A method for reducing residual solvents in palonosetron hydrochloride

Abstract

The application discloses a method for reducing residual solvents in palonosetron hydrochloride, which comprises the following steps: subjecting palonosetron hydrochloride to at least one water-vapor saturated drying step to obtain low-solvent-residual palonosetron hydrochloride, wherein the water-vapor saturated drying step is as follows: adding 0.01-0.5 times the weight of the palonosetron hydrochloride to the palonosetron hydrochloride, and then vacuum drying. The water-vapor saturated drying method can control the residual solvents in the palonosetron hydrochloride to be less than 100 ppm.

Description

Technical Field

[0001] This invention relates to the field of active pharmaceutical ingredient synthesis technology, and in particular to a method for reducing residual solvent in palonosetron hydrochloride, and a method for preparing high-purity palonosetron hydrochloride with low residual solvent. 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] In the purification process of palonosetron hydrochloride, although most of the residual solvent in the product has been removed by crystallization and drying, there will still be some solvent residue in the obtained pure palonosetron hydrochloride. The current method can only ensure that the solvent residue is no more than 5000 ppm (0.5%), and the total amount of residual solvent cannot meet the requirement of not exceeding 100 ppm.

[0006] Currently, there is no method for preparing palonosetron hydrochloride with low residual solvent (total residual solvent not exceeding 100 ppm), which cannot meet the demands of the high-end market where residual solvent control is extremely stringent. For patients undergoing chemotherapy for moderate to severe emetogenic tumors, the residual solvent in this drug may cause them discomfort and adverse effects. Palonosetron hydrochloride with low residual solvent can provide convenience and benefit treatment. Therefore, developing a method for preparing palonosetron hydrochloride with low residual solvent (total residual solvent not exceeding 100 ppm) is extremely urgent. Summary of the Invention

[0007] The inventors tried methods from the literature and optimized crystallization and drying methods, but the total residual solvent could not meet the requirement of not exceeding 100 ppm. Even after vacuum drying at 120°C for 24 hours, although the sample appearance had changed color, the total residual solvent only decreased to 333 ppm. After continuous attempts, and with other methods proving ineffective, the method of this invention was developed, effectively solving the problem of solvent residue not reaching below 100 ppm.

[0008] One of the objectives of this invention is to provide a method for reducing residual solvent in palonosetron hydrochloride.

[0009] The second objective of this invention is to provide a method for preparing palonosetron hydrochloride.

[0010] The third objective of this invention is to provide a method for preparing palonosetron hydrochloride.

[0011] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:

[0012] In a first aspect, the present invention provides a method for reducing residual solvent in palonosetron hydrochloride, the method comprising the following steps:

[0013] The purified palonosetron hydrochloride is subjected to at least one water-saturated drying step to obtain pure palonosetron hydrochloride with low solvent residue. The water-saturated drying step is as follows: 0.01 to 0.5 (e.g., 0.05 to 0.5, 0.1 to 0.5, 0.2 to 0.5) water by weight of the purified palonosetron hydrochloride is added to the purified product, and then vacuum dried.

[0014] The total residual solvent in the pure product obtained by this method is no higher than 100 ppm.

[0015] The number of times the water-saturated drying step is performed depends on the amount of water added. For example, in one embodiment, the weight ratio of water to refined product is 0.1:1, and the step needs to be repeated two or three times to ensure that the total residual solvent is not higher than 100 ppm; the weight ratio of water to refined product is 0.05:1, and the step needs to be repeated three or four times to ensure that the total residual solvent is not higher than 100 ppm; in another embodiment, the weight ratio of water to refined product is 0.2 to 0.5:1, and the step only needs to be performed once to ensure that the total residual solvent is not higher than 100 ppm.

[0016] When the weight ratio of water added is less than 0.01, this step needs to be repeated multiple times, which is inefficient; when it is greater than 0.5, the sample dissolves. Therefore, a ratio of 0.01 to 0.5 is selected. At this water volume, the residual solvent can be below 100 ppm, which meets the requirements.

[0017] In some embodiments, the vacuum drying temperature is not higher than 60°C, preferably 20–45°C or 45–60°C.

[0018] In a second aspect, the present invention provides a method for preparing palonosetron hydrochloride, comprising the step of performing the above-mentioned method for reducing residual solvent in palonosetron hydrochloride after obtaining a refined palonosetron hydrochloride product.

[0019] To further improve the purity of palonosetron hydrochloride while reducing residual solvent, in some embodiments, the method includes the following steps:

[0020] (1) (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride reacts with (S)-3-aminoquinine cycloamine to generate intermediate 2;

[0021] (2) Intermediate 2 undergoes a reduction reaction to obtain crude intermediate 3;

[0022] (3) The crude intermediate 3 was purified to obtain the pure intermediate 3;

[0023] (4) The pure intermediate 3 was subjected to a triphosgene cyclization reaction to obtain crude palonosetron hydrochloride.

[0024] (5) The crude palonosetron hydrochloride was purified to obtain the refined palonosetron hydrochloride.

[0025] (6) The method for reducing residual solvent in palonosetron hydrochloride is carried out to obtain pure palonosetron hydrochloride.

[0026] The synthetic route is as follows:

[0027]

[0028] Step (1)

[0029] 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.

[0030] By controlling the reaction temperature, the isomers of intermediate 2 are reduced to less than 5%.

[0031] 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.

[0032] In step (1), the solvent can be one or more selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran and heptane.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] Step (2)

[0038] 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.

[0039] In step (2), the solvent can be one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and diethyl ether.

[0040] In step (2), the reducing agent may be one or more selected from sodium borohydride and lithium aluminum hydride; and / or

[0041] The weight ratio of the reducing agent to intermediate 2 can be 0.4:1 to 0.6:1.

[0042] In step (2), the catalyst may be one or more selected from boron trifluoride diethyl ether and aluminum chloride; and / or

[0043] The weight ratio of catalyst to intermediate 2 can be 2.1:1 to 2.5:1.

[0044] In step (2), the reduction reaction temperature can be from 60°C to reflux.

[0045] 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.

[0046] 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.

[0047] Step (3)

[0048] In this step, purification is achieved through recrystallization.

[0049] 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.

[0050] 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.

[0051] Purifying intermediate 3 before proceeding with subsequent reactions can reduce the impurity content in the palonosetron hydrochloride product.

[0052] Step (4)

[0053] In this step, pure intermediate 3 undergoes a ring-closure reaction with pretreated pyridine and triphosgene in the presence of a solvent. A catalyst is added to continue the reaction. After post-treatment and drying, crude palonosetron hydrochloride is obtained. The pretreated pyridine is obtained by adding red aluminum to pyridine and performing vacuum distillation, collecting the first 5% to 50% of the volume of the distillate.

[0054] Adding pyridine pretreated by a specific method can further reduce the impurity content in palonosetron hydrochloride products.

[0055] In some embodiments, the amount of red aluminum added is 0.5% to 5% of the weight of pyridine.

[0056] In some embodiments, the temperature for vacuum distillation is 40°C to 80°C.

[0057] In step (4), the solvent can be toluene.

[0058] In step (4), the weight ratio of pure intermediate 3, pretreated pyridine and triphosgene can be 8-12:1-3:6-11.

[0059] In step (4), the catalyst may be boron trifluoride diethyl ether; and / or

[0060] The weight ratio of the catalyst to pure intermediate 3 can be 1.5:1 to 1.9:1.

[0061] In step (4), the reaction temperature of the acyl chloride intermediate can be 0 to 10 °C.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] Step (5)

[0066] 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 purified palonosetron hydrochloride.

[0067] In some implementations, step (5) includes:

[0068] 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.

[0069] 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 the purified palonosetron hydrochloride product.

[0070] 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.

[0071] Step (6)

[0072] This step is the same as the step in the method for reducing residual solvent in palonosetron hydrochloride in the first aspect, and will not be repeated here.

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

[0074] By using the methods described above to reduce residual solvent and improve purity, palonosetron hydrochloride with a purity of not less than 99.99%, a single impurity of not more than 0.01%, and a solvent residue of not more than 100 ppm can be obtained.

[0075] Thirdly, the present invention provides palonosetron hydrochloride prepared by the above method, wherein the total residual solvent of the palonosetron hydrochloride is not higher than 100 ppm.

[0076] Furthermore, the purity of the palonosetron hydrochloride is not less than 99.98%, or even not less than 99.99%, and the individual impurity in the palonosetron hydrochloride is not higher than 0.01%, and the total impurities are not higher than 0.01%.

[0077] Beneficial effects

[0078] 1. The present invention uses a water vapor saturation drying method to control the residual solvent of palonosetron hydrochloride to below 100 ppm.

[0079] 2. Further investigation and research revealed that when using Route 1 to synthesize palonosetron, the reaction temperature of (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride with (S)-3-aminoquinine cycloamine to generate intermediate 2 was controlled at -80℃ to -40℃, and the isomers were effectively controlled. Intermediate 3 was purified using isopropanol / purified water. When preparing crude palonosetron, pyridine pretreated by a specific pretreatment method was added, and after purification, palonosetron hydrochloride with a purity of not less than 99.99% and a single impurity and total impurity not exceeding 0.01% could be obtained.

[0080] 3. This invention optimizes the process to obtain a method for preparing palonosetron hydrochloride with ultra-high purity and ultra-low residual solvent, which is suitable for industrial production. The quality of the obtained palonosetron hydrochloride meets or exceeds existing pharmaceutical standards, enabling it to enter the market with high standards for any single impurity, total impurities and residues in the raw material, bringing more convenience to patients and benefiting treatment.

[0081] 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.

[0082] 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%. Detailed Implementation

[0083] 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.

[0084] Unless otherwise specified, the raw materials, reagents, and methods used in the embodiments are all conventional raw materials, reagents, and methods in the art.

[0085] Main instruments:

[0086] 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.

[0087] 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.

[0088] All other reagents were commercially available industrial grade or chemically pure.

[0089] Detection method:

[0090] 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:

[0091]

[0092] I. Related substances of palonosetron hydrochloride:

[0093] 1. Related substances (ABAC, i.e., intermediate 3):

[0094] 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.

[0095] 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.

[0096] 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%.

[0097] Table 1. Mobile Phase Gradient Table

[0098]

[0099] 2. Related substances (specified impurities: impurities A, B, diastereomers of palonosetron hydrochloride (impurities C and D), impurity E, enantiomers of palonosetron hydrochloride):

[0100] 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.

[0101] 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.

[0102] 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 ℃.

[0103] 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%.

[0104] Table 2 Correction Factor Table

[0105]

[0106] 3. Related substances (unspecified impurities, including but not limited to RRT 0.88 impurities):

[0107] 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 ml, which will be used as the sensitivity solution.

[0108] 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℃.

[0109] 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%.

[0110] The total amount of impurities (the sum of specified impurities, unspecified impurities, and ABAC) must not exceed 0.5%.

[0111] II. Purity of palonosetron hydrochloride:

[0112] Purity % = 100% - Total impurities.

[0113] III. Residual solvent of palonosetron hydrochloride:

[0114] 1. Isopropanol, tetrahydrofuran, diethyl ether, pyridine, toluene, and methyl tert-butyl ether:

[0115] Accurately weigh 0.1 g of this product and place it in a headspace vial. Accurately add 0.2 ml of N,N-dimethylformamide, seal, and use as the test solution. Accurately weigh appropriate amounts of isopropanol, tetrahydrofuran, diethyl ether, pyridine, toluene, and methyl tert-butyl ether, and quantitatively dilute with N,N-dimethylformamide to prepare a mixed solution containing approximately 1 mg of isopropanol, 0.25 mg of tetrahydrofuran, 0.25 mg of diethyl ether, 5 μg of pyridine, 0.35 mg of toluene, and 1 mg of methyl tert-butyl ether per ml. Accurately measure 0.2 ml of this solution and place it in a headspace vial, seal, and use as the reference solution.

[0116] According to the residual solvent determination method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0861), a capillary column (GRACE EC-WAX 30m × 0.53mm × 1.2μm suitable) with polyethylene glycol as the stationary phase was used. A programmed temperature ramp was employed: an initial temperature of 40℃ was maintained for 5 minutes, the temperature was increased to 100℃ at a rate of 10℃ per minute, and then increased to 240℃ at a rate of 20℃ per minute, and maintained for 25 minutes. A flame ionization detector (FID) was used with a detector temperature of 250℃ and an injection port temperature of 230℃. Headspace sampling was performed, with the headspace vial equilibrated at 120℃ for 30 minutes, and an injection volume of 1 ml.

[0117] Inject the reference solution and test solution into the headspace separately and record the chromatograms. The relative standard deviation (RSD) of the pyridine peak area in the reference solution should not exceed 20%, and the RSD of the peak areas of all other analyte solvents should not exceed 10%. The signal-to-noise ratio (SNR) of pyridine should not be less than 20. Calculated by peak area using the external standard method, the content of isopropanol should not exceed 0.2%, tetrahydrofuran should not exceed 0.05%, toluene should not exceed 0.07%, methyl tert-butyl ether should not exceed 0.2%, diethyl ether should not exceed 0.05%, pyridine should not exceed 0.002%, and total residual solvent should not exceed 0.5%.

[0118] 2. 2-Chloropropane:

[0119] Accurately weigh 0.1 g of this product and place it in a headspace vial. Accurately add 0.2 ml of N,N-dimethylformamide, seal, and use as the test solution. Accurately weigh an appropriate amount of 2-chloropropane and quantitatively dilute it with N,N-dimethylformamide to prepare a solution containing approximately 0.4 mg per ml. Accurately measure 0.2 ml of this solution and place it in a headspace vial, seal, and use as the reference solution.

[0120] According to the residual solvent determination method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0861), a capillary column (Agilent DB-624 60m × 0.32mm × 1.8μm suitable) with 6% cyanopropyl-94% methylpolysiloxane as the stationary phase was used. A programmed temperature ramp was employed: an initial temperature of 50℃ was maintained for 3 minutes, followed by a ramp to 230℃ at a rate of 15℃ per minute, and maintained for 15 minutes. A flame ionization detector (FID) was used with a detector temperature of 250℃ and an injection port temperature of 230℃. Headspace sampling was performed, with the headspace vial equilibrated at 100℃ for 30 minutes, and an injection volume of 1 ml.

[0121] Inject the reference solution and test solution separately into the headspace and record the chromatograms. The relative standard deviation (RSD) of the 2-chloropropane peak area in the reference solution should not exceed 10%. Calculated by peak area using the external standard method, the 2-chloropropane content should not exceed 0.01%.

[0122] Preparation Example

[0123] (1) Synthesis of (S)-3-aminoquinine cyclic amine

[0124] 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.

[0125] (2) Preparation of intermediate 2

[0126] 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).

[0127] Start stirring and cool 4150g of a toluene solution of (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride (containing 367g of (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride) to -80℃ to -60℃. Add dropwise 1859g of a toluene solution of (S)-3-aminoquinine cycloamine prepared in step (1) (containing 237.9g ​​of (S)-3-aminoquinine cycloamine), maintaining the reaction temperature at -80℃ to -60℃. After the addition is complete, stir for at least 2 hours. Raise the temperature to 20-30℃ and stir for at least 6 hours. Filter, wash the filter cake twice with 412g of toluene, and dry at no higher than 50℃ to obtain intermediate 2.

[0128] (3) Preparation of intermediate 3

[0129] Add 1250g of intermediate 2 and 6665g of tetrahydrofuran prepared in step (2) to the reactor. Under nitrogen protection, at a temperature not exceeding 25℃, add 589g of sodium borohydride in batches and 287g of boron trifluoride ether dropwise, controlling the temperature at 0-10℃. Heat to reflux until the reaction is complete. Add hydrochloric acid solution dropwise and heat to reflux until the reaction is complete. Cool to 20-30℃, 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, at a temperature not exceeding 20℃. Cool to not higher than -5℃, 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 and wash twice with sodium chloride solution. Concentrate under reduced pressure, cool the concentrate to 0-5℃, 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.

[0130] (4) Purification of intermediate 3

[0131] The reactor is equipped with a mechanical stirrer, a nitrogen-purged reflux condenser, a thermometer (covering -30 to 100°C), and a dropping funnel. Add 1145 g of crude intermediate 3 prepared in step (3), 8995 g of isopropanol, and 802 g of purified water. Stir and heat to reflux. Stir for at least 10 minutes. Stop heating and cool to -5 to 0°C. Continue stirring at -5 to 0°C for at least 1 hour. Filter and collect the filter cake. Vacuum dry at no higher than 50°C to obtain pure intermediate 3.

[0132] (5) Preparation of crude palonosetron hydrochloride

[0133] 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.

[0134] Add 2.49 kg of purified water, 820 g of the pure intermediate 3 prepared in step (4), and 7.13 kg of toluene to the reaction vessel under nitrogen protection. Keep 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 7.13 kg of toluene, combine the organic phases, and wash once with sodium chloride aqueous solution. Heat the organic phase to reflux and dehydrate. Cool to no higher than -5°C, add 160 g of the pretreated pyridine, and add triphosgene toluene solution dropwise (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, control the temperature to no higher than 10°C, add 1370 g of boron trifluoride diethyl ether dropwise, stir for more than 2 hours, and reflux the reaction for more than 8 hours. After the reaction is complete, the temperature is lowered to no higher than 10°C, and hydrochloric acid aqueous solution (784g concentrated hydrochloric acid dissolved in 2.66kg purified water) is added dropwise. The mixture is then refluxed for at least 2 hours. The mixture is cooled, the layers are separated, and the aqueous phase is collected. 7.13kg toluene and 2.94kg tetrahydrofuran are added, and sodium hydroxide aqueous solution is added dropwise until the pH is ≥12. The aqueous phase is extracted with 4.30kg toluene and 2.21kg tetrahydrofuran. The organic phases are combined, washed once with water, and concentrated under reduced pressure until no fraction flows out. 1.92kg isopropanol is added, the temperature is lowered, and isopropanol hydrochloride is added dropwise until the pH is ≤2. The mixture is cooled and stirred for at least 1 hour. The mixture is filtered, and the filter cake is washed with 369g isopropanol. The mixture is then dried under vacuum at 30–40°C to obtain crude palonosetron hydrochloride. The RRT0.88 impurity content is 0.006%, and the purity of the crude palonosetron hydrochloride is 99.0%.

[0135] (6) Preparation of palonosetron hydrochloride purified product

[0136] Add 3.83 kg of 95% ethanol and 684 g of crude palonosetron hydrochloride prepared in step (5) to the reactor 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 to 50°C to obtain the primary purified palonosetron hydrochloride.

[0137] 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.

[0138] Add 280g of purified water, 3280g of isopropanol, and 305g of the 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. Controlling the temperature below -5℃, add 1125g of methyl tert-butyl ether dropwise. After the addition is complete, maintain the temperature at -10 to -5℃ and stir for at least 1 hour. 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 the purified palonosetron hydrochloride product. The maximum single impurity (RRT 0.92) is 0.0035%, the total impurities are 0.006%, and the purity of palonosetron hydrochloride is 99.99%. The total residual solvent is 540ppm.

[0139] Purification Example 1

[0140] Take 20g of the prepared palonosetron hydrochloride product (purified product) from the preparation example, add 2g of purified water and mix well. Dry under vacuum at 60℃ for 16 hours to obtain pure palonosetron hydrochloride. The total residual solvent was 169ppm.

[0141] After repeating the above process twice more, the total residual solvent was 57 ppm.

[0142] Purification Example 2

[0143] Take 20g of the prepared palonosetron hydrochloride product (purified product), add 4g of purified water and mix well. Dry under vacuum at 20°C for 16 hours and then under vacuum at 45°C for 4 hours to obtain pure palonosetron hydrochloride. The total residual solvent was measured to be 89ppm.

[0144] Purification Example 3

[0145] Take 20g of the prepared palonosetron hydrochloride product (purified product) and add 10g of purified water to mix well (the sample has a tendency to dissolve and is not easy to handle). After vacuum drying at 20°C for 16 hours, it is then vacuum dried at 45°C for 4 hours to obtain pure palonosetron hydrochloride. The total residual solvent was found to be 49ppm.

[0146] Therefore, when the amount of purified water is small, multiple operations are required to reduce the solvent level to a low level. However, when the weight ratio of purified water is 0.2 to 0.5, only one operation is needed to reduce the solvent level to a low level.

[0147] Comparative purification examples 1-11

[0148] The palonosetron hydrochloride products from the preparation examples were subjected to different treatments, and the total residual solvent was measured. The treatment methods and results for each comparative purification example are detailed in the table below:

[0149]

[0150]

[0151] As can be seen, the method of the present invention is simple and effective, and can reduce the total amount of residual solvent in the sample to below 100 ppm, thus meeting the high-quality requirements.

[0152] 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 method for reducing residual solvent in palonosetron hydrochloride, characterized in that, 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; (4) The pure intermediate 3 was subjected to a triphosgene cyclization reaction to obtain crude palonosetron hydrochloride; (5) The crude palonosetron hydrochloride was purified to obtain the refined palonosetron hydrochloride; (6) The refined palonosetron hydrochloride is subjected to at least one water-saturated drying step to obtain pure palonosetron hydrochloride with low solvent residue. The reaction temperature in step (1) is -80℃ to -40℃; 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. Step (3) Purification is carried out by recrystallization. The solvent used for recrystallization is a mixture of isopropanol and water, with a volume ratio of isopropanol to water of (8-12):0.

7. Step (4) includes: reacting intermediate 3 pure product with pretreated pyridine and triphosgene in the presence of solvent, adding catalyst, continuing the reaction, and after post-treatment and drying to obtain crude palonosetron hydrochloride, wherein the pretreated pyridine is obtained by adding red aluminum to pyridine and performing vacuum distillation, collecting the first 5% to 50% volume of the distillate. In step (6), the water vapor saturation drying step is as follows: add 0.1 to 0.5 times the weight of the refined palonosetron hydrochloride product to water, and then vacuum dry it, wherein the vacuum drying temperature is not higher than 60°C.

2. The method according to claim 1, characterized in that, In step (6), vacuum drying includes the following steps: vacuum drying at 20°C for 16 hours, followed by vacuum drying at 45°C for 4 hours.

3. The method according to claim 1, characterized in that, In step (6), the weight ratio of water to refined product is 0.2 to 0.5:

1.

4. The method according to claim 1, characterized in that, In step (6), the vacuum drying temperature is 20-45°C or 45-60°C.

5. The method according to claim 1, characterized in that, The reaction temperature in step (1) is -80℃ to -60℃.

6. The method according to claim 1, characterized in that, In step (2), the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and diethyl ether; The reducing agent is selected from one or more of sodium borohydride and lithium aluminum hydride; The catalyst is selected from one or more of boron trifluoride diethyl ether and aluminum chloride.

7. 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.

8. The method according to claim 1, characterized in that, In step (4), the catalyst is boron trifluoride diethyl ether.

9. The method according to claim 1, characterized in that, In step (4), the amount of red aluminum added is 0.5% to 5% of the weight of pyridine.

10. The method according to claim 1, characterized in that, In step (4), the temperature of vacuum distillation is 40℃~80℃.

11. The method according to claim 1, characterized in that, Step (5) includes: The crude palonosetron hydrochloride was mixed with 95% ethanol at a weight ratio of 1:(5-15), heated to 50-70°C to dissolve and clarify, then cooled to -5-5°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 the purified palonosetron hydrochloride product.

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