081] At room temperature, acrylic acid and calcium oxide in a molar ratio of 1:0.5 were mixed with water 3 times the weight of acrylic acid, stirred for 0.5 h, and filtered to obtain an aqueous solution of calcium acrylate with a concentration of 1.65 mol / L.

[0082] The above calcium acrylate aqueous solution was mixed with an appropriate amount of 25 wt % ammonia water through a microchannel reactor premixer to obtain a reaction solution with a molar ratio of acrylate to ammonia water (calculated as NH 3 ) of 1:30.

[0083] The reaction solution was pumped into a microchannel reactor with a volume of 60 mL and a channel cross-sectional area of ​​0.0724 cm 2 The flow rate of the reaction liquid at the inlet was 2 mL / min, and the contact reaction lasted for 30 min. The temperature in the microchannel reactor was controlled to be 200° C. and the pressure was 4 MPa.

[0084] The liquid flowing out of the microchannel reactor was cooled to 20°C, and after the remaining ammonia was recovered by an ammonia recovery pump, it was distilled under reduced pressure at 65°C and 0.09MPa to a syrupy state, and then methanol 3 times the mass of the acrylic acid feed was added to dissolve it, and refluxed at 65°C for 1 hour, and the content of calcium acrylic acid in the liquid was measured, and the conversion rate of acrylic acid was calculated to be 95.1%. Then it was cooled to 10°C for crystallization, and the precipitated crystals were filtered and dried to obtain the calcium β-aminopropionate product.

[0085] The purity of calcium beta-alanine in the product is 99.1%, and the yield of calcium beta-alanine is 90.6%.

[0086] Example 6

[0087] At room temperature, acrylic acid and calcium oxide in a molar ratio of 1:0.5 were mixed with an appropriate amount of water, stirred for 0.5 h, and filtered to obtain an aqueous solution of calcium acrylate with a concentration of 1.65 mol / L.

[0088] The calcium acrylate aqueous solution was mixed with an appropriate amount of 25 wt% ammonia water to obtain a reaction solution with a molar ratio of acrylate to ammonia water (in terms of NH3) of 1:10. The reaction solution was put into an autoclave and reacted at 160°C and 2.3 MPa for 12 hours.

[0089] After that, the liquid in the kettle was taken out and cooled to 20°C. After the remaining ammonia was recovered by an ammonia recovery pump, it was distilled under reduced pressure at 65°C and 0.09MPa to a syrupy state, and then methanol 3 times the mass of the acrylic acid feed was added to dissolve it. The mixture was refluxed at 65°C for 1 hour, and the content of calcium acrylate in the liquid was determined. The conversion rate of acrylic acid was calculated to be 96.3%. Then, it was cooled to 10°C for crystallization, and the precipitated crystals were filtered and dried to obtain calcium β-aminopropionate product.

[0090] The purity of calcium beta-alanine in the product is 81.5%, and the yield of calcium beta-alanine is 71.8%.

[0091] Comparative Example 1

[0092] At room temperature, 1.65 mol / L acrylic acid aqueous solution was mixed with an appropriate amount of 25 wt % ammonia water to obtain a reaction solution with a molar ratio of acrylic acid to NH 3 of 1:10.

[0093] The reaction solution was pumped into a microchannel reactor with a volume of 60 mL and a channel cross-sectional area of ​​0.0724 cm 2 The flow rate of the reaction liquid at the inlet was 1 mL / min, and the contact reaction lasted for 60 min. The temperature in the microchannel reactor was controlled to be 160° C. and the pressure was 2.3 MPa.

[0094] The liquid flowing out of the microchannel reactor was cooled to 20°C, and after the remaining ammonia was recovered by an ammonia recovery pump, it was distilled under reduced pressure at 65°C and 0.09MPa to a syrupy state, and then methanol 3 times the mass of the acrylic acid feed was added to dissolve it, and refluxed at 65°C for 1h, and the acrylic acid content in the liquid was measured, and the conversion rate of acrylic acid was calculated to be 95.2%. Then it was cooled to 10°C for crystallization, and the precipitated crystals were filtered and dried to obtain the β-aminopropionic acid product.

[0095] The purity of β-alanine in the product is 85.2%, and the yield of β-alanine is 83.5%.

[0096] It can be seen from the results of the above examples and comparative examples that, compared with the technical solution of direct amination in the prior art, the technical solution of first calcifying acrylic acid and then aminating it provided by the present invention has higher raw material conversion rate and product yield, and the corresponding product purity is also higher.

[0097] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing calcium β-alanine, characterized in that: The method includes: (1) mixing acrylic acid and a calcifying agent in the presence of a solvent and filtering; (2) contacting the filtrate obtained in step (1) with an ammonia source; (3) The mixture obtained in step (2) is concentrated, heated to reflux and crystallized in sequence to obtain calcium β-alanine.

2. The method according to claim 1, characterized in that The calcifying agent is selected from at least one of calcium oxide, calcium hydroxide and calcium carbonate, preferably calcium oxide.

3. The method according to claim 1 or 2, characterized in that: The ammonia source is selected from ammonia and / or ammonium salts.

4. The method according to any one of claims 1 to 3, characterized in that: The molar ratio of the acrylic acid to the calcifying agent is 1:0.4-0.

6.

5. The method according to any one of claims 1 to 4, characterized in that: The molar ratio of the acrylic acid to the amino group in the ammonia source is 1:5-30, preferably 1:8-20.

6. The method according to any one of claims 1 to 5, characterized in that: In step (2), the contact temperature is 140-200°C; Preferably, the contact pressure is 1.5-4 MPa; Preferably, the contact time is 30-90 minutes.

7. The method according to any one of claims 1 to 6, characterized in that: Step (2) is carried out in a microchannel reactor; Preferably, the cross-sectional area of ​​the channel of the microchannel reactor is 0.01-0.1 cm 2 .

8. The method according to claim 7, characterized in that The filtrate obtained in step (1) is premixed with an ammonia source to obtain a reaction solution, and the reaction solution is passed into a microchannel reactor to perform the contact in step (2).

9. The method according to claim 8, characterized in that The flow rate of the reaction liquid at the inlet of the microchannel reactor is 0.6-2 mL / min, preferably 0.8-1.2 mL / min.

10. The method according to any one of claims 1 to 9, characterized in that: The heating reflux temperature in step (3) is 60-70° C. and the time is 1-3 h.