A preparation and purification method of a high-purity perospirone hydrochloride intermediate and its application

Abstract

The present invention relates to a method for preparing and purifying a high-purity compound of formula I, comprising the following steps: 1) placing a desired amount of a compound of formula II and 1,4-dibromobutane in a solvent a, reacting them under stirring in the presence of a base, filtering the resulting reaction solution, collecting the filtrate and concentrating it under reduced pressure to 25% to 50% of its original volume, crystallizing, filtering, and drying to obtain a crude compound of formula I; and 2) adding the crude compound of formula I to a solvent b, stirring, filtering, washing the filter cake, and drying to obtain a purified compound of formula I. The resulting purified compound of formula I has high purity (purity ≥99%, the amount of compound of formula III contained ≤0.1% and other unknown impurities ≤0.1%) and low residual mutagenic 1,4-dibromobutane (≤15 ppm), thereby improving drug quality and achieving controllable drug quality, thereby ensuring the effectiveness and safety of clinical medication. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a preparation and purification method of a high-purity perospirone hydrochloride intermediate and an application thereof. Background Art

[0002] Perospirone hydrochloride (N-{4-[4-(1,2-benzisothiazol-3-yl)-1-piperazine]butyl}cyclohexane-1,2-dicarboximide hydrochloride dihydrate) is an atypical antipsychotic that acts by affecting dopamine metabolic pathways and blocking dopamine-2 and 5-HT2 receptors. It is clinically used to treat schizophrenia. Compared with haloperidol, perospirone hydrochloride has stronger selectivity for the striatum and is less likely to cause extrapyramidal reactions, offering better selectivity and clinical safety.

[0003]

[0004] Perospirone hydrochloride is prepared by reacting cis-hexahydrophthalimide with 1,4-dibromobutane to produce the intermediate cis-N-4-bromobutyl-hexahydrophthalimide. In this reaction, the molar ratio of 1,4-dibromobutane (a mutagen): cis-hexahydrophthalimide is greater than 5 to avoid the formation of disubstituted byproducts. However, the large-scale use of 1,4-dibromobutane (a mutagen) poses health risks to operators and affects product purity and safety. Therefore, a new method for preparing perospirone hydrochloride is needed to improve its purity and yield while effectively controlling the safety limit of 1,4-dibromobutane. Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing and purifying a high-purity compound of formula I, comprising the following steps:

[0006] 1) placing the required amount of the compound of formula II and 1,4-dibromobutane in solvent a, reacting with stirring in the presence of a base, filtering the resulting reaction solution, collecting the filtrate and concentrating it under reduced pressure to 25% to 50% of its original volume, crystallizing, filtering, and drying to obtain a crude compound of formula I;

[0007]

[0008] 2) The crude compound of formula I is added to solvent b, stirred, filtered, and the filter cake is washed and dried to obtain a purified compound of formula I.

[0009] In a preferred technical solution of the present invention, in step 1), the solvent a is selected from an aqueous polar solution or a non-aqueous polar solvent.

[0010] In a preferred technical solution of the present invention, the water content in the polar solution is 0.5-15% (volume ratio).

[0011] In a preferred technical solution of the present invention, the polar solvent is selected from any one of acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, n-butanol, and butanediol, or a combination thereof.

[0012] In a preferred technical solution of the present invention, in step 1), the volume mass ratio of the solvent a to the compound of formula II is 2 to 10:1 mL / g, preferably 3 to 8:1 mL / g.

[0013] In a preferred technical solution of the present invention, in step 1), the molar ratio of the compound of formula II to 1,4-dibromobutane is 1:1 to 1.5, preferably 1:1 to 1.05.

[0014] According to a preferred technical solution of the present invention, in step 1), the base is an inorganic base and / or an organic base.

[0015] According to a preferred technical solution of the present invention, the inorganic base is selected from any one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate, or a combination thereof.

[0016] According to a preferred technical solution of the present invention, the organic base is selected from any one of triethylamine and pyridine or a combination thereof.

[0017] According to a preferred technical solution of the present invention, in step 1), the molar ratio of the compound of formula II to the base is 1:1-6, preferably 1:1-3.

[0018] According to a preferred technical solution of the present invention, in step 1), the reaction temperature is 15 to 80°C.

[0019] According to a preferred technical solution of the present invention, in step 1), the crystallization temperature is 0-10°C.

[0020] According to a preferred technical solution of the present invention, in step 1), the crystallization time is 0.5 to 1 h.

[0021] According to a preferred technical solution of the present invention, in step 2), the solvent b is any one of an alkane solvent, an ester solvent, and an ether solvent, or a combination thereof.

[0022] According to a preferred technical solution of the present invention, the alkane solvent is selected from any one of dichloromethane, chloroform, and 1,2-dichloroethane, or a combination thereof.

[0023] According to a preferred technical solution of the present invention, the ester solvent is selected from any one of ethyl acetate, methyl acetate, and butyl acetate, or a combination thereof.

[0024] According to a preferred technical solution of the present invention, the ether solvent is selected from any one of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, or a combination thereof.

[0025] According to a preferred technical solution of the present invention, in step 2), the volume mass ratio of the solvent b to the crude compound of formula I is 1 to 10:1 mL / g, preferably 2 to 7:1 mL / g.

[0026] According to a preferred technical solution of the present invention, in step 2), the stirring temperature is 0 to 60°C, preferably 10 to 55°C.

[0027] According to a preferred technical solution of the present invention, in step 2), the stirring time is 0.5 to 3 hours, preferably 1 to 2 hours.

[0028] According to a preferred technical solution of the present invention, in step 2), the washing solvent is selected from any one of an alkane solvent, an ester solvent, and an ether solvent, or a combination thereof.

[0029] According to a preferred technical solution of the present invention, the washing solvent is selected from any one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methyl acetate, butyl acetate, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, or a combination thereof.

[0030] In a preferred technical solution of the present invention, in step 1) and step 2), the drying is selected from any one of reduced pressure drying, vacuum drying, spray drying, or a combination thereof.

[0031] In a preferred technical solution of the present invention, the drying temperature is 25-80°C, preferably 30-50°C.

[0032] In a preferred technical solution of the present invention, the purity of the purified compound of formula I is ≥99%, preferably ≥99.9%.

[0033] In the preferred technical solution of the present invention, the content of the compound of formula III in the purified product of the compound of formula I is ≤0.1%, and other unknown impurities are ≤0.1%.

[0034]

[0035] In a preferred technical solution of the present invention, the content of the compound of formula III in the purified product of the compound of formula I is ≤0.05%.

[0036] In a preferred technical solution of the present invention, the 1,4-dibromobutane content in the purified compound of formula I is ≤15 ppm, preferably ≤10 ppm, and more preferably ≤5 ppm.

[0037] Another object of the present invention is to provide a high-purity compound of formula I, wherein the purity of the compound of formula I is ≥99%, preferably ≥99.9%.

[0038] In the preferred technical solution of the present invention, the content of the compound of formula III in the compound of formula I is ≤0.1%, and other unknown impurities are ≤0.1%.

[0039]

[0040] In a preferred technical solution of the present invention, the content of the compound of formula III in the compound of formula I is ≤0.05%.

[0041] In a preferred technical solution of the present invention, the content of 1,4-dibromobutane in the compound of formula I is ≤15 ppm, preferably ≤10 ppm, and more preferably ≤5 ppm.

[0042] Another object of the present invention is to provide a method for preparing high-purity perospirone hydrochloride, comprising the steps of reacting the compound of formula I prepared by the present invention with cis-hexahydrophthalimide to prepare perospirone, then salifying the prepared perospirone with hydrochloric acid, and then purifying the prepared perospirone hydrochloride by recrystallization, separating, washing, and drying to obtain,

[0043]

[0044] In a preferred technical solution of the present invention, the molar ratio of the compound of formula I to cis-hexahydrophthalimide is 1:1.0-1.2.

[0045] In a preferred technical solution of the present invention, the reaction temperature of the compound of formula I and cis-hexahydrophthalimide is 90-150°C, preferably 100-145°C.

[0046] In a preferred technical solution of the present invention, the reaction time of the compound of formula I and cis-hexahydrophthalimide is 1 to 5 hours, preferably 1.5 to 3 hours.

[0047] In a preferred technical solution of the present invention, the recrystallization solvent is any one of a methanol solution, an ethanol solution, and an isopropanol solution or a combination thereof with a water content of 5 to 25%, and the water content of the recrystallization solvent is preferably 10 to 20%.

[0048] In a preferred technical solution of the present invention, the separation is selected from any one of centrifugation, filtration, and membrane separation, or a combination thereof.

[0049] In a preferred technical solution of the present invention, the washing solvent is selected from any one of water, methanol, ethanol, isopropanol, or a combination thereof.

[0050] In a preferred technical solution of the present invention, the drying is selected from any one of reduced pressure drying, vacuum drying, spray drying, or a combination thereof.

[0051] In a preferred technical solution of the present invention, the drying temperature is 25-80°C, preferably 30-50°C.

[0052] The object of the present invention is to provide a compound of formula III or a pharmaceutically acceptable salt thereof,

[0053]

[0054] In a preferred technical solution of the present invention, the pharmaceutically acceptable salt is an acid addition salt thereof.

[0055] According to a preferred technical solution of the present invention, the acid is any one of an organic acid or an inorganic acid.

[0056] According to a preferred technical solution of the present invention, the organic acid is selected from any one of formic acid, acetic acid, citric acid, fumaric acid, maleic acid, succinic acid, and methanesulfonic acid, or a combination thereof.

[0057] According to a preferred technical solution of the present invention, the inorganic acid is selected from any one of hydrochloric acid, sulfuric acid, nitric acid, and hydrobromic acid, or a combination thereof.

[0058] In a preferred technical solution of the present invention, the purity of the compound of formula III is ≥97%, preferably ≥98%.

[0059] Another object of the present invention is to provide a method for preparing a compound of formula III or a pharmaceutically acceptable salt thereof, comprising the steps of placing a compound of formula II and a compound of formula I in a solvent, introducing carbon dioxide into the reaction system under pressure in the presence of a base, reacting under stirring, filtering the obtained reaction solution, and concentrating the filtrate under reduced pressure to obtain a crude compound of formula III.

[0060]

[0061] According to a preferred technical solution of the present invention, the solvent is selected from any one of ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, or a combination thereof.

[0062] According to a preferred technical solution of the present invention, in the reaction system, the volume mass ratio of the solvent to the compound of formula II is 1.5 to 20:1 mL / g, preferably 3 to 10:1 mL / g.

[0063] According to a preferred technical solution of the present invention, in the reaction system, the molar ratio of the compound of formula II to the compound of formula I is 1:1-3, preferably 1:1.2-2.

[0064] According to a preferred technical solution of the present invention, the base is an inorganic base.

[0065] According to a preferred technical solution of the present invention, the inorganic base is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, or a combination thereof.

[0066] In a preferred technical solution of the present invention, the molar ratio of the compound of formula II to the base is 1:0.5-5, preferably 1:1-3.

[0067] According to a preferred technical solution of the present invention, the reaction system also includes a phase transfer catalyst.

[0068] According to a preferred technical solution of the present invention, the phase transfer catalyst is selected from any one of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, and benzyltriethylammonium chloride, or a combination thereof.

[0069] According to a preferred technical solution of the present invention, the molar ratio of the compound of formula II to the phase transfer catalyst is 1:0.01-0.2, preferably 1:0.05-0.15.

[0070] According to a preferred technical solution of the present invention, the pressure of the reaction system is 0.1 to 10 MPa, preferably 2 to 5 MPa.

[0071] According to a preferred technical solution of the present invention, the reaction temperature of the reaction system is 20 to 120°C, preferably 50 to 100°C.

[0072] According to a preferred technical solution of the present invention, the reaction time of the reaction system is 1 to 24 hours, preferably 5 to 10 hours.

[0073] According to a preferred technical solution of the present invention, the obtained crude compound of formula III is purified by silica gel column chromatography.

[0074] According to a preferred technical solution of the present invention, the eluent for the silica gel column chromatography is a mixed solvent consisting of a halogenated alkane solvent and an alcohol solvent.

[0075] According to a preferred technical solution of the present invention, the halogenated alkane solvent is selected from any one of dichloromethane and dichloroethane, or a combination thereof.

[0076] According to a preferred technical solution of the present invention, the alcohol solvent is selected from any one of methanol, ethanol, and isopropanol, or a combination thereof.

[0077] According to a preferred technical solution of the present invention, the volume ratio of the halogenated alkane solvent to the alcohol solvent is 10 to 30:1, preferably 20 to 25:1.

[0078] According to the preferred technical solution of the present invention, the purity of the compound of formula III obtained is ≥97%, preferably ≥98%.

[0079] Another object of the present invention is to provide the use of the compound of formula III or a pharmaceutically acceptable salt thereof as a standard or reference substance for detecting the purity of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0080]

[0081] The object of the present invention is to provide a high performance liquid chromatography method for detecting the purity of the compound of formula I, wherein the chromatographic column stationary phase is filled with octadecylsilane bonded silica gel, the mobile phase is a mixed solution of buffered saline solution and acetonitrile, wherein the volume ratio of buffered saline solution to acetonitrile in the mobile phase is 70:30 to 20:80 for gradient elution, the detection wavelength is 210 to 240 nm, the flow rate is 0.7 to 0.9 mL / min, the column temperature is 28 to 32 ° C, and the injection volume is 10 to 20 μL.

[0082] According to a preferred technical solution of the present invention, the content of the compound of formula III in the compound of formula I is ≤0.1%, preferably ≤0.05%.

[0083] According to a preferred technical solution of the present invention, the detector is selected from a diode array detector or an ultraviolet detector.

[0084] According to a preferred technical solution of the present invention, the buffered saline solution is a phosphate solution.

[0085] According to a preferred technical solution of the present invention, the phosphate is selected from any one of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, or a combination thereof.

[0086] According to a preferred technical solution of the present invention, the concentration of the phosphate solution is 0.5 to 3 mg / mL, preferably 1 to 2.5 mg / mL.

[0087] According to a preferred technical solution of the present invention, the buffered salt solution optionally contains an ion pair reagent.

[0088] According to a preferred technical solution of the present invention, the ion pair reagent is selected from any one of sodium heptane sulfonate, sodium pentane sulfonate, sodium hexane sulfonate, sodium octane sulfonate, and sodium decane sulfonate, or a combination thereof.

[0089] According to a preferred technical solution of the present invention, the concentration of the ion pair reagent in the buffered saline solution is 0.5 to 3 mg / mL, preferably 1 to 2.5 mg / mL.

[0090] According to a preferred technical solution of the present invention, the buffered salt solution optionally contains a pH regulator.

[0091] According to a preferred technical solution of the present invention, the pH regulator is any one of hydrochloric acid, trifluoroacetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, or a combination thereof.

[0092] According to a preferred technical solution of the present invention, the buffered salt solution has a pH of 2 to 5, preferably a pH of 3 to 4.

[0093] In a preferred technical solution of the present invention, the dilution solvent is used to prepare, dissolve and dilute the test solution and the reference solution.

[0094] According to a preferred technical solution of the present invention, the dilution solvent is selected from any one of water, methanol, acetonitrile and mobile phase.

[0095] According to a preferred technical solution of the present invention, the diameter of the chromatographic column is 3 to 5 mm, the length of the chromatographic column is 100 to 300 mm, and the particle size of the filler in the chromatographic column is 3 to 5 μm.

[0096] According to a preferred technical solution of the present invention, the chromatographic column is selected from Waters Symmetry C18, 3.9×150 mm, 5 μm.

[0097] According to a preferred technical solution of the present invention, the chromatographic column is selected from an octadecyl bonded silica gel reverse phase column, and the volume ratio of the buffered salt solution to acetonitrile in the mobile phase is 85:15 to 20:80.

[0098] According to a preferred technical solution of the present invention, the mobile phase consists of a mobile phase A and a mobile phase B, wherein the mobile phase is composed of a buffer solution containing 0.1% potassium dihydrogen phosphate and 0.1% sodium heptane sulfonate and acetonitrile in a volume ratio of 90:10, and the mobile phase B is composed of a buffer solution containing 0.1% potassium dihydrogen phosphate and 0.1% sodium heptane sulfonate and acetonitrile in a volume ratio of 20:80.

[0099] According to the preferred technical solution of the present invention, the column temperature is 30°C, the flow rate is 0.8 mL / min, and the injection volume is 10 μL.

[0100] The preferred technical solution of the present invention is that the gradient program is:

[0101] Time (min) Mobile phase A (%) Mobile phase B (%) 0 85 15 10 70 30 40 20 80 45 20 80 50 85 15

[0102] Unless otherwise specified, the present invention uses gas chromatography to detect the residual 1,4-dibromobutane in the compound of formula I.

[0103] Main reagents: methanol (chromatographic grade), 1,4-dibromobutane (analytical grade).

[0104] Main instruments: gas chromatograph, electronic balance (0.01 mg).

[0105] (1) Chromatographic conditions

[0106] Chromatographic column: DB-17, stationary phase: 50% phenyl-50% dimethylpolysiloxane, 30m×0.32mm, 0.25μm quartz capillary column;

[0107] Column temperature: starting at 60°C, increasing at a rate of 10°C per minute to 270°C, and maintaining for 10 minutes;

[0108] Carrier gas: nitrogen;

[0109] Carrier gas flow rate: 2.0 mL / min;

[0110] Inlet temperature: 250°C;

[0111] Injection volume: 1.0 μL; split ratio: 2:1;

[0112] Detector: flame ionization detector (FID);

[0113] Detector temperature: 300°C;

[0114] Hydrogen flow rate: 40 mL / min;

[0115] Air flow rate: 400mL / min.

[0116] (2) Solution preparation

[0117] Blank solution: methanol.

[0118] 1,4-Dibromobutane reference stock solution: Weigh 30 mg of 1,4-dibromobutane (analytical grade) into a 20 mL volumetric flask, dilute to the mark with methanol, and shake well; accurately measure 1.0 mL of the solution into a 100 mL volumetric flask, dilute to the mark with methanol, and shake well.

[0119] 1,4-Dibromobutane reference solution: Accurately measure the 1,4-dibromobutane reference stock solution and place it in a 10mL volumetric flask. Add methanol to dilute to the mark and shake well. Prepare fresh solution before use.

[0120] Test solution: Accurately weigh 1.0 g of compound of formula I into a 10 mL volumetric flask. Dissolve in methanol and dilute to volume. Shake well. Prepare two portions by the same method. Prepare fresh immediately before use.

[0121] (3) Determination

[0122] Take blank solution, 1,4-dibromobutane control solution and test solution and inject them respectively, and record the chromatogram.

[0123] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentages are volume / volume percentages; when the present invention relates to the percentage between liquids and solids, the percentages are volume / weight percentages; when the present invention relates to the percentage between solids and liquids, the percentages are weight / volume percentages; and the rest are weight / weight percentages.

[0124] Compared with the prior art, the present invention has the following beneficial technical effects:

[0125] 1. The preparation and purification method of the compound of formula I provided by the present invention has the advantages of simple operation, high yield (yield ≥80%), economy, safety, environmental protection, and suitability for industrial production. The obtained compound of formula I has high purity (purity ≥99%, the amount of the compound of formula III contained ≤0.1% and other unknown impurities ≤0.1%) and low residual mutagenic substance 1,4-dibromobutane (≤15ppm), which is beneficial to improving the quality of drugs and achieving controllable drug quality, ensuring the effectiveness and safety of clinical drugs.

[0126] 2. The present invention achieves the separation, identification, and synthetic preparation of the compound of formula III for the first time. The obtained purified compound of formula III has high purity and can be used as a standard or reference substance for detecting the purity of the compound of formula I or its pharmaceutically acceptable salt, which is beneficial to improving the quality of drugs and achieving controllable drug quality, thereby ensuring the effectiveness and safety of clinical drugs.

[0127] 3. The present invention studies and screens the chromatographic conditions and elution conditions of the high-performance liquid chromatography method for detecting the compound of formula I. The obtained high-performance liquid chromatography method has the advantages of good specificity, high separation, and excellent sensitivity, which facilitates the realization of drug quality control and ensures the effectiveness and safety of clinical drug use. BRIEF DESCRIPTION OF THE DRAWINGS

[0128] Figure 1 LC-MS spectrum of the compound of formula III prepared in Example 1;

[0129] Figure 2 H NMR spectrum of the compound of formula III prepared in Example 1;

[0130] Figure 3 A magnified view of the H NMR spectrum of the compound of formula III prepared in Example 1;

[0131] Figure 4 The carbon NMR spectrum of the compound of formula III prepared in Example 1;

[0132] Figure 5 HPLC test results of the purified compound of formula I obtained in Example 4. DETAILED DESCRIPTION

[0133] The following further describes the above contents of the present invention in detail through specific embodiments, but this should not be understood as any limitation to the subject matter of the present invention. All technical solutions implemented based on the above contents of the present invention belong to the scope of the present invention.

[0134] Example 1 Preparation and purification of compound of formula III

[0135] The preparation and purification of the compound of formula III comprises the following steps:

[0136] 1) Add 5.0 g of the compound of Formula II, 9.7 g of the compound of Formula I, 734 mg of tetrabutylammonium bromide, 6.3 g of potassium carbonate, and 50 mL of N,N-dimethylformamide to an autoclave. Pipe carbon dioxide into the autoclave 2-3 times to displace the air. Continue bubbling carbon dioxide until the pressure reaches 2 MPa. Heat to 80°C with stirring and react for 5 h. Cool the reaction system to 20±5°C, slowly release unreacted carbon dioxide, filter the reaction solution, and concentrate the filtrate to dryness under reduced pressure at 45±5°C to obtain a crude compound of Formula III.

[0137] 2) 25 mL of dichloromethane was added to the crude compound of Formula III to dissolve it. The product was then separated and purified by column chromatography (300-400 mesh silica gel, eluent: dichloromethane:methanol = 25:1) to obtain 7.9 g of the compound of Formula III. HPLC analysis showed a purity of 97.88%.

[0138] The compound of formula III (see Figure 1 ), and obtained the quasi-molecular ion peak m / z: 537 (M+H) + .

[0139] The H NMR spectrum of the compound of formula III (see Figure 2 、 Figure 3 ) and carbon spectrum (see Figure 4 ):

[0140] 1 H NMR (400MHz, CDCl3), δ=7.917~7.880(t, 2H), 7.834~7.793 (t, 2H), 7.504~7.439(m, 2H), 7.397~7.329(m, 2H), 4.192~4.160 (t, 2H), 3.730~3.705 (t, 4H), 3.588~3.503 (m, 8H), 2.699~2.675 (t, 4H), 2.500~2.463 (t, 2H), 1.773~1.613 (m, 4H).

[0141] 13 C NMR (100MHz, CDCl3), δ=163.933~163.655, 155.610, 152.834~152.746, 128.042~127.539, 124.125~123.651, 120.675~120.580, 65.543, 58.304, 53.071, 50.072, 43.658, 27.095, 23.413.

[0142] Example 2 Preparation and purification of compound of formula III

[0143] The preparation and purification of the compound of formula III comprises the following steps:

[0144] 1) Add 5.0 g of the compound of formula II, 12.1 g of the compound of formula I, 421 mg of tetrabutylammonium iodide, 7.4 g of cesium carbonate, and 15 mL of N,N-dimethylformamide to an autoclave. Pipe carbon dioxide into the autoclave to displace the air 2-3 times. Continue to pipette carbon dioxide until the pressure reaches 4 MPa. Heat to 80°C with stirring and react for 5 h. Cool the reaction system to 20±5°C, slowly release unreacted carbon dioxide, filter the reaction solution, and concentrate the filtrate to dryness under reduced pressure at 45±5°C to obtain a crude compound of formula III.

[0145] 2) 30 mL of dichloromethane was added to the crude product of Formula III to dissolve the product. The product was separated and purified by column chromatography (300-400 mesh silica gel, eluent: dichloromethane:methanol = 25:1) to obtain 7.4 g of Formula III. HPLC analysis showed a purity of 97.52%.

[0146] Example 3 Preparation and purification of compound of formula III

[0147] The preparation and purification of the compound of formula III comprises the following steps:

[0148] 1) Add 5.0 g of the compound of Formula II, 16.2 g of the compound of Formula I, 950 mg of tetrabutylammonium chloride, 14.5 g of potassium phosphate, and 30 mL of N,N-dimethylformamide to an autoclave. Pipe carbon dioxide into the autoclave 2-3 times to displace the air in the autoclave. Continue to introduce carbon dioxide until the autoclave pressure reaches 5 MPa. Heat to 80°C with stirring and react for 6 h. Cool the reaction system to 20±5°C, slowly release unreacted carbon dioxide, filter the reaction solution, and concentrate the filtrate under reduced pressure at 45±5°C to dryness to obtain a crude compound of Formula III.

[0149] 2) 35 mL of dichloromethane was added to the crude product of Formula III to dissolve it. The product was separated and purified by column chromatography (300-400 mesh silica gel column, eluent: dichloromethane:methanol = 25:1) to obtain 7.6 g of Formula III compound. The purity was 98.06% by HPLC.

[0150] Example 4 Preparation and purification of compounds of formula I

[0151] The preparation and purification of the compound of formula I comprises the following steps:

[0152] 1) Add 50.0 g of the compound of Formula II, 51.5 g of 1,4-dibromobutane, 75.5 g of potassium carbonate, and 200 mL of 95% ethanol to a 500 mL reaction flask. Heat to 80°C with stirring until the reaction is complete. Filter the reaction solution while hot, collect the filtrate, and concentrate it to 50% of its original volume. Cool to 5±5°C with stirring, and stir for 1 hour to allow crystallization. Filter, wash the filter cake with 25 mL of anhydrous ethanol, and dry under reduced pressure at 40±5°C for 4 hours ± 10 minutes to obtain 74.0 g of a crude compound of Formula I.

[0153] 2) The crude compound of Formula I was added to 300 mL of dichloromethane and stirred at 20±5°C for 2 h. Filtered, the filter cake was washed with 100 mL of dichloromethane, and then dried under reduced pressure at 40±5°C for 4 h±10 min to obtain 69.0 g of the purified compound of Formula I.

[0154] Example 5 Purity test of compound of formula I

[0155] The purity of the compound of formula I obtained in Example 4 was determined by high performance liquid chromatography (HPLC).

[0156] (1) Chromatographic conditions

[0157] Chromatographic column: The stationary phase was octadecylsilane bonded silica gel (Waters Symmetry C18 3.9*150mm 5μm);

[0158] Detection wavelength: 230nm;

[0159] Injection volume: 10 μL;

[0160] Flow rate: 0.8 mL / min;

[0161] Column temperature: 30℃.

[0162] Mobile phase A: buffer (containing 0.1% potassium dihydrogen phosphate and 0.1% sodium heptanesulfonate, adjusted to pH 3.0 with phosphoric acid) - acetonitrile = (90:10, v / v)

[0163] Mobile phase B: buffer (containing 0.1% potassium dihydrogen phosphate and 0.1% sodium heptanesulfonate, adjusted to pH 3.0 with phosphoric acid) - acetonitrile = (20:80, v / v)

[0164] Detection wavelength: 230nm

[0165] Column temperature: 30°C

[0166] Flow rate: 0.8 mL / min

[0167] Injection volume: 10 μL

[0168] Blank solution: mobile phase A-mobile phase B (65:35, v / v)

[0169] Gradient program:

[0170] Time (min) Mobile phase A (%) Mobile phase B (%) 0 85 15 10 70 30 40 20 80 45 20 80 50 85 15

[0171] (2) Solution preparation

[0172] Diluent: mobile phase A-mobile phase B (65:35, v / v).

[0173] Buffer solution: Dissolve 1.0 g of potassium dihydrogen phosphate and 1.0 g of sodium heptanesulfonate in 1000 mL of water and adjust the pH to 3.0 with phosphoric acid.

[0174] Stock solution of the compound of formula III: Accurately weigh 5 mg of the compound of formula III prepared in Example 1, place it in a 100 mL volumetric flask, add diluent to dissolve it and dilute it to the scale, shake well, and obtain the solution.

[0175] Separation solution: Accurately weigh 50 mg of the reference compound of formula I and place it in a 100 mL volumetric flask. Add 1.0 mL of the stock solution of the compound of formula III and dissolve it in a diluent and dilute to the mark. Shake well to obtain the solution.

[0176] Test solution: Accurately weigh 50 mg of the purified compound of formula I obtained in Example 4, place it in a 100 mL volumetric flask, dissolve it in a diluent and dilute it to the mark, shake well, and obtain the solution.

[0177] (3) Determination

[0178] Accurately measure the blank solution, separation solution and test solution, measure according to the above chromatographic conditions, and record the chromatogram (see Figure 5 If there are impurity peaks in the chromatogram of the test solution, calculate them using the area normalization method.

[0179] According to the method described in the present invention, the purity of the compound of formula I was 99.9604%, the content of the compound of formula III was 0.0237%, and 1,4-dibromobutane was not detected.

[0180] Example 6 Preparation and purification of compounds of formula I

[0181] The preparation and purification of the compound of formula I comprises the following steps:

[0182] 1) Add 50.0 g of the compound of Formula II, 49.2 g of 1,4-dibromobutane, 94.5 g of potassium carbonate, and 200 mL of isopropanol to a 500 mL reaction flask. Heat to 82°C with stirring until the reaction is complete. Filter the reaction solution while hot, collect the filtrate, and concentrate it to 50% of its original volume. Cool to 5±5°C with stirring, and stir for 1 hour to allow crystallization. Filter, wash the filter cake with 25 mL of anhydrous ethanol, and dry under reduced pressure at 40±5°C for 4 hours ± 10 minutes to obtain 73.8 g of a crude compound of Formula I.

[0183] 2) The crude compound of Formula I was added to 150 mL of 1,2-dichloroethane and stirred at 15±5°C for 2 h. Filtered, the filter cake was washed with 100 mL of 1,2-dichloroethane, and dried under reduced pressure at 40±5°C for 4 h±10 min to obtain 67.5 g of the purified compound of Formula I.

[0184] According to the method described in the present invention, the purity of the compound of formula I is 99.9245%, the content of the compound of formula III is 0.0334%, and the content of 1,4-dibromobutane is 4 ppm.

[0185] Example 7 Preparation and purification of compounds of formula I

[0186] The preparation and purification of the compound of formula I comprises the following steps:

[0187] 1) Add 50.0 g of the compound of Formula II, 51.5 g of 1,4-dibromobutane, 60.4 g of sodium carbonate, and 400 mL of methanol to a 1000 mL reaction flask. Heat to 65°C with stirring until the reaction is complete. Filter the reaction solution while hot, collect the filtrate, and concentrate it to 50% of its original volume. Cool to 5±5°C with stirring, and stir for 1 hour to allow crystallization. Filter, wash the filter cake with 25 mL of anhydrous ethanol, and dry the filter cake under reduced pressure at 40±5°C for 4 hours ± 10 minutes to obtain 73.0 g of a crude compound of Formula I.

[0188] 2) The crude compound of Formula I was added to 360 mL of chloroform and stirred at 20±5°C for 2 h. Filtered, the filter cake was washed with 100 mL of chloroform, and dried under reduced pressure at 40±5°C for 4 h±10 min to obtain 67.0 g of the purified compound of Formula I.

[0189] According to the method described in the present invention, the purity of the compound of formula I is 99.9349%, the content of the compound of formula III is 0.0148%, and the content of 1,4-dibromobutane is 3 ppm.

[0190] Example 8 Preparation and purification of compounds of formula I

[0191] The preparation and purification of the compound of formula I comprises the following steps:

[0192] 1) Add 50.0 g of the compound of Formula II, 51.5 g of 1,4-dibromobutane, 111.4 g of cesium carbonate, and 150 mL of 95% ethanol to a 500 mL reaction flask. Heat to 80°C with stirring until the reaction is complete. Filter the reaction solution while hot, collect the filtrate, and concentrate it to 50% of its original volume. Cool to 5±5°C with stirring, and stir for 1 hour to crystallize. Filter, wash the filter cake with 25 mL of anhydrous ethanol, and dry the filter cake under reduced pressure at 40±5°C for 4 hours ± 10 minutes to obtain 72.5 g of a crude compound of Formula I.

[0193] 2) The crude compound of Formula I was added to 500 mL of ethyl acetate and stirred at 45±5°C for 4 h. Filtered, the filter cake was washed with 200 mL of ethyl acetate, and then dried under reduced pressure at 40±5°C for 4 h±10 min to obtain 65.0 g of the purified compound of Formula I.

[0194] According to the method described in the present invention, the purity of the compound of formula I was 99.9041%, the content of the compound of formula III was 0.0543%, and the content of 1,4-dibromobutane was 1 ppm.

[0195] Example 9 Preparation and purification of compounds of formula I

[0196] The preparation and purification of the compound of formula I comprises the following steps:

[0197] 1) Add 50.0 g of the compound of Formula II, 51.5 g of 1,4-dibromobutane, 111.4 g of cesium carbonate, and 200 mL of 95% ethanol to a 500 mL reaction flask. Heat to 80°C with stirring until the reaction is complete. Filter the reaction solution while hot, collect the filtrate, and concentrate it to 50% of its original volume. Cool to 5±5°C with stirring, and stir for 1 hour to crystallize. Filter, wash the filter cake with 25 mL of anhydrous ethanol, and dry the filter cake under reduced pressure at 40±5°C for 4 hours ± 10 minutes to obtain 72.9 g of a crude compound of Formula I.

[0198] 2) The crude compound of Formula I was added to 510 mL of tetrahydrofuran and stirred at 40±5°C for 3 h. Filtered, the filter cake was washed with 200 mL of tetrahydrofuran, and then dried under reduced pressure at 40±5°C for 4 h±10 min to obtain 66.5 g of the purified compound of Formula I.

[0199] According to the method described in the present invention, the purity of the compound of formula I is 99.9148%, the content of the compound of formula III is 0.0642%, and the content of 1,4-dibromobutane is 3 ppm.

[0200] Example 10 Preparation and purification of compounds of formula I

[0201] The preparation and purification of the compound of formula I comprises the following steps:

[0202] 1) Add 50.0 g of the compound of Formula II, 51.5 g of 1,4-dibromobutane, 75.5 g of potassium carbonate, and 200 mL of 95% ethanol to a 500 mL reaction flask. Heat to 80°C with stirring until the reaction is complete. Filter the reaction solution while hot, collect the filtrate, and concentrate it to 50% of its original volume. Cool to -5°C with stirring, and stir for 2 hours to allow crystallization. Filter, wash the filter cake with 25 mL of anhydrous ethanol, and dry under reduced pressure at 40±5°C for 4 hours±10 minutes to obtain 75.8 g of a crude compound of Formula I.

[0203] 2) The crude compound of Formula I was added to 300 mL of toluene and stirred at 40±5°C for 2 h. Filtered, the filter cake was washed with 100 mL of toluene, and then dried under reduced pressure at 40±5°C for 4 h±10 min to obtain 72.5 g of the purified compound of Formula I.

[0204] According to the method described in the present invention, the purity of the compound of formula I was 97.3702%, the content of the compound of formula III was 2.5245%, and the content of 1,4-dibromobutane was 5 ppm.

[0205] Example 11 Preparation and purification of compounds of formula I

[0206] The preparation and purification of the compound of formula I comprises the following steps:

[0207] 1) Add 50.0 g of the compound of Formula II, 51.5 g of 1,4-dibromobutane, 75.5 g of potassium carbonate, and 200 mL of 95% ethanol to a 500 mL reaction flask. Heat to 80°C with stirring until the reaction is complete. Filter the reaction solution while hot, collect the filtrate, and concentrate it to 50% of its original volume. Cool to 5±5°C with stirring, and stir for 3 hours to allow crystallization. Filter, wash the filter cake with 25 mL of anhydrous ethanol, and dry under reduced pressure at 40±5°C for 4 hours ± 10 minutes to obtain 75.0 g of a crude compound of Formula I.

[0208] 2) The crude compound of Formula I was added to 300 mL of acetonitrile and stirred at 20±5°C for 2 h. Filtered, the filter cake was washed with 100 mL of acetonitrile, and dried under reduced pressure at 40±5°C for 4 h±10 min to obtain 62.6 g of the purified compound of Formula I.

[0209] According to the method described in the present invention, the purity of the compound of formula I was 98.3421%, the content of the compound of formula III was 1.5414%, and the residual amount of 1,4-dibromobutane was 5 ppm.

[0210] Example 12Preparation and purification of compounds of formula I

[0211] The preparation and purification of the compound of formula I comprises the following steps:

[0212] 1) Add 50.0 g of the compound of Formula II, 51.5 g of 1,4-dibromobutane, 75.5 g of potassium carbonate, and 200 mL of 95% ethanol to a 500 mL reaction flask. Heat to 80°C with stirring until the reaction is complete. Filter the reaction solution while hot, collect the filtrate, and concentrate it to 50% of its original volume. Cool to 5±5°C with stirring, and stir for 1 hour to allow crystallization. Filter, wash the filter cake with 25 mL of anhydrous ethanol, and dry under reduced pressure at 40±5°C for 4 hours ± 10 minutes to obtain 73.7 g of a crude compound of Formula I.

[0213] 2) The crude compound of Formula I was added to 300 mL of acetone and stirred at 25±5°C for 2 h. Filtered, the filter cake was washed with 100 mL of acetone, and then dried under reduced pressure at 40±5°C for 4 h±10 min to obtain 70.4 g of the purified compound of Formula I.

[0214] According to the method described in the present invention, the purity of the compound of formula I was 98.8708%, the content of the compound of formula III was 0.8948%, and the content of 1,4-dibromobutane was 6 ppm.

[0215] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. The present invention is not limited to the embodiments shown herein but is to be embodied in the widest possible manner consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing and purifying a high-purity compound of formula I, comprising the following steps: 1) placing the required amount of the compound of formula II and 1,4-dibromobutane in solvent a, reacting at 15-80° C. under stirring and in the presence of a base, filtering the obtained reaction solution, collecting the filtrate and concentrating it under reduced pressure to 25%-50% of the original volume, stirring and crystallizing at 0-10° C. for 0.5-1 h, filtering, washing, and drying under reduced pressure at 30-50° C. to obtain a crude compound of formula I, wherein the molar ratio of the compound of formula II to 1,4-dibromobutane is 1:1-1.05, the volume mass ratio of solvent a to the compound of formula II is 3-8:1 mL / g, the solvent a is selected from any one of methanol, ethanol, and isopropanol, or a combination thereof, the molar ratio of the compound of formula II to the base is 1:1-3, and the base is selected from any one of sodium carbonate, potassium carbonate, and cesium carbonate, or a combination thereof; 2) adding the obtained crude compound of formula I to solvent b, stirring at 10-55° C. for 0.5-3 h, filtering, washing the filter cake, and drying under reduced pressure at 30-50° C. to obtain a purified compound of formula I, wherein the volume-to-mass ratio of solvent b to the crude compound of formula I is 2-7:1 mL / g. The solvent b is selected from any one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, and tetrahydrofuran, or a combination thereof.

2. The method according to claim 1, wherein in step 2), the stirring time is 1 to 2 hours.

3. The method according to claim 1, wherein in step 2), the washing solvent is selected from any one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, and tetrahydrofuran, or a combination thereof.

4. The method according to any one of claims 1 to 3, wherein the purity of the purified compound of formula I is ≥99%.

5. The method according to claim 4, wherein the purity of the purified compound of formula I is ≥99.9%.

6. The method according to any one of claims 1 to 3, wherein the content of the compound of formula III in the purified compound of formula I is ≤ 0.1%, and other unknown impurities are ≤ 0.1%.

7. The method according to claim 6, wherein the content of the compound of formula III in the purified compound of formula I is ≤0.05%.

8. The method according to any one of claims 1 to 3, wherein the 1,4-dibromobutane content in the purified compound of formula I is ≤5 ppm.

9. A high-purity compound of formula I prepared by the method according to any one of claims 1 to 8, wherein the purity of the compound of formula I is ≥99%, the content of the compound of formula III in the compound of formula I is ≤0.1%, and the content of 1,4-dibromobutane in the compound of formula I is ≤5 ppm.

10. The compound according to claim 9, wherein the purity of the compound of formula I is ≥99.9%.

11. The compound according to any one of claims 9-10, wherein other unknown impurities are ≤ 0.1%.

12. The compound according to claim 9, wherein the content of the compound of formula III in the compound of formula I is ≤0.05%.

13. A method for preparing high-purity perospirone hydrochloride, comprising the steps of reacting a high-purity compound of formula I prepared by the method according to any one of claims 1 to 8 or a high-purity compound of formula I according to any one of claims 9 to 12 with cis-hexahydrophthalimide to obtain perospirone, salifying the obtained perospirone with hydrochloric acid, purifying the obtained perospirone hydrochloride by recrystallization, separating, washing, and drying to obtain:

14. The method according to claim 13, wherein the molar ratio of the compound of formula I to cis-hexahydrophthalimide is 1:1.0-1.

2.

15. The method according to claim 13, wherein the reaction temperature of the compound of formula I and cis-hexahydrophthalimide is 100-145°C.

16. The method according to claim 13, wherein the reaction time of the compound of formula I and cis-hexahydrophthalimide is 1.5 to 3 hours.

17. The method according to claim 13, wherein the recrystallization solvent is any one of a methanol solution, an ethanol solution, and an isopropanol solution with a water content of 10-20%, or a combination thereof. The method according to claim 13 , wherein the separation is selected from any one of centrifugation, filtration, membrane separation, or a combination thereof.

19. The method according to claim 13, wherein the washing solvent is selected from any one of water, methanol, ethanol, isopropanol or a combination thereof.

20. The method according to claim 13, wherein the drying is selected from any one of reduced pressure drying and spray drying or a combination thereof.

21. The method according to claim 13, wherein the drying temperature is 30-50°C.

22. A high performance liquid chromatography method for detecting the purity of a high-purity compound of formula I prepared by the method according to any one of claims 1 to 8, wherein the chromatographic column is selected from Waters Symmetry C18, 3.9×150 mm, 5 μm, and the mobile phase consists of mobile phase A and mobile phase B, wherein: Mobile phase A was prepared by a buffer solution containing 0.1% potassium dihydrogen phosphate and 0.1% sodium heptane sulfonate and acetonitrile in a volume ratio of 90:

10. Mobile phase B was prepared by a buffer solution containing 0.1% potassium dihydrogen phosphate and 0.1% sodium heptane sulfonate and acetonitrile in a volume ratio of 20:

80. The buffer solution was adjusted to pH 3.0 with phosphoric acid. The detection wavelength was 230 nm, the column temperature was 30° C., the flow rate was 0.8 mL / min, the injection volume was 10 μL, and the gradient program was: 。

Images