A preparation method of proparacaine hydrochloride

Abstract

The invention discloses a method for preparing proparacaine hydrochloride. The method uses 4-chloro-3-nitrobenzoic acid as a starting material, undergoes an alkoxylation reaction, an esterification reaction, a reduction reaction, and an acidification salt formation step, wherein n-propanol and sodium hydride are used in the alkoxylation reaction, and the molar ratio of IIa to n-propanol to sodium hydride is 1.0:2.0-3.0:1.4-2.2; and a decolorization operation is performed after the reduction reaction. The method prepares proparacaine hydrochloride without the need for refining, has low impurities, and particularly does not contain impurity F. The method is simple, has good process reproducibility, and has mild reaction conditions. No refining is required, low temperature or high pressure reactions are not involved, and the equipment requirements are low, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of proparacaine hydrochloride. Background Art

[0002] Proparacaine hydrochloride (CAS: 5875-06-9), also known as 2-(N,N-diethylamino)ethyl 3-amino-4-propoxybenzoate hydrochloride, has a molecular formula of C16H 26 N2O3·HCl, molecular weight is 330.85, and its structural formula is as follows:

[0003]

[0004] Proparacaine hydrochloride is an ester local anesthetic that primarily exerts its anesthetic effect by reducing the permeability of nerve cells to sodium, promoting nerve membrane stability and blocking the generation and conduction of nerve electrical impulses. It is less likely to cause cross-sensitivity with other local anesthetics and is less irritating to the eye than the similar ester local anesthetic, oxybuprocaine hydrochloride. It has better ocular tolerance and a higher safety profile. It is clinically used for surface anesthesia in various ophthalmic surgeries and examinations, such as cataract surgery.

[0005] Regarding the synthesis route of proparacaine hydrochloride, current industrial production mainly uses 4-chloro-3-nitrobenzoic acid and 2-diethylaminoethyl chloride hydrochloride as raw materials, and is prepared through alkoxylation, esterification, salt formation, and hydrogenation reduction. The prior art reports on the synthesis of proparacaine hydrochloride are as follows:

[0006] Patent US3775464 describes the use of p-hydroxy-4-nitro-benzoic acid as a raw material, followed by hydroxyalkoxylation of a phenylalkyl sulfonate, followed by saponification under alkaline conditions to obtain the intermediate 4-propoxy-3-nitrobenzoic acid. The intermediate is then esterified with 2-diethylaminoethyl chloride hydrochloride or reacted with diethylethanolamine and the nitro group reduced to obtain proparacaine hydrochloride. This synthetic route requires the use of a phenylalkyl sulfonate as an alkoxylating agent, which is expensive, and requires saponification and hydrolysis steps to prepare the intermediate. The synthetic steps are relatively cumbersome and unsuitable for industrial production. The synthetic route for the intermediate 4-propoxy-3-nitrobenzoic acid is as follows:

[0007]

[0008] Furthermore, US Patent No. 3,775,464 describes a process in which 4-chloro-3-nitrobenzoic acid is used as a raw material and sodium n-propoxide is alkoxylated in an aprotic solvent to obtain the intermediate 4-propoxy-3-nitrobenzoic acid. This intermediate is then subjected to: i) esterification with 2-diethylaminoethyl chloride hydrochloride, acidification with anhydrous HCl to form a salt, and reduction with NO2 over Pd / C catalysis to obtain proparacaine hydrochloride; or ii) the intermediate is first subjected to chlorination with thionyl chloride, esterification with diethylethanolamine, acidification with anhydrous HCl to form a salt, and Pd / C catalytic reduction to obtain proparacaine hydrochloride. This route requires the use of sodium n-propoxide, which is highly hygroscopic and prone to deterioration during transportation and storage. Furthermore, experimenters have found that using sodium n-propoxide to prepare the intermediate results in a high impurity content and the generation of difficult-to-remove impurities, which affect the quality of the final proparacaine hydrochloride product. Furthermore, this route utilizes the expensive Pd / C noble metal reagent for hydrogenation, which is costly and unsuitable for industrial production. The two synthetic routes are as follows:

[0009] Route i:

[0010]

[0011] The literature (Identification, synthesis and structural confirmation of process-related impurities in proparacaine hydrochloride) uses 4-chloro-3-nitrobenzoic acid as the raw material, uses n-propanol and sodium hydride to react to prepare the intermediate, and then prepares proparacaine hydrochloride through esterification with 2-diethylaminochloroethane hydrochloride, Pd / C catalytic reduction, and HCl acidification to form a salt, and analyzes the impurities of the resulting product. The purification of the intermediate in this synthetic route requires silica gel column chromatography, which is cumbersome and not conducive to industrial production. In addition, the experimenters found that when this route was scaled up to the pilot reaction, the resulting product had a large number of impurities and required multiple purifications, which increased production costs and low yields, making it difficult to achieve large-scale industrial production. The synthetic route is shown below:

[0012]

[0013] Intermediate impurities, side reaction impurities, or degradation impurities introduced during the drug production process may affect the drug's properties and safety. According to the public draft of the national drug standard for proparacaine hydrochloride, proparacaine hydrochloride should appear as white or off-white crystals or crystalline powder. Based on information from various national pharmacopoeias, literature, and actual production practices, in addition to the starting materials, the main impurities of proparacaine hydrochloride include impurities A, C, F, G, H, I, Q, and R, as well as other unknown, difficult-to-remove impurities. The structural and chemical formulas of known impurities are shown in the following table:

[0014] Table 1: Impurity Information of Proparacaine Hydrochloride

[0015]

[0016]

[0017]

[0018] In summary, existing methods for synthesizing proparacaine hydrochloride suffer from shortcomings such as material deterioration during transportation and storage, the need for expensive precious metal catalysts, low yields, and high production costs. Therefore, to ensure drug safety, developing or improving existing preparation methods and providing a method for synthesizing proparacaine hydrochloride that is simple to operate, has mild reaction conditions, high yields, and low impurities has significant research value and promising application prospects. Summary of the Invention

[0019] The present invention aims to overcome the shortcomings of the prior art by providing a method for the large-scale industrial production of the local anesthetic proparacaine hydrochloride that is safe, simple, reproducible, and employs mild reaction conditions without requiring low temperatures or high pressures. The method also provides a high reaction yield, a high-purity product, and utilizes readily available, inexpensive raw materials without the use of expensive reagents.

[0020] The purpose of the present invention is achieved through the following technical solutions:

[0021] A method for preparing proparacaine hydrochloride, characterized in that the method comprises: using 4-chloro-3-nitrobenzoic acid as a starting material, undergoing alkoxylation reaction, esterification reaction, reduction reaction and acidification to form a salt, and the reaction process is as follows:

[0022]

[0023] The preparation method comprises the following specific steps:

[0024] Step S1: Dissolve 4-chloro-3-nitrobenzoic acid (IIa) in dimethyl sulfoxide (DMSO) at room temperature, and dissolve n-propanol and sodium hydride in THF (tetrahydrofuran). Add the DMSO solution containing IIa dropwise to the THF solution containing n-propanol and sodium hydride while stirring at 15-25°C. Stir and react for 0.5-4 hours. After the reaction, add water and adjust the pH to 2-3 with hydrochloric acid. Filter to obtain a crude product, which is recrystallized once from ethanol-water to obtain 4-propoxy-3-nitrobenzoic acid (Intermediate III). The molar ratio of IIa to n-propanol to sodium hydride is 1:2.0-3.0:1.4-2.2, the mass-to-volume ratio of IIa to DMSO is 1:1-5, and the mass-to-volume ratio of sodium hydride to THF is 1:6-16.

[0025] Step S2: Add intermediate III, 2-diethylaminoethyl chloride hydrochloride (IIb), potassium carbonate, and an organic solvent to a reactor, raise the temperature to 60-120°C, and react with stirring for 0.5-4 hours. After the reaction, cool to room temperature, filter, add ethyl acetate to the filtrate, and stir; then add 15%-20% aqueous sodium chloride solution, separate the liquids, and concentrate the organic phase to obtain (Intermediate IV), which is used directly in the next step. The molar ratio of III to IIb to potassium carbonate is 1:1.0-1.3:2.0-2.5, and the mass-to-volume ratio of III to organic solvent is 1:4-8.

[0026] Step S3: Disperse intermediate IV in a reaction solvent, add iron powder and ammonium chloride, raise the temperature to 60-100°C, and stir to react for 0.2-2 hours. After completion of the reaction, decolorize and concentrate to obtain proparacaine (BMKY), wherein the molar ratio of III, iron powder, and ammonium chloride is 1:3.0-4.0:4.0-5.0. The reaction solvent is water and alcohol.

[0027] Step S4: dissolving BMKY in an organic solvent to obtain a BMKY solution, adding concentrated hydrochloric acid, keeping warm, stirring to crystallize, filtering, and drying to obtain proparacaine hydrochloride (BMKY-HCl), wherein the mass volume ratio of BMKY to the organic solvent is 1:5-9, and the mass ratio of BMKY to concentrated hydrochloric acid is 1:0.28-0.38.

[0028] In the preparation method of proparacaine hydrochloride of the present invention, the water can be purified water or distilled water.

[0029] In the preparation method of proparacaine hydrochloride of the present invention, the mass-to-volume ratio is the relationship between g and mL.

[0030] In the present method for preparing proparacaine hydrochloride, in step S1, the substrate feed ratio, solvent, and temperature control in the reaction system are key to achieving the technical effect. Technicians have discovered that when the molar ratio of substrate IIa, n-propanol, and sodium hydride is 1:2.0-3.0:1.4-2.2, the mass-to-volume ratio of IIa to DMSO is 1:1-5, and the mass-to-volume ratio of sodium hydride to THF is 1:6-16, and the reaction temperature is controlled between 15 and 25°C, the reaction can be completed in 0.5 to 4 hours, ensuring optimal reaction conversion and preventing agglomeration of the reaction materials. Technicians have found that when the sodium hydride feed amount is too high or too low, the system impurities increase significantly, particularly the byproduct impurity III-1 (4-hydroxy-3-nitrobenzoic acid, which is carried over to form impurity A) and difficult-to-remove impurities. When the reaction temperature is below 15°C, the reaction system experiences agglomeration, resulting in incomplete reaction. Impurities also increase significantly, making purification difficult. When the temperature is above 25°C, although the reaction rate is improved and the yield of the crude intermediate product is increased, various impurities will increase significantly. Among them, the increase in impurity III-1 is significant. Analysis shows that the alkoxylation reaction system is alkaline. When the temperature is increased, the presence of carboxyl and nitro electron-withdrawing groups in the ortho and para positions of IIa makes the -Cl group more susceptible to hydrolysis and conversion to -OH.

[0031] Specifically, in step S1, the molar ratio of IIa, n-propanol and sodium hydride is 1:2.2-2.8:1.6-2.0, more specifically 1:2.5:1.8.

[0032] Specifically, in step S1, the mass volume ratio of sodium hydride to THF is 1:8-14, more specifically 1:10-12.

[0033] Specifically, in step S1, the mass-to-volume ratio of IIa to DMSO is 1:2-4, more specifically 1:2.5-3.5.

[0034] Specifically, in step S1, the reaction temperature is 15-20°C.

[0035] Specifically, in step S1, the reaction time is 1 to 3 hours, more specifically 2 hours.

[0036] The sodium hydride content of the present invention is 60%.

[0037] After the reaction is complete, water equivalent to 9 to 12 times the volume of DMSO needs to be added, followed by acidification with hydrochloric acid. Preferably, the pH is adjusted to 2.0-3.5, preferably pH 3, to obtain a crude product with high purity, high yield, good color, and simple post-processing. When the pH is too high, the product yield decreases, impurities increase, and multiple purification steps are required.

[0038] In the present invention's method for preparing proparacaine hydrochloride, in step S2, the molar ratio of intermediates III and IIb to potassium carbonate is 1:1.0-1.3:2.0-2.5, and the mass-to-volume ratio of III to the organic solvent is 1:4-8. The temperature is raised to 60-120°C, and the reaction is stirred for 0.5-4 hours. The feed ratio of intermediates III and IIb to potassium carbonate (K2CO3) and the reaction temperature in step S2 are crucial for achieving the technical effect. Technicians have discovered that in step S2, the reaction system is alkaline, and adding too much K2CO3 results in a waste of raw materials, a low conversion rate of intermediate III, an increased residue, and a low yield. This may be because excessive K2CO3 increases the alkalinity of the system and accelerates the degradation of IIb. When the reaction temperature is too high, impurities increase significantly, the reaction is too slow, the reaction degree is low, or even no reaction occurs. Specifically, the molar ratio of III, IIb, and K2CO3 is 1:1.1-1.2:2.1-2.3, the temperature is raised to 70-100°C, the mass volume ratio of III to the organic solvent is 1:5-7, and the reaction is stirred for 1-3 hours to ensure a good reaction effect. More specifically, the mass ratio of II, IIb, and K2CO3 is 1:1.15:2.2, the mass volume ratio of III to the organic solvent is 1:5.5-6.5, the temperature is raised to 80°C, and the stirring time is 2 hours. The organic solvent can be one of tetrahydrofuran (THF) or ethyl acetate, or a combination thereof in any proportion, preferably tetrahydrofuran.

[0039] The intermediate product obtained in step S2 of the present invention is washed with ethyl acetate having a volume equivalent to 1-2 times that of the solvent and a 15% to 20% sodium chloride aqueous solution having a volume equivalent to that of the solvent, and concentrated without further purification and directly used in the next reaction.

[0040] In the method for preparing proparacaine hydrochloride of the present invention, in step S3, the reaction substrate charge ratio and the reaction solvent are key to achieving the technical effect. The reaction solvents are water and ethanol. Technicians have found that when too much iron powder is added, it is easy to cause iron powder sedimentation, insufficient system stirring, and low nitro reduction degree; when too little iron powder is added, the reaction is incomplete. When using iron powder to carry out the nitro reduction process, the reaction system needs to maintain a weakly acidic environment. When the acidity is strong or weak, the reaction effect is insufficient. Ammonium chloride, hydrochloric acid, or acetic acid can be added to adjust or maintain the weakly acidic environment of the reaction system. Ammonium chloride (NH4Cl) is selected in the present invention. Because the intermediate IV obtained in step S2 of the present invention is an oily substance and difficult to weigh, technicians have found that the reaction substrate charge ratio in step S3 can be calculated by using the amount of IIa charged in step S2. Specifically, technicians found that when the molar ratio of intermediate III, iron powder and ammonium chloride is 1:3.0~4.0:4.0~5.0, the mass volume ratio of III, water and ethanol is 1:7.0~11.0:0.6~1.4, the reaction temperature is 60-100°C, and the stirring reaction is 0.2~2h, the reaction is sufficient, the by-products are small, and the yield is high.

[0041] Specifically, in the step S3, the molar ratio of intermediate III, iron powder and ammonium chloride is 1:3.2-3.8:4.2-4.8, the mass volume ratio of III, water and ethanol is 1:8.0-10.0:0.8-1.2, the reaction temperature is 70-90°C, and the stirring reaction is carried out for 0.3-0.8h.

[0042] More specifically, in step S3, the molar ratio of intermediate III, iron powder and ammonium chloride is 1:3.5:4.5, the mass volume ratio of III, water and ethanol is 1:8.5-9.5:0.9-1.1, the reaction temperature is 80°C, and the reaction is stirred for 0.5h.

[0043] In the method for preparing proparacaine hydrochloride of the present invention, the post-treatment decolorization process in step S3 is a key technology. Intermediate IV has a nitrobenzene structure. During the metal reduction process, azo compounds are easily formed. Furthermore, nitrobenzene is reduced with iron powder to form impurities such as aniline and iron oxide, resulting in a yellowish color in the resulting crude proparacaine product. For the decolorization of aniline compounds, most conventional synthesis processes achieve decolorization through purification, activated carbon decolorization, filtration, and other methods in the final step. However, technicians have discovered that the proparacaine hydrochloride prepared according to conventional methods has a yellowish color, and decolorization of the product by purification, activated carbon filtration, and other methods also fails to meet quality control requirements. The technicians of the present application surprisingly discovered that after the reduction reaction, the crude proparacaine product is decolorized, and the proparacaine hydrochloride obtained by the subsequent salt formation reaction does not require further purification, and the purity and color of the proparacaine hydrochloride meet quality control requirements.

[0044] Specifically, in step S3, the decolorization process includes the following steps: after the reaction is completed, cooling to room temperature, adding ethyl acetate and a small amount of antioxidant, adjusting the pH to 7-9 with 15% sodium hydroxide solution, filtering, separating, and collecting the organic phase; washing with 5% EDTA-2Na solution, collecting the organic phase; adding water, adjusting the pH to 3-5 with 20-30% hydrochloric acid, separating, and collecting the aqueous phase; adding activated carbon to the aqueous phase for decolorization, filtering, and collecting the filtrate; adding a small amount of antioxidant to the filtrate, adjusting the pH to 7-9 with 15% sodium hydroxide solution, adding ethyl acetate for extraction, separating, collecting the organic phase, and concentrating to obtain BMKY oil. The addition of the antioxidant can prevent proparacaine from oxidative deterioration, and the addition of the antioxidant and the control of the system pH can synergistically achieve the effects of decolorization and impurity removal. The antioxidant dosage is preferably 0.05-0.3% of the system solution mass. Excessive antioxidant dosage increases material costs and is prone to residue generation. Excessive antioxidant dosage can easily lead to the finished product's medium impurity content exceeding quality control requirements. Preferably, the antioxidant is potassium metabisulfite, sodium metabisulfite, or anhydrous sodium sulfite. More preferably, the antioxidant is anhydrous sodium sulfite.

[0045] More specifically, in the S3 step, the decolorization process includes the following process: after the reaction is completed, cooling to room temperature, adding ethyl acetate and a small amount of anhydrous sodium sulfite equivalent to 1 to 3 times the volume of the reaction solvent, adjusting the pH to 8 with 15% sodium hydroxide solution, filtering, separating, and collecting the organic phase; washing with 5% EDTA-2Na solution, separating, and collecting the organic phase; adding water, adjusting the pH to 4 with 25% hydrochloric acid, separating, and collecting the aqueous phase; adding an appropriate amount of activated carbon to the aqueous phase for decolorization, filtering, and collecting the filtrate; adding a small amount of anhydrous sodium sulfite to the filtrate, adjusting the pH to 8 with 15% sodium hydroxide solution, adding ethyl acetate for extraction, separating, collecting the organic phase, and concentrating to obtain proparacaine (BMKY) as an oily substance, wherein the amounts of ethyl acetate, 5% EDTA-2Na solution, and water used in the process are equivalent.

[0046] In the method for preparing proparacaine hydrochloride of the present invention, the amounts of organic solvent and hydrochloric acid used in step S4 are important factors in achieving the technical effect. Too little organic solvent results in poor dissolution of the crude product, uneven distribution of proparacaine in the solution, and reduced salt formation and crystallization particle size. Too much organic solvent affects the subsequent precipitation amount and reduces the yield. Adding too little hydrochloric acid during salt formation slows the salt formation reaction and results in incomplete salt formation. Adding too much hydrochloric acid results in poor product color, uneven particle size, a yellowish color, and low purity.

[0047] Specifically, in the aforementioned step S4, the mass volume ratio of proparacaine to the organic solvent is 1:5-9, and the mass ratio of proparacaine to hydrochloric acid is 1:0.28-0.38. Furthermore, the mass volume ratio of proparacaine to the organic solvent is 1:6-8, and the mass ratio of proparacaine to hydrochloric acid is 1:0.30-0.36. More specifically, the mass volume ratio of proparacaine to the organic solvent is 1:6.5-7.5, and the mass ratio of proparacaine to hydrochloric acid is 1:0.32-0.34. The organic solvent is one or a combination of two or more of acetonitrile, acetone, methanol, ethanol, and isopropanol in any proportion, preferably acetone and acetonitrile.

[0048] In the present invention, after the addition of hydrochloric acid is completed, the crystallization temperature (holding temperature) and the stirring crystallization time are also important influencing factors. Suitable crystallization conditions are very critical for the formation of good crystals. Specifically, in the preparation method of proparacaine hydrochloride of the present invention, in the aforementioned step S4, after the addition of hydrochloric acid is completed, the holding temperature is 20-30°C, and the stirring crystallization is carried out for 0.5-1h. More specifically, in the aforementioned step S4, after the addition of hydrochloric acid is completed, the holding temperature is 25°C, the stirring crystallization is carried out for 0.5h, filtration is carried out, and drying is carried out to obtain the target product proparacaine hydrochloride (BMKY-HCl).

[0049] A preferred method for preparing proparacaine hydrochloride of the present invention comprises the following steps:

[0050] Step S1: Dissolve IIa in DMSO at room temperature; dissolve n-propanol and sodium hydride in THF; add the DMSO solution containing IIa dropwise to the THF solution containing n-propanol and sodium hydride while stirring at 15-20°C. Stir and react for 2 hours at 15-20°C. After the reaction, add water approximately 9-12 times the volume of DMSO, and adjust the pH to 3 with hydrochloric acid. Filter to obtain a crude product, which is recrystallized once from ethanol and water to obtain 4-propoxy-3-nitrobenzoic acid (Intermediate III). The molar ratio of IIa to n-propanol to sodium hydride is 1.0:2.5:1.8; the mass-to-volume ratio of IIa to DMSO is 1.0:2.5-3.5; and the mass-to-volume ratio of sodium hydride to THF is 1:10-12.

[0051] Step S2: Add Intermediate III, IIb, potassium carbonate, and THF to a reactor, raise the temperature to 80°C, and stir for 2 hours. After the reaction, cool to room temperature, filter, and add ethyl acetate (approximately 1-2 times the volume of THF) to the filtrate, stirring. Then, add a 15%-20% sodium chloride aqueous solution (equivalent to the volume of THF), separate the liquids, collect the organic phase, and concentrate to obtain (Intermediate IV), which is used directly in the next step. The molar ratio of III to IIb to potassium carbonate is 1:1.15:2.2, and the mass-to-volume ratio of III to THF is 1:5.5-6.5.

[0052] Step S3: Disperse intermediate IV in water and ethanol, add iron powder and ammonium chloride, heat to 80°C, and stir to react for 0.5h. After the reaction is completed, the temperature is lowered to room temperature, ethyl acetate and a small amount of anhydrous sodium sulfite equivalent to 1 to 3 times the volume of water and ethanol are added, the pH is adjusted to 8 with 15% sodium hydroxide solution, the mixture is filtered, the liquid is separated, and the organic phase is collected; the organic phase is washed with 5% EDTA-2Na solution, and the organic phase is collected; water is added, the pH is adjusted to 4 with 25% hydrochloric acid, the liquid is separated, and the aqueous phase is collected; an appropriate amount of activated carbon is added to the aqueous phase for decolorization, the mixture is filtered, and the filtrate is collected; a small amount of anhydrous sodium sulfite is added to the filtrate, the pH is adjusted to 8 with 15% sodium hydroxide solution, ethyl acetate is added for extraction, the liquid is separated, and the organic phase is concentrated to obtain proparacaine (BMKY) oil, wherein the molar ratio of III, iron powder and ammonium chloride is 1:3.5:4.5, and the mass volume ratio of III, water and ethanol is 1:8.5-9.5:0.9-1.1. After the reaction is completed, the amounts of ethyl acetate, 5% EDTA-2Na solution and water added during the process are equivalent.

[0053] Step S4: dissolving BMKY in acetone to obtain a BMKY solution, adding concentrated hydrochloric acid, keeping warm, stirring and crystallizing, filtering, and drying to obtain proparacaine hydrochloride (BMKY-HCl), wherein the mass volume ratio of BMKY to acetone is 1:6.5-7.5, and the mass ratio of BMKY to hydrochloric acid is 1:0.32-0.34, the keeping temperature is 25° C., stirring and crystallizing for 0.5 h, filtering, and drying to obtain the target product proparacaine hydrochloride (BMKY-HCl).

[0054] The present invention has the following advantages and beneficial effects compared to the prior art:

[0055] 1. The present invention adopts a mixed system of n-propanol and sodium hydride to prepare the synthetic intermediate III. By regulating the feed ratio and reaction temperature parameters, the formation of impurities that are difficult to remove is avoided. At the same time, the process does not require the use of column chromatography or multiple recrystallization purification steps, which is more conducive to industrialization.

[0056] 2. The present invention performs a decolorization operation after the reduction reaction is completed, and no refining or purification is required. The obtained proparacaine hydrochloride has a high yield and purity, qualified color, high uniformity, and is easy to industrialize.

[0057] 3. The overall process design is reasonable and easy to operate. It does not require high pressure or high temperature conditions. The raw materials are easily available and the cost is low. The product yield and purity are high, meeting the raw material standards required for preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 HPLC spectrum of intermediate III prepared in Example 1.

[0059] Figure 2 HPLC spectrum of proparacaine hydrochloride prepared in Example 1.

[0060] Figure 3 HPLC spectrum of intermediate III prepared in Comparative Example 1.

[0061] Figure 4 HPLC spectrum of intermediate III prepared in Comparative Example 2.

[0062] Figure 5 HPLC spectrum of intermediate III prepared in Comparative Example 3.

[0063] Figure 6 HPLC spectrum of proparacaine hydrochloride prepared in Comparative Example 5.

[0064] Figure 7 HPLC spectrum of proparacaine hydrochloride prepared in Comparative Example 6.

[0065] Figure 8 HPLC spectrum of proparacaine hydrochloride prepared in Comparative Example 7.

[0066] Special note: In the "Name" of the HPLC spectrum, "XQP017", "XQP017-IIa", "XQP017-III or BMKY-III" refers to proparacaine hydrochloride, raw material IIa (4-chloro-3-nitrobenzoic acid) and intermediate III (4-propoxy-3-nitrobenzoic acid). DETAILED DESCRIPTION

[0067] The present invention will be further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0068] The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present invention should all be equivalent replacement methods and are included in the protection scope of the present invention. Unless otherwise specified, the drugs and reagents used in the present invention can be purchased from the market. The purity of the 4-chloro-3-nitrobenzoic acid (IIa) and 2-diethylaminoethyl chloride hydrochloride (IIb) used in the present invention is >98%.

[0069] Unless otherwise specified, the total yield of the product is calculated by multiplying the yields of S1, S3 and S4. In Comparative Examples 4-7, the yield of S1 is calculated based on the yield of Example 1.

[0070] The testing of the finished product proparacaine hydrochloride refers to taking 0.10 g of the proparacaine hydrochloride prepared in the examples and comparative examples, adding 10 mL of water to dissolve it, and judging whether it is qualified by referring to the draft public draft of the national drug standard for proparacaine hydrochloride: the solution should be clear and colorless (qualified); if turbid, it should not be thicker than the No. 1 turbidity standard solution (qualified); if colored, it should not be darker than the yellow No. 1 standard colorimetric solution (qualified).

[0071] Example 1

[0072] Proparacaine hydrochloride was prepared using the following steps:

[0073] S1 step:

[0074] At room temperature, IIa (20.2 g, 0.10 mol) was dissolved in 60 mL of DMSO; n-propanol (15.1 g, 0.25 mol) and sodium hydride (7.2 g, 0.18 mol, 60%) were dissolved in 75 mL of THF. With stirring and controlling the temperature at 15-20°C, the DMSO solution containing IIa was added dropwise to the THF solution containing n-propanol and sodium hydride. The reaction was stirred for 2 hours. After completion of the reaction, 600 mL of purified water was added, and the pH was adjusted to 3 with hydrochloric acid. The crude product was filtered and recrystallized once from ethanol-water. After drying, 21.6 g of intermediate III was obtained as a white solid in a 96.0% yield.

[0075] S2 step:

[0076] Add Intermediate III (20.3 g, 0.09 mol), IIb (17.3 g, 0.10 mol), potassium carbonate (27.7 g, 0.20 mol), and 120 mL of THF to a reactor, raise the temperature to 80°C, and stir for 2 h. After completion, cool the reaction to room temperature and filter. Add 140 mL of ethyl acetate to the filtrate, stir, and then add 120 mL of a 15%-20% aqueous sodium chloride solution. Separate the layers, collect the organic phase, and concentrate to obtain Intermediate IV as an oil, which is used directly in the next step.

[0077] S3 steps:

[0078] Intermediate IV was dispersed in 180 mL of water and 20 mL of ethanol, and iron powder (17.6 g, 0.315 mol) and ammonium chloride (21.7 g, 0.405 mol) were added. The reaction was stirred at 80°C for 0.5 h. After completion of the reaction, the mixture was cooled to room temperature, and 400 mL of ethyl acetate and 0.6 g of anhydrous sodium sulfite were added. The pH was adjusted to 8 with 15% sodium hydroxide solution. The mixture was filtered, separated, and the organic phase was collected. The mixture was washed with 400 mL of 5% EDTA-2Na solution, separated, and the organic phase was collected. 400 mL of water was added, and the pH was adjusted to 4 with 25% hydrochloric acid. The aqueous phase was separated and the aqueous phase was collected. Activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and the filtrate was collected. 0.4 g of anhydrous sodium sulfite was added to the filtrate, and the pH was adjusted to 8 with 15% sodium hydroxide solution. 400 mL of ethyl acetate was added, separated, and the organic phase was collected. The mixture was concentrated to obtain a crude BMKY oil weighing 25.1 g, with a yield of 94.7%.

[0079] S4 step:

[0080] Dissolve 22g of BMKY in 160mL of acetone to obtain a BMKY solution. Add 7.3g of concentrated hydrochloric acid dropwise. After the addition of hydrochloric acid is complete, maintain the mixture at 25°C and stir for 0.5h to allow crystallization. Filter and dry to obtain 23.8g of proparacaine hydrochloride (BMKY-HCl) as a white crystalline solid in a 96.4% yield.

[0081] The total yield of proparacaine hydrochloride was 87.6%. Testing showed that the finished product solution was clear and colorless, meeting the pharmacopoeia standards.

[0082] In Example 1, by regulating the alkoxylation reaction conditions, the formation of difficult-to-remove impurities is avoided / reduced, and a high-purity intermediate III is obtained. Further combined with the subsequent reduction and salt-forming reaction conditions, the impurity content of proparacaine hydrochloride can be effectively controlled to be far below the standard content, with a purity of up to 99.9%, and a high overall reaction yield. The HPLC test results of the intermediate III and proparacaine hydrochloride prepared in Example 1 are as follows: Figure 1 and Figure 2 shown.

[0083] Example 2

[0084] Proparacaine hydrochloride was prepared using the following steps:

[0085] S1 step:

[0086] At room temperature, IIa (20.2 g, 0.10 mol) was dissolved in 60 mL of DMSO, and n-propanol (13.3 g, 0.22 mol) and sodium hydride (7.2 g, 0.18 mol, 60%) were dissolved in 75 mL of THF. With stirring and controlling the temperature at 15-20°C, the DMSO solution containing IIa was added dropwise to the THF solution containing n-propanol and sodium hydride. The reaction was stirred for 3 hours. After completion of the reaction, 600 mL of purified water was added, and the pH was adjusted to 3 with hydrochloric acid. The crude product was filtered and recrystallized once from ethanol-water. Drying afforded 21.5 g of intermediate III as a white solid in a 95.6% yield.

[0087] S2 step:

[0088] Add Intermediate III (20.2 g, 0.09 mol), IIb (17.2 g, 0.10 mol), potassium carbonate (26.3 g, 0.19 mol), and 130 mL of THF to a reactor, raise the temperature to 85°C, and stir for 2 h. After completion, cool the reaction to room temperature and filter. Add 140 mL of ethyl acetate to the filtrate, stir, and then add 130 mL of a 15%-20% aqueous sodium chloride solution. Separate the layers, collect the organic phase, and concentrate to obtain Intermediate IV as an oil, which is used directly in the next step.

[0089] S3 steps:

[0090] Intermediate IV was dispersed in 185 mL of water and 20 mL of ethanol, and iron powder (18.1 g, 0.324 mol) and ammonium chloride (20.8 g, 0.387 mol) were added. The reaction was stirred at 85°C for 0.3 h. After completion of the reaction, the mixture was cooled to room temperature, and 450 mL of ethyl acetate and 0.7 g of anhydrous sodium sulfite were added. The pH was adjusted to 8 with 15% sodium hydroxide solution. The mixture was filtered, separated, and the organic phase was collected. The mixture was washed with 450 mL of 5% EDTA-2Na solution, separated, and the organic phase was collected. 450 mL of water was added, and the pH was adjusted to 4 with 25% hydrochloric acid. The aqueous phase was separated and the aqueous phase was collected. Activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and the filtrate was collected. 0.5 g of anhydrous sodium sulfite was added to the filtrate, and the pH was adjusted to 8 with 15% sodium hydroxide solution. 450 mL of ethyl acetate was added, separated, and the organic phase was collected. The mixture was concentrated to obtain a crude BMKY oil weighing 24.5 g, with a yield of 92.4%.

[0091] S4 step:

[0092] Dissolve 20 g of BMKY in 150 mL of acetone to obtain a BMKY solution. Add 6.4 g of concentrated hydrochloric acid dropwise. After the addition of hydrochloric acid is complete, stir and crystallize at 25°C for 0.5 h. Filter and dry to obtain 21.4 g of proparacaine hydrochloride (BMKY-HCl) as a white crystalline powder (95.5% yield).

[0093] The total yield of proparacaine hydrochloride was 84.4%. Testing showed that the finished product solution was clear and colorless, meeting the pharmacopoeia standards.

[0094] Example 3

[0095] Proparacaine hydrochloride was prepared using the following steps:

[0096] S1 step:

[0097] At room temperature, IIa (20.2 g, 0.10 mol) was dissolved in 60 mL of DMSO, and n-propanol (16.9 g, 0.28 mol) and sodium hydride (8.0 g, 0.20 mol, 60%) were dissolved in 90 mL of THF. With stirring and controlling the temperature at 15-20°C, the DMSO solution containing IIa was added dropwise to the THF solution containing n-propanol and sodium hydride. The reaction was stirred for 2 hours. After completion of the reaction, 650 mL of purified water was added, and the pH was adjusted to 2 with hydrochloric acid. The crude product was filtered and recrystallized once from ethanol-water. Drying afforded 21.4 g of intermediate III as a white solid in a 95.1% yield.

[0098] S2 step:

[0099] Add Intermediate III (20.2 g, 0.09 mol), IIb (17.2 g, 0.10 mol), potassium carbonate (26.3 g, 0.19 mol), and 130 mL of THF to a reactor, raise the temperature to 80°C, and stir for 1 hour. After completion, cool to room temperature and filter. Add 140 mL of ethyl acetate to the filtrate, stir, and then add 130 mL of a 15%-20% aqueous sodium chloride solution. Separate the layers, collect the organic phase, and concentrate to obtain Intermediate IV as an oil, which is used directly in the next step.

[0100] S3 steps:

[0101] Intermediate IV was dispersed in 185 mL of water and 20 mL of ethanol, and iron powder (16.1 g, 0.288 mol) and ammonium chloride (22.2 g, 0.414 mol) were added. The reaction was stirred at 80°C for 0.8 h. After completion of the reaction, the mixture was cooled to room temperature, and 450 mL of ethyl acetate and 0.7 g of anhydrous sodium sulfite were added. The pH was adjusted to 8 with 15% sodium hydroxide solution. The mixture was filtered, separated, and the organic phase was collected. The mixture was washed with 450 mL of 5% EDTA-2Na solution, separated, and the organic phase was collected. 450 mL of water was added, and the pH was adjusted to 4 with 25% hydrochloric acid. The aqueous phase was separated and the aqueous phase was collected. Activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and the filtrate was collected. 0.5 g of anhydrous sodium sulfite was added to the filtrate, and the pH was adjusted to 8 with 15% sodium hydroxide solution. 450 mL of ethyl acetate was added, separated, and the organic phase was collected. The mixture was concentrated to obtain a crude BMKY oil weighing 24.3 g, with a yield of 91.7%.

[0102] S4 step:

[0103] Dissolve 20 g of BMKY in 130 mL of acetonitrile to obtain a BMKY solution. Add 6.8 g of concentrated hydrochloric acid dropwise. After the addition of hydrochloric acid is complete, stir and crystallize at 25°C for 0.5 h. Filter and dry to obtain 21.2 g of proparacaine hydrochloride (BMKY-HCl) as a white crystalline powder (yield 94.6%).

[0104] The total yield of proparacaine hydrochloride was 82.5%. Testing showed that the finished product solution was clear and colorless, meeting the pharmacopoeia standards.

[0105] Example 4

[0106] Proparacaine hydrochloride was prepared using the following steps:

[0107] S1 step:

[0108] At room temperature, IIa (1007.9 g, 5.0 mol) was dissolved in 3000 mL of DMSO, and n-propanol (751.5 g, 12.5 mol) and sodium hydride (360.5 g, 9.0 mol, 60%) were dissolved in 4000 mL of THF. With stirring and controlling the temperature at 15-20°C, the DMSO solution containing IIa was added dropwise to the THF solution containing n-propanol and sodium hydride. The reaction was stirred for 2 hours. After completion of the reaction, 30,000 mL of purified water was added, and the pH was adjusted to 3 with hydrochloric acid. The crude product was filtered and recrystallized once from ethanol-water. After drying, 1041.6 g of intermediate III was obtained as a white solid in a yield of 92.5%.

[0109] S2 step:

[0110] To a reactor, add Intermediate III (1000.0 g, 4.44 mol), IIb (880.0 g, 5.11 mol), potassium carbonate (1350.4 g, 9.77 mol), and 6000 mL of THF. The temperature was raised to 80°C and stirred for 2 h. After completion, the reaction was cooled to room temperature and filtered. 8000 mL of ethyl acetate was added to the filtrate, stirred, and then 6000 mL of a 15%-20% aqueous sodium chloride solution was added. The layers were separated, and the organic phase was collected and concentrated to afford Intermediate IV as an oil, which was used directly in the next step.

[0111] S3 steps:

[0112] Intermediate IV was dispersed in 9000 mL of water and 1000 mL of ethanol, and iron powder (868.0 g, 15.54 mol) and ammonium chloride (1068.8 g, 19.98 mol) were added. The reaction temperature was 80° C. and stirred for 0.5 h. After the reaction was completed, the temperature was lowered to room temperature, 20,000 mL of ethyl acetate and 30 g of anhydrous sodium sulfite were added, the pH was adjusted to 8 with 15% sodium hydroxide solution, the mixture was filtered, the liquid was separated, and the organic phase was collected; the mixture was washed with 20,000 mL of 5% EDTA-2Na solution, the liquid was separated, and the organic phase was collected; 20,000 mL of water was added, the pH was adjusted to 4 with 25% hydrochloric acid, the liquid was separated, and the aqueous phase was collected; activated carbon was added to the aqueous phase for decolorization, the mixture was filtered, and the filtrate was collected; 20 g of anhydrous sodium sulfite was added to the filtrate, the pH was adjusted to 8 with 15% sodium hydroxide solution, 20,000 mL of ethyl acetate was added, the liquid was separated, the organic phase was collected, and the mixture was concentrated to obtain a crude BMKY oil weighing 1150.4 g with a yield of 88.0%.

[0113] S4 step:

[0114] Dissolve 1000g of BMKY in 7000mL of acetone to obtain a BMKY solution. Add 330.1g of concentrated hydrochloric acid dropwise. After the addition of hydrochloric acid is complete, maintain the solution at 25°C and stir to allow crystallization for 0.5h. Filter and dry to obtain 1045.1g of proparacaine hydrochloride as a white crystalline powder (yield: 93.0%).

[0115] Example 4 is a pilot scale reaction of the present invention. The total yield of proparacaine hydrochloride was 75.7%. Testing showed that the finished product solution was clear and colorless, meeting the pharmacopoeia standards.

[0116] Comparative Example 1

[0117] Proparacaine hydrochloride was prepared by the following steps, as described in Example 1 of US Patent No. 3775464, using sodium n-propoxide as an alkoxylating agent to prepare intermediate III. The remaining steps S2-S4 were the same as those in Example 1:

[0118] S1 step:

[0119] At room temperature, IIa (20.1 g, 0.10 mol) was dissolved in 100 mL of DMSO. The temperature was maintained at 40°C, and sodium n-propoxide (18.1 g, 0.22 mol) was added portionwise. The reaction was stirred for 0.5 h. After cooling to room temperature, the mixture was poured into 1000 mL of ice water and acidified to pH 3 with dilute sulfuric acid. The mixture was allowed to stand for 30 min and centrifuged to obtain a crude product, which was white to slightly yellow. The crude product was recrystallized twice from ethanol-water to obtain 18.2 g of intermediate III as a white solid, with a yield of 80.9%.

[0120] Finally, 21.3 g of proparacaine hydrochloride was obtained, which was white to slightly yellow, with a total yield of 59.5%. Upon testing, the solution showed color, which was comparable to the yellow standard colorimetric solution No. 1; the solution was turbid, which was comparable to the turbidity of the No. 1 turbidity standard solution.

[0121] In Comparative Example 1, sodium n-propoxide was used as an alkoxylate to prepare intermediate III. The results showed that the crude intermediate obtained had a low purity, resulting in a yellowish appearance. After two recrystallization purifications, the impurity content in intermediate III could not be reduced to meet the requirements (each single impurity <0.15%), and the yield was low. In particular, the impurity III-14 with a retention time of about 17.75 was too high, and the impurities in intermediate III continued to proparacaine hydrochloride, resulting in a yellowish color in the final product and poor solution color detection. The HPLC analysis results of intermediate III prepared in Comparative Example 1 are shown in FIG. Figure 3 shown.

[0122] Comparative Example 2

[0123] Proparacaine hydrochloride was prepared using the following steps. The preparation of intermediate III is described in the supporting information of the reference "Identification, synthesis and structural confirmation of process-related impurities in proparacaine hydrochloride". The remaining steps S2-S4 were the same as in Example 1:

[0124] S1 step:

[0125] Sodium hydride (9.3 g, 0.23 mol, 60%) was dissolved in 150 mL of DMSO at room temperature. 100 mL of n-propanol was added dropwise with stirring, followed by 20 min of stirring. Then, IIa (20.2 g, 0.10 mol) was added, and the temperature was controlled at 40°C. The reaction was stirred for 10 h. After completion of the reaction, 2000 mL of ice water was added, the pH was adjusted to 5 with hydrochloric acid, and the mixture was filtered to yield a yellow solid. The crude product was recrystallized twice from ethanol-water to obtain 16.8 g of intermediate III as a white to light yellow solid, with a yield of 76.2%.

[0126] Finally, 20.9 g of proparacaine hydrochloride was obtained, which was white to slightly yellow, with a total yield of 53.2%. Upon testing, the solution showed color, which was darker than the yellow No. 1 standard colorimetric solution.

[0127] In Comparative Example 2, intermediate III was prepared according to the literature scheme. The results showed that the intermediate III could not be purified by recrystallization to reduce its content to meet the requirements (each single impurity <0.15%), and the purity and yield were low. In particular, the impurity III-14 with a retention time of about 17.75 was too high, resulting in a yellowish appearance of the product. The impurities in intermediate III continued to proparacaine hydrochloride, resulting in a yellowish color of the final product, and the detection did not meet the requirements. The HPLC analysis results of the intermediate III prepared in Comparative Example 2 are as follows: Figure 2 shown.

[0128] Comparative Example 3

[0129] Proparacaine hydrochloride was prepared by the following steps. Intermediate III was prepared by the following steps. The remaining steps S2-S4 were the same as those in Example 1:

[0130] S1 step:

[0131] At room temperature, IIa (20.2 g, 0.10 mol) was dissolved in 60 mL of DMSO; n-propanol (15.1 g, 0.25 mol) and sodium hydride (7.2 g, 0.18 mol, 60%) were dissolved in 75 mL of THF. The DMSO solution containing IIa was added dropwise to the THF solution containing n-propanol and sodium hydride with stirring at 30°C. The reaction was stirred for 2 hours. After completion of the reaction, 600 mL of purified water was added, and the pH was adjusted to 5 with hydrochloric acid. The crude product was filtered and recrystallized once from ethanol-water. Drying afforded 19.0 g of intermediate III as a white to slightly yellow solid in an 84.4% yield.

[0132] Finally, 21.1 g of proparacaine hydrochloride was obtained, which was white to slightly yellow, with a total yield of 59.8%. Testing showed that the solution color was lighter than the yellow No. 1 standard colorimetric solution, meeting the pharmacopoeia standard.

[0133] In Comparative Example 3, the reaction temperature was too high and the acidification pH was adjusted too much, resulting in an excessively high content of the by-product impurity III-1, which was yellowish in color. Impurity III-1 could not be purified by recrystallization to meet the quality control standard (each single impurity <0.15%). The HPLC analysis results were as follows: Figure 3 Although the intermediate III obtained in Comparative Example 3 was continued to be added to proparacaine hydrochloride, and the color test of the finished product solution met the standard, the overall yield of the reaction was low, so the scheme of Comparative Example 3 was not preferred.

[0134] Comparative Example 4

[0135] Proparacaine hydrochloride was prepared by the following steps. Intermediate III and intermediate IV were prepared according to steps S1 and S2 in Example 1:

[0136] S3 steps:

[0137] Intermediate IV was dispersed in 180 mL of water and 20 mL of ethanol, and iron powder (17.6 g, 0.315 mol) and ammonium chloride (21.7 g, 0.405 mol) were added. The reaction was stirred at 80°C for 0.5 h. After completion, the reaction was cooled to room temperature, and 400 mL of ethyl acetate and 0.6 g of anhydrous sodium sulfite were added. The pH was adjusted to 8 with 15% sodium hydroxide solution. The mixture was filtered, separated, and the organic phase was collected. The mixture was then washed with 400 mL of 5% EDTA-2Na solution, separated, and the organic phase was collected. The mixture was concentrated to obtain a crude BMKY oil weighing 24.8 g, with a yield of 93.6%.

[0138] S4 step:

[0139] Dissolve 22g of BMKY in 160mL of acetone to obtain a BMKY solution, then add 7.3g of concentrated hydrochloric acid dropwise. After the addition of hydrochloric acid is complete, stir and crystallize at 25°C for 0.5h. Filter and dry to obtain 24.1g of proparacaine hydrochloride (BMKY-HCl), which is light yellow. Furthermore, dissolve BMKY-HCl in ethanol and water, heat to 65-75°C, add activated carbon, stir, and filter while hot. Cool the filtrate to 25°C and crystallize for 2h. Centrifuge, rinse with anhydrous ethanol, and dry to obtain 19.3g of proparacaine hydrochloride as a light yellow powder in a 78.2% yield.

[0140] The total yield of the product, proparacaine hydrochloride, was 70.2%. Upon testing, the finished solution was yellow, darker in color than the yellow No. 1 standard colorimetric solution, and did not meet pharmaceutical quality standards. In Comparative Example 4, in step S3, following the conventional synthesis process, after the nitroreduction reaction was completed, the decolorization process described in this application was not performed. After salt formation, the product was decolorized by refining and activated carbon filtration. The resulting proparacaine hydrochloride had a yellowish color and did not meet pharmaceutical quality standards upon testing. The experimenters also attempted to use solvents such as ethyl acetate, acetone, and acetonitrile for recrystallization and decolorization, but found that it was difficult to obtain proparacaine hydrochloride with a color that met the requirements and a good total yield (greater than 50%). It can be seen from this that for proparacaine hydrochloride, if the side reaction impurities and iron oxide produced during the reduction reaction are not controlled before salt formation, the color of the resulting finished product will be difficult to meet quality control requirements.

[0141] Comparative Example 5

[0142] Proparacaine hydrochloride was prepared by the following steps. Intermediate III was prepared according to step S1 in Example 1:

[0143] S2 step:

[0144] To a reactor, add Intermediate III (11.3 g, 0.05 mol), IIb (10.0 g, 0.058 mol), potassium carbonate (15.2 g, 0.11 mol), and 70 mL of THF. The temperature was raised to 80°C and stirred for 2 h. After completion of the reaction, the temperature was lowered to room temperature and filtered. The filtrate was added with 100 mL of ethyl acetate and stirred, followed by the addition of 70 mL of a 15%-20% aqueous sodium chloride solution. The layers were separated, and the organic phase was collected and concentrated to afford Intermediate IV as an oil, which was used directly in the next step.

[0145] S3 steps:

[0146] Intermediate IV was dispersed in 100 mL of water and 12 mL of ethanol, and iron powder (9.8 g, 0.175 mol) and ammonium chloride (14.8 g, 0.275 mol) were added. The reaction was stirred at 80°C for 0.5 h. After completion of the reaction, the mixture was cooled to room temperature, and 250 mL of ethyl acetate and 0.4 g of anhydrous sodium sulfite were added. The pH was adjusted to 8 with 15% sodium hydroxide solution. The mixture was filtered, separated, and the organic phase was collected. The mixture was washed with 250 mL of 5% EDTA-2Na solution, separated, and the organic phase was collected. 250 mL of water was added, and the pH was adjusted to 4 with 25% hydrochloric acid. The aqueous phase was separated and the aqueous phase was collected. Activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and the filtrate was collected. 0.3 g of anhydrous sodium sulfite was added to the filtrate, and the pH was adjusted to 8 with 15% sodium hydroxide solution. 250 mL of ethyl acetate was added, separated, and the organic phase was collected. The mixture was concentrated to obtain a crude BMKY oil weighing 11.1 g, with a yield of 75.5%.

[0147] S4 step:

[0148] Dissolve 10 g of BMKY in 70 mL of acetone to obtain a BMKY solution. Add 3.3 g of concentrated hydrochloric acid dropwise. After the addition of hydrochloric acid is complete, maintain the solution at 25°C and stir for 0.5 h to allow crystallization. Filter and dry to obtain 9.7 g of proparacaine hydrochloride as a white powder (yield 86.6%).

[0149] The total yield of the proparacaine hydrochloride product was 62.8%. Testing revealed that the finished product solution was clear and colorless, meeting pharmacopoeia standards. However, compared with Examples 1-4, the total yield was lower.

[0150] Comparative Example 6

[0151] Proparacaine hydrochloride was prepared by the following steps. Intermediate III was prepared according to step S1 in Example 1:

[0152] S2 step:

[0153] To a reactor, add Intermediate III (11.3 g, 0.05 mol), IIb (10.0 g, 0.058 mol), potassium carbonate (15.2 g, 0.11 mol), and 70 mL of THF. The temperature was raised to 80°C and stirred for 2 h. After completion of the reaction, the temperature was lowered to room temperature and filtered. The filtrate was added with 100 mL of ethyl acetate and stirred, followed by the addition of 70 mL of a 15%-20% aqueous sodium chloride solution. The layers were separated, and the organic phase was collected and concentrated to afford Intermediate IV as an oil, which was used directly in the next step.

[0154] S3 steps:

[0155] Intermediate IV was dispersed in 100 mL of water and 12 mL of ethanol, and iron powder (9.8 g, 0.175 mol) and ammonium chloride (12.1 g, 0.225 mol) were added. The reaction was stirred at 80°C for 0.5 h. After completion of the reaction, the mixture was cooled to room temperature, and 250 mL of ethyl acetate and 0.4 g of anhydrous sodium sulfite were added. The pH was adjusted to 8 with 15% sodium hydroxide solution. The mixture was filtered, separated, and the organic phase was collected. The mixture was washed with 250 mL of 5% EDTA-2Na solution, separated, and the organic phase was collected. 250 mL of water was added, the phases were separated, and the aqueous phase was collected. Activated carbon was added to the aqueous phase for decolorization, and the filtrate was filtered and collected. 0.3 g of anhydrous sodium sulfite was added to the filtrate, and the pH was adjusted to 8 with 15% sodium hydroxide solution. 250 mL of ethyl acetate was added, the phases were separated, and the organic phase was collected. The mixture was concentrated to obtain a crude BMKY oil weighing 12.6 g, with a yield of 85.7%.

[0156] S4 step:

[0157] Dissolve 10 g of BMKY in 70 mL of acetone to obtain a BMKY solution. Add 3.3 g of concentrated hydrochloric acid dropwise. After the addition of hydrochloric acid is complete, maintain the mixture at 25°C and stir for 0.5 h to allow crystallization. Filter and dry to obtain 8.4 g of proparacaine hydrochloride as a white solid (yield 75.0%).

[0158] The total yield of the product proparacaine hydrochloride was 61.7%. Testing showed that the finished product solution was clear and colorless, meeting the pharmacopoeia standards. However, compared with Examples 1-4, the total yield of the product was lower.

[0159] Comparative Example 7

[0160] Proparacaine hydrochloride was prepared using the following steps. Intermediate III was prepared according to step S1 in Example 1. Steps S2-S4 were prepared according to the supporting information described in the document "Identification, synthesis and structural confirmation of process-related impurities in proparacaine hydrochloride":

[0161] S2 step:

[0162] To a reactor, add Intermediate III (11.3 g, 0.050 mol), IIb (9.3 g, 0.054 mol), potassium carbonate (15.3 g, 0.110 mol), and 140 mL of ethyl acetate. The reaction was heated to 80°C and stirred for 8 h (the reaction was considered complete when the residual amount of III was <2%). After the reaction, the temperature was cooled to room temperature, filtered, and the filtrate was concentrated to obtain Intermediate IV as an oil, weighing 14.6 g, which was set aside for future use. The yield was 90.0%.

[0163] S3 steps:

[0164] Intermediate IV oil (10 g, 0.031 mol) was dispersed in 20 mL of ethanol, 2 g of Pd / C was added, and then formic acid (11.48 g, 0.249 mol) was added dropwise. The mixture was stirred at 35°C for 4 h. After the reaction was completed, the mixture was condensed under vacuum to obtain a concentrate weighing 7.8 g, with a yield of 85.7%. The concentrate was dissolved in 50 mL of DCM (dichloromethane) and washed with 40 mL of 20% sodium carbonate solution. The phase was separated to obtain 45 mL of DCM for later use.

[0165] S4 step:

[0166] To the DCM solution obtained in step S3 above, 20 mL of isopropanol was added, and 10% hydrochloric acid was added dropwise. The mixture was stirred at room temperature for 2 h, and the product was filtered and dried to obtain 8.2 g of proparacaine hydrochloride as a white powder with a yield of 94.3%.

[0167] The total yield of the product proparacaine hydrochloride was 77.6% (by multiplying S1, S2, S3, and S4). Testing showed that the finished product solution was clear and colorless, meeting the pharmacopoeia standards. However, compared with Examples 1-3, the total yield of the product decreased.

[0168] It can be seen from Examples 1-4 and Comparative Examples 1-7 that the selection of reaction conditions for the synthesis of Intermediate III has a significant impact on the purity, appearance and yield of Intermediate III and the quality of the final product, proparacaine hydrochloride.

[0169] Test 1 Impurity Analysis of Examples 1-4 and Comparative Examples 5-7

[0170] Table 2: Impurity analysis of Examples 1-4 and Comparative Examples 5-7

[0171]

[0172]

[0173] Analysis of the data in Table 2 shows that when the intermediate III prepared in step S1 of the present invention is used to prepare proparacaine hydrochloride, although the appearance of the product meets the test requirements, some impurities still exist and do not meet the quality control standards.

[0174] In Comparative Example 5, the proportion of ammonium chloride in step S3 was too high, and the product had too many impurities, such as impurity F, impurity H and total impurity contents of about 7.90% and 1.13%, respectively, and the total impurity content was 10.75%, which did not meet the quality control standards. The HPLC test results were as follows: Figure 6 As shown;

[0175] In Comparative Example 6, during the decolorization process in step S3, water was omitted and 20-30% hydrochloric acid was used to adjust the pH to 3-5. The product had more impurities, such as impurity F, impurity G, impurity Q and impurity R, with contents of 2.58%, 0.24%, 0.28% and 0.29% respectively, and a total impurity content of 9.57%, which did not meet the quality control standards. The HPLC test results were as follows: Figure 7 shown.

[0176] It can be seen from Comparative Examples 5-6 that the feed ratio of the reaction substrate and the decolorization step operation in step S3 of the present invention are crucial to the control of impurities in the final product.

[0177] In Comparative Example 7, proparacaine hydrochloride was prepared according to the literature scheme. The results showed that the impurity content did not meet the standard and there were multiple unknown impurities with high content. The HPLC test results were as follows: Figure 8 shown.

[0178] From the impurity conditions of Examples 1 to 4, it can be seen that by regulating the reaction conditions such as the substrate content and solvent in each step of the present application, the formation of difficult-to-remove impurities can be avoided / reduced, and the impurity content of proparacaine hydrochloride can be effectively controlled to be far lower than the standard content, with a purity of up to 99.9% and a high overall reaction yield. Among them, the HPLC test results of proparacaine hydrochloride in Example 1 are as follows: Figure 1 shown.

[0179] In particular, in Example 1, the reaction parameters of each step are the most preferred in the present invention. Example 4 is an amplified pilot reaction of the scheme of the present invention. The results show that this scheme can also effectively control the generation of impurities in the industrial amplification reaction, with ideal purity and yield, mild reaction conditions, and is suitable for industrial amplification production.

[0180] Experiment 2 Preparation and Stability Evaluation

[0181] The proparacaine hydrochloride obtained in Examples 1 and 4 was used to prepare 0.5% proparacaine hydrochloride eye drops, and the stability of the resulting preparation was investigated. Preparation method: 90 mL of water for injection was added with 2.4% glycerol, 0.01% benzalkonium chloride, and 0.5% proparacaine hydrochloride, and stirred to dissolve; the pH was adjusted to 4.5-4.8 with dilute hydrochloric acid, the volume was made up to 100 mL with water for injection, filtered, and filled.

[0182] Table 3: Stability study of proparacaine hydrochloride preparations

[0183]

[0184] From the data in Table 3, it can be seen that the proparacaine hydrochloride prepared by this scheme is used in preparations, and the obtained preparation has good stability and meets the pharmacopoeia standards.

[0185] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A method for preparing proparacaine hydrochloride, characterized in that: The preparation method comprises the following specific steps: Step S1: dissolving compound IIa in DMSO and dissolving n-propanol and sodium hydride in THF at room temperature; adding the DMSO solution containing IIa dropwise to the THF solution containing n-propanol and sodium hydride under stirring and controlling the temperature at 15-20°C, stirring and reacting for 0.5-4 hours; after the reaction, adding water and adjusting the pH to 2-3 with hydrochloric acid; filtering to obtain a crude product, and recrystallizing it once from ethanol-water to obtain intermediate III, wherein the molar ratio of IIa, n-propanol and sodium hydride is 1:2.2-2.8:1.6-2.0, the mass volume ratio of sodium hydride to THF is 1:8-14, and the mass volume ratio of IIa to DMSO is 1:2-4; Step S2: Add intermediate III, compound IIb, potassium carbonate and an organic solvent to a reactor, raise the temperature to 60-120°C, stir and react for 0.5-4h, cool to room temperature, filter, add ethyl acetate to the filtrate and stir; then add 15%-20% sodium chloride aqueous solution, separate the liquids, and concentrate the organic phase to obtain intermediate IV, which is directly used in the next step, wherein the molar ratio of III, IIb to potassium carbonate is 1:1.0-1.3:2.0-2.5, and the mass volume ratio of III to the organic solvent is 1:4-8; wherein the organic solvent is THF; Step S3: Disperse the intermediate IV in a reaction solvent, add iron powder and ammonium chloride, heat to 70-90°C, stir and react for 0.3-0.8h, and after the reaction is completed, decolorize and concentrate to obtain BMKY, wherein the reaction solvent is water and alcohol; the molar ratio of the intermediate III, iron powder and ammonium chloride is 1:3.2-3.8:4.2-4.8, and the mass volume ratio of III, water and ethanol is 1:8.0-10.0:0.8-1.2; wherein the decolorization process comprises the following steps: after the reaction is completed, cool to room temperature, add ethyl acetate and a small amount of antioxidant, and use 15% The method comprises the following steps: adjusting the pH value to 7-9 with sodium hydroxide solution, filtering, separating the liquids, and collecting the organic phase; washing with a 5% EDTA-2Na solution, and collecting the organic phase; adding water, adjusting the pH value to 3-5 with 20-30% hydrochloric acid, separating the liquids, and collecting the aqueous phase; adding activated carbon to the aqueous phase for decolorization, filtering, and collecting the filtrate; adding a small amount of antioxidant to the filtrate, adjusting the pH value to 7-9 with a 15% sodium hydroxide solution, extracting with ethyl acetate, separating the liquids, collecting the organic phase, and concentrating to obtain a BMKY oily substance. After the reaction is completed, the amount of ethyl acetate and 5% EDTA-2Na solution added during the process is equivalent to the amount of water used; Step S4: dissolving BMKY in an organic solvent to obtain a BMKY solution, adding concentrated hydrochloric acid, keeping warm, stirring to crystallize, filtering, and drying to obtain BMKY-HCl, wherein the mass volume ratio of BMKY to the organic solvent is 1:5-9, and the mass ratio of BMKY to concentrated hydrochloric acid is 1:0.28-0.38; wherein the organic solvent is acetone.

2. The method for preparing proparacaine hydrochloride according to claim 1, wherein In step S2, the molar ratio of III, IIb and K2CO3 is 1:1.1-1.2:2.1-2.3, the temperature is raised to 70-100°C, the mass volume ratio of III to the organic solvent is 1:5-7, and the reaction is stirred for 1-3 hours.

3. A method for preparing proparacaine hydrochloride according to claim 1 or 2, characterized in that, The sodium hydride content is 60%.

4. The method for preparing proparacaine hydrochloride according to claim 1, wherein In step S4, the mass volume ratio of BMKY to the organic solvent is 1:5-9, and the mass volume ratio of BMKY to hydrochloric acid is 1:0.28-0.

38.

5. A method for preparing proparacaine hydrochloride according to claim 1, comprising the following steps: Step S1: Dissolve IIa in DMSO at room temperature; dissolve n-propanol and sodium hydride in THF; add the DMSO solution containing IIa dropwise to the THF solution containing n-propanol and sodium hydride while stirring at 15-20°C, and stir for 2 hours. After the reaction, add water approximately 9-12 times the volume of DMSO, and adjust the pH to 3 with hydrochloric acid. Filtration was performed to obtain a crude product, which was recrystallized once with water and ethanol to obtain intermediate III, wherein: the molar ratio of IIa, n-propanol and sodium hydride is 1.0:2.5:1.8, the mass volume ratio of IIa to DMSO is 1.0:2.5-3.5; the mass volume ratio of sodium hydride to THF is 1:10-12; Step S2: Add intermediate III, IIb, potassium carbonate and THF to a reactor, raise the temperature to 80°C, stir and react for 2 hours, cool to room temperature after the reaction, filter, add ethyl acetate equivalent to 1 to 2 times the volume of THF to the filtrate, and stir; then add a 15% to 20% sodium chloride aqueous solution equivalent to the volume of THF, separate the liquids, collect the organic phase, and concentrate to obtain intermediate IV, which is directly used in the next step, wherein the molar ratio of III, IIb to potassium carbonate is 1:1.15:2.2, and the mass volume ratio of III to THF is 1:5.5 to 6.5; Step S3: Disperse intermediate IV in water and ethanol, add iron powder and ammonium chloride, heat to 80°C, and stir to react for 0.5h; after the reaction is completed, cool to room temperature, add ethyl acetate equivalent to 1 to 3 times the volume of water and ethanol and a small amount of anhydrous sodium sulfite, adjust the pH to 8 with 15% sodium hydroxide solution, filter, separate the liquid, and collect the organic phase; wash with 5% EDTA-2Na solution, and collect the organic phase; add water, adjust the pH to 4 with 25% hydrochloric acid, separate the liquid, and collect the aqueous phase; add Decolorize with an appropriate amount of activated carbon, filter, and collect the filtrate; add a small amount of anhydrous sodium sulfite to the filtrate, adjust the pH to 8 with 15% sodium hydroxide solution, extract with ethyl acetate, separate the liquids, and concentrate the organic phase to obtain a BMKY oil, wherein the molar ratio of III, iron powder, and ammonium chloride is 1:3.5:4.5, and the mass volume ratio of III, water, and ethanol is 1:8.5-9.5:0.9-1.

1. After the reaction is completed, the amounts of ethyl acetate, 5% EDTA-2Na solution, and water are equivalent; Step S4: dissolving BMKY in acetone to obtain a BMKY solution, adding concentrated hydrochloric acid, keeping warm, crystallizing, filtering, and drying to obtain BMKY-HCl, wherein the mass volume ratio of BMKY to acetone is 1:6.5-7.5, and the mass ratio of BMKY to hydrochloric acid is 1:0.32-0.

34. The temperature is kept at 25° C., stirring and crystallizing for 0.5 h, filtering, and drying to obtain the target product, proparacaine hydrochloride.

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