A process for the preparation of palonosetron hydrochloride

Abstract

This invention discloses a method for preparing palonosetron hydrochloride, comprising the following steps: (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride reacts with (S)-3-aminoquinine cycloamine to generate intermediate 2; intermediate 2 undergoes a reduction reaction to obtain crude intermediate 3; crude intermediate 3 is purified to obtain pure intermediate 3; pure intermediate 3 undergoes a triphosgene cyclization reaction to obtain crude palonosetron hydrochloride; crude palonosetron hydrochloride is purified to obtain pure palonosetron hydrochloride. This invention, through process optimization, provides a method for preparing ultra-high purity palonosetron hydrochloride, with a purity not less than 99.99% and single and total impurities not exceeding 0.01%, suitable for industrial production. The obtained palonosetron hydrochloride meets and exceeds existing pharmaceutical standards, providing greater convenience for patients and benefiting treatment.

Description

Technical Field

[0001] This invention relates to the field of active pharmaceutical ingredient synthesis technology, and in particular to a method for preparing high-purity palonosetron hydrochloride. Background Technology

[0002] Palonosetron hydrochloride (trade name Aloxi) is a selective 5-HT3 receptor antagonist developed by Helsinn AG in Switzerland. Its chemical name is (3aS)-2-[(3S)-1-azabicyclo[2,2,2]octyl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-phenylhydrazine[de]isoquinoline hydrochloride, and its molecular structure is as follows.

[0003]

[0004] On July 25, 2003, this product was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute and delayed nausea and vomiting caused by moderate to severe chemotherapy. Palonosetron hydrochloride is the fourth approved 5-HT3 receptor antagonist and currently the only long-acting 5-HT3 receptor antagonist with a long half-life of approximately 40 hours, while other 5-HT3 receptor antagonists have half-lives of only a few hours. Furthermore, palonosetron hydrochloride selectively binds to the 5-HT3 receptor, exhibiting strong affinity—almost 100 times stronger than other 5-HT3 receptor antagonists. Clinically, it is primarily used to treat acute and delayed nausea and vomiting caused by moderate to severe emetogenic chemotherapy. Originally developed in Switzerland and marketed in the United States, it is now approved in the U.S. for the treatment of nausea and vomiting caused by moderate to severe emetogenic chemotherapy, as well as postoperative nausea and vomiting. Palonosetron hydrochloride has become one of the most widely used antiemetic drugs in clinical practice. Palonosetron hydrochloride is the first 5-HT3 receptor antagonist approved by the US FDA for monotherapy to treat delayed vomiting in patients undergoing chemotherapy for moderate to severe emetogenic tumors. The approved dosage form is an injection.

[0005] Currently, there are three main synthetic routes for palonosetron hydrochloride (palonosetron hydrochloride) reported in the literature:

[0006] Route 1:

[0007]

[0008] Route 2:

[0009]

[0010] Route 3:

[0011]

[0012] Palonosetron was prepared according to routes two and three, both of which involved a double-bond intermediate. This intermediate is an important impurity in palonosetron (palonosetron impurity E). The impurities were all present, with concentrations exceeding 0.05%. Furthermore, these impurities continued to be generated during purification, making it impossible to significantly reduce their concentration further through purification. Additionally, routes two and three resulted in low product yields, unstable product quality, and the presence of intermediates or other impurities that were difficult to purify.

[0013] Although Route 1 does not pass through impurity E, this impurity will still be generated during the production process, with a content higher than 0.02%, and its content cannot be further reduced by recrystallization. In addition, Route 1 will also generate an impurity with a relative retention time (RRT) of approximately 0.88 (hereinafter referred to as RRT0.88 impurity), the content of which is generally around 0.02%, and its content also cannot be further reduced by recrystallization.

[0014] The crude palonosetron hydrochloride obtained by these synthetic methods contains most of the target compound palonosetron hydrochloride, as well as other isomers of palonosetron hydrochloride and other related impurities introduced by the synthetic process. Therefore, how to obtain high-purity palonosetron hydrochloride has become the focus of research. Although it can be purified by recrystallization, the purity can only reach about 99%. Current technology has also proposed using column chromatography, but the purity of the obtained product can only reach 99.5%, and the purity of a single impurity can only reach no more than 0.1%. Moreover, the use of column chromatography is not conducive to industrial production.

[0015] Currently, there is no method to prepare high-purity (above 99.98%) palonosetron hydrochloride with no more than 0.01% of individual impurities, which cannot meet the demands of the high-end market. For patients undergoing chemotherapy for moderate to severe emetogenic tumors, any impurities in this drug could cause suffering and adverse effects. High-purity palonosetron hydrochloride, on the other hand, would provide convenience and benefit treatment. Therefore, developing a method for preparing high-purity palonosetron hydrochloride (above 99.98% purity, with no more than 0.01% of individual impurities) is extremely urgent. Summary of the Invention

[0016] The present invention has found that, in the synthesis of palonosetron according to route one, the RRT0.88 impurity is particularly difficult to remove. If intermediate 3 is not purified, the content of the RRT0.88 impurity in the crude palonosetron will exceed 0.02%, and the content of the RRT0.88 impurity will further increase after purification.

[0017] Furthermore, in the preparation of crude palonosetron, without the use of pyridine, the reaction proceeds incompletely, resulting in a low yield. The increased purification steps due to incomplete progress also exacerbate the formation of the RRT0.88 impurity. However, if pyridine is used without proper pretreatment, the resulting palonosetron hydrochloride will have a slightly pale yellow tint, potentially failing to meet quality standards, and the content of both the RRT0.88 impurity and impurity E will exceed 0.01%.

[0018] Furthermore, when (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride, prepared from (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride, reacts with (S)-3-aminoquinine cycloamine to generate intermediate 2, the reaction temperature is from 0°C to reflux, resulting in intermediate 2 having an isomer content generally above 10%. Although this isomer can be removed by multiple recrystallizations, the operation is cumbersome and the yield is low.

[0019] Therefore, intermediate 3 is purified before preparing crude palonosetron, resulting in better removal of impurities, especially RRT0.88. Furthermore, pyridine pretreated using a specific pretreatment method is added during the preparation of crude palonosetron, ensuring that the RRT0.88 impurity content in the purified palonosetron hydrochloride does not exceed 0.01%. Then, during the formation of intermediate 2, the reaction temperature is controlled between -80°C and -40°C, effectively controlling the isomers. Ultimately, palonosetron hydrochloride with a purity of not less than 99.98% and a single impurity content not exceeding 0.01% can be obtained, thus yielding the present invention.

[0020] One of the objectives of this invention is to provide a method for preparing palonosetron hydrochloride.

[0021] The second objective of this invention is to provide a method for preparing palonosetron hydrochloride.

[0022] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:

[0023] In a first aspect, the present invention provides a method for preparing palonosetron hydrochloride, the method comprising the following steps:

[0024] (1) (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride reacts with (S)-3-aminoquinine cycloamine to generate intermediate 2;

[0025] (2) Intermediate 2 undergoes a reduction reaction to obtain crude intermediate 3;

[0026] (3) The crude intermediate 3 was purified to obtain the pure intermediate 3;

[0027] (4) The pure intermediate 3 was subjected to a triphosgene cyclization reaction to obtain crude palonosetron hydrochloride.

[0028] (5) The crude palonosetron hydrochloride was purified to obtain pure palonosetron hydrochloride.

[0029] The synthetic route is as follows:

[0030]

[0031] Step (1)

[0032] In this step, (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride (intermediate 1) reacts with (S)-3-aminoquinine cycloamine (starting material B) in the presence of a solvent. After post-treatment and drying, intermediate 2 is obtained. The reaction temperature is -80°C to -40°C, preferably -80°C to -60°C.

[0033] By controlling the reaction temperature, the isomers of intermediate 2 are reduced to less than 5%.

[0034] In step (1), the weight ratio of (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride to (S)-3-aminoquinine cycloamine can be 1.4:1 to 1.7:1.

[0035] In step (1), the solvent can be one or more selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran and heptane.

[0036] There are no particular limitations on the post-treatment method; it can be any treatment method known in the art, such as filtration, washing (e.g., washing with the solvents described above), but is not limited thereto.

[0037] There are no special restrictions on the drying method and temperature; any drying method known in the field of synthesis can be used, and drying can be carried out at any temperature without affecting the properties of the product, such as a drying temperature not exceeding 60°C.

[0038] In some embodiments, the (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride (intermediate 1) in step (1) is obtained by treating (S)-1,2,3,4-tetrahydro-1-naphthoic acid with sulfoxide. Specifically, it can be obtained by following, for example, the reaction process of 1,2,3,4-tetrahydro-1-naphthoic acid and sulfoxide in route one of the background section.

[0039] In some embodiments, the (S)-3-aminoquinine cyclic amine (starting material B) in step (1) is obtained by neutralizing (S)-3-aminoquinine cyclic amine hydrochloride with an alkali and then post-treatment. Specific steps may include: stirring (S)-3-aminoquinine cyclic amine hydrochloride and methanol and cooling to -10 to 0°C; adding an alkali (such as potassium hydroxide) to adjust the pH to ≥12; heating to 10 to 20°C, stirring, then cooling to 0 to 5°C, continuing stirring, filtering, and washing to obtain (S)-3-aminoquinine cyclic amine.

[0040] Step (2)

[0041] In this step, intermediate 2 undergoes a reduction reaction in the presence of a solvent, a reducing agent, and a catalyst. After post-treatment and drying, crude intermediate 3 is obtained.

[0042] In step (2), the solvent can be one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and diethyl ether.

[0043] In step (2), the reducing agent may be one or more selected from sodium borohydride and lithium aluminum hydride; and / or

[0044] The weight ratio of the reducing agent to intermediate 2 can be 0.4:1 to 0.6:1.

[0045] In step (2), the catalyst may be one or more selected from boron trifluoride diethyl ether and aluminum chloride; and / or

[0046] The weight ratio of catalyst to intermediate 2 can be 2.1:1 to 2.5:1.

[0047] In step (2), the reduction reaction temperature can be from 60°C to reflux.

[0048] There are no particular restrictions on the post-processing method; it can be any processing method known in the art, such as extraction, filtration, and washing, but is not limited thereto.

[0049] There are no special restrictions on the drying method and temperature; any drying method known in the field of synthesis can be used, and drying can be carried out at any temperature that does not affect the properties of the product, such as a drying temperature not exceeding 60°C.

[0050] Step (3)

[0051] In this step, purification is achieved through recrystallization.

[0052] In some embodiments, the solvent used for recrystallization is a mixture of isopropanol and water, with a volume ratio of isopropanol to water of 8:0.7 to 12:0.7.

[0053] In some embodiments, step (3) includes: adding isopropanol and water to the crude intermediate 3, stirring, heating to reflux, stirring for at least 10 minutes; stopping heating, cooling to -5 to 0°C, and continuing to stir for at least 1 hour; filtering, collecting the filter cake; and vacuum drying to obtain the pure intermediate 3.

[0054] Purifying intermediate 3 before proceeding with subsequent reactions can reduce the impurity content in the palonosetron hydrochloride product.

[0055] Step (4)

[0056] In this step, the pure intermediate 3 reacts with pretreated pyridine and triphosgene in the presence of a solvent at a temperature of 0–10°C. A catalyst is added, and the reaction continues. After post-treatment and drying, crude palonosetron hydrochloride is obtained. The pretreated pyridine is obtained by adding red aluminum to the pyridine and performing vacuum distillation, collecting the first 5% to 50% of the volume of the distillate.

[0057] Adding pyridine pretreated by a specific method can further reduce the impurity content in palonosetron hydrochloride products.

[0058] In some embodiments, the amount of red aluminum added is 0.5% to 5% of the weight of pyridine.

[0059] In some embodiments, the temperature for vacuum distillation is 40°C to 80°C.

[0060] In step (4), the solvent can be toluene.

[0061] In step (4), the weight ratio of pure intermediate 3, pretreated pyridine and triphosgene can be 8-12:1-3:6-11.

[0062] In step (4), the catalyst may be boron trifluoride diethyl ether; and / or

[0063] The weight ratio of the catalyst to pure intermediate 3 can be 1.5:1 to 1.9:1.

[0064] There are no particular restrictions on the post-processing method; it can be any processing method known in the art, such as extraction, filtration, and washing, but is not limited thereto.

[0065] There are no special restrictions on the drying method and temperature; any drying method known in the field of synthesis can be used, and drying can be carried out at any temperature that does not affect the properties of the product, such as a drying temperature not exceeding 60°C.

[0066] In step (4), the intermediate 3 pure product is the intermediate 3 pure product after alkali neutralization and post-treatment. The specific steps are as follows: mix the intermediate 3 pure product, water and solvent, adjust the pH to not less than 12, separate the layers, extract the aqueous phase twice with solvent, combine the organic phases, wash, heat to reflux, dehydrate, and obtain the intermediate 3 pure product after alkali neutralization and post-treatment.

[0067] Step (5)

[0068] In this step, purification can be performed using a palonosetron purification process known in the art, such as crystallizing crude palonosetron hydrochloride (recrystallizing multiple times) to obtain pure palonosetron hydrochloride.

[0069] In some implementations, step (5) includes:

[0070] The crude palonosetron hydrochloride was mixed with 95% ethanol at a weight ratio of 1:5 to 1:15, heated to 50 to 70°C to dissolve and clarify, then cooled to -5 to 5°C, stirred while maintaining the temperature, filtered, and dried to obtain the primary purified palonosetron hydrochloride; the above operation was repeated to obtain the secondary purified palonosetron hydrochloride.

[0071] The purified water, isopropanol, and palonosetron hydrochloride secondary purified product were mixed in a weight ratio of 0.7-1.1:10-14:0.9-1.1, heated to 50-70℃ to dissolve, then cooled to -10--5℃, kept warm and stirred, and methyl tert-butyl ether was added dropwise below -5℃, while continuing to keep warm and stir. The product was discharged and filtered, the filter cake was washed, filtered again, and dried to obtain pure palonosetron hydrochloride.

[0072] There are no special restrictions on the drying method and temperature; any drying method known in the field of synthesis can be used, and drying can be carried out at any temperature that does not affect the properties of the product, such as a drying temperature not exceeding 60°C.

[0073] Unless otherwise specified, all water used in each step is purified water.

[0074] Secondly, the present invention provides palonosetron hydrochloride prepared by the above method, wherein the purity of the palonosetron hydrochloride is not less than 99.98%, or even not less than 99.99%, and the single impurity in the palonosetron hydrochloride is not higher than 0.01%, and the total impurities are not higher than 0.01%.

[0075] Beneficial effects

[0076] Through extensive investigation and research, this invention has found that using Route 1 to synthesize palonosetron, when (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride reacts with (S)-3-aminoquinine cycloamine to generate intermediate 2, controlling the reaction temperature between -80℃ and -40℃ effectively controls the isomers; intermediate 3 is purified using isopropanol / purified water; when preparing crude palonosetron, pyridine pretreated by a specific pretreatment method is added, and after purification, palonosetron hydrochloride with a purity of not less than 99.99% and single impurities and total impurities not exceeding 0.01% can be obtained.

[0077] This invention optimizes the process to obtain a method for preparing ultra-high purity palonosetron hydrochloride, which is suitable for industrial production. The quality of the obtained palonosetron hydrochloride meets or exceeds existing pharmaceutical standards, which can bring more convenience to patients and is beneficial to treatment.

[0078] The present invention has been described in detail above; however, the above embodiments are merely illustrative in nature and are not intended to limit the invention. Furthermore, this document is not limited to the foregoing prior art or the invention itself, or to any theory described in the following embodiments.

[0079] Unless otherwise expressly stated, numerical ranges throughout the application include any subranges therein and any numerical values ​​incremented by the smallest subunit of a given value. Unless otherwise expressly stated, numerical values ​​throughout the application represent approximate measures or limitations on the range of embodiments including minor deviations from a given value and having approximately the mentioned value as well as having the mentioned precise value. Except in the detailed description of the working embodiments provided at the end, all numerical values ​​of parameters (e.g., quantities or conditions) in this application (including the appended claims) should in all cases be understood to be modified by the term “approximately,” regardless of whether “approximately” actually precedes the numerical value. “Approximately” indicates that the stated numerical value allows for slight inaccuracies (some close to precision at that value; approximately or reasonably close to the value; approximate). If the inaccuracy provided by “approximately” is not understood in this common sense in the art, then “approximately” as used herein at least indicates a variation that can be produced by common methods of measuring and using these parameters. For example, “approximately” can include variations less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5%. Attached Figure Description

[0080] Figure 1 The HPLC chromatogram of related substances for crude palonosetron hydrochloride in Example 5 is shown.

[0081] Figure 2 The HPLC chromatogram of related substances for high-purity palonosetron hydrochloride in Example 6 is shown.

[0082] Figure 3 The HPLC chromatogram of related substances for crude palonosetron hydrochloride in Comparative Example 1 is shown.

[0083] Figure 4 The HPLC chromatogram of related substances for palonosetron hydrochloride in Comparative Example 2 is shown. Detailed Implementation

[0084] The present invention will be further described below with reference to the embodiments. It should be noted that the following embodiments are provided for illustrative purposes only and do not constitute a limitation on the scope of protection of the present invention.

[0085] Unless otherwise specified, the raw materials, reagents, and methods used in the embodiments are all conventional raw materials, reagents, and methods in the art.

[0086] Main instruments:

[0087] Agilent 1120 liquid chromatograph, Agilent Technologies; Buchi R-100 rotary evaporator, Buchi GmbH, Switzerland; DZX-3 vacuum drying oven, Shanghai Fuma Experimental Equipment Co., Ltd.; SHZ-CD circulating water multi-purpose vacuum pump, Gongyi Yuhua Instrument Co., Ltd.

[0088] Raw materials: The main starting materials, S-1,2,3,4-tetrahydro-1-naphthoic acid and S-3-aminoquinine cycloamine, have an optical purity of over 99.5% and are purchased from Chengdu Xinhengchuang Pharmaceutical Co., Ltd.

[0089] All other reagents were commercially available industrial grade or chemically pure.

[0090] Detection method:

[0091] The related substances (ABAC), specified impurities (including impurities A, B, C, D, and E) and unspecified impurities mentioned below refer to the impurities defined in the United States Pharmacopeia 34th Edition, with the following specific structures:

[0092]

[0093] I. Related substances of palonosetron hydrochloride:

[0094] 1. Related substances (ABAC, i.e., intermediate 3):

[0095] Accurately weigh an appropriate amount of this product, dissolve it in mobile phase A, and quantitatively dilute it to prepare a solution containing approximately 2 mg per ml, as the test solution; separately, accurately weigh an appropriate amount of [S-(R*,R*)]-N-[(1,2,3,4-tetrahydro-1-naphthyl)methyl]-1-azabicyclo[2.2.2]octane-3-amine dihydrochloride (ABAC) reference standard, dissolve it in mobile phase A, and dilute it to prepare a solution containing approximately 2 mg per ml. Accurately measure an appropriate amount, dilute it with 0.05% phosphoric acid solution to prepare a solution containing approximately 3 μg per ml, as the reference solution.

[0096] The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0512). Octylsilane-bonded silica gel was used as the stationary phase (YMC-Pack C8, 5μm, 12nm, suitable for 250mm×4.6mm columns). The mobile phase A was buffer solution (9.0g sodium dihydrogen phosphate dihydrate and 3.48g sodium pentanesulfonate dissolved in 1000ml of water, pH adjusted to 3.5 with phosphoric acid solution)-acetonitrile-isopropanol (75:22.5:2.5), and the mobile phase B was buffer solution-acetonitrile (1:1). Gradient elution was performed according to Table 1, with a flow rate of 1ml / min, a column temperature of 30℃, and a detection wavelength of 215nm.

[0097] Take 10 μl of the reference solution and inject it 6 times. The signal-to-noise ratio of the ABAC peak should not be less than 100, and the relative standard deviation (RSD) of the retention time and peak area should not be greater than 5%. Accurately measure 10 μl of the test solution and inject it into the liquid chromatograph, recording the chromatogram. Calculate the ABAC content by peak area using the external standard method; it should not exceed 0.10%.

[0098] Table 1. Mobile Phase Gradient Table

[0099]

[0100] 2. Related substances (specified impurities: impurities A, B, diastereomers of palonosetron hydrochloride (impurities C and D), impurity E, enantiomers of palonosetron hydrochloride):

[0101] Accurately weigh an appropriate amount of this product, dissolve and dilute it in buffer solution (1.5 g / L ammonium acetate solution, adjusted to pH 6.0 with acetic acid) to prepare a solution containing approximately 0.7 mg per ml, as the test solution; dissolve and dilute an appropriate amount of impurity D reference standard in methanol to prepare a solution containing approximately 0.35 mg per ml. Accurately measure an appropriate amount, dilute it in buffer solution to prepare a solution containing approximately 3.5 μg per ml, as the reference solution. Accurately measure another appropriate amount, dilute it in buffer solution to prepare a solution containing approximately 0.35 μg per ml, as the sensitivity solution.

[0102] Take appropriate amounts of each of impurities A, B, C, D, E, and their enantiomer reference standards, dissolve and dilute them in methanol to prepare a mixed solution containing approximately 0.07 mg of each impurity per ml, as the system suitability stock solution. Separately, take appropriate amounts of palonosetron hydrochloride reference standard and the system suitability stock solution, dissolve and dilute them in buffer solution to prepare a mixed solution containing approximately 0.7 mg of palonosetron hydrochloride and 3.5 μg of each impurity per ml, as the system suitability solution.

[0103] The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition, Part IV, General Chapter 0512), using vancomycin as the packing material (AstecChirobiotic–V 250×4.6mm, suitable for 5μm column), and buffer-tetrahydrofuran (90:10) as the mobile phase; the flow rate was 1.5 ml / min, the detection wavelength was 238 nm, and the column temperature was 35 ℃.

[0104] Inject 100 μl of the system suitability solution into the liquid chromatograph. The resolution between impurity D and its enantiomer peak should be no less than 1.4, and the resolution between impurity E and its enantiomer peak should be no less than 1.2. The tailing factor of impurity E should be no greater than 2.5. Accurately measure 100 μl of the sensitivity solution and inject it into the liquid chromatograph. The signal-to-noise ratio of impurity D should be no less than 10. Inject 100 μl of the reference solution 6 times. The relative standard deviation (RSD) of the peak area of ​​impurity D should be no greater than 5%. Inject 100 μl of the test solution into the liquid chromatograph and record the chromatogram up to 2.5 times the retention time of the main peak. If the chromatogram of the test solution contains specified impurities, calculate the content of impurities A, B, E, and enantiomers using the external standard method (divided by the correction factor, see Table 2). The content of diastereomers (the sum of impurities C and D) should not exceed 0.10%.

[0105] Table 2 Correction Factor Table

[0106]

[0107] 3. Related substances (unspecified impurities, including but not limited to RRT 0.88 impurities):

[0108] Accurately weigh an appropriate amount of this product, dissolve and dilute it in methanol to prepare a solution containing approximately 0.175 mg per ml; accurately measure an appropriate amount, dilute it with the mobile phase to prepare a solution containing approximately 0.035 mg per ml, as the test solution; separately, take appropriate amounts of reference standards A, B, D, and E, dissolve and dilute them in methanol to prepare a mixed solution containing approximately 0.07 mg of each impurity per ml, as the peak identification stock solution. Separately, take an appropriate amount of palonosetron hydrochloride reference standard, dissolve and dilute it in methanol to prepare a solution containing approximately 0.7 mg per ml, as the palonosetron hydrochloride stock solution. Take appropriate amounts of both the peak identification stock solution and the palonosetron hydrochloride stock solution, dilute them with the mobile phase to prepare a mixed solution containing approximately 3.5 μg of palonosetron hydrochloride and 0.07 μg of each impurity per ml, as the peak identification solution. Take an appropriate amount of palonosetron hydrochloride stock solution and dilute it with the mobile phase to prepare a solution containing approximately 0.0175 μg per 1 ml, which will be used as the sensitivity solution.

[0109] The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition, Part IV, 0512), using octylsilane-bonded silica gel as the stationary phase (suitable for ZORBAX SB-C8, 5μm, 250mm×4.6mm column), acetonitrile-water-trifluoroacetic acid (280:720:0.67) as the mobile phase, with a flow rate of 1ml / min, a detection wavelength of 210nm, and a column temperature of 30℃.

[0110] Inject 80 μl of the sensitivity solution into the liquid chromatograph; the signal-to-noise ratio of palonosetron hydrochloride should be no less than 10. Accurately measure 80 μl of the peak identification solution and inject it into the liquid chromatograph to determine the retention times of impurities A, B, D, and E. Inject 80 μl of the test solution into the liquid chromatograph and record the chromatogram up to 2.5 times the retention time of the main peak. Calculate using the area normalization method; none of the non-specified impurities should exceed 0.10%.

[0111] The total amount of impurities (the sum of specified impurities, unspecified impurities, and ABAC) must not exceed 0.5%.

[0112] II. Purity of palonosetron hydrochloride:

[0113] Purity % = 100% - Total impurities.

[0114] Example 1: Synthesis of (S)-3-aminoquinine cycloamine

[0115] Under nitrogen protection, 704 g of (S)-3-aminoquinine cycloamine hydrochloride and 3892 g of methanol were added sequentially to the reaction vessel. The mixture was then stirred and cooled to -10 to 0°C. 533 g of potassium hydroxide was added, maintaining a pH of ≥12. The temperature was raised to 10–20°C, and stirring was continued at this temperature for 3 hours. The reaction solution was then cooled to 0–5°C, and stirring was continued at this temperature for 30 minutes. The mixture was filtered, and the filter cake was washed with 1224 g of toluene. The filtrate and washings were combined and distilled under reduced pressure until almost no distillate was observed. Another 1224 g of toluene was added, and the mixture was distilled again under reduced pressure until almost no distillate was observed. Then, 1224 g of toluene was added to the residue, and the mixture was stirred, filtered, and the filter cake was washed with 603 g of toluene. The filtrate and washings were combined and distilled under reduced pressure until almost no distillate was observed. Another 1224 g of toluene was added, and the mixture was stirred and concentrated. 2450 g of toluene was added, and the mixture was stirred until homogeneous, yielding a (S)-3-aminoquinine cycloamine toluene solution, which was directly used in the next step.

[0116] Preparation of Intermediate 2 in Example 2

[0117] Under nitrogen protection, 476.3 g of (S)-1,2,3,4-tetrahydro-1-naphthoic acid, 4124 g of toluene, and 4.4 g of DMF were added to the reactor. The mixture was stirred and cooled to no higher than 5°C, and 482 g of SOCl2 was added dropwise, maintaining the temperature below 5°C. The temperature was then raised to 15–25°C and stirred for at least 3 hours. After concentration, 1238 g of toluene was added to dissolve the solution, followed by further concentration and the addition of 7698 g of toluene to obtain a toluene solution of (S)-1,2,3,4-tetrahydro-1-naphthoic acid chloride (intermediate 1).

[0118] Stirring was started and 4150 g of a toluene solution of (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride (containing 367 g of (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride) was cooled to -80°C to -60°C. 1859 g of a toluene solution of (S)-3-aminoquinine cycloamine prepared in Example 1 (containing 237.9 g of (S)-3-aminoquinine cycloamine) was added dropwise, maintaining the reaction temperature at -80°C to -60°C. After the addition was complete, stirring was continued for at least 2 hours. The temperature was then raised to 20-30°C and stirring was continued for at least 6 hours. The mixture was filtered, and the filter cake was washed twice with 412 g of toluene and dried at a temperature not exceeding 50°C to obtain intermediate 2.

[0119] Preparation of intermediate 3 in Example 3

[0120] Add 1250g of intermediate 2 prepared in Example 2 and 6665g of tetrahydrofuran to the reaction vessel. Under nitrogen protection, at a temperature not exceeding 25°C, add 589g of sodium borohydride in batches, followed by 287g of boron trifluoride diethyl ether dropwise, maintaining the temperature between 0 and 10°C. Heat to reflux until the reaction is complete. Add hydrochloric acid solution dropwise, and heat to reflux until the reaction is finished. Cool to 20–30°C, add 2166g of toluene for extraction and separation. Extract the toluene layer once with water, combine the aqueous layers, and add sodium hydroxide solution dropwise until the pH is not lower than 12, maintaining the temperature not exceeding 20°C. Cool to not higher than -5°C, add 5636g of ethyl acetate, stir, and then filter. Wash the filter cake twice with 2821g of ethyl acetate, and allow the filtrate to stand and separate. Extract the lower aqueous layer twice with ethyl acetate, combine the ethyl acetate layers, and wash twice with sodium chloride solution. Concentrate under reduced pressure, cool the concentrate to 0–5°C, and add isopropanol hydrochloride dropwise until the pH is not higher than 1. Cool to -5 to 0°C and stir for at least 1 hour. Filter, and wash the filter cake with 1125 g of ethyl acetate. Dry at no higher than 50°C to obtain crude intermediate 3.

[0121] Example 4: Purification of Intermediate 3

[0122] The reaction vessel was equipped with a mechanical stirrer, a nitrogen-purged reflux condenser, a thermometer (covering temperatures from -30°C to 100°C), and a dropping funnel. 1145 g of crude intermediate 3 prepared in Example 3 was added, along with 8995 g of isopropanol and 802 g of purified water. The mixture was stirred and heated to reflux. Stirring was continued for at least 10 minutes. Heating was stopped, and the mixture was cooled to -5°C to 0°C. Stirring was continued at -5°C to 0°C for at least 1 hour. The mixture was filtered, and the filter cake was collected. The mixture was then vacuum dried at a temperature not exceeding 50°C to obtain pure intermediate 3.

[0123] Example 5: Preparation of crude palonosetron hydrochloride

[0124] Pretreatment of pyridine: Add 500g of pyridine to the reaction flask, start stirring, and add 10g of red aluminum dropwise. Stir for at least 5 minutes, distill under reduced pressure at a temperature not exceeding 80℃, collect the fraction between the first 5% and the first 50%, seal, and set aside for later use.

[0125] Add 2.49 kg of purified water, 820 g of the pure intermediate 3 prepared in Example 4, and 7.13 kg of toluene to the reaction vessel under nitrogen protection. Maintain the internal temperature no higher than 0°C, and add the prepared sodium hydroxide aqueous solution dropwise until the pH is no lower than 12. The mixture separates into layers; the aqueous phase is extracted twice with 7.13 kg of toluene, and the combined organic phases are washed once with sodium chloride aqueous solution. The organic phase is heated to reflux for dehydration. Cool to no higher than -5°C, add 160 g of the pretreated pyridine, and add a triphosgene toluene solution (708 g of triphosgene dissolved in 3.05 kg of toluene). After the addition is complete, raise the temperature to 0–10°C and stir the reaction for at least 4 hours. After the reaction is complete, degas the reaction solution under vacuum at 0–10°C, and add 1370 g of boron trifluoride diethyl ether dropwise while controlling the temperature no higher than 10°C. Stir for at least 2 hours and reflux for at least 8 hours. After the reaction is complete, cool to no higher than 10°C, add hydrochloric acid aqueous solution (784g concentrated hydrochloric acid dissolved in 2.66kg purified water), and reflux for at least 2 hours. Cool, separate into layers, collect the aqueous phase, add 7.13kg toluene and 2.94kg tetrahydrofuran, and add sodium hydroxide aqueous solution dropwise until pH ≥ 12. Extract the aqueous phase with 4.30kg toluene and 2.21kg tetrahydrofuran, combine the organic phases, wash once with water, and concentrate under reduced pressure until no fraction flows out. Add 1.92kg isopropanol, cool, and add isopropanol hydrochloride dropwise until pH ≤ 2. Cool and stir for at least 1 hour. Filter, and wash the filter cake with 369g isopropanol. Dry under vacuum at 30–40°C to obtain crude palonosetron hydrochloride. Its liquid chromatogram according to the related substances of palonosetron hydrochloride is shown below. Figure 1 (Unless otherwise specified, the tests were conducted under the relevant substance testing conditions described in Section 1.3 above). The RRT 0.88 impurity content was 0.006%, and the purity of the crude palonosetron hydrochloride was 99.0%.

[0126] Example 6: Preparation of high-purity palonosetron hydrochloride

[0127] Add 3.83 kg of 95% ethanol and 684 g of crude palonosetron hydrochloride prepared in Example 5 to the reaction vessel under nitrogen protection. Heat to reflux and stir for at least 10 minutes. Slowly cool to -5 to 5°C and maintain the temperature with stirring for at least 2 hours. Discharge and filter. Wash the filter cake once with 540 g of 95% ethanol. Dry at 40–50°C to obtain the primary purified palonosetron hydrochloride product.

[0128] Add 2.92 kg of 95% ethanol and 522 g of primary purified palonosetron hydrochloride to a reaction vessel under nitrogen protection. Heat to 50–70°C and stir for at least 10 minutes. Slowly cool to -5–5°C and maintain this temperature with stirring for at least 2 hours. Discharge and filter the mixture. Wash the filter cake once with 0.42 kg of 95% ethanol. Dry at 40–50°C to obtain secondary purified palonosetron hydrochloride.

[0129] Add 280g of purified water, 3280g of isopropanol, and 305g of secondary purified palonosetron hydrochloride to a reaction vessel. Heat to 50-70℃ and stir for 20-30 minutes. Slowly cool to -10 to -5℃ and stir for at least 1 hour. While maintaining the temperature below -5℃, add 1125g of methyl tert-butyl ether dropwise, maintaining the temperature at -10 to -5℃ and stirring for at least 1 hour after the addition is complete. Filter the mixture, and wash the filter cake once with a mixture of 326g isopropanol and 113g methyl tert-butyl ether. Dry at 50-60℃ for at least 10 hours to obtain high-purity palonosetron hydrochloride. The liquid chromatogram of its related substances is shown below. Figure 2 The maximum single impurity (RRT 0.92) was 0.0035%, the total impurities were 0.006%, and the purity of the high-purity palonosetron hydrochloride product was 99.99%.

[0130] Comparative Example 1: Preparation of crude palonosetron hydrochloride

[0131] Add 30g of purified water, 10g of crude intermediate 3 prepared in Example 3, and 85g of toluene to the reaction vessel under nitrogen protection. Maintain the internal temperature no higher than 0°C and add the prepared sodium hydroxide aqueous solution dropwise until the pH is no lower than 12. Separate the layers; extract the aqueous phase twice with 51g of toluene, combine the organic phases, and wash once with sodium chloride aqueous solution. Heat the organic phase to reflux for dehydration. Cool to no higher than -5°C, add 1.2g of pyridine, and add a triphosgene toluene solution dropwise (8.5g of triphosgene dissolved in 36.4g of toluene). After the addition is complete, raise the temperature to 0–10°C and stir the reaction for at least 4 hours. After the reaction is complete, degas the reaction solution under vacuum at 0–10°C, control the temperature ≤10°C, add 16.4g of boron trifluoride diethyl ether dropwise, stir for at least 2 hours, and reflux for at least 4 hours. After the reaction is complete, cool to no higher than 30°C, add hydrochloric acid aqueous solution (9.4g concentrated hydrochloric acid dissolved in 31.4g purified water) dropwise, and reflux for at least 2 hours. Cool to 10–25°C, separate into layers, and collect the lower aqueous phase and transfer it to the reaction vessel. Add 85g toluene and 35g tetrahydrofuran, and add sodium hydroxide aqueous solution (10.5g sodium hydroxide dissolved in 42g purified water) dropwise until pH 11–13, separate into layers. Extract the aqueous phase with 51g toluene and 26g tetrahydrofuran, combine the organic phases, wash once with water, and concentrate under reduced pressure until no fraction flows out. Add 23g isopropanol, cool to 0–5°C, and add isopropanol hydrochloride dropwise until pH ≤ 2. Stir for at least 1 hour. Filter, and wash the filter cake with 4.5g isopropanol. Dry at 30–40°C to obtain crude palonosetron hydrochloride, yield 65%. The liquid chromatogram of its related substances is shown below. Figure 3 The RRT0.88 impurity content was 0.0269%, and the purity of the crude palonosetron hydrochloride was 98.89%. Comparative Example 2: Preparation of Palonosetron Hydrochloride

[0132] Add 138 ml of isopropanol and 10 g of crude palonosetron hydrochloride prepared in Comparative Example 1 to the reaction vessel, and heat to reflux for 20–30 minutes. Slowly cool to -10 to -5°C and maintain this temperature with stirring for at least 1 hour. Controlling the temperature below -5°C, add 67 ml of methyl tert-butyl ether dropwise, maintaining the temperature at -10 to -5°C with stirring for at least 1 hour after the addition is complete. Filter the mixture, and wash the filter cake once with a mixture of isopropanol / methyl tert-butyl ether (14 ml: 7 ml). Dry at 30–40°C to obtain a purified product with a yield of 82.8%.

[0133] Add 4.2 g of purified water, 64 ml of isopropanol, and 4.7 g of the primary purified palonosetron hydrochloride to the reaction vessel, and heat to reflux for 20–30 minutes. Slowly cool to -10 to -5°C and maintain this temperature with stirring for at least 1 hour. While keeping the temperature below -5°C, add 32 ml of methyl tert-butyl ether dropwise, maintaining the temperature at -10 to -5°C with stirring for at least 1 hour after the addition is complete. Filter the mixture, and wash the filter cake once with a mixture of isopropanol / methyl tert-butyl ether. Dry the palonosetron hydrochloride at 30–40°C, yielding 78.6%. The liquid chromatogram of related substances is shown below. Figure 4 The purity of palonosetron hydrochloride is 99.90%.

[0134] The following is a list of impurities that are close to or greater than 0.01% (area normalization method):

[0135] RRT 0.31 0.009％ RRT 0.88 0.032％ Impurity E 0.012％ RRT 1.19 0.028％ RRT 1.92 0.008％

[0136] The impurities are too large, which does not meet the requirements.

[0137] Results analysis:

[0138] Palonosetron hydrochloride was prepared using unpurified intermediate 3 and untreated pyridine, resulting in a product with a purity of only 99.90% and five impurities close to or greater than 0.01%, with the impurity at RRT 0.88 reaching 0.032%. However, the preparation of palonosetron hydrochloride using intermediate 3 purified by the method of this invention and pyridine pretreated by the method of this invention yielded a product with a purity of over 99.99%, with all impurities less than 0.01%. This demonstrates that the method of this invention is necessary and effective.

[0139] The above embodiments are merely illustrative of the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein, without departing from the spirit and substance defined by the claims of the present invention; and such modifications or substitutions are still within the scope defined by the claims of the present invention.

Claims

1. A process for the preparation of palonosetron hydrochloride, characterized in that, As shown in the reaction equation below, the method includes the following steps: (1) (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride and ( S )-3-aminoquinine cycloamine reacts to form intermediate 2; (2) Intermediate 2 undergoes a reduction reaction to obtain crude intermediate 3; (3) The crude intermediate 3 was purified to obtain the pure intermediate 3; wherein, the purification was carried out by recrystallization, and the solvent used for recrystallization was a mixed solvent of isopropanol and water, with a volume ratio of isopropanol to water of 8:0.7 to 12:0.

7. (4) The pure intermediate 3 is subjected to a triphosgene ring-closing reaction to obtain crude palonosetron hydrochloride; wherein, the pure intermediate 3 is reacted with pretreated pyridine and triphosgene in the presence of solvent, a catalyst is added, the reaction is continued, and after post-treatment and drying, crude palonosetron hydrochloride is obtained, wherein the pretreated pyridine is obtained by adding red aluminum to pyridine and performing vacuum distillation, and collecting the first 5% to 50% volume of the distillate. (5) The crude palonosetron hydrochloride was purified to obtain pure palonosetron hydrochloride.

2. The method of claim 1, wherein, The reaction temperature in step (1) is -80℃ to -40℃. (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride reacts with (S)-3-aminoquinine cycloamine in the presence of a solvent. After post-treatment and drying, intermediate 2 is obtained.

3. The method of claim 2, wherein, The reaction temperature in step (1) is -80℃ to -60℃, and (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride reacts with ( S The weight ratio of 3-aminoquinine cycloamine is 1.4:1 to 1.7:1; the solvent is one or more selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran and heptane.

4. The method of claim 1, wherein, The (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride in step (1) is obtained by treating (S)-1,2,3,4-tetrahydro-1-naphthoic acid with sulfoxide; and / or The -3-aminoquinuclidine of step (1) is S The -3-aminoquinuclidine hydrochloride salt is obtained after neutralization with a base and work-up. S The -3-aminoquinuclidine hydrochloride salt is obtained after neutralization with a base and work-up.

5. The method of claim 1, wherein, In step (2), intermediate 2 undergoes a reduction reaction in the presence of a solvent, a reducing agent, and a catalyst. After post-treatment and drying, crude intermediate 3 is obtained. The reduction reaction temperature is 60°C to reflux. The solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and diethyl ether. The reducing agent is one or more selected from sodium borohydride and lithium aluminum hydride. The weight ratio of the reducing agent to intermediate 2 is 0.4:1 to 0.6:

1. The catalyst is one or more selected from boron trifluoride diethyl ether and aluminum chloride. The weight ratio of the catalyst to intermediate 2 is 2.1:1 to 2.5:

1.

6. The method according to claim 1, characterized in that, Step (3) includes: adding isopropanol and water to the crude intermediate 3, stirring, heating to reflux, stirring for at least 10 minutes; stopping heating, cooling to -5 to 0 °C, continuing to stir for at least 1 hour; filtering, collecting the filter cake; vacuum drying to obtain the pure intermediate 3.

7. The method of claim 1, wherein, In step (4), the solvent is toluene; the weight ratio of pure intermediate 3, pretreated pyridine and triphosgene is 8-12: 1-3: 6-11; the catalyst is boron trifluoride ether; the weight ratio of catalyst to pure intermediate 3 is 1.5:1-1.9:

1.

8. The method of claim 1, wherein, The amount of red aluminum added is 0.5% to 5% of the weight of pyridine; the temperature of vacuum distillation is 40℃ to 80℃.

9. The method according to claim 1, characterized in that, The pure intermediate 3 is the pure intermediate 3 after alkali neutralization and post-treatment. The steps are as follows: Mix the pure intermediate 3, water, and solvent, adjust the pH to not less than 12, separate the layers, extract the aqueous phase twice with solvent, combine the organic phases, wash, heat to reflux, dehydrate, and obtain the pure intermediate 3 after alkali neutralization and post-treatment.

10. The method of claim 1, wherein, Step (5) includes: The crude palonosetron hydrochloride was mixed with 95% ethanol at a weight ratio of 1:5 to 1:15, heated to 50 to 70°C to dissolve and clarify, then cooled to -5 to 5°C, stirred while maintaining the temperature, filtered, and dried to obtain the primary purified palonosetron hydrochloride; the above operation was repeated to obtain the secondary purified palonosetron hydrochloride. The purified water, isopropanol, and palonosetron hydrochloride secondary purified product were mixed in a weight ratio of 0.7–1.1 : 10–14 : 0.9–1.1, heated to 50–70°C to dissolve, then cooled to -10–-5°C, kept warm and stirred, and methyl tert-butyl ether was added dropwise below -5°C. The mixture was kept warm and stirred, discharged and filtered, the filter cake was washed, filtered again, and dried to obtain pure palonosetron hydrochloride.

Images