A process for the preparation of s-2-chloropropionic acid

Abstract

The application relates to a preparation method of S-2-chloropropionic acid and belongs to the technical fields of medicines and chemical industry, and specifically provides a diazotization reaction method based on a 18%-22% constant-boiling acid system. Through construction of a stable strong acid buffer environment and accurate kinetic control, the reaction yield is improved to above 92%, the reaction conversion rate and the product yield are improved, the diazotization reaction system is stabilized, the occurrence of side reactions is inhibited, the reaction period is shortened, the time-space efficiency of the device is improved, the energy consumption and the discharge of the three wastes are reduced, and the green manufacturing level is improved.

Description

Technical Field

[0001] This invention relates to a method for preparing S-2-chloropropionic acid, belonging to the field of pharmaceutical and chemical technology. Background Technology

[0002] Currently, the industrial preparation of S-2-chloropropionic acid mainly adopts the third-generation traditional chemical diazotization process, using L-alanine as raw material, which reacts with sodium nitrite in a hydrochloric acid system. The ratio of raw material: sodium nitrite: hydrochloric acid is usually 1:2.5:4, the reaction temperature is controlled at -5℃~5℃, and the reaction time is about 32 hours. Its defects are as follows: (1) Low yield and large fluctuation: The conversion rate of the traditional process is only between 72% and 82%. The diazonium salt intermediate is extremely unstable and is prone to decomposition and coupling side reactions. (2) Unstable acidity environment: The acid concentration fluctuates drastically with consumption during the reaction, resulting in non-uniform reaction kinetics. Insufficient local acidity will lead to incomplete conversion. (3) Insufficient temperature control precision: The traditional circulating water heat exchange has thermal resistance and is difficult to cope with the instantaneous exothermic reaction of diazotization. Local overheating leads to an increase in by-products. (4) Long reaction cycle: The residence time of up to 32 hours increases the risk of secondary degradation and racemization of the product.

[0003] Therefore, there is a need to develop a method for the high-yield diazotization preparation of S-2-chloropropionic acid. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the purpose of this invention is to provide a method for preparing S-2-chloropropionic acid, which aims to overcome the yield bottleneck and instability problems in the existing diazotization process. It provides a diazotization reaction method based on an 18% to 22% azeotropic acid system. By constructing a stable strong acid buffer environment and precise kinetic control, the reaction yield can be increased to over 92%, while shortening the reaction cycle and achieving energy saving and emission reduction.

[0005] The present invention provides a high-yield method for preparing S-2-chloropropionic acid by diazotization, which improves reaction conversion and product yield; stabilizes the diazotization reaction system and inhibits side reactions; shortens the reaction cycle and improves the space-time efficiency of the equipment; reduces energy consumption and emissions of "three wastes" and improves the level of green manufacturing.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a method for preparing S-2-chloropropionic acid, comprising the following steps:

[0007] (1) Construction of the reaction substrate: A constant-boiling acid solution was prepared in advance as the reaction substrate;

[0008] (2) Material preparation: The L-alanine, sodium nitrite aqueous solution and hydrochloric acid are prepared according to a certain molar ratio and added to the reaction matrix;

[0009] (3) Catalytic system initiation: Add a composite co-catalyst at a dosage of 0.1% to 0.5% of the mass of L-alanine;

[0010] (4) Precision diazotization: After pre-activating the precision temperature control system of ethylene glycol and lowering and stabilizing the system temperature to -5℃~0℃, the composite co-catalyst is then applied. In the presence of the solution, a 42% sodium nitrite solution was added dropwise at a uniform rate. The hydrochloric acid concentration in the system was maintained within the range of 18% to 22% throughout the process, and the acidity fluctuation did not exceed 0.5%, in order to ensure the uniformity of the diazotization reaction kinetics and the stability of the diazonium salt intermediate.

[0011] (5) Temperature-sensitive reaction maintenance: Maintain the above temperature and continue the reaction for several hours.

[0012] In a preferred embodiment of the present invention, the constant-boiling acid solution is an aqueous solution of hydrogen chloride, and the mass concentration of the constant-boiling acid solution is 18% to 22%.

[0013] In a preferred embodiment of the present invention, the mass concentration of the constant-boiling acid solution is 20%.

[0014] The optimal mass concentration range of the constant boiling acid solution is 18% to 22%. A concentration below 18% can easily lead to the decomposition of diazonium salts, while a concentration above 22% increases the difficulty and cost of subsequent separation.

[0015] In a preferred embodiment of the present invention, in step (2), the molar ratio of L-alanine, sodium nitrite aqueous solution and hydrochloric acid is 1:1.8:3; the mass concentration of sodium nitrite aqueous solution is 42% and the mass concentration of hydrochloric acid is 20%.

[0016] In a preferred embodiment of the present invention, in step (3), the composite co-catalyst comprises cuprous chloride and zinc chloride, wherein the cuprous chloride (CuCl) and the zinc chloride (… The mass ratio of cuprous chloride to zinc chloride is 9:1. The combined use of cuprous chloride and zinc chloride utilizes a synergistic effect to lower the energy barrier of the substitution reaction.

[0017] In a preferred embodiment of the present invention, the amount of the composite co-catalyst is 0.1% to 0.5% of the mass of L-alanine.

[0018] In a preferred embodiment of the present invention, in step (4), the temperature of the system is -0.5℃ to 0℃, and the mass concentration of the sodium nitrite solution is 42%.

[0019] Ethylene glycol is used as a heat exchange medium. It has a large specific heat capacity and good low-temperature fluidity, enabling temperature control accuracy of ±1℃.

[0020] In a preferred embodiment of the present invention, the reaction in step (5) lasts for 24 hours.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] (1) The method for preparing S-2-chloropropionic acid provided by the present invention, with the precise balance of materials (L-alanine, sodium nitrite aqueous solution and hydrochloric acid in a molar ratio of 1:1.8:3) and their contribution to the conversion rate, results in a significant increase in yield, which is increased from the traditional 78% to 92%, and the utilization rate of raw materials is greatly improved.

[0023] (2) The method for preparing S-2-chloropropionic acid provided by the present invention has a highly stable reaction environment. The method of using an 18% to 22% azeotropic acid system as the initial matrix for the diazotization reaction provides a strong acidity buffer, inhibits the thermal decomposition of diazonium salts, and reduces the rate of by-product formation.

[0024] (3) The method for preparing S-2-chloropropionic acid provided by the present invention has high space-time efficiency, shortening the reaction time from 32 hours to 24 hours, and significantly improving the production capacity of the monomer equipment;

[0025] (4) The preparation method of S-2-chloropropionic acid provided by the present invention is green and low-carbon: the overall production cost is reduced by about 25%, energy saving and emission reduction reach 30% to 50%, and the pressure of "three wastes" treatment is effectively reduced.

[0026] The specific implementation methods do not correspond.

[0027] To better illustrate the purpose, technical solution, and advantages of this invention, the invention will be further described below with reference to specific embodiments. Unless otherwise specified, the experimental methods used in the embodiments are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0028] Example 1: This example demonstrates the preparation of S-2-chloropropionic acid using the method of the present invention (constant boiling acid concentration 20%, temperature controlled from -3℃ to -0.5℃).

[0029] The preparation method of S-2-chloropropionic acid includes the following steps: In a 2000L enamel-lined reactor, 800 kg of a 20% constant-boiling acid (hydrogen chloride aqueous solution) obtained from the previous batch is added as the reaction matrix, and the temperature is controlled to drop to -3℃. Then, L-alanine, sodium nitrite aqueous solution, and 20% hydrochloric acid are added in a molar ratio of 1:1, 8:3, along with a composite co-catalyst. (CuCl and) In the presence of a mass ratio of 9:1, a 42% sodium nitrite solution was slowly added dropwise, followed by the addition of ethylene glycol. A precise temperature control system was used to ensure that the reaction temperature rose by -0.5℃. After 24 hours of reaction, a sample was taken for testing to obtain S-2-chloropropionic acid.

[0030] The L-alanine conversion rate was 94.2%, the product yield after separation was 92.1%, and the optical purity (ee value) was ≥99.5%.

[0031] Example 2: This example demonstrates the preparation of S-2-chloropropionic acid using the method of the present invention (constant boiling acid concentration of 18%, temperature control of -3℃ to 0℃).

[0032] The preparation method of S-2-chloropropionic acid includes the following steps: In a 2000L enamel-lined reactor, 800 kg of a constant-boiling acid (hydrogen chloride aqueous solution) with a mass concentration of 18% is added as the reaction matrix. The temperature is controlled to drop to -3℃. Then, L-alanine, sodium nitrite aqueous solution, and 20% hydrochloric acid are added in a molar ratio of 1:1 and 8:3, and a composite co-catalyst is added. (CuCl and) In the presence of a mass ratio of 9:1, a 42% sodium nitrite solution was slowly added dropwise, followed by the addition of ethylene glycol. A precise temperature control system was used to ensure that the reaction temperature rose to 0°C. After 24 hours of reaction, a sample was taken for testing to obtain S-2-chloropropionic acid.

[0033] The L-alanine conversion rate was 94.2%, the product yield after separation was not less than 92%, and the optical purity (ee value) was ≥99%.

[0034] Example 3: This example demonstrates the preparation of S-2-chloropropionic acid using the method of the present invention (constant boiling acid concentration 22%, temperature controlled from -3℃ to 0℃).

[0035] The preparation method of S-2-chloropropionic acid includes the following steps: In a 2000L enamel-lined reactor, 800 kg of a 22% constant-boiling acid (hydrogen chloride aqueous solution) is added as the reaction matrix. The temperature is controlled to drop to -3℃. Then, L-alanine, sodium nitrite aqueous solution, and 20% hydrochloric acid are added in a molar ratio of 1:1 and 8:3, and a composite co-catalyst is added. (CuCl and) In the presence of a mass ratio of 9:1, a 42% sodium nitrite solution was slowly added dropwise, followed by the addition of ethylene glycol. A precise temperature control system was used to ensure that the reaction temperature rose to 0°C. After 24 hours of reaction, a sample was taken for testing to obtain S-2-chloropropionic acid.

[0036] The L-alanine conversion rate was 93.8%, the product yield after separation was 91.5%, and the optical purity (ee value) was ≥99%.

[0037] Comparative Example 1: This comparative example demonstrates the preparation of S-2-chloropropionic acid using conventional methods.

[0038] The preparation method of S-2-chloropropionic acid includes the following steps: 800 kg of 32% hydrochloric acid is added to a 2000 L enamel reactor as the reaction matrix, the temperature is controlled to drop to -5℃, and then the reaction is carried out at a molar ratio of L-alanine, sodium nitrite and hydrogen chloride of 1:2.5:3 for 32 hours. After the reaction is completed, a sample is taken for testing to obtain S-2-chloropropionic acid.

[0039] The conversion rate of S-2-chloropropionic acid was tested to be 80%, the yield of the separated product was 72%, and the optical purity (ee value) was ≥95%.

[0040] Comparative Example 2: This example illustrates the preparation of S-2-chloropropionic acid using the process described in this invention.

[0041] The preparation method of S-2-chloropropionic acid includes the following steps: 800 kg of 35% hydrochloric acid is added to a 2000 L enamel reactor as the reaction matrix, the temperature is controlled to drop to 5℃, and then the reaction is carried out at a molar ratio of L-alanine, sodium nitrite and hydrogen chloride of 1:2.8:3 for 32 hours. After the reaction is completed, a sample is taken for testing to obtain S-2-chloropropionic acid.

[0042] The conversion rate of S-2-chloropropionic acid was tested to be 85%, the yield of the separated product was 82%, and the optical purity (ee value) was ≥95%.

[0043] Experimental Example 1

[0044] The yield, conversion rate, and optical purity (ee value) of Examples 1-3 and Comparative Examples 1-2 were tested.

[0045] (a) Reaction conversion rate

[0046] Detection method: High performance liquid chromatography (HPLC, external standard method) was used.

[0047] Chromatographic conditions: C18 reversed-phase column (250 mm × 4.6 mm, 5 μm); mobile phase: 0.1% phosphoric acid aqueous solution / acetonitrile (v / v 85:15); detection wavelength: 210 nm; column temperature: 30℃; flow rate: 1.0 mL / min. After the reaction, a sample was taken, diluted with ultrapure water to an appropriate concentration, and then injected for detection. The residual amount of raw material was quantified by the peak area of ​​L-alanine. Calculation formula:

[0048]

[0049] Where n is the amount of substance (mol), which is obtained by converting the concentration of each component after quantitative calculation using the HPLC external standard method.

[0050] (ii) Product yield

[0051] Detection method: After the reaction, S-2-chloropropionic acid product was obtained by extraction, washing and drying. The mass of the final dried product was weighed by analytical balance and the actual effective product mass was calculated by combining HPLC purity detection (external standard method).

[0052] Calculation formula:

[0053]

[0054] in:

[0055] Ms-2-chloropropionic acid = 108.52 g / mol; the purity of product W is the mass fraction determined by HPLC.

[0056] (iii) Optical purity (ee value)

[0057] Detection method: Chiral high-performance liquid chromatography (chiral HPLC) was used.

[0058] Chromatographic conditions: Chiral stationary column (e.g., Chiralpak IA or AD-H column, 250 mm × 4.6 mm); mobile phase: n-hexane / isopropanol / trifluoroacetic acid (v / v 95:5:0.1); detection wavelength: 210 nm; column temperature: 25℃; flow rate: 0.8 mL / min. The peak areas of the S-type (target product) and R-type (enantiomer) were determined separately. Calculation formula:

[0059]

[0060] Where As represents the peak area corresponding to S-2-chloropropionic acid, and AR represents the peak area corresponding to R-2-chloropropionic acid.

[0061] The higher the ee value, the better the chiral selectivity of the product. The ee values ​​of the process examples 1 to 3 of this invention are all ≥99%, which is significantly better than the ≥95% of the traditional process, indicating that the azeotropic acid system and low-temperature precision temperature control effectively suppress racemization in the reaction process.

[0062] (iv) Calculation formula for yield improvement

[0063] The yield improvement is calculated as the absolute increase in product yield of each embodiment relative to the baseline yield of the comparative example. The baseline yield is the average product yield of Comparative Example 1 and Comparative Example 2 (i.e., the representative yield of the conventional process).

[0064]

[0065]

[0066] Table 1. Results of yield, conversion rate, and optical purity (ee value) tests for Examples 1-3 and Comparative Examples 1-2.

[0067]

[0068] The results in Table 1 show that in Examples 1-3, the constant acid system significantly improved the effective conversion efficiency of the diazotization reaction and greatly increased the utilization rate of raw materials. In Comparative Examples 1-2, the acidity fluctuated continuously with the reaction; the diazonium salt intermediate had poor stability; the reaction cycle was long; and the risk of side reactions was high.

[0069] Experiment Example 2

[0070] (a) Acidity fluctuation

[0071] Detection method: The online potentiometric method (pH / acidity online monitor) was adopted. An acidity probe was set in the reaction vessel, and the mass concentration value of hydrochloric acid in the system was automatically recorded every 5 minutes. The acid concentration change curve during the entire 24-hour reaction process was recorded.

[0072] Judgment criteria: Based on the initial acid concentration of the reaction, the maximum deviation value (ΔCmax) throughout the entire process is calculated as an indicator of acidity fluctuation.

[0073]

[0074] In the process of this invention, the acidity fluctuation of the azeotropic acid system is ≤0.5% (absolute deviation of mass concentration), while in the traditional process, the acidity fluctuation can reach 3% to 5%.

[0075] (II) Decomposition of Diazonium Salts

[0076] Detection method: Gas chromatography detection combined with HPLC for dual verification.

[0077] ①Gas phase detection: An online nitrogen oxide (NOx) detector is installed at the tail gas outlet of the reactor. The degree of diazonium salt decomposition is indirectly characterized by the amount of NO released in the tail gas; the higher the NO release rate, the more severe the diazonium salt decomposition.

[0078] ②HPLC validation: Samples were taken every 4 hours, and the concentration change of the diazonium salt intermediate in the reaction solution was detected by HPLC; the rate of decrease of the diazonium salt peak area was used to quantitatively characterize its decomposition rate.

[0079] Judgment criteria: The degree of decomposition inhibition is measured by the selectivity of diazonium salt to product at the end of the reaction (target product yield / total amount of diazonium salt converted × 100%). The selectivity of the process of this invention is ≥97%, while the selectivity of the conventional process is about 85% to 90%.

[0080] (iii) Amount of by-products generated

[0081] Detection method: HPLC impurity scanning was used (same HPLC conditions as in Question 1). After the reaction, a full spectrum scan of the product solution was performed, and the total impurity amount was calculated by the ratio of the sum of the peak areas of each impurity to the total peak area (area normalization method).

[0082]

[0083] The total amount of process byproducts in this invention is ≤1.5%, while the total amount of process byproducts in traditional processes is usually 4% to 8%.

[0084] (iv) Reaction time

[0085] Detection method: The reaction endpoint is determined by an L-alanine conversion rate of ≥93% (HPLC detection, same as in Question 1). The effective reaction time is the time elapsed from the start of adding sodium nitrite solution until the endpoint is reached. The reaction time of this invention is 24 hours, while the traditional process is 32 hours.

[0086] (v) Capacity of individual equipment

[0087] Testing method: The cumulative output (kg) of qualified products from a single 2000 L enamel-lined reactor within the same statistical period (year) is used as the single unit's capacity indicator. The calculation formula is as follows:

[0088]

[0089] The reaction time of this invention is shortened to 24 hours (25% shorter than the traditional 32 hours). Under the same feed rate and yield conditions, the annual production capacity of a single unit is increased by approximately 33%, based on the following calculations:

[0090]

[0091] Table 2. Verification of acidity fluctuation, diazonium salt decomposition, by-product generation, reaction time, and green and low-carbon effects of individual equipment capacity in Examples 1-3 and Comparative Examples 1-2.

[0092]

[0093] The green and low-carbon effect verification results in Table 2 show that the preparation method of S-2-chloropropionic acid provided by the present invention allows for the recycling of boiling acid, reducing the consumption of fresh acid; reducing side reactions, lowering the load of wastewater and nitrogen-containing waste gas; reducing the overall production cost by about 25%; and achieving energy saving and emission reduction effects of 30% to 50%.

Claims

1. A method for preparing S-2-chloropropionic acid, characterized in that, Includes the following steps: (1) Construction of the reaction substrate: A constant-boiling acid solution was prepared in advance as the reaction substrate; (2) Material preparation: The L-alanine, sodium nitrite aqueous solution and hydrochloric acid are prepared according to a certain molar ratio and added to the reaction matrix; (3) Catalytic system initiation: Add a composite co-catalyst at a dosage of 0.1% to 0.5% of the mass of L-alanine; (4) Precision diazotization: The ethylene glycol precision temperature control system is turned on in advance to lower and stabilize the system temperature within the cooling temperature range. Sodium nitrite solution is added dropwise at a uniform rate in the presence of the composite co-catalyst. The hydrochloric acid mass concentration of the system is maintained in the range of 18% to 22% throughout the process by online acidity monitoring, and the acidity fluctuation does not exceed 0.5%. (5) Temperature-sensitive reaction maintenance: Maintain the above temperature and continue the reaction for several hours.

2. The method for preparing S-2-chloropropionic acid as described in claim 1, characterized in that, The constant-boiling acid solution is composed of an aqueous solution of hydrogen chloride, and the mass concentration of the constant-boiling acid solution is 18% to 22%.

3. The method for preparing S-2-chloropropionic acid as described in claim 2, characterized in that, The mass concentration of the constant-boiling acid solution is 20%.

4. The method for preparing S-2-chloropropionic acid as described in claim 1, characterized in that, In step (2), the molar ratio of L-alanine, sodium nitrite aqueous solution, and hydrochloric acid is 1:1.8:3; the mass concentration of the sodium nitrite aqueous solution is 42%, and the mass concentration of the hydrochloric acid is 20%.

5. The method for preparing S-2-chloropropionic acid as described in claim 1, characterized in that, In step (3), the composite cocatalyst comprises cuprous chloride and zinc chloride, and the mass ratio of cuprous chloride to zinc chloride is 9:

1.

6. The method for preparing S-2-chloropropionic acid as described in claim 5, characterized in that, The amount of the composite cocatalyst is 0.1% to 0.5% of the mass of L-alanine.

7. The method for preparing S-2-chloropropionic acid according to claim 1, characterized in that, In step (4), the cooling temperature of the system is -5℃ to 0℃, and the mass concentration of the sodium nitrite solution is 42%.

8. The method for preparing S-2-chloropropionic acid as described in claim 1, characterized in that, In step (5), the reaction lasts for 24 hours.

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