Continuous crystallization process of calcium D-pantothenate

Abstract

The present invention relates to a continuous crystallization process for calcium D-pantothenate, belonging to the technical field of chemical synthesis. The process comprises the following steps: S1, pre-cooling the calcium aminopropionate methanol solution and the D-pantolactone methanol solution respectively; S2, after the pre-cooling is completed, adding the two raw materials into a kettle A in a continuous feeding manner. The kettle A adopts a double cooling method of external circulation cooling and the jacket of the reaction kettle to control the reaction temperature in the kettle A at -10 to -5°C. After the liquid level in the kettle rises to 80%, continuous overflow discharging starts to a kettle B; S3, the kettle B adopts a double cooling method of external circulation cooling and the jacket of the reaction kettle to reduce the temperature of the material to -15 to -10°C. After the liquid level in the kettle B rises to 80%, continuous overflow discharging starts to a kettle C; S4, controlling the reaction temperature in the kettle C at -18 to -12°C. After the liquid level in the kettle C rises to 80%, continuous overflow discharging starts to a kettle D. After the liquid level is stable, centrifugation is carried out to obtain the wet product of calcium D-pantothenate.

Description

Technical Field

[0001] The present invention relates to a continuous crystallization process for calcium D-pantothenate, belonging to the technical field of chemical synthesis. Background Art

[0002] Calcium pantothenate is a kind of vitamin B, and it is one of the essential nutrients for normal biological growth. It appears as white or slightly yellowish needle-shaped crystals or powder, soluble in water, methanol, glycerol, slightly soluble in ethanol and acetone, hygroscopic, slightly sweet at first and then slightly bitter. It is used to treat vitamin B deficiency and peripheral neuritis, as well as intestinal colic after surgery. Combined with vitamin C, it can treat disseminated lupus erythematosus, and can also be used in the treatment of gastrointestinal and respiratory diseases. With the enhancement of people's health awareness, the demand for calcium D-pantothenate is on the rise.

[0003] At present, in the industrial synthesis of calcium D-pantothenate, the acylation condensation reaction is carried out between calcium aminopropionate and D-pantolactone in a methanol system. Since the calcium aminopropionate solution usually contains about 3% water, and the heat released during the acylation reaction causes the reverse reaction to intensify, resulting in a slow reaction rate. Usually, the reaction rate in industrial production is 94%, and the yield is about 88%. The reaction takes more than 16 hours to complete, and after the reaction is completed, the crystal growth time needs to be continued for about 10 hours, and the material centrifugation takes about 2 hours. That is, the single-batch production time needs more than 28 hours, with the characteristics of long equipment occupation time and low production capacity. In industrial production, the amount of calcium pantothenate produced by a single 5000-liter kettle running at full load per day is only about 1 ton. For the production capacity requirement of 5000 tons of calcium pantothenate per year and calculated based on a production time of 250 days, 20 5000L reaction kettles are required to run continuously. Summary of the Invention

[0004] The purpose of the present invention is to provide a continuous crystallization process for calcium D-pantothenate, which can greatly improve the reaction efficiency and shorten the industrial production time.

[0005] The technical solution adopted by the present invention to solve its technical problems is as follows:

[0006] A continuous crystallization process for calcium D-pantothenate, which process comprises the following steps:

[0007] S1. Pre-cool the calcium aminopropionate methanol solution and the D-pantolactone methanol solution respectively, wherein the calcium aminopropionate methanol solution is pre-cooled to -10°C to 0°C, and the D-pantolactone methanol solution is pre-cooled to 0 to 5°C;

[0008] S2. After the pre-cooling is completed, add the two raw materials to kettle A in a continuous feeding manner. Kettle A adopts the double cooling method of external circulation cooling and the reaction kettle jacket to control the reaction temperature in kettle A at -10 to -5°C. After the liquid level in the kettle rises to 80%, start continuous overflow discharging to kettle B;

[0009] During continuous feeding, control the molar ratio of raw material calcium aminopropionate to D-pantolactone to be 1:1.02 - 1.05;

[0010] S3. The B kettle adopts the method of external circulation cooling and double cooling of the reactor jacket to reduce the material temperature to -15°C to -10°C. After the liquid level in the B kettle rises to 80%, start continuous overflow discharging to the C kettle;

[0011] S4. Control the reaction temperature in the C kettle to be -18°C to -15°C. After the liquid level in the C kettle rises to 80%, start continuous overflow discharging to the D kettle,

[0012] The D kettle controls the material temperature in the kettle to be -18°C to -15°C, stores the reacted material, and centrifuges after the liquid level is stable to obtain wet D-calcium pantothenate.

[0013] The technical difficulties of the present invention are as follows:

[0014] 1. The difference in the overall crystallization method, replacing the batch crystallization in the traditional process with continuous crystallization;

[0015] 2. Key control parameters:

[0016] ①. The temperature of the 4 continuous crystallization kettles, the A kettle is -5°C to -10°C, the B kettle is -10°C to -15°C, the C kettle is -15°C to -18°C, and the D kettle is -15°C to -18°C.

[0017] ②. The residence time is 10 - 15 hr;

[0018] ③. In the reaction ratio, the molar ratio of calcium aminopropionate in the calcium aminopropionate methanol solution to D-pantolactone in the D-pantolactone methanol solution is 1:1.02 - 1.05.

[0019] Preferably, in the calcium aminopropionate methanol solution, the mass concentration of calcium aminopropionate is 20% - 25%.

[0020] Preferably, in the D-pantolactone methanol solution, the mass concentration of D-pantolactone is 50% - 55%.

[0021] Preferably, when controlling the continuous feeding of raw materials, the molar ratio of calcium aminopropionate to D-pantolactone is 1:1.02.

[0022] Preferably, the residence time of the material in the continuous crystallization equipment is 10 - 15 h, preferably 12 h.

[0023] As preferably, the feed rate of D-pantoic acid lactone methanol solution is 462kg / hr, and the feed rate of calcium alanine methanol solution is 870kg / hr. The feed rate is mainly for controlling the residence time of materials in the whole set of equipment, that is, the time from the material entering the first kettle to the material exiting the last kettle. According to the gross volume of the reactor and the expected material residence time, the feed rate of D-pantoic acid lactone methanol solution is 462kg / hr, and the feed rate of calcium alanine methanol solution is 870kg / hr, and the total feed rate is 1332kg / hr. The residence time can fluctuate within the range of 10 to 15hr, but the proportion of the two materials cannot be adjusted, and the molar ratio of the two needs to be accurately controlled.

[0024] The beneficial effects of the present invention are:

[0025] 1. The present invention adopts a continuous crystallization method in the acylation reaction and crystallization process. The acylation reaction and crystallization are carried out by connecting four reactors ABCD in series. The AB reactor adds an external circulation cooling method to improve the cooling effect. Since the continuous crystallization method is adopted, crystals are precipitated in the four reactors ABCD. After the calcium pantothenate crystals are precipitated, the water in the system can be absorbed as crystal water. After the water is absorbed, the reaction speed is accelerated. At the same time, since calcium pantothenate crystals are precipitated in the four reactors ABCD, the calcium pantothenate generated by the new reaction can be quickly induced to precipitate, eliminating the crystal precipitation and crystal cultivation time in the traditional process. Therefore, the process of the present invention can greatly shorten the reaction time and improve the equipment capacity.

[0026] 2. By adopting the continuous crystallization process provided by the present invention, taking 4 reactors in series as an example, the residence time of the materials in the 4 reactors is controlled to be 3 hours, and the crystallization effect in traditional production can be achieved, that is, a single 5000L reactor produces about 2.5 tons of calcium pantothenate per day, and the production capacity is increased to 2.5 times.

[0027] 3. At the same time, since the crystals in the process of the present invention accelerate the reaction equilibrium to move toward the square after precipitation, and reduce the generation of side reactions during the reaction process, the reaction rate in the continuous crystallization process of the present invention is about 97%, the yield is about 92%, and under continuous operation, a single 5000L kettle produces 1.86 tons to 2.8 tons of calcium pantothenate per day. Compared with the existing process, the acylation reaction rate is increased by about 3%, and the product yield is increased by about 4%. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further described in detail below through specific embodiments. It should be understood that the implementation of the present invention is not limited to the following embodiments, and any form of modification and / or change made to the present invention will fall within the protection scope of the present invention.

[0029] In the present invention, unless otherwise specified, all parts and percentages are by weight, and the equipment and raw materials used can be purchased from the market or are commonly used in the art. The methods in the following examples are conventional methods in the art unless otherwise specified.

[0030] Example 1

[0031] A continuous crystallization process for calcium D-pantothenate, the process comprising the following steps:

[0032] ① Four 5000L reactors are connected in series. Prepare 20% - 25% calcium aminopropionate methanol solution and 55% D-pantolactone methanol solution in advance and pre-cool them. The calcium aminopropionate methanol solution is pre-cooled to -8°C, and the D-pantolactone methanol solution is pre-cooled to 2°C.

[0033] ② Use metering pumps to continuously feed the calcium aminopropionate methanol solution and the D-pantolactone methanol solution into reactor A. The feeding rate of the D-pantolactone methanol solution is 462 kg / hr, and the feeding rate of the calcium aminopropionate methanol solution is about 870 kg / hr (control the molar ratio of calcium aminopropionate in the calcium aminopropionate methanol solution to D-pantolactone in the D-pantolactone methanol solution to be 1:1.02). After feeding for about 1 hour, turn on the external circulation cooling system of reactor A, control the temperature in reactor A to be -5 to -10°C. When the liquid level reaches the overflow port, it overflows to reactor B.

[0034] ③ After feeding reactor B for about 1 hour, turn on the external circulation cooling system of reactor B, control the temperature in reactor B to be -10 to -15°C. When the liquid level reaches the overflow port, it overflows to reactor C.

[0035] ④ After feeding reactor C for about 1 hour, turn on the external circulation cooling system of reactor B, control the temperature in reactor B to be -15 to -18°C. When the liquid level reaches the overflow port, it overflows to reactor D.

[0036] ⑤ Control the temperature of reactor D to be -15 to -18°C. After feeding for about 2 hours, turn on the centrifuge. After discharging and centrifuging to dry, it is the wet product of calcium pantothenate. This is a continuous crystallization and centrifugation process. Control the liquid level in reactor D to be not less than 30% for centrifugal discharging.

[0037] Application Example 1

[0038] Using the above parameter control, the continuous crystallization process runs continuously for 48 hours, among which:

[0039] The temperatures of the four reactors A, B, C, and D are -6°C, -11°C, -14°C, and -16°C respectively. The content of calcium aminopropionate in the calcium aminopropionate methanol solution is 24.5%, the total input is 42720 kg, and the net weight of calcium aminopropionate is 10469 kg. The content of D-pantolactone in the D-pantolactone methanol solution is 55.8%, the total input is 22176 kg, and the net weight of D-pantolactone is 12374 kg.

[0040] A total of 26897 kg of wet calcium pantothenate was produced, with a net weight of 20684 kg of calcium pantothenate. The yield of D-pantolactone to calcium pantothenate was 91.3%. The residence time of the material in a single reactor was 3 hours, and the cumulative residence time of the four reactors was 12 hr. The net weight of calcium pantothenate produced per single reactor per day was 2.58 tons.

[0041] Application Example 2

[0042] Using the above parameter control, the continuous crystallization process was continuously operated for 48 hr, where:

[0043] The temperatures of the four reactors A, B, C, and D are -5°C, -14°C, -16°C, and -17°C respectively. The content of calcium aminopropionate in the calcium aminopropionate methanol solution is 24.14%, the total input is 42048 kg, and the net weight of calcium aminopropionate is 101529 kg. The content of D-pantolactone in the D-pantolactone methanol solution is 54.7%, the total input is 22179 kg, and the net weight of D-pantolactone is 12132 kg.

[0044] A total of 26206 kg of wet calcium pantothenate was produced, with a net weight of 20546 kg of calcium pantothenate. The yield of D-pantolactone to calcium pantothenate was 92.5%. The residence time of the material in a single reactor was 3.5 hours, and the cumulative residence time of the four reactors was 14 hr. The net weight of calcium pantothenate produced per single reactor per day was 2.57 tons.

[0045] Application Example 3

[0046] Using the above parameter control, the continuous crystallization process was continuously operated for 48 hr, where:

[0047] The temperatures of the four reactors A, B, C, and D are -8°C, -12°C, -16°C, and -16°C respectively. The content of calcium aminopropionate in the calcium aminopropionate methanol solution is 24.51%, the total input is 41664 kg, and the net weight of calcium aminopropionate is 10211 kg. The content of D-pantolactone in the D-pantolactone methanol solution is 55.9%, the total input is 22176 kg, and the net weight of D-pantolactone is 12396 kg.

[0048] A total of 27,873 kg of calcium pantothenate wet product was produced, with a net weight of 21,016 kg of calcium pantothenate. The yield of D-pantolactone to calcium pantothenate was 92.6%. The residence time of the material in a single reactor was 2.8 hours, and the cumulative residence time of 4 reactors was 11.2 hours. The net weight of calcium pantothenate produced by a single reactor per day was 2.63 tons.

[0049] In summary, the present invention can solve the problems of low reaction rate, low yield, and low production capacity caused by long equipment occupation time in the existing production of calcium pantothenate. Compared with the prior art, the reaction rate of the acylation step in the production of calcium pantothenate by the present invention can be increased from 94% to about 97%, the product yield can be increased from 88% to about 92%, and at the same time, the equipment occupation time of a single reactor can be reduced from 28 hours to about 12 hours, greatly improving the rate of material output by the equipment, which is beneficial to reducing the product cost and enhancing the product competitiveness.

[0050] In this specification, each embodiment is described in a progressive manner. The key point of each embodiment is to illustrate the differences from other embodiments. The same or similar parts among the embodiments can be referred to each other. For the device disclosed in the embodiments, since it corresponds to the method disclosed in the embodiments, the description is relatively simple, and the relevant parts can be referred to the description of the method part.

[0051] The continuous crystallization process of D-calcium pantothenate provided by the present invention has been introduced in detail above. Specific examples are used herein to elaborate on the principle and implementation manner of the present invention. The description of the above embodiments is only used to help understand the method and its core idea of the present invention. It should be noted that for those of ordinary skill in the art of this technology, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A continuous crystallization process for calcium D-pantothenate, characterized in that this process comprises the following steps: S1. Pre-cool the calcium aminopropionate methanol solution and the D-pantolactone methanol solution respectively. The calcium aminopropionate methanol solution is pre-cooled to -10°C to 0°C, and the D-pantolactone methanol solution is pre-cooled to 0 to 5°C; S2. After pre-cooling, add the two raw materials to reactor A in a continuous feeding manner. Reactor A uses a dual cooling method of external circulation cooling and the jacket of the reaction kettle to control the reaction temperature in reactor A at -10 to -5°C. After the liquid level in the kettle rises to 80%, start continuous overflow discharging to reactor B; during continuous feeding, control the molar ratio of the raw materials calcium aminopropionate to D-pantolactone at 1:1.02 to 1.05; S3. Reactor B uses a dual cooling method of external circulation cooling and the jacket of the reaction kettle to reduce the material temperature to -15 to -10°C. After the liquid level in reactor B rises to 80%, start continuous overflow discharging to reactor C; S4. Control the reaction temperature in reactor C at -18 to -15°C. After the liquid level in reactor C rises to 80%, start continuous overflow discharging to reactor D, Reactor D controls the material temperature in the kettle at -18 to -15°C, stores the reacted material, and after the liquid level is stable, centrifuge to obtain wet calcium D-pantothenate; In the calcium aminopropionate methanol solution, the mass concentration of calcium aminopropionate is 20% to 25%; In the D-pantolactone methanol solution, the mass concentration of D-pantolactone is 50% to 55%; The residence time of the material in the continuous crystallization equipment is 10 to 15 h.

2. The continuous crystallization process for calcium D-pantothenate according to claim 1, characterized in that: When controlling the continuous feeding of the raw materials, the molar ratio of calcium aminopropionate to D-pantolactone is 1:1.02 to 1.

03.

3. The continuous crystallization process for calcium D-pantothenate according to claim 1, characterized in that: The residence time of the material in the continuous crystallization equipment is 12 h.

4. The continuous crystallization process for calcium D-pantothenate according to claim 1, characterized in that: The feeding rate of the D-pantolactone methanol solution is 462 kg / hr, and the feeding rate of the calcium aminopropionate methanol solution is 870 kg / hr.