An upatinib bulk drug intermediate and a preparation method thereof

Abstract

This invention belongs to the field of pharmaceutical chemical intermediates and provides an intermediate for utpatinib active pharmaceutical ingredient and its preparation method. By constructing (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid cinconidine salt and matching it with ethanol and ethyl acetate dissolution, cinconidine salt formation, n-heptane antisolvent crystallization, controlled cooling aging and low-pressure drying processes, this invention achieves synergistic control of salt composition, free acid, moisture, stereoisomers, particle size and residual solvent. It solves the problem of difficulty in balancing crystallization yield and stereopurity, and particle integrity and drying residue. This invention is suitable for the large-scale preparation of key intermediates for utpatinib active pharmaceutical ingredient.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical intermediate preparation, specifically to an intermediate for utpatinib active pharmaceutical ingredient and its preparation method. Background Technology

[0002] Upatinib, as a key representative of selective JAK inhibitors, places high demands on the quality stability, scalability, and impurity control of its chiral intermediates during its API preparation. In the preparation of such pharmaceutical intermediates, intermediates containing a chiral pyrrolidine carboxylic acid skeleton typically need to balance salt stability, stereoconfiguration retention, crystallization yield, particle filterability, drying efficiency, and the quality of subsequent free acid release. For large-scale preparation, if the solvent composition, salt formation ratio, antisolvent addition, cooling rate, and aging process of the crystallization system are not properly matched, it can easily lead to fluctuations in crystal particle size distribution, high levels of residual free acid, and difficulties in controlling moisture or residual solvents, thus affecting the consistency of filtration, washing, drying, and subsequent reaction feed. Therefore, developing an utpatinib API intermediate and its preparation method that achieves a balance between yield, stereopurity, particle morphology, and residue control is of great significance for improving the quality control level of API intermediates in industrial production.

[0003] Publicly available technologies have proposed various preparation routes for utpatinib and its pyrrolidine carboxylic acid intermediates. For example, US patent application US20210163409A1 discloses an alternative process for preparing utpatinib intermediate 4-ethylpyrrolidine-3-carboxylic acid and its esters or salts, and points out that existing routes still need improvement in terms of achieving the desired quality and yield on a large scale. Chinese patent CN113248416B discloses the preparation and application of 1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid, indicating that this type of compound can be used to prepare key intermediates related to selective JAK1 inhibitors. Although existing technologies can provide the target skeleton or subsequent intermediates, the comprehensive control over the salt form of cinconidine salt is still insufficient in terms of salt formation ratio, mixed solvent, antisolvent crystallization, cooling aging, particle size, free acid release, and cinconidine recovery. It is difficult to simultaneously reduce non-target stereoisomers, improve crystallization operability, and control drying residues. Summary of the Invention

[0004] The purpose of this invention is to provide an intermediate of utpatinib active pharmaceutical ingredient and its preparation method, which solves the problem that it is difficult to simultaneously achieve yield and stereopurity, particle integrity and residue control in the current crystallization of cinconidine salt.

[0005] Existing technologies often enhance the antisolvent driving force to improve crystallization yield, but this easily reduces stereoselectivity. Conversely, improving stereopurity often requires enhancing selective crystallization at the expense of yield. Meanwhile, larger and denser crystals are beneficial for particle integrity but detrimental to residual solvent migration. This invention achieves a synergistic balance between these two contradictory properties by matching the salt formation ratio, mixed solvent, n-heptane crystallization, controlled cooling aging, and low-pressure drying.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] An intermediate for utpatinib active pharmaceutical ingredient, wherein the intermediate is (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt, wherein the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt is composed of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid anion and occonidine cation;

[0008] The molar ratio of the total amount of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid contained in the intermediate to the total amount of cinconidine is 1:0.95–1.05.

[0009] Based on the total mass of the intermediate, the content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.02–2.00 wt%, the content of water is 0.05–1.50 wt%, and the total amount of non-target stereoisomers is 0.02–0.80 wt%.

[0010] The non-target stereoisomers mentioned in this article refer to stereoisomers of 1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid other than the (3R,4S) configuration.

[0011] Furthermore, the intermediate is a crystalline particle with a D50 of 50–300 µm.

[0012] Further, the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt is prepared by the following steps:

[0013] A1. (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is added to a mixed solvent of ethanol and ethyl acetate, wherein the mass ratio of ethanol to ethyl acetate is 1:0.5–3.0, and stirred at 35–65°C to dissolve, thereby obtaining an acidic solution;

[0014] A2. Add 0.95–1.05 molar equivalents of cinconidine to the acidic solution and keep it at 35–65°C for 0.5–3.0 h to obtain a salt-forming reaction solution;

[0015] A3. Add n-heptane to the salt-forming reaction solution, cool it to 0–25°C at a cooling rate of 0.05–0.40°C / min, and age it for 2–10 hours to obtain a crystalline slurry;

[0016] A4. The crystalline slurry is filtered, washed, and dried at 35–55°C and 0.005–0.030 MPa for 4–16 h to obtain the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt;

[0017] A5. The product quality indicators of the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt are as follows: the molar ratio of the total amount of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid to the total amount of occonidine in the intermediate is 1:0.95–1.05, the content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.02–2.00 wt%, the moisture content is 0.05–1.50 wt%, the total amount of non-target stereoisomers is 0.02–0.80 wt%, and the D50 is 50–300 µm.

[0018] The present invention also provides a method for releasing (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid from the above-mentioned (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt, comprising the following steps:

[0019] B1. Add the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt to a two-phase system of ethyl acetate and deionized water;

[0020] B2. Add 0.5–2.0 mol / L hydrochloric acid aqueous solution at 5–30℃ to adjust the pH of the aqueous phase to 1.0–2.5, and stir for 0.5–3.0 h;

[0021] B3. Allow the mixture to stand and separate into layers, collect the organic phase, and wash it with a saturated sodium chloride aqueous solution;

[0022] B4. The washed organic phase was concentrated and dried at 25–50 °C and 0.005–0.030 MPa to obtain free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid;

[0023] B5. The amount of cinchonidine residue in the obtained free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.001–0.20 wt%, and the total amount of non-target stereoisomers is 0.02–0.80 wt%.

[0024] Furthermore, the method for releasing (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid further includes the step of treating the cinconidine-containing aqueous phase obtained in step B3 to recover cinconidine:

[0025] C1. At 0–30°C, add 10–30 wt% sodium hydroxide aqueous solution to the cinconidine-containing aqueous phase to adjust the pH to 9.5–11.5;

[0026] C2. Extract with ethyl acetate and combine the organic phases;

[0027] C3. The organic phase is concentrated at 25–50 °C and 0.005–0.030 MPa, and then recrystallized from ethanol and deionized water;

[0028] C4. Obtain recovered cinconidine with a purity of 95.0–99.9 wt% and a recovery rate of 80–98% based on the initial cinconidine.

[0029] The present invention also provides a method for recrystallizing and purifying the above-mentioned (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt, wherein the recrystallization comprises the following steps:

[0030] D1. The (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt is added to a mixed solvent of isopropanol and ethyl acetate and stirred to dissolve at 35–60°C;

[0031] D2. Add activated carbon and keep warm at 35–60℃;

[0032] D3. Filter to remove activated carbon, add n-heptane to the filtrate, cool to 0–25℃ and age;

[0033] D4. Filter, wash and dry at 35–55 °C and 0.005–0.030 MPa to obtain (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt after recrystallization purification.

[0034] D5. The total amount of non-target stereoisomers in the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt purified by recrystallization is 0.02–0.50 wt%, and the content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.02–1.00 wt%.

[0035] Furthermore, in the method for releasing (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, the proportion of particles smaller than 10 µm in the cinconidine salt is 0.1–10.0 wt%, and the residual amount of cinconidine in the resulting free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.001–0.10 wt%.

[0036] Furthermore, after the cinconidine-containing aqueous phase is treated in steps C1–C4, the recovery rate of cinconidine is 85–96%.

[0037] As a concept of this invention, the design of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid cinconidine salt is mainly used to achieve a synergistic balance between crystallization yield and stereoisomer purity. In the prior art, to improve crystallization yield, the antisolvent effect is usually increased or crystal precipitation is accelerated, but local supersaturation increases the risk of non-target stereoisomer entrainment and free acid residue. To improve stereopurity, selective crystallization or recrystallization is often strengthened, which increases mother liquor loss and reduces the overall yield. This invention, through the construction of the salt form of acid anion and cinconidine cation, control of the acid to cinconidine molar ratio, control of free acid content, control of moisture, and control of non-target stereoisomers, achieves a synergistic effect of salt formation integrity, crystal precipitation, and impurity removal, thereby improving the operability of industrial preparation while maintaining the quality of the target salt.

[0038] This invention also discloses a method for preparing the aforementioned utpatinib active pharmaceutical ingredient intermediate, comprising the following steps:

[0039] S1. Dissolve (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid in a mixed solvent of ethanol and ethyl acetate to obtain an acidic solution;

[0040] S2. Add cinconidine to the acidic solution, wherein the molar ratio of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid to cinconidine is 1:0.95–1.05, and react at 35–65°C for 0.5–3.0 h to obtain a salt-forming reaction solution.

[0041] S3. Add n-heptane as an antisolvent to the salt-forming reaction solution, cool it to 0–25°C at a cooling rate of 0.05–0.40°C / min, and age it for 2–10 hours to form cinconidine salt crystals;

[0042] S4. The cinconidine salt crystals are filtered, washed, and dried at 35–55 °C and 0.005–0.030 MPa for 4–16 h to obtain (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid cinconidine salt.

[0043] Further, in step S1, the feed concentration of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 5–25 wt%, and the feed concentration is expressed as a percentage of the mass of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid to the total mass of the mixed solvent of the acid, ethanol, and ethyl acetate, wherein the mass ratio of ethanol to ethyl acetate is 1:0.5–3.0; in step S2, cinconidine is added in batches, and the temperature is maintained after the addition is completed, and the content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid in the salt formation reaction solution is 0.02–5.00 wt%.

[0044] Further, in step S3, the amount of n-heptane added is 2–12 times the mass of the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid; in step S4, the water content of the dried cinconidine salt is 0.05–1.50 wt%, and the total amount of residual ethanol and residual ethyl acetate is 50–5000 ppm.

[0045] Furthermore, the preparation method further includes the step of acidifying the obtained cinconidine salt with an aqueous hydrochloric acid solution to release free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, wherein the acidification step is carried out at 5–30 °C and pH 1.0–2.5 for 0.5–3.0 h; the aqueous phase containing cinconidine after the acidification step is adjusted to pH 9.5–11.5 with an aqueous sodium hydroxide solution and then extracted with ethyl acetate to recover cinconidine.

[0046] Furthermore, when the preparation method is carried out in batches of 1–100 kg based on the feed amount of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, the yield of cinconidine salt is 80–98%, and the inter-batch D50 coefficient of variation is 2–20%. The yield of cinconidine salt is the ratio of the actual mass of cinconidine salt obtained after separation and drying to the theoretical mass of cinconidine salt calculated based on the limited components in the feed acid and cinconidine; the inter-batch D50 coefficient of variation is the ratio of the standard deviation to the average value of D50 for each batch under the same process conditions.

[0047] Further, using 100 parts by mass of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as a reference, the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid was added to 300–1200 parts by mass of a mixed solvent of ethanol and ethyl acetate, with a mass ratio of ethanol to ethyl acetate of 1:0.5–3.0, and stirred to dissolve at 35–65°C; then, cinconidine was added in batches over 0.5–2.0 h, so that the molar ratio of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid to cinconidine was 1:0.95–1.05. After the addition was completed, the mixture was kept at 35–65°C for another 0.5–3.0 h to obtain the salt-forming reaction solution.

[0048] Further, using 100 parts by mass of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as a reference, 200–1200 parts by mass of n-heptane were added to the salt-forming reaction solution, and the solution was cooled to 0–25°C at a cooling rate of 0.05–0.40°C / min and aged at 0–25°C for 2–10 h to obtain a crystalline slurry. The crystalline slurry was subjected to solid-liquid separation, washed 1–3 times with a mixed washing solution of ethanol and n-heptane, and dried at 35–55°C and 0.005–0.030 MPa for 4–16 h to obtain occonidine salt of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid.

[0049] Further, using 100 parts by mass of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt as a reference, the occonidine salt was added to a two-phase system of ethyl acetate and deionized water (300–1000 parts by mass). A 0.5–2.0 mol / L hydrochloric acid aqueous solution was added at 5–30 °C to adjust the pH of the aqueous phase to 1.0–2.5, and the mixture was stirred for 0.5–3.0 h. After standing and separating the phases, the organic phase was collected and washed with a saturated sodium chloride aqueous solution. The washed organic phase was concentrated 1–3 times and dried at 25–50 °C and 0.005–0.030 MPa for 4–12 h to obtain free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid. The free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid contained 0.001–0.20 wt% cinconidine residue and 0.02–0.80 wt% total amount of non-target stereoisomers.

[0050] Further, the aqueous phase containing cinconidine obtained after acidification and separation is added to a 10–30 wt% sodium hydroxide aqueous solution at 0–30 °C to adjust the pH to 9.5–11.5, and then extracted with ethyl acetate 2–4 times and the organic phases are combined; the organic phase is concentrated at 25–50 °C and 0.005–0.030 MPa, and recrystallized with ethanol and deionized water to obtain recovered cinconidine with a purity of 95.0–99.9 wt% and a recovery rate of 80–98% based on the initial cinconidine.

[0051] Further, using 100 parts by weight of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt as a reference, the occonidine salt was added to 300–1000 parts by weight of a mixed solvent of isopropanol and ethyl acetate, and stirred to dissolve at 35–60°C; 0.20–2.00 parts by weight of activated carbon were added to the solution, and the mixture was kept at 35–60°C for 0.5–2.0 h, then filtered to remove the activated carbon. 200–1000 parts by weight of n-heptane were added to the filtrate, and the mixture was cooled to 0– The sample was aged at 25°C and 0–25°C for 2–8 h; filtered, washed, and dried at 35–55°C and 0.005–0.030 MPa for 4–16 h to obtain purified (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt. The total amount of non-target stereoisomers in the purified occonidine salt was 0.02–0.50 wt%, and the content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid was 0.02–1.00 wt%.

[0052] As another aspect of this invention, the preparation process involves dissolving the product in ethanol and ethyl acetate, batch salt formation of cinconidine, antisolvent crystallization with n-heptane, controlled cooling aging, and low-pressure drying. This process is primarily used to achieve, fix, or scale up the aforementioned synergistic effects. Existing technologies, by simply enhancing the antisolvent crystallization driving force, easily lead to rapid crystal nucleation and the generation of fine powder, thus affecting filtration, washing, and residual control during drying. Simply prolonging crystallization or intensifying purification may improve stereoselectivity but result in yield loss. This invention, through the coupling of the mixed solvent ratio, cinconidine molar ratio, batch feeding, cooling rate, aging temperature, drying temperature, and low-pressure conditions, coordinates the salt formation reaction, crystal growth, impurity removal, particle integrity, and residual solvent migration, thereby achieving unified product quality control and batch scale-up stability.

[0053] (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid and cinconidine mainly address the issues of salt formation selectivity and stereoisomer control. The mixed solvent of ethanol and ethyl acetate, along with the antisolvent of n-heptane, primarily addresses dissolution, nucleation, crystal growth, and particle integrity. If only cinconidine salt formation is emphasized without appropriate solvent and antisolvent control, uneven salt precipitation, residual free acid, and crystal size fluctuations can easily occur. Conversely, if only antisolvent crystallization is emphasized without considering the salt formation ratio and the order of batch addition, rapid supersaturation changes may increase impurity entrainment. This invention, through molar ratio matching, mixed solvent polarity adjustment, batch addition of cinconidine, controlled n-heptane crystallization, and aging processes, achieves mutual correction between salt formation integrity, crystal growth, and impurity removal, ultimately balancing crystallization yield, stereoisomer purity, particle integrity, and residue control.

[0054] Beneficial technical effects

[0055] 1. This invention converts (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid into cinconidine salt and controls the molar ratio of total acid to total cinconidine within a specific range, so that the integrity of salt formation corresponds to the control of free acid residue, which helps to reduce impurity fluctuations when releasing free acid in the future.

[0056] 2. This invention uses a mixed solvent of ethanol and ethyl acetate in conjunction with n-heptane as an antisolvent for crystallization. By matching the solubility, crystallization driving force and crystal growth rate, the risk of fine powder and impurities caused by rapid crystallization is reduced, which helps to balance crystallization yield, stereoisomer control and filtration and washing operability.

[0057] 3. By controlling the cooling rate, aging temperature, aging time, number of washing cycles, and low-pressure drying conditions, this invention enables the crystal particles to maintain a relatively stable particle size distribution during the formation, maturation, and drying processes. This helps to reduce moisture and residual ethanol and ethyl acetate, while avoiding the risk of particle breakage due to excessive drying.

[0058] 4. This invention connects the acidification release of free acid and the aqueous phase recovery process of cinconidine. Through hydrochloric acid acidification, stratification, brine washing, alkalization, extraction and recrystallization, the residual cinconidine in the target free acid is controlled and cinconidine can be recycled, which helps to reduce the loss of process materials.

[0059] 5. The present invention further includes steps of recrystallization in a mixed solvent of isopropanol and ethyl acetate, activated carbon treatment, and n-heptane crystallization purification, which further controls non-target stereoisomers and free acid residues, providing process support for quality consistency under different batches and the stability of subsequent API intermediate feeding. Attached Figure Description

[0060] Figure 1The graph shows the effect of the molar equivalent of cinconidine feed on the yield of cinconidine salt and the content of free acid.

[0061] Figure 2 The graph shows the effect of the ethyl acetate / ethanol mass ratio on the yield and particle size D50 of cinconidine salt.

[0062] Figure 3 The graph shows the effect of n-heptane addition on the yield of cinconidine salt and the proportion of fine particles smaller than 10 µm.

[0063] Figure 4 The graph shows the effect of cooling rate on the yield of cinconidine salt and the total amount of non-target stereoisomers.

[0064] Figure 5 The graph shows the relative molar ratio of free acid content to salt-forming chiral base in HPLC for Examples 1, 1, 2, and 9.

[0065] Figure 6 The above is a statistical chart of the total amount of chiral non-target stereoisomers by HPLC in Examples 1, 6, and 9.

[0066] Figure 7 The particle size distribution curves of cinconidine salts in Examples 1, 7, 10 and 11 are shown.

[0067] Figure 8 The cumulative particle size distribution curves of cinconidine salts for Examples 1, 7, 10 and 11 are shown.

[0068] Figure 9 The chart shows the total amount of moisture and residual solvent in Examples 1, 8, and 10.

[0069] Figure 10 The graph shows the residue and purity of cinconidine in the free acid of Example 1, Comparative Example 1, and Comparative Example 2.

[0070] Figure 11 This is a comparison of macroscopic optical photographs of the purified (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt from Example 1 and the occonidine salt obtained in Comparative Example 11; wherein, Figure 11 Figure a in the image is a macroscopic optical photograph of the final product of Example 1. Figure 11 Figure b in the figure is a macroscopic optical photograph of the final product of Comparative Example 11.

[0071] Figure 12 The images show the SEM morphology and SEM-EDS comparison of the purified (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt from Example 1 and the occonidine salt obtained in Comparative Example 11; where, Figure 12Figure a in the image is a low-magnification SEM image of the final product of Example 1. Figure 12 Image b in the figure is a low-magnification SEM image of the final product of Comparative Example 11. Figure 12 Figure c in the image is a medium-magnification SEM image of the final product of Example 1. Figure 12 Image d in the figure is a medium-magnification SEM image of the final product of Comparative Example 11. Figure 12 Image e in the image is a high-magnification SEM image of the final product of Example 1. Figure 12 Figure f in the image is a high-magnification SEM image of the final product of Comparative Example 11. Figure 12 Image g in the image is a SEM-EDS surface scan image of the final product of Example 1. Figure 12 The h-image in the figure is a SEM-EDS surface scan image of the final product of Comparative Example 11.

[0072] Figure 13 The images show the TEM structure and TEM / STEM-EDS surface scan comparison of the purified (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt from Example 1 and the occonidine salt obtained in Comparative Example 11; where, Figure 13 Figure a in the image is a bright-field TEM image of the final product crystal fragment from Example 1. Figure 13 Figure b in the figure is a bright-field TEM image of the final product crystal fragments in Comparative Example 11. Figure 13 Figure c in the image is an HRTEM image of the final product of Example 1. Figure 13 Image d in the figure is the HRTEM image of the final product of Comparative Example 11. Figure 13 Figure e in the diagram is the SAED diagram of the final product of Example 1. Figure 13 Figure f in the diagram is the SAED plot of the final product of Comparative Example 11. Figure 13 Image g in the image is a TEM / STEM-EDS surface scan image of the final product of Example 1. Figure 13 The h-image in the figure is a TEM / STEM-EDS surface scan image of the final product of Comparative Example 11. Detailed Implementation

[0073] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0074] Unless otherwise stated, all pressures mentioned herein are absolute pressures. The contents of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid and salt-forming chiral bases were determined using HPLC with external standard method. The total amount of non-target stereoisomers was determined using chiral HPLC. Moisture content was determined using the Karl Fischer method. The total amounts of residual ethanol and residual ethyl acetate were determined using gas chromatography. The proportion of D50 and particles smaller than 10 µm was determined using laser diffraction particle size analysis combined with microscopic image statistical analysis. The relative molar ratio of salt-forming chiral bases refers to the relative molar number of total salt-forming chiral bases with the total number of moles of acid as 1. Except for quinine in Comparative Example 9, the salt-forming chiral base of all other samples was cinconidine. The free acid content, moisture, total amount of non-target stereoisomers, D50, proportion of particles smaller than 10µm, and total residual solvent of cinconidine salt all refer to cinconidine salt samples obtained by crystallization, washing, and drying; the residual chiral base and total amount of non-target stereoisomers in the free acid all refer to free acid samples obtained by acidification, release, and drying; the purity and recovery rate of the recovered chiral base refer to recovered chiral base samples obtained by alkalization, extraction, concentration, and recrystallization.

[0075] In the same embodiment, the acidification to release free acid and the recrystallization purification used cinconidine salt samples prepared separately according to the salt formation, crystallization, and drying steps of this embodiment as starting materials. The data listed in Tables 1-1 and 1-2 are the average ± standard deviation of three parallel experiments conducted on each sample under the corresponding process conditions; the test results for Examples 1 to 4 without a standard deviation indicated in the text are the corresponding average values. The inter-batch D50 coefficient of variation mentioned at the end of Examples 1 to 4 is calculated from the results of three separate batches prepared under the corresponding scale-up conditions and is not confused with the standard deviation of D50 in Table 1-1.

[0076] Example 1

[0077] Raw materials and proportions: In this embodiment, the preparation scale is based on 100.0 g of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid. This acid is a commercially available or purified white to off-white solid prepared via conventional methods, with a purity ≥98.5%, a total amount of non-target stereoisomers ≤1.0 wt%, and a moisture content ≤0.5 wt%. Cinconidine is a commercially available chemically pure solid with a purity ≥98.0%. Ethanol, ethyl acetate, n-heptane, and isopropanol are chemically pure solvents with a moisture content ≤0.2 wt%. Hydrochloric acid aqueous solution, sodium hydroxide aqueous solution, saturated sodium chloride aqueous solution, and deionized water are all prepared according to conventional laboratory or workshop quality requirements. Activated carbon is pharmaceutical-grade or chemically pure decolorizing powder.

[0078] Step 1: Prepare an acidic solution

[0079] 100.0 g of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid was added to a reaction vessel equipped with a mechanical stirrer, thermometer, and dropping device. A mixed solvent of 300.0 g of ethanol and ethyl acetate (200.0 g ethanol and 100.0 g ethyl acetate, with a mass ratio of ethanol to ethyl acetate of 1:0.5) was added, and the acid concentration was 25.0 wt%. The mixture was stirred at 200 rpm under normal pressure, heated to 35 °C, and maintained for 0.5 h to obtain an acidic solution.

[0080] Step 2: Salt formation reaction

[0081] At 35°C, 0.95 molar equivalents of cinconidine were added to an acidic solution in three batches over a total time of 0.5 h. After each batch was added, the mixture was stirred at 200 rpm for 10 min, and then kept at 35°C for another 0.5 h. A small amount of the salt-forming reaction solution was taken and analyzed by HPLC. The content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid was 5.00 wt%, thus obtaining the salt-forming reaction solution.

[0082] Step 3: Antisolvent crystallization and aging

[0083] Add 200.0 g of n-heptane to the salt-forming reaction solution at a rate of approximately 10 g / min, with the amount of n-heptane added being twice the mass of the acid. Maintain stirring at 200 rpm and cool the system to 0°C at a rate of 0.05°C / min. Aging at 0°C for 2 hours yields a crystalline slurry. At the end of aging, the slurry is filterable, and microscopic observation reveals irregular short columnar or granular crystals.

[0084] Step 4: Solid-liquid separation and drying

[0085] The crystallized slurry was filtered at 0–5°C and washed once with a 50.0 g washing solution of a mixture of ethanol and n-heptane in a 1:2 mass ratio. The filter cake was dried at 35°C and 0.005 MPa for 4 h to obtain (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt. The drying endpoint was determined by a difference of ≤0.5 wt% between two consecutive weighings and a moisture content of 0.05–1.50 wt%.

[0086] Step 5: Acidification to release free acid and recovery of cinconidine

[0087] 100.0 g of cinconidine salt from this embodiment was added to 300.0 g of a two-phase system of ethyl acetate and deionized water (180.0 g of ethyl acetate and 120.0 g of deionized water). A 0.5 mol / L hydrochloric acid aqueous solution was added at 5 °C to adjust the pH of the aqueous phase to 1.0, and the mixture was stirred for 0.5 h. After standing and separating the layers, the organic phase was collected and washed once with 50.0 g of saturated sodium chloride aqueous solution. The organic phase was concentrated at 25 °C and 0.005 MPa and dried for 4 h to obtain free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid. The cinconidine-containing aqueous phase was added at 0 °C with 10 wt% sodium hydroxide aqueous solution to adjust the pH to 9.5, and extracted twice with ethyl acetate (100.0 g each time). The organic phases were combined, concentrated at 25 °C and 0.005 MPa, and recrystallized from ethanol and deionized water to obtain recovered cinconidine.

[0088] Step Six: Recrystallization and Purification

[0089] Take 100.0 g of cinconidine salt from this embodiment and add 300.0 g of a mixed solvent of isopropanol and ethyl acetate, wherein 150.0 g of isopropanol and 150.0 g of ethyl acetate. Dissolve the solution by stirring at 200 rpm at 35°C. Add 0.20 g of activated carbon to the solution and keep it at 35°C for 0.5 h. Filter to remove the activated carbon. Add 200.0 g of n-heptane to the filtrate, cool to 0°C, and age for 2 h. After filtering and washing, the resulting solid is dried at 35°C and 0.005 MPa for 4 h to obtain purified (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid cinconidine salt.

[0090] Quality testing methods and results: According to the above testing methods, the yield of cinconidine salt obtained in step four was 80.5%, the molar ratio of total acid to total cinconidine was 1:0.95, the free acid content was 1.95 wt%, the moisture content was 1.46 wt%, the total amount of non-target stereoisomers was 0.78 wt%, the D50 was 52 µm, the proportion of particles smaller than 10 µm was 9.8 wt%, and the total amount of residual ethanol and residual ethyl acetate was 4800 ppm. The residual cinconidine in the free acid obtained from acidification release was 0.095 wt%, and the total amount of non-target stereoisomers was 0.78 wt%. The purity of the recovered cinconidine was 95.2 wt%, and the recovery rate based on the initial cinconidine was 80.5%. This example was repeated three times under simulated conditions with a 1 kg batch size, and the inter-batch D50 coefficient of variation was 19.5%.

[0091] Features and application scenarios of this embodiment: This embodiment adopts a relatively conservative low ratio scheme and mild process conditions, which is suitable for evaluating the feasibility of lower cinconidine feed amount, lower mixed solvent amount, slower cooling process and shorter drying time. It is suitable for small-scale process exploration and early process screening scenarios that are sensitive to free acid residue.

[0092] Example 2

[0093] Key parameters are listed below: In this embodiment, the amount of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid added is 100.0g; the total amount of the mixed solvent of ethanol and ethyl acetate is 1200.0g, with 300.0g of ethanol and 900.0g of ethyl acetate, and a mass ratio of 1:3.0; the acid concentration is 7.7wt%; the amount of cinconidine added is 1.05 molar equivalents; the batch addition time of cinconidine is 2.0h; the salt formation temperature is 65℃; the salt formation holding time is 3.0h; the amount of n-heptane added is 1200.0g; the cooling rate is 0.40℃ / min; the aging temperature is 25℃; the aging time is 10h; the drying temperature of cinconidine salt is 55℃, the drying pressure is 0.030MPa, and the drying time is 16h.

[0094] Preparation process: 100.0 g of acid was added to a reaction vessel, followed by 1200.0 g of a mixed solvent of ethanol and ethyl acetate. The mixture was stirred at 350 rpm at 65 °C until dissolved, yielding an acidic solution. 1.05 molar equivalents of cinconidine were added to the acidic solution in 5 batches, with a total addition time of 2.0 h. Stirring was continued for 20–30 min after each batch addition. After the addition was complete, the mixture was kept at 65 °C for 3.0 h. HPLC analysis of the sample showed that the free acid content in the salt formation reaction solution was 0.02 wt%.

[0095] The crystallization, washing, and drying process was as follows: 1200.0 g of n-heptane was added to the salt-forming reaction solution at 65 °C, and the mixture was stirred at 350 rpm. After the addition was complete, the temperature was lowered to 25 °C at a rate of 0.40 °C / min and the mixture was aged for 10 h. The resulting crystalline slurry was filtered and washed three times with a mixture of ethanol and n-heptane in a mass ratio of 1:2, with 60.0 g of washing solution used each time. The filter cake was dried at 55 °C and 0.030 MPa for 16 h to obtain (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt.

[0096] Acidification release and recovery operation: 100.0 g of cinconidine salt from this embodiment was added to a two-phase system of 1000.0 g ethyl acetate and deionized water (650.0 g ethyl acetate and 350.0 g deionized water). A 2.0 mol / L hydrochloric acid aqueous solution was added at 30°C to adjust the pH of the aqueous phase to 2.5, and the mixture was stirred for 3.0 h. After standing and separation, the organic phase was collected and washed three times with 70.0 g of saturated sodium chloride aqueous solution each time. The organic phase was concentrated at 50°C and 0.030 MPa and dried for 12 h to obtain free acid. The cinconidine-containing aqueous phase was added at 30°C with 30 wt% sodium hydroxide aqueous solution to adjust the pH to 11.5, and extracted four times with ethyl acetate (120.0 g each time). The organic phases were combined, concentrated at 50°C and 0.030 MPa, and recrystallized from ethanol and deionized water to obtain recovered cinconidine.

[0097] Recrystallization purification: Take 100.0 g of cinconidine salt from this example, add 1000.0 g of a mixed solvent of isopropanol and ethyl acetate (500.0 g of isopropanol and 500.0 g of ethyl acetate), and stir to dissolve at 60°C. Add 2.00 g of activated carbon, keep warm at 60°C for 2.0 h, filter, add 1000.0 g of n-heptane, cool to 25°C and age for 8 h. After filtration and washing, dry at 55°C and 0.030 MPa for 16 h to obtain purified cinconidine salt.

[0098] Quality testing methods and results: According to the above testing methods, the yield of cinconidine salt obtained from crystallization, washing, and drying was 97.0%, the molar ratio of total acid to total cinconidine was 1:1.05, the free acid content was 0.03 wt%, the moisture content was 0.06 wt%, the total amount of non-target stereoisomers was 0.08 wt%, the D50 was 295 µm, the proportion of particles smaller than 10 µm was 0.2 wt%, and the total amount of residual ethanol and residual ethyl acetate was 80 ppm. The residual cinconidine in the free acid obtained from acidification release was 0.006 wt%, and the total amount of non-target stereoisomers was 0.08 wt%. The purity of the recovered cinconidine was 99.5 wt%, and the recovery rate based on the initial cinconidine was 97.0%. This example was repeated three times under simulated 20 kg batch conditions, and the inter-batch D50 coefficient of variation was 2.5%.

[0099] The features of this embodiment are: This embodiment uses a relatively high amount of cinconidine feed, a relatively high amount of mixed solvent, a relatively high amount of strong anti-solvent, a relatively high drying temperature, and a relatively long aging time. It is suitable for screening process conditions that emphasize salt formation integrity, reduce free acid residue, reduce moisture, and reduce the proportion of fine powder.

[0100] Example 3

[0101] The utpatinib active pharmaceutical ingredient intermediate of this embodiment was prepared as follows.

[0102] I. Formation of Acidic Solution: Using 100.0 g of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid as the feed standard, the acid was added to a mixed solvent of 750.0 g of ethanol and ethyl acetate, wherein 300.0 g of ethanol and 450.0 g of ethyl acetate were present in a mass ratio of 1:1.5, and the acid concentration was 11.8 wt%. The system was dissolved at 50 °C, atmospheric pressure, and mechanical stirring at 250 rpm for 0.8 h to form a clear acidic solution.

[0103] II. Addition and Incubation of Cinconidine: 1.00 mol equivalent of cinconidine was added to the acidic solution in four batches, with a total addition time of 1.2 h. During the addition process, the mixture was stirred at 50 °C and 250 rpm. After the addition was completed, the mixture was incubated at 50 °C for another 1.5 h. HPLC analysis of the sample revealed a free acid content of 1.20 wt% in the salt-forming reaction solution, indicating that the system was a homogeneous salt-forming reaction solution.

[0104] III. Crystallization and Solid-Liquid Separation: 700.0 g of n-heptane was added to the salt-forming reaction solution, the amount of n-heptane being 7 times the mass of the acid. After the addition was complete, the temperature was lowered to 10℃ at a rate of 0.20℃ / min, and aged at 10℃ for 6 hours. The resulting slurry was filtered and washed twice with a mixed washing solution of ethanol and n-heptane in a mass ratio of 1:2, with 55.0 g of washing solution used each time. The filter cake was dried at 45℃ and 0.015 MPa for 10 hours to obtain cinconidine salt.

[0105] IV. Free Acid Release and Cinconidine Recovery: 100.0 g of cinconidine salt from this example was added to a two-phase system of 600.0 g ethyl acetate and deionized water (360.0 g ethyl acetate and 240.0 g deionized water). A 1.0 mol / L hydrochloric acid aqueous solution was added at 15°C to adjust the pH of the aqueous phase to 1.6, and the mixture was stirred for 1.5 h. After separation, the organic phase was collected and washed twice with 60.0 g of saturated sodium chloride aqueous solution each time. The organic phase was concentrated at 35°C and 0.015 MPa and dried for 8 h to obtain free acid. The cinconidine-containing aqueous phase was adjusted to pH 10.5 by adding 20 wt% sodium hydroxide aqueous solution at 15°C, and extracted three times with ethyl acetate (110.0 g each time). The organic phases were combined and concentrated at 35°C and 0.015 MPa. The recovered cinconidine was recrystallized from ethanol and deionized water.

[0106] V. Recrystallization Purification: Take 100.0 g of cinconidine salt from this example and add 650.0 g of a mixed solvent of isopropanol and ethyl acetate (325.0 g of isopropanol and 325.0 g of ethyl acetate). Dissolve by stirring at 45°C. Add 1.00 g of activated carbon and keep warm at 45°C for 1.0 h. After filtration, add 600.0 g of n-heptane to the filtrate, cool to 10°C, and age for 5 h. After solid-liquid separation, dry at 45°C and 0.015 MPa for 10 h to obtain purified cinconidine salt.

[0107] VI. Quality Inspection and Judgment: According to the above detection methods, the yield of cinconidine salt obtained in step three was 89.0%, the molar ratio of total acid to total cinconidine was 1:1.00, the free acid content was 0.65 wt%, the moisture content was 0.70 wt%, the total amount of non-target stereoisomers was 0.35 wt%, the D50 was 150 µm, the proportion of particles smaller than 10 µm was 4.0 wt%, and the total amount of residual ethanol and residual ethyl acetate was 1200 ppm. The residual cinconidine in the free acid obtained from acidification release was 0.050 wt%, and the total amount of non-target stereoisomers was 0.35 wt%. The purity of the recovered cinconidine was 97.8 wt%, and the recovery rate based on the initial cinconidine was 90.0%. This example was repeated three times under simulated conditions of a 50 kg batch, and the inter-batch D50 coefficient of variation was 8.0%.

[0108] The applicable scenarios for this embodiment are as follows: This embodiment uses the proportions and process conditions of the intermediate region, which is suitable for process confirmation, balance assessment before batch scale-up, and continuous process connection of the entire process of crystallization, filtration, drying and acidification release.

[0109] Example 4

[0110] In this embodiment, a 100kg batch process is set up. 100.0kg of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is added to a glass-lined reactor, along with 800.0kg of a mixed solvent of ethanol and ethyl acetate (266.7kg ethanol and 533.3kg ethyl acetate, with an ethanol-to-ethyl acetate mass ratio of 1:2.0). The acid concentration is 11.1wt%. The purity of the raw acid is ≥98.5%, and the purity of cinconidine is ≥98.0%. All solvents are commercially available chemically pure or pharmaceutical-grade solvents, and have passed moisture and appearance checks before use.

[0111] The solution was first dissolved at 60℃ and 120 rpm for 0.8 h to obtain an acidic solution. Then, 1.02 molar equivalents of cinconidine were added in 5 batches over 1.8 h, maintaining the temperature at 60℃ during the addition process. After the addition was complete, the solution was kept at this temperature for another 2.5 h, and the free acid content in the salt-forming reaction solution was measured to be 0.30 wt%. 1000.0 kg of n-heptane was added to the salt-forming reaction solution, with the amount of n-heptane added being 10 times the mass of the acid, while maintaining stirring at 120 rpm during the addition. The solution was then cooled to 20℃ at a rate of 0.30℃ / min and aged at 20℃ for 8 h to form a crystalline slurry with relatively intact particles.

[0112] After filtration, the crystallized slurry was washed three times with a 1:2 mixture of ethanol and n-heptane, with 5.0 kg of washing solution used each time. The filter cake was dried at 50 °C and 0.020 MPa for 12 h to obtain (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt. During the drying process, samples were taken every 2 h to determine moisture and residual solvent. Drying was terminated after two consecutive measurements showed that the moisture content was within the control range of 0.05–1.50 wt% and the total residual ethanol and ethyl acetate content was within the control range of 50–5000 ppm.

[0113] 100.0 kg of cinconidine salt from this embodiment was added to a two-phase system of 800.0 kg ethyl acetate and deionized water (520.0 kg ethyl acetate and 280.0 kg deionized water). A 2.0 mol / L hydrochloric acid aqueous solution was added at 30°C to adjust the pH of the aqueous phase to 2.5, and the mixture was stirred for 3.0 h. After standing and separating into layers, the organic phase was collected and washed three times with 40.0 kg of saturated sodium chloride aqueous solution each time. The washed organic phase was concentrated at 50°C and 0.030 MPa and dried for 12 h to obtain free acid. The cinconidine-containing aqueous phase was adjusted to pH 11.5 by adding 30 wt% sodium hydroxide aqueous solution at 30°C, and extracted four times with 100.0 kg of ethyl acetate each time. The organic phases were combined, concentrated at 50°C and 0.030 MPa, and recrystallized from ethanol and deionized water to obtain recovered cinconidine.

[0114] 100.0 kg of cinconidine salt from this embodiment was recrystallized and purified. A mixed solvent of 900.0 kg isopropanol and ethyl acetate (450.0 kg isopropanol and 450.0 kg ethyl acetate) was added and dissolved by stirring at 60°C. 2.00 kg of activated carbon was added, and the mixture was kept at 60°C for 2.0 h. The activated carbon was then removed by filtration. 1000.0 kg of n-heptane was added to the filtrate, and the mixture was cooled to 25°C and aged for 8 h. After filtration and washing, the solution was dried at 55°C and 0.030 MPa for 16 h to obtain the purified cinconidine salt.

[0115] Detection and Quality Control: Following the above detection methods, the yield of cinconidine salt obtained from crystallization, washing, and drying was 95.0%. The molar ratio of total acid to total cinconidine was 1:1.02. The free acid content was 0.20 wt%, water content was 0.25 wt%, total non-target stereoisomers were 0.20 wt%, D50 was 240 µm, the proportion of particles smaller than 10 µm was 1.5 wt%, and the total residual ethanol and ethyl acetate content was 500 ppm. The residual cinconidine in the free acid obtained from acidification release was 0.001 wt%, and the total non-target stereoisomers were 0.02 wt%. The recovered cinconidine purity was 99.9 wt%, and the recovery rate based on initial cinconidine was 96.0%. This example was repeated three times in a 100 kg batch, with an inter-batch D50 coefficient of variation of 2.0%.

[0116] The process features and application directions of this embodiment: This embodiment adopts a high batch size, a high purification intensity, and a relatively complete washing and recovery path, which is suitable for process window confirmation before pilot-scale amplification and industrial verification. It can demonstrate the quality control capability and the operability of the recovery path under a wide range of process conditions.

[0117] Except for the differences explicitly listed in each comparative example, the preparation, acidification release, salt formation chiral base recovery, and detection conditions of comparative examples 1–11 were the same as those in Example 1.

[0118] Comparative Example 1: Using Example 1 as the anchor point, the difference lies in adjusting the amount of cinconidine added in step two to 0.85 molar equivalents. The key conditions, without change, are fully listed as follows: acid addition 100.0g, ethanol 200.0g, ethyl acetate 100.0g, dissolution temperature 35℃, total time for cinconidine addition in batches 0.5h, salt formation holding time 0.5h, n-heptane addition 200.0g, cooling rate 0.05℃ / min, final crystallization temperature 0℃, aging time 2h, washing once, salt drying temperature 35℃, salt drying pressure 0.005MPa, salt drying time 4h, acidification temperature 5℃, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, acidification time 0.5h, free acid drying temperature 25℃, free acid drying pressure 0.005MPa, free acid drying time 4h.

[0119] Comparative Example 2: Using Example 1 as the anchor point, the difference is that the amount of cinconidine added in step two is adjusted to 1.15 molar equivalents. The key conditions that remain unchanged are as follows: acid addition 100.0g, ethanol 200.0g, ethyl acetate 100.0g, dissolution temperature 35℃, total time for cinconidine addition in batches 0.5h, salt formation holding time 0.5h, n-heptane addition 200.0g, cooling rate 0.05℃ / min, final crystallization temperature 0℃, aging time 2h, washing once, salt drying temperature 35℃, salt drying pressure 0.005MPa, salt drying time 4h, acidification temperature 5℃, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, acidification time 0.5h, free acid drying temperature 25℃, free acid drying pressure 0.005MPa, free acid drying time 4h.

[0120] Comparative Example 3: Using Example 1 as the anchor point, the difference is that the mass ratio of ethanol to ethyl acetate in step one is adjusted to 1:0.2, with 250.0g of ethanol and 50.0g of ethyl acetate, and the total amount of mixed solvent remains at 300.0g. The key conditions that remain unchanged are as follows: acid feed amount 100.0g, dissolution temperature 35℃, cinconidine feed amount 0.95 molar equivalent, total time for cinconidine batch addition 0.5h, salt formation holding time 0.5h, n-heptane addition amount 200.0g, cooling rate 0.05℃ / min, final crystallization temperature 0℃, aging time 2h, washing times 1, salt drying temperature 35℃, salt drying pressure 0.005MPa, salt drying time 4h, acidification temperature 5℃, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, and acidification time 0.5h.

[0121] Comparative Example 4: Using Example 1 as the anchor point, the difference is that the mass ratio of ethanol to ethyl acetate in step one is adjusted to 1:4.0, with 60.0g of ethanol and 240.0g of ethyl acetate, and the total amount of mixed solvent remains at 300.0g. The key conditions that remain unchanged are as follows: acid feed amount 100.0g, dissolution temperature 35℃, cinconidine feed amount 0.95 molar equivalent, total time for cinconidine batch addition 0.5h, salt formation holding time 0.5h, n-heptane addition amount 200.0g, cooling rate 0.05℃ / min, final crystallization temperature 0℃, aging time 2h, washing times 1, salt drying temperature 35℃, salt drying pressure 0.005MPa, salt drying time 4h, acidification temperature 5℃, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, and acidification time 0.5h.

[0122] Comparative Example 5: Using Example 1 as the anchor point, the difference is that the salt formation reaction temperature in step two is adjusted to 25℃, and the dissolution in step one is also carried out at 25℃. The key conditions that remain unchanged are fully listed as follows: acid feed amount 100.0g, ethanol 200.0g, ethyl acetate 100.0g, cinconidine feed amount 0.95 molar equivalent, total time for cinconidine batch addition 0.5h, salt formation holding time 0.5h, n-heptane addition amount 200.0g, cooling rate 0.05℃ / min, final crystallization temperature 0℃, aging time 2h, washing times 1, salt drying temperature 35℃, salt drying pressure 0.005MPa, salt drying time 4h, acidification temperature 5℃, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, acidification time 0.5h.

[0123] Comparative Example 6: Using Example 1 as the anchor point, the difference is that the salt formation reaction temperature in step two is adjusted to 75℃, and the dissolution in step one is also carried out at 75℃. The key conditions that remain unchanged are fully listed as follows: acid feed amount 100.0g, ethanol 200.0g, ethyl acetate 100.0g, cinconidine feed amount 0.95 molar equivalent, total time for cinconidine batch addition 0.5h, salt formation holding time 0.5h, n-heptane addition amount 200.0g, cooling rate 0.05℃ / min, final crystallization temperature 0℃, aging time 2h, washing times 1, salt drying temperature 35℃, salt drying pressure 0.005MPa, salt drying time 4h, acidification temperature 5℃, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, acidification time 0.5h.

[0124] Comparative Example 7: Using Example 1 as the anchor point, the difference is that the cooling rate in step three was adjusted to 0.80℃ / min. The key conditions that remained unchanged are as follows: acid feed amount 100.0g, ethanol 200.0g, ethyl acetate 100.0g, dissolution temperature 35℃, cinconidine feed amount 0.95 molar equivalent, total time for cinconidine batch addition 0.5h, salt formation holding time 0.5h, n-heptane addition amount 200.0g, final crystallization temperature 0℃, aging time 2h, washing times 1, salt drying temperature 35℃, salt drying pressure 0.005MPa, salt drying time 4h, acidification temperature 5℃, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, acidification time 0.5h.

[0125] Comparative Example 8: Using Example 1 as the anchor point, the difference is that the drying temperature of cinconidine salt in step four is adjusted to 25°C. The key conditions that remain unchanged are as follows: acid feed amount 100.0g, ethanol 200.0g, ethyl acetate 100.0g, dissolution temperature 35°C, cinconidine feed amount 0.95 molar equivalent, total time for cinconidine batch addition 0.5h, salt formation holding time 0.5h, n-heptane addition amount 200.0g, cooling rate 0.05°C / min, final crystallization temperature 0°C, aging time 2h, washing times 1, salt drying pressure 0.005MPa, salt drying time 4h, acidification temperature 5°C, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, acidification time 0.5h.

[0126] Comparative Example 9: Using Example 1 as the anchor point, the difference lies in replacing cinconidine with an equimolar amount of quinine in step two, while retaining the mixed solvent of ethanol and ethyl acetate and the n-heptane crystallization operation. The key conditions, without change, are fully listed as follows: acid feed amount 100.0 g, ethanol 200.0 g, ethyl acetate 100.0 g, dissolution temperature 35°C, total time for batch addition of chiral base 0.5 h, salt formation holding time 0.5 h, n-heptane addition amount 200.0 g, cooling rate 0.05°C / min, final crystallization temperature 0°C, aging time 2 h, washing once, salt drying temperature 35°C, salt drying pressure 0.005 MPa, and salt drying time 4 h. This comparative example was used to investigate the synergistic relationship between (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid and cinconidine.

[0127] Comparative Example 10: Using Example 1 as the anchor point, the difference is that n-heptane was not added in step three. After the salt-forming reaction solution was kept at 35°C, it was directly cooled to 0°C at a rate of 0.05°C / min and aged for 2 hours. The key conditions, without change, are listed as follows: acid feed amount 100.0g, ethanol 200.0g, ethyl acetate 100.0g, dissolution temperature 35°C, cinconidine feed amount 0.95 molar equivalent, cinconidine batch addition time 0.5 hours, salt-forming holding time 0.5 hours, crystallization final temperature 0°C, aging time 2 hours, washing once, salt drying temperature 35°C, salt drying pressure 0.005MPa, salt drying time 4 hours, acidification temperature 5°C, hydrochloric acid aqueous solution concentration 0.5mol / L, acidification pH 1.0, acidification time 0.5 hours. This comparative example is used to investigate the synergistic relationship between the mixed solvent of ethanol and ethyl acetate and the antisolvent of n-heptane for crystallization.

[0128] Comparative Example 11: Using Example 1 as the anchor point, the difference is that after forming the acidic solution in step one, 200.0 g of n-heptane was added first, followed by the addition of 0.95 molar equivalents of cinconidine in batches at 35°C. The key conditions, without alteration, are as follows: acid feed amount 100.0 g, ethanol 200.0 g, ethyl acetate 100.0 g, dissolution temperature 35°C, total time for batch addition of cinconidine 0.5 h, salt formation holding time 0.5 h, n-heptane addition amount 200.0 g, cooling rate 0.05°C / min, final crystallization temperature 0°C, aging time 2 h, washing once, salt drying temperature 35°C, salt drying pressure 0.005 MPa, and salt drying time 4 h. This comparative example is used to investigate the synergistic relationship between the batch salt formation sequence of cinconidine and the crystallization sequence of n-heptane.

[0129] Figures 1 to 4 The single-factor comparisons in these examples are all based on the remaining process conditions of Example 1; Examples 2 to 4 simultaneously changed multiple process parameters, and their test results were used for the comprehensive evaluation of the corresponding examples, and were not considered as... Figures 1 to 4 Direct comparison of single-factor trends.

[0130] In the selective crystallization purification stage of salt formation, it is first necessary to determine the effect of cinconidine dosage on salt formation sufficiency and free acid residue. Figure 1 This diagram illustrates the effect of the molar equivalent of cinconidine feed on the cinconidine salt yield and free acid content in this scheme. Based on the salt-forming selective crystallization purification process of Example 1, the solvent system, crystallization temperature, and cooling method were fixed, with only the molar equivalent of cinconidine feed changed to 0.90, 0.95, 0.98, 1.00, 1.02, 1.05, and 1.10. Figure 1 It is evident that when the molar equivalent of cinconidine is too low, salt formation is incomplete, and the free acid content increases; conversely, when the molar equivalent is too high, there is an excess of cinconidine in the system, which is detrimental to subsequent purification and residue control. When the molar equivalent of cinconidine is controlled at approximately 0.98–1.02, the cinconidine salt yield remains at a high level, while the free acid content is significantly reduced. This indicates that an appropriate amount of salt-forming agent can reduce the residue of unsalted free acid while ensuring salt formation efficiency, providing a stable material basis for subsequent selective crystallization.

[0131] After completing the screening of salt formation ratios, the effect of the mixed solvent system on the crystallization behavior and crystal size was further investigated. Figure 2 The graph shows the effect of the ethyl acetate / ethanol mass ratio on the yield and D50 of cinconidine salt in this scheme. Using the solvent crystallization system of Example 1 as a baseline, the molar equivalent of cinconidine feed, the amount of n-heptane added, and the cooling rate were kept constant, while only the ethyl acetate / ethanol mass ratio was varied to 0.20, 0.50, 1.00, 1.50, 2.20, 3.00, and 3.50. The results show that when the ethyl acetate / ethanol mass ratio is too low, the system's solubility and crystallization driving force are not well matched, resulting in weak crystal size control. When the ethyl acetate / ethanol mass ratio is too high, the crystallization process is prone to excessively rapid nucleation or uneven crystal growth. When the ethyl acetate / ethanol mass ratio is approximately 1.00–2.20, the cinconidine salt yield is high, and the D50 is within a suitable range, indicating that this mixed solvent ratio can simultaneously achieve both salt precipitation efficiency and controllable crystal particle size.

[0132] Based on the determined mixed solvent system, the amount of antisolvent n-heptane added directly affects the rate of supersaturation formation and the proportion of fine powder. Figure 3 This diagram illustrates the effect of the amount of n-heptane added on the yield of cinconidine salt and the proportion of particles smaller than 10 µm. Using the antisolvent crystallization process of Example 1 as a baseline, the molar equivalent of cinconidine feed, the ethyl acetate / ethanol mass ratio, and the cooling rate were kept constant, while only the amount of n-heptane added was varied to 100, 200, 500, 700, 1000, 1200, and 1500 parts by mass. Figure 3It is evident that insufficient n-heptane leads to a weak antisolvent driving force, incomplete crystallization, and limited yield improvement. Under the aforementioned single-factor conditions, excessive n-heptane increases the system's supersaturation, easily inducing the formation of numerous fine crystals and increasing the proportion of particles smaller than 10µm. Controlling the n-heptane addition to approximately 500–1000 parts by mass yields a higher yield and a lower proportion of fine powder, indicating that an appropriate amount of antisolvent can avoid the problems of reduced stereoselectivity and particle integrity caused by solely relying on a high antisolvent driving force.

[0133] Besides solvent and antisolvent factors, the cooling rate has a significant impact on nucleation, growth, and selective crystallization processes. Figure 4 The graph shows the effect of cooling rate on the yield of cinconidine salt and the total amount of non-target stereoisomers in this scheme. Using the temperature-controlled crystallization process of Example 1 as a baseline, the molar equivalent of cinconidine feed, the ratio of mixed solvents, and the amount of antisolvent added were fixed, while only the cooling rate was varied to 0.02, 0.05, 0.10, 0.20, 0.30, 0.40, and 0.60 °C / min. The results show that when the cooling rate is too slow, the crystallization cycle is prolonged, and the yield improvement is limited. Under the above single-factor conditions, when the cooling rate is too fast, the entrainment of non-target stereoisomers in the system increases, and the crystal growth stability decreases. When the cooling rate is controlled at approximately 0.10–0.30 °C / min, the yield of cinconidine salt is higher, and the total amount of non-target stereoisomers is lower, indicating that mild and controlled cooling can improve crystallization efficiency while enhancing selective crystallization, thereby alleviating the contradiction in existing processes where "increasing yield easily reduces stereopurity."

[0134] The above single-factor results indicate that the salt formation ratio, mixed solvent composition, antisolvent dosage, and cooling rate are not independent influencing factors, but rather collectively determine the salt stability, crystallization selectivity, and powder state. To further verify the salt formation state and impurity control effect of the products obtained under the conditions of Example 1, HPLC and chiral HPLC analyses were performed on different samples. Figure 5 HPLC free acid content and relative molar ratio of chiral base for salt formation are statistically analyzed for different samples in this scheme. HPLC quantitative analysis was performed on Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 9 to compare the changes in free acid content and relative molar ratio of chiral base for salt formation. The results show that the free acid content of Example 1 is approximately 1.95 wt%, and the relative molar ratio of chiral base for salt formation is approximately 0.95, indicating sufficient salt formation and no significant excess of cinconidine. Its free acid content is lower than that of Comparative Example 1 (which had insufficient cinconidine) and Comparative Example 9 (which used quinine as the chiral base for salt formation). In Comparative Example 9, the chiral base for salt formation is quinine, and its relative molar ratio of chiral base for salt formation is not used as data for determining the composition of the cinconidine salt. In contrast, samples deviating from suitable ratios or process conditions showed more significant fluctuations in free acid content and relative molar ratio of chiral base for salt formation, indicating that the salt formation system of Example 1 has better compositional stability.

[0135] In terms of stereo purity, Figure 6 This is a statistical chart showing the total amount of non-target stereoisomers in different samples using chiral HPLC. Chiral HPLC was performed on Examples 1, 6, and 9 to compare the total amount of non-target stereoisomers. The results show that the total amount of non-target stereoisomers in Example 1 was approximately 0.78 wt%, significantly lower than the isomer levels in samples that deviated significantly from the process conditions. This result indicates that Example 1, through appropriate salt formation ratios, antisolvent crystallization intensity, and controlled cooling, preferentially precipitates the target configuration salt and reduces the entrainment of non-target stereoisomers, thereby achieving a synergistic improvement in yield and stereopurity.

[0136] Regarding crystal particle size and powder processing performance, Example 1 and the comparative sample were further compared by particle size distribution. Figure 7 The particle size distribution curves of cinconidine salt from different samples in this scheme are shown, comparing the particle size distributions of Example 1, Comparative Example 7, Comparative Example 10, and Comparative Example 11. Figure 7 As can be seen, the particle size distribution of Example 1 is relatively concentrated, with a D50 of approximately 52 µm, indicating that the obtained cinconidine salt is mainly composed of crystals of moderate particle size. In contrast, samples with improper cooling conditions, antisolvent conditions, or improper feeding sequence are prone to exhibiting excessively fine, coarse, or broadened particle sizes, leading to decreased stability during filtration, washing, and drying processes. This result demonstrates that the solvent composition, antisolvent addition, and cooling control methods used in Example 1 can effectively prevent excessive nucleation or abnormal crystal growth.

[0137] Furthermore, Figure 8 The cumulative particle size distribution curves of cinconidine salt for different samples in this scheme are shown, comparing the cumulative particle size distributions of Example 1, Comparative Example 7, Comparative Example 10, and Comparative Example 11. The results show that the cumulative particle size distribution curve of Example 1 has a relatively smooth transition, with a D50 of approximately 52 µm and a proportion of fine particles smaller than 10 µm of approximately 9.8 wt%, indicating that the proportion of fine particles is within a controllable range, and that no excessive large or dense particles that are difficult to dry are formed. Compared with the abnormally crystallized samples, the particle size structure of Example 1 is more balanced, which is beneficial for maintaining the integrity of crystal particles and for facilitating the migration of mother liquor and residual solvent from the interparticle gaps, thus providing a structural basis for subsequent residue control.

[0138] Regarding residue control, there are interrelationships between crystal size, particle integrity, and drying conditions. While larger and denser crystals help maintain particle integrity, they may hinder the migration of residual solvents; an excessively high proportion of fine powder can easily adsorb the mother liquor and increase the drying burden. Figure 9This chart shows the total moisture and residual solvent content of different samples from this scheme. The total moisture, residual ethanol, and residual ethyl acetate content of Examples 1, 8, and 10 are compared. The results show that Example 1 has a moisture content of approximately 1.46 wt% and a total residual solvent content of approximately 4800 ppm, indicating that it achieves good control over moisture and volatile solvents while maintaining a suitable crystal particle size and a controllable proportion of fine powder. Samples with insufficient solvent replacement, uneven crystal structure, or mismatched drying conditions show significantly higher moisture and residual solvent contents. This result demonstrates that the mixed solvent, n-heptane crystallization, controlled aging, and low-pressure drying processes in Example 1 form a good process connection, helping to solve the problem of "difficulty in simultaneously achieving particle integrity and residual solvent control."

[0139] Meanwhile, the selective crystallization purification process for salt formation also needs to take into account both material utilization efficiency and the operability of the subsequent free acid release process. Figure 10 This diagram presents a statistical analysis of cinconidine residues and the purity of recovered cinconidine in the free acid of different samples from this scheme. The residues and purity of recovered cinconidine in the free acid of Example 1, Comparative Example 1, and Comparative Example 2 are compared. The results show that the cinconidine residue in the free acid of Example 1 is approximately 0.095 wt%, and the purity of the recovered cinconidine is approximately 95.2 wt%. This indicates that after acidification to release the free acid, the cinconidine residue is low, and the cinconidine has good recovery quality. These results demonstrate that Example 1 not only yields a cinconidine salt with stable composition and high stereochemical purity but also reduces the residual salt-forming agent in subsequent free acid products and improves the feasibility of recycling.

[0140] To compare the powder state, particle morphology, and elemental spatial distribution of the sample purified in step six of Example 1 with those of Comparative Example 11, macroscopic optical observation, SEM, SEM-EDS, TEM, HRTEM, SAED, and TEM / STEM-EDS characterization were performed on the two samples. Figure 11 Used to compare the macroscopic powder state of samples. Figure 12 Used to compare the particle morphology and elemental spatial distribution of samples. Figure 13 Used to compare the local morphology and diffraction characteristics of sample crystal fragments. The above images are used to assist in comparing particle state, morphology, and elemental distribution, and are not used as the sole basis for determining the salt type composition, stereoisomer content, or salt homogeneity of cinconidine salt.

[0141] Figure 11 This is a macroscopic optical photograph comparison between the purified (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt of Example 1 and the occonidine salt obtained in Comparative Example 11, used to compare the final crystal powder state of different samples. Figure 11Figure a in the image is a macroscopic optical photograph of the final product of Example 1, showing that it is a white to off-white crystalline powder; Figure 11 Figure b in the figure is a macroscopic optical photograph of the final product of Comparative Example 11, showing that its powder is more prone to local agglomeration, flocculent precipitation or uneven crystal state.

[0142] Figure 12 The images show the SEM morphology and SEM-EDS surface scan comparison of the purified (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt from Example 1 and the occonidine salt obtained in Comparative Example 11. These images are used to compare the crystal morphology, particle uniformity, and elemental spatial distribution of different samples. Figure 12 Figure a in the figure is a low-magnification SEM image of the final product of Example 1, showing that the overall distribution of the crystal powder is relatively uniform, and the particle group is mainly composed of crystals in the tens of micrometers. Figure 12 Figure b in the figure is a low-magnification SEM image of the final product of Comparative Example 11, showing that its particle distribution uniformity has decreased and local agglomeration and fine powder aggregation are more obvious. Figure 12 Figure c in the image is a medium-magnification SEM image of the final product of Example 1, showing that the crystals are mainly irregular short columnar or granular. Figure 12 The d-image in the figure is a medium-magnification SEM image of the final product of Comparative Example 11, showing that the crystal morphology is more irregular and the particle size distribution is more dispersed. Figure 12 Image e in the image is a high-magnification SEM image of the final product of Example 1, showing that the crystal edges and crystal plane outlines are relatively clear; Figure 12 Figure f in the figure is a high-magnification SEM image of the final product of Comparative Example 11, showing that local broken crystals, fine powder adhesion, and agglomeration contact are more prominent. Figure 12 The g-image in the figure is a SEM-EDS surface scan image of the final product of Example 1, showing the correspondence between C, N, and O signals and crystal contours; Figure 12 The h-figure in the figure is a SEM-EDS surface scan image of the final product of Comparative Example 11, showing the distribution of elemental signals with heterogeneous particles and agglomerated regions.

[0143] Based on SEM observation, the local structural features of the crystal were further analyzed using TEM, HRTEM, SAED, and TEM / STEM-EDS. Figure 13 The TEM structure and TEM / STEM-EDS surface scan comparison images of the purified (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt of Example 1 and the occonidine salt obtained in Comparative Example 11 are used to compare the local morphology, diffraction characteristics and elemental spatial correspondence of different samples. Figure 13 Figure a in the image is a bright-field TEM image of the final product crystal fragments from Example 1, showing that the local crystal edges are relatively clear and the fragment outlines are complete. Figure 13Figure b in the figure is a bright-field TEM image of the final product crystal fragments in Comparative Example 11, showing that the local fragment boundaries are more irregular and the thickness distribution is more uneven. Figure 13 Figure c in the figure is an HRTEM image of the final product of Example 1, showing that the local crystal regions have observable ordered structural features; Figure 13 The d-image in the figure is an HRTEM image of the final product of Comparative Example 11, which shows that the continuity and order of the local crystal regions are relatively weak. Figure 13 Figure e in the figure is the SAED diagram of the final product of Example 1, showing that the crystal has local diffraction characteristics; Figure 13 Figure f in the diagram is the SAED pattern of the final product of Comparative Example 11, showing that the diffraction features are relatively dispersed. Figure 13 The g-image in the image is a TEM / STEM-EDS surface scan image of the final product of Example 1, showing the correspondence between C, N, and O signals and crystal fragment regions. Figure 13 The h-figure in the figure is a TEM / STEM-EDS image of the final product of Comparative Example 11, showing the distribution of elemental signals along the irregular fragment region.

[0144] Table 1-1 Crystallization and Quality Indicators of Cinconidine Salt

[0145]

[0146] Table 1-2 Free Acid Release and Cinconidine Recovery Indicators

[0147]

[0148] In Tables 1-1 and 1-2, except for Comparative Example 9 where the chiral base of salt formation is quinine, the chiral base of salt formation for the other samples is cinconidine. The yield of salt formation products, the relative molar ratio of chiral bases of salt formation, the residual chiral base of salt formation in free acid, the purity of recovered chiral base of salt formation, and the recovery rate of chiral base of salt formation for Comparative Example 9 are statistically analyzed according to quinine salt and quinine, respectively.

[0149] As can be seen from the performance of the examples and comparative examples in Tables 1-1 and 1-2, Examples 1–4 show a relatively consistent trend in terms of salt-forming product yield, relative molar ratio of chiral bases in salt formation, free acid content, moisture, total amount of non-target stereoisomers, D50, fine powder ratio, residual solvent, residual chiral bases in free acid, and quality of chiral base recovery in salt formation. The conventional single-variable comparative examples show that deviations in cinconidine dosage, solvent ratio, temperature, excessively rapid cooling, or insufficient drying all lead to fluctuations in the corresponding quality indicators. The synergistic comparative examples show that replacing cinconidine, removing n-heptane, or changing the order of addition weakens the synergistic effect between salt formation and crystallization processes.

[0150] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. An intermediate for utpatinib active pharmaceutical ingredient, characterized in that, The intermediate is (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt, which is composed of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid anion and occonidine cation; The molar ratio of the total amount of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid contained in the intermediate to the total amount of cinconidine is 1:0.95–1.

05. Based on the total mass of the intermediate, the content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.02–2.00 wt%, the content of water is 0.05–1.50 wt%, and the total amount of non-target stereoisomers is 0.02–0.80 wt%.

2. The utpatinib active pharmaceutical ingredient intermediate according to claim 1, characterized in that, The (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt is prepared by the following steps: A1. (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is added to a mixed solvent of ethanol and ethyl acetate, wherein the mass ratio of ethanol to ethyl acetate is 1:0.5–3.0, and stirred at 35–65°C to dissolve, thereby obtaining an acidic solution; A2. Add 0.95–1.05 molar equivalents of cinconidine to the acidic solution and keep it at 35–65°C for 0.5–3.0 h to obtain a salt-forming reaction solution; A3. Add n-heptane to the salt-forming reaction solution, cool it to 0–25°C at a cooling rate of 0.05–0.40°C / min, and age it for 2–10 hours to obtain a crystalline slurry; A4. The crystalline slurry is filtered, washed, and dried at 35–55°C and 0.005–0.030 MPa for 4–16 h to obtain the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt; A5. The product quality indicators of the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt are as follows: the molar ratio of the total amount of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid to the total amount of occonidine in the intermediate is 1:0.95–1.05, the content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.02–2.00 wt%, the moisture content is 0.05–1.50 wt%, the total amount of non-target stereoisomers is 0.02–0.80 wt%, and the D50 is 50–300 µm.

3. A method for releasing (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid from the cinconidine salt of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid according to any one of claims 1 or 2, characterized in that, Includes the following steps: B1. Add the (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid occonidine salt to a two-phase system of ethyl acetate and deionized water; B2. Add 0.5–2.0 mol / L hydrochloric acid aqueous solution at 5–30℃ to adjust the pH of the aqueous phase to 1.0–2.5, and stir for 0.5–3.0 h; B3. Allow the mixture to stand and separate into layers, collect the organic phase, and wash it with a saturated sodium chloride aqueous solution; B4. The washed organic phase was concentrated and dried at 25–50 °C and 0.005–0.030 MPa to obtain free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid; B5. The amount of cinchonidine residue in the obtained free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.001–0.20 wt%, and the total amount of non-target stereoisomers is 0.02–0.80 wt%.

4. The method according to claim 3, characterized in that, The aqueous phase containing cinconidine obtained in step B3 is treated in the following steps to recover cinconidine: C1. At 0–30°C, add 10–30 wt% sodium hydroxide aqueous solution to the cinconidine-containing aqueous phase to adjust the pH to 9.5–11.5; C2. Extract with ethyl acetate and combine the organic phases; C3. The organic phase is concentrated at 25–50 °C and 0.005–0.030 MPa, and then recrystallized from ethanol and deionized water; C4. Obtain recovered cinconidine with a purity of 95.0–99.9 wt% and a recovery rate of 80–98% based on the initial cinconidine.

5. The method according to claim 3, characterized in that, The proportion of particles smaller than 10 µm in the cinconidine salt is 0.1–10.0 wt%, and the residual amount of cinconidine in the resulting free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 0.001–0.10 wt%.

6. A method for preparing the utpatinib active pharmaceutical ingredient intermediate as described in any one of claims 1 or 2, characterized in that, Includes the following steps: S1. Dissolve (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid in a mixed solvent of ethanol and ethyl acetate to obtain an acidic solution; S2. Add cinconidine to the acidic solution, wherein the molar ratio of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid to cinconidine is 1:0.95–1.05, and react at 35–65°C for 0.5–3.0 h to obtain a salt-forming reaction solution. S3. Add n-heptane as an antisolvent to the salt-forming reaction solution, cool it to 0–25°C at a cooling rate of 0.05–0.40°C / min, and age it for 2–10 hours to form cinconidine salt crystals; S4. The cinconidine salt crystals are filtered, washed, and dried at 35–55 °C and 0.005–0.030 MPa for 4–16 h to obtain (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid cinconidine salt.

7. The preparation method according to claim 6, characterized in that, In step S1, the concentration of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid is 5–25 wt%, and the concentration is expressed as a percentage of the mass of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid to the total mass of the acid, ethanol, and ethyl acetate in the mixed solvent. The mass ratio of ethanol to ethyl acetate is 1:0.5–3.

0. In step S2, cinconidine is added in batches, and the temperature is maintained after the addition is completed. The content of free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid in the salt formation reaction solution is 0.02–5.00 wt%.

8. The preparation method according to claim 6, characterized in that, In step S3, the amount of n-heptane added is 2–12 times the mass of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid; in step S4, the water content of the dried cinconidine salt is 0.05–1.50 wt%, and the total amount of residual ethanol and residual ethyl acetate is 50–5000 ppm.

9. The preparation method according to claim 6, characterized in that, The preparation method further includes the step of acidifying the obtained cinconidine salt with aqueous hydrochloric acid to release free (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, wherein the acidification step is carried out at 5–30 °C and pH 1.0–2.5 for 0.5–3.0 h; the aqueous phase containing cinconidine after the acidification step is adjusted to pH 9.5–11.5 with aqueous sodium hydroxide solution and then extracted with ethyl acetate to recover cinconidine.

10. The preparation method according to claim 6, characterized in that, When the preparation method is carried out in batches of 1–100 kg based on the feed amount of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid, the yield of cinconidine salt is 80–98%, and the batch-to-batch D50 coefficient of variation is 2–20%.

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