CN110724095B - Preparation method of indacaterol acetate - Google Patents
Preparation method of indacaterol acetate Download PDFInfo
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a preparation method of indacaterol acetate, which has the advantages of simple preparation process, small three-waste discharge, low preparation cost, high yield and high product purity, is favorable for large-scale commercial production, has high economic value, and the obtained crystal form of the target product is consistent with the report of a literature and is characterized by the characteristic absorption peak of an X-ray diffraction pattern of the crystal form.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of indacaterol acetate.
Background
Indacaterol acetate, system named: (R) -5- [2- (5, 6-Diethylindan-2-ylamino) -1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one acetate of formula: c (C) 26 H 32 N 2 O 5 Molecular weight: 452.55, cas No.: 1000160-96-2, the structural formula is shown as follows:
indanterol acetate is a long-acting beta 2 receptor agonist, suitable for patients with Chronic Obstructive Pulmonary Disease (COPD), and is currently in clinical phase three. In 5 months 2019, north China announced that a phase III QUARTZ study of its inhaled combination therapeutic drug QMF149 (the major components indacaterol acetate and mometasone furoate) has reached primary and key secondary endpoints in patients with poorly controlled asthma. The once daily fixed dose showed a significant improvement in lung function and asthma control compared to Inhaled Corticosteroids (ICS).
Some methods have been provided in the prior art to obtain indacaterol acetate in which alcoholic solvents are used. However, the indacaterol base has very poor solubility in isopropanol or other alcohol solvents, the indacaterol base and acetic acid have very short clarifying process in isopropanol at 80 ℃, and further amplification experiments show that indacaterol acetate crystals are separated out when the indacaterol base is not completely dissolved at 80 ℃, and at lower temperature, the phenomenon is more obvious, so that the indacaterol base is easy to be entrapped in the product, and great difficulty is caused for subsequent quality control and preparation work.
The indacaterol base has very small solubility in the conventional solvents, and even if acetic acid is added into the commonly used ester and ether solvents, acetone, acetonitrile and other solvents, the indacaterol base cannot be dissolved; if alcohols are used alone as solvents, indacaterol base is hardly dissolved therein. If a proper amount of acetic acid is added to the alcohol solvent, the solubility of indacaterol base slightly increases, but the amount of solvent required for dissolution is large, the required dissolution temperature is high, and the requirement on the reaction conditions is too high. For example, using methanol requires 20 volumes to 60 ℃, ethanol requires 40 volumes to 70 ℃, and isopropanol requires 60 volumes to 80 ℃, which increases both production costs and three emissions. In addition, the target product indacaterol acetate can not be obtained by crystallization after cooling by using methanol as a solvent, and the crystallization yield is lower after cooling by using ethanol or isopropanol as a solvent.
Therefore, a new process for synthesizing indacaterol acetate needs to be developed, the high purity and the high yield of the indacaterol acetate are ensured, the solvent consumption is reduced as much as possible, the cost is reduced, and the obtained product is convenient to filter, so that the preparation processing and the clinical application are facilitated.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a novel preparation method of indacaterol acetate, which avoids the defects that the indacaterol acetate and the indacaterol acetate have poor solubility in a single solvent such as isopropanol and the like, and the mixed substance of the indacaterol acetate and the indacaterol acetate is easy to generate during large-scale preparation. In addition, the method has mild reaction conditions, no high-temperature step and less solvent consumption, and the obtained product is easy to filter and is more suitable for large-scale commercial production.
In order to achieve the above object, the present invention adopts the following technical scheme:
in one aspect, the invention provides a preparation method of indacaterol acetate, wherein the method comprises the steps of dissolving acetic acid in halogenated hydrocarbon solution of indacaterol alkali shown in a formula I, adding a proper amount of mixed solvent of alcohol and ester, and crystallizing to obtain indacaterol acetate shown in a formula II;
the halogenated hydrocarbon solution is selected from one or more of dichloromethane, trichloromethane and 1, 2-dichloroethane, preferably dichloromethane;
the mixed solvent of the alcohol and the ester is a mixture of the alcohol solvent and the ester solvent, preferably the alcohol solvent is one or more selected from ethanol, isopropanol and tert-butanol, more preferably isopropanol;
preferably the ester solvent is selected from one or more of butyl acetate, ethyl formate, isobutyl acetate, methyl acetate and propyl acetate, more preferably ethyl acetate;
in the process provided by the invention, the volume ratio of the halogenated hydrocarbon solution to the alcohol solvent is from 1:1 to 1:5, preferably from 1:2 to 1:3.5, most preferably 1:2.
In the process provided by the invention, the volume ratio of the ester solvent to the alcohol solvent is 0 to 1.5:1, preferably 1:1.
In the process provided by the present invention, the concentration of indacaterol base in the halogenated hydrocarbon solution is 0.1 to 0.5g/mL, preferably 0.3 to 0.4g/mL, more preferably 0.3g/mL, based on indacaterol base.
In the process provided by the invention, the molar ratio of indacaterol base to acetic acid is 1:2 to 1:5, preferably 1:2.5 to 1:3.5, more preferably 1:3.5.
In the method provided by the invention, after the acetic acid is dissolved in the halogenated hydrocarbon solution of indacaterol alkali shown in the formula I, the method further comprises the step of heating the reaction system to the reaction temperature before adding a proper amount of mixed solvent of alcohol and ester; preferably, the reaction temperature is 10 to 45 ℃, more preferably 30 to 40 ℃, still more preferably 35 ℃;
in the method provided by the invention, after adding a proper amount of mixed solvent of alcohol and ester, the method further comprises the step of heat preservation; preferably, the time of the incubation is 0.5 to 4 hours, more preferably 1 to 2 hours, still more preferably 1 hour;
in the method provided by the invention, the crystallization is carried out for 5-10 hours at the temperature of 5-10 ℃; preferably, the crystallization is performed at 5 to 10 ℃ for 10 hours.
In the process provided by the invention, all operations are carried out with stirring.
In one embodiment of the present invention, the present invention provides a process for the preparation of indacaterol acetate, wherein the process comprises: dissolving acetic acid in dichloromethane solution of indacaterol alkali shown in formula I, dropwise adding acetic acid, stirring for dissolving, heating to a reaction temperature of 35 ℃, adding mixed solvent of isopropanol and ethyl acetate, keeping the temperature for 1 hour, cooling to 5-10 ℃, stirring for crystallization for 10 hours, and obtaining indacaterol acetate shown in formula II;
wherein the volume ratio of dichloromethane to isopropanol is 1:2, the volume ratio of ethyl acetate to isopropanol is 1:1, the concentration of indacaterol base in halogenated hydrocarbon solution is 0.3g/mL, and the molar ratio of indacaterol base to acetic acid is 1:3.5.
In another aspect, the present invention also provides a method for preparing indacaterol base represented by formula I, the method comprising:
the indacaterol salt is subjected to neutralization reaction in an alcohol solution of alkali metal hydroxide to obtain indacaterol alkali shown in a formula I;
preferably, the invention also provides a preparation method of indacaterol base shown in formula I, which comprises the following steps: adding indacaterol maleate into alcohol solution of alkali metal hydroxide under stirring, stirring at a certain temperature, adding proper amount of water to quench reaction, filtering and drying the product.
Preferably, the indacaterol salt is indacaterol maleate, indacaterol tartrate, indacaterol benzoate or indacaterol mesylate, more preferably indacaterol maleate.
Preferably, the alkali metal hydroxide is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, more preferably sodium hydroxide.
Preferably, the alcoholic solution is selected from one or more of methanol, ethanol, propanol and isopropanol, preferably methanol, which are fully miscible with water.
Preferably, the molar ratio of indacaterol salt to alkali metal hydroxide is 1:1 to 1:5; preferably, the reaction concentration is 0.2-2.0 mmol/mL based on indacaterol salt; preferably, the reaction temperature is 10 to 45 ℃ and the reaction time is 0.5 to 4 hours.
The inventor tries to search a solvent system capable of completely dissolving indacaterol base, and finds that common solvents such as methanol, ethanol, isopropanol, butanol, tertiary butanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, methyl tertiary butyl ether, methylene dichloride and the like have extremely poor solubility to indacaterol base, and dimethyl sulfoxide and N, N-dimethylformamide have better solubility to indacaterol base. In contrast, according to the invention, indacaterol alkali is respectively dissolved in two solvent systems, namely dimethyl sulfoxide and N, N-dimethylformamide, and an isopropanol solution of acetic acid is added, and stirred for crystallization, but the yield of a target product is generally low. In addition, the indacaterol acetate is prepared by selecting high boiling point solvents such as dimethyl sulfoxide, N-dimethylformamide and the like, the solvent residue is obviously higher, and the indacaterol acetate is difficult to remove and is not beneficial to the production of subsequent pharmaceutical preparations.
The invention provides a novel preparation method of indacaterol acetate, which has simple preparation process, higher yield and product purity, is favorable for industrial production, and has higher economic value because the obtained specific crystal form is consistent with the report of the literature. In addition, the invention also provides a method for preparing the solid indacaterol base, so that the solid indacaterol base with better properties is obtained, and the solid indacaterol base can be used for preparing other salts of indacaterol.
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The invention will be further described with reference to the accompanying drawings.
FIG. 1 is a nuclear magnetic resonance spectrum of indacaterol acetate prepared in example 7;
FIG. 2 is an X-ray diffraction pattern of indacaterol acetate prepared in example 7.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way. Furthermore, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the teachings herein, and such equivalents are intended to fall within the scope of the claims appended hereto.
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials and reagent materials used in the examples below are all commercially available products unless otherwise specified.
In the following examples and comparative examples, the detection conditions of the X-ray diffraction were:
instrument model: bruker D8 Advance
Test conditions: x-ray source: cu-K
Operating current: 40mA
Operating voltage: 40KV
A detector: PSD (phase-sensitive detector)
Initial angle: 4 ° (2 θ)
End angle: 40 ° (2 θ)
Increment: 0.05 DEG/step
Scanning speed: 1 second/step
Example 1: preparation of indacaterol base
Sodium hydroxide (7.00 g,175.00 mmol) and 300mL of methanol were added to the reaction flask and stirred until the sodium hydroxide was completely dissolved. Indamaterol maleate (40.14 g,78.93 mmol) was added and stirred for 1 hour at 35℃for reaction. After the reaction, 300ml of water is added, the mixture is continuously stirred for 30 minutes under heat preservation, the mixture is filtered, a filter cake is washed by a small amount of water, and the filter cake is dried under reduced pressure at 50 ℃ and has water content not higher than 3 percent. Yellow-green indacaterol base (30.64 g,78.06 mmol) was obtained. The yield was 98.90% and the purity was 99.13%.
Example 2: preparation of indacaterol base
Lithium hydroxide monohydrate (7.26 g,173.35 mmol) and 300mL of methanol were added to the reaction flask and stirred until the lithium hydroxide was completely dissolved. Heating to 35 deg.C, adding indacaterol maleate (40.04 g,78.73 mmol), and stirring for 1 hr. After the reaction, 300ml of water is added, the mixture is continuously stirred for 30 minutes under heat preservation, the mixture is filtered, a filter cake is washed by a small amount of water, and the filter cake is dried under reduced pressure at 50 ℃ and has water content not higher than 3 percent. Yellow-green indacaterol base (30.85 g,78.60 mmol) was obtained. The yield was 99.84% and the purity was 98.92%.
Example 3: preparation of indacaterol base
Potassium hydroxide (9.80 g,174.75 mmol) and 300mL of ethanol were added to the reaction flask and stirred until the sodium hydroxide was completely dissolved. Heating to 35 deg.C, adding indacaterol maleate (40.00 g,78.65 mmol), and stirring for 1 hr. After the reaction, 300ml of water is added, the mixture is continuously stirred for 30 minutes under heat preservation, the mixture is filtered, a filter cake is washed by a small amount of water, and the filter cake is dried under reduced pressure at 50 ℃ and has water content not higher than 3 percent. Yellow-green indacaterol base (30.75 g,78.34 mmol) was obtained. The yield was 99.61% and the purity was 99.10%.
Example 4: preparation of indacaterol acetate
Indantrolene base (10.00 g,25.50 mmol) and methylene chloride (30 ml) were added to a reaction flask, acetic acid (5.40 g,90.00 mmol) was added dropwise, and dissolved with stirring. Isopropyl alcohol (100 ml) was added thereto at a reaction temperature of 10℃and stirred for 1 hour with a constant temperature. The suspension was stirred at 5℃to 10℃for 10 hours, then filtered, the filter cake was washed with a small amount of isopropanol, and the filter cake was dried under reduced pressure at 50℃for 20 hours to give indacaterol acetate (8.03 g,17.75 mmol) as white. The yield thereof was found to be 69.61% and the purity thereof was found to be 99.59%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 5: preparation of indacaterol acetate
Indantrolene base (25.02 g,63.75 mmol) and methylene chloride (75 ml) were added to a reaction flask, acetic acid (7.66 g,127.49 mmol) was added dropwise and dissolved with stirring. Heated to 35℃and isopropanol (250 ml) was added thereto, and stirred for 1 hour with heat preservation. The temperature was reduced to 5℃to 10℃and the suspension was stirred for 10 hours, then filtered, the filter cake was washed with a small amount of isopropanol and dried under reduced pressure at 50℃for 20 hours to give white indacaterol acetate (23.66 g,52.29 mmol). Yield 82.02% and purity 99.79%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
EXAMPLE 6 preparation of indacaterol acetate
Indantrolene base (25.01 g,63.72 mmol) and methylene chloride (75 ml) were added to the reaction flask, acetic acid (9.57 g,159.30 mmol) was added dropwise and dissolved with stirring. Heated to 35℃and isopropanol (250 ml) was added thereto, and stirred for 1 hour with heat preservation. The temperature was reduced to 5℃to 10℃and the suspension was stirred for 10 hours, then filtered, the filter cake was washed with a small amount of isopropanol and dried under reduced pressure at 50℃for 20 hours to give white indacaterol acetate (24.83 g,54.88 mmol). Yield 86.13% and purity 99.80%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
EXAMPLE 7 preparation of indacaterol acetate
Indantrolene base (100.02 g,254.83 mmol) and methylene chloride (300 ml) were added to a reaction flask, acetic acid (53.56 g,891.90 mmol) was added dropwise and dissolved with stirring. Heated to 35℃and isopropanol (1000 ml) was added thereto, and the mixture was stirred at a constant temperature for 1 hour. The temperature is reduced to 5-10 ℃, the suspension is stirred for 10 hours, then filtered, the filter cake is washed with a small amount of isopropanol, and the filter cake is dried under reduced pressure for 20 hours at 50 ℃ to obtain white indacaterol acetate (102.65 g,226.87 mmol). Yield 89.03% and purity 99.81%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The X-ray diffraction pattern of indacaterol acetate obtained in this example is shown in fig. 2, and specific results are shown in table I.
Table I X-ray powder diffraction data for indacaterol acetate salt
Example 8: preparation of indacaterol acetate
Indantrolene base (25.00 g,63.69 mmol) and methylene chloride (75 ml) were added to the reaction flask, acetic acid (16.08 g,267.69 mmol) was added dropwise and dissolved with stirring. Heated to 35℃and isopropanol (250 ml) was added thereto, and stirred for 1 hour with heat preservation. The temperature was lowered to 5℃to 10℃and the suspension was stirred for 10 hours, then filtered, the filter cake was washed with a small amount of isopropanol and dried under reduced pressure at 50℃for 20 hours to give white indacaterol acetate (21.62 g,47.78 mmol). Yield 75.02% and purity 99.79%. The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 9: preparation of indacaterol acetate
Indantrolene base (10.00 g,25.50 mmol) and methylene chloride (100 ml) were added to a reaction flask, acetic acid (5.40 g,90.00 mmol) was added dropwise and dissolved with stirring. Heated to a reaction temperature of 25 ℃, isopropyl alcohol (100 ml) was added, and stirred for 1 hour with heat preservation. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (8.96 g,19.81 mmol) was obtained. Yield 77.68% and purity 99.62%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 10: preparation of indacaterol acetate
Indantrolene base (15.00 g,38.20 mmol) and methylene chloride (75 ml) were added to a reaction flask, acetic acid (8.10 g,135.00 mmol) was added dropwise, and dissolved with stirring. Isopropanol (150 ml) was added thereto by heating to a reaction temperature of 35℃and stirring was carried out for 1 hour with a constant temperature. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (13.47 g,29.77 mmol) was obtained. Yield 77.93% and purity 99.79%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 11: preparation of indacaterol acetate
Indantrolene base (25.02 g,63.75 mmol) and methylene chloride (75 ml) were added to the reaction flask, acetic acid (13.40 g,223.33 mmol) was added dropwise and dissolved with stirring. Isopropanol (375 ml) was added thereto by heating to a reaction temperature of 35℃and stirring was carried out for 1 hour with a constant temperature. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (21.10 g,46.64 mmol) was obtained. Yield 73.16% and purity 99.81%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 12: preparation of indacaterol acetate
Indantrolene base (100.14 g,254.78 mmol) and methylene chloride (300 ml) were added to a reaction flask, acetic acid (53.62 g,892.97 mmol) was added dropwise, and dissolved with stirring. Heated to 35℃and a mixed solvent of isopropyl alcohol (600 ml) and ethyl acetate (600 ml) was added thereto, followed by stirring for 1 hour at a constant temperature. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (108.06 g,238.80 mmol) was obtained. Yield 93.73% and purity 99.77%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 13: preparation of indacaterol acetate
Indantrolene base (30.02 g,76.43 mmol) and methylene chloride (90 ml) were added to a reaction flask, acetic acid (16.08 g,268.00 mmol) was added dropwise, and dissolved with stirring. Heated to 35℃and mixed solvent of ethanol (180 ml) and ethyl acetate (180 ml) was added thereto, followed by stirring for 1 hour under heat preservation. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (27.53 g,60.83 mmol) was obtained. Yield 79.59% and purity 99.76%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 14: preparation of indacaterol acetate
Indantrolene base (20.01 g,50.98 mmol) and methylene chloride (60 ml) were added to a reaction flask, acetic acid (10.90 g,181.67 mmol) was added dropwise, and the mixture was dissolved with stirring. Heated to 35℃and a mixed solvent of isopropyl alcohol (120 ml) and ethyl acetate (180 ml) was added thereto, followed by stirring for 1 hour at a constant temperature. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (18.28 g,40.40 mmol) was obtained. Yield 79.25% and purity 99.54%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 15: preparation of indacaterol acetate
Indantrolene base (20.04 g,51.06 mmol) and methylene chloride (60 ml) were added to a reaction flask, acetic acid (10.92 g,182.00 mmol) was added dropwise and dissolved with stirring. Heated to 35℃and a mixed solvent of isopropyl alcohol (120 ml) and ethyl acetate (60 ml) was added thereto, followed by stirring for 1 hour at a constant temperature. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (20.69 g,45.73 mmol) was obtained. Yield 89.57% and purity 99.76%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Example 16: preparation of indacaterol acetate
Indantrolene base (30.14 g,76.79 mmol) and chloroform (90 ml) were added to a reaction flask, acetic acid (16.10 g,268.11 mmol) was added dropwise, and the mixture was dissolved with stirring. Heated to 35℃and isopropanol (300 ml) was added thereto, and the mixture was stirred at a constant temperature for 1 hour. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (27.79 g,61.40 mmol) was obtained. Yield 79.96% and purity 99.77%.
The 1HNMR spectrum of the obtained indacaterol acetate is shown in FIG. 1.
The product of this example gave an X-ray diffraction pattern substantially in accordance with FIG. 2, as measured using a Bruker D8 advanced X-ray diffractometer.
Comparative example 1: preparation of indacaterol acetate
Indamaterol base (100.00 g,254.78 mmol) and acetic acid (53.55 g,891.72 mmol) were added to isopropanol (2750 ml) at 80deg.C, the indacaterol base was partially dissolved while a white solid was precipitated; gradually cooling to 35 ℃ and preserving heat for 1 hour, cooling to 5-10 ℃, stirring the suspension for 17 hours, then filtering, washing the filter cake with 10ml of isopropanol, and drying at 50 ℃/about 10 mbar for 20 hours to obtain white indacaterol acetate (80.73 g,178.40 mmol). Yield 70.02% and purity 99.51%.
Comparative example 2: preparation of indacaterol acetate
Indamaterol base (2.02 g,5.15 mmol) and isopropanol (120 mL) were added to the reaction flask, heated to a reaction temperature of 80℃and acetic acid (1.08 g,17.98 mmol) was added dropwise, and the indaterol base dissolved rapidly. Cooling to 35 deg.c, separating out crystal and maintaining for 2 hr. Continuously cooling to the reaction temperature of 5-10 ℃ and stirring for 17 hours. The mixture was filtered, and the filter cake was washed with a small amount of isopropanol and dried under reduced pressure. Indanterol acetate (0.78 g,1.73 mmol) was obtained. Yield 33.64% and purity 99.84%.
Comparative example 3: preparation of indacaterol acetate
Indamaterol base (5.00 g,12.74 mmol) was dissolved in 10mL N, N-dimethylformamide, acetic acid (2.6 g,43.33 mmol) isopropanol (50 mL) was added dropwise to the reaction flask, the reaction temperature was maintained at 35℃and stirring was continued for 1 hour, then the temperature was lowered to 5℃to 10℃and stirring was continued for 17 hours. The mixture was filtered, and the filter cake was washed with a small amount of isopropanol and dried under reduced pressure. Indanterol acetate (3.39 g,7.50 mmol) was obtained in a yield of 58.84% with a purity of 99.55%.
Comparative example 4: preparation of indacaterol acetate
Indamaterol base (5.00 g,12.74 mmol) was dissolved in 10mL dimethyl sulfoxide, acetic acid (2.6 g,43.33 mmol) isopropanol (50 mL) was added dropwise to the reaction flask, the reaction temperature was maintained at 35℃and stirring was continued for 1 hour, then the temperature was lowered to 5℃to 10℃and stirring was continued for 17 hours. The mixture was filtered, and the filter cake was washed with a small amount of isopropanol and dried under reduced pressure. Indanterol acetate (3.14 g,6.95 mmol) was obtained in 54.55% yield and 99.67% purity.
Comparative example 5: preparation of indacaterol acetate
Indantrolene base (5.04 g,12.84 mmol) and methylene chloride (15 ml) were added to the reaction flask, acetic acid (2.73 g,45.50 mmol) was added dropwise and dissolved with stirring. Heated to 35℃and isopropanol (15 ml) was added thereto and stirred for 1 hour with heat preservation. Cooling to 5-10 deg.c, stirring the solution for 10 hr without crystal precipitation, heating to 35 deg.c, adding isopropanol (75 ml), maintaining for 1 hr with small amount of crystal precipitation, cooling to 5-10 deg.c and stirring for 17 hr. Filtering, and drying the filter cake at 50 ℃ under reduced pressure for 20 hours. White indacaterol acetate (0.61 g,1.35 mmol) was obtained. The yield was 10.50% and the purity was 99.89%.
Comparative example 6: preparation of indacaterol acetate
Indantrolene base (10.02 g,25.53 mmol) and methylene chloride (30 ml) were added to a reaction flask, acetic acid (5.36 g,89.33 mmol) was added dropwise and dissolved with stirring. Heated to 35℃and methanol (100 ml) was added thereto, followed by stirring for 1 hour with heat preservation. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (0.58 g,1.28 mmol) was obtained. The yield was 5.02% and the purity was 99.89%.
Comparative example 7: preparation of indacaterol acetate
Indantrolene base (10.00 g,25.48 mmol) and methylene chloride (30 ml) were added to a reaction flask, acetic acid (5.36 g,89.33 mmol) was added dropwise, and dissolved with stirring. Heated to 35℃and mixed solvent of methanol (60 ml) and ethyl acetate (60 ml) was added thereto, followed by stirring for 1 hour at a constant temperature. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (1.14 g,2.52 mmol) was obtained. The yield was 9.89% and the purity was 99.52%.
Comparative example 8: preparation of indacaterol acetate
Indantrolene base (9.98 g,25.43 mmol) and methylene chloride (30 ml) were added to the reaction flask, acetic acid (2.29 g,38.14 mmol) was added dropwise, the indacaterol base was stirred without complete dissolution, and acetic acid (6.87 g,114.42 mmol) was added continuously. Heated to 35℃and isopropanol (100 ml) was added thereto, and the mixture was stirred at a constant temperature for 1 hour. Cooling to 5-10 deg.c, stirring the suspension for 10 hr, filtering, washing the filter cake with small amount of isopropanol, and decompression drying the filter cake at 50 deg.c for 20 hr. White indacaterol acetate (4.72 g,10.43 mmol) was obtained. Yield 41.02% and purity 99.76%.
Comparative example 9: preparation of indacaterol acetate
Indantrolene base (15.11 g,38.50 mmol) and methylene chloride (45 ml) were added to a reaction flask, acetic acid (8.09 g,134.74 mmol) was added dropwise, and dissolved with stirring. The reaction mixture was heated to 35℃and a mixed solvent of isopropyl alcohol (90 ml) and ethyl acetate (180 ml) was added thereto, whereby a solid was immediately precipitated, and the mixture was stirred at a constant temperature for 1 hour. The temperature is reduced to 5-10 ℃, the suspension is stirred for 10 hours, then filtered, the filtration is extremely difficult, the filter cake is washed by a small amount of isopropanol, and the filter cake is dried for 20 hours under reduced pressure at 50 ℃. White indacaterol acetate (15.79 g,34.89 mmol) was obtained. The yield was 90.63% and the purity was 99.58%.
The product obtained in this example was amorphous as measured by Bruker D8 advanced X-ray diffractometer.
In a word, the invention provides a novel preparation method of indacaterol acetate, which has simple preparation process, higher yield and product purity, is favorable for industrial production, has higher economic value, and the crystal form of the obtained target product is consistent with the report of the literature. Meanwhile, the invention also provides a method for obtaining the solid indacaterol alkali, and the obtained solid indacaterol alkali with better properties can be used for preparing other salt forms of indacaterol.
Claims (22)
1. The method comprises the steps of dissolving acetic acid in halogenated hydrocarbon solution of indacaterol alkali shown in a formula I, adding a proper amount of mixed solvent of alcohol and ester, and crystallizing to obtain indacaterol acetate shown in a formula II;
wherein the halogenated hydrocarbon solution is one or more selected from dichloromethane and chloroform;
the mixed solvent of the alcohol and the ester is a mixture of an alcohol solvent and an ester solvent, wherein the alcohol solvent is isopropanol, and the ester solvent is ethyl acetate;
the volume ratio of the ester solvent to the alcohol solvent is 1:1;
the volume ratio of the halogenated hydrocarbon solution to the alcohol solvent is 1:1-1:5;
wherein, after the acetic acid is dissolved in the halogenated hydrocarbon solution of indacaterol alkali shown in the formula I, the method further comprises the step of heating the reaction system to the reaction temperature, wherein the reaction temperature is 30-40 ℃ before adding a proper amount of mixed solvent of alcohol and ester.
2. The process according to claim 1, wherein the volume ratio of the halogenated hydrocarbon solution to the alcohol solvent is from 1:2 to 1:3.5.
3. The process according to claim 1, wherein the concentration of indacaterol base in the halogenated hydrocarbon solution is 0.1 to 0.5g/mL based on indacaterol base.
4. A process according to claim 3, wherein the concentration of indacaterol base in the halogenated hydrocarbon solution is 0.3 to 0.4g/mL based on indacaterol base.
5. The process of claim 1, wherein the molar ratio of indacaterol base to acetic acid is from 1:2 to 1:5.
6. The process of claim 5, wherein the molar ratio of indacaterol base to acetic acid is from 1:2.5 to 1:3.5.
7. The method of claim 1, further comprising the step of incubating after adding an appropriate amount of the mixed solvent of alcohol and ester.
8. The method of claim 7, wherein the incubation time is 0.5 to 4 hours.
9. The method of claim 8, wherein the incubation time is 1-2 hours.
10. The method of claim 1, wherein the crystallization is performed at 5-10 ℃ for 5-10 hours.
11. The method of claim 1, wherein all operations of the method are performed with agitation.
12. The process of claim 1, wherein the indacaterol base of formula I is prepared by: the indacaterol salt is subjected to neutralization reaction in an alcohol solution of alkali metal hydroxide to obtain the indacaterol base shown in the formula I.
13. The process of claim 1, wherein the indacaterol base of formula I is prepared by: adding indacaterol maleate into alcohol solution of alkali metal hydroxide under stirring, stirring at a certain temperature, adding proper amount of water to quench reaction, filtering and drying the product.
14. The process of claim 12, wherein the indacaterol salt is selected from indacaterol maleate, indacaterol tartrate, indacaterol benzoate, or indacaterol mesylate.
15. The process of claim 14, wherein the indacaterol salt is indacaterol maleate.
16. The method of claim 12, wherein the alkali metal hydroxide is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide.
17. The method of claim 16, wherein the alkali metal hydroxide is sodium hydroxide.
18. The method of claim 12, wherein the alcoholic solution is selected from one or more of methanol, ethanol, propanol and isopropanol, which are fully miscible with water.
19. The method of claim 18, wherein the alcoholic solution is methanol.
20. The process of claim 12, wherein the molar ratio of indacaterol salt to alkali metal hydroxide is 1:1 to 1:5.
21. The process of claim 12, wherein the reaction concentration is 0.2 to 2.0mmol/mL as indacaterol salt.
22. The process of claim 12, wherein the reaction temperature is 10 to 45 ℃ and the reaction time is 0.5 to 4 hours.
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