CN116730851A - Violet salt type compound and preparation method and application thereof - Google Patents

Violet salt type compound and preparation method and application thereof Download PDF

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Publication number
CN116730851A
CN116730851A CN202310202214.6A CN202310202214A CN116730851A CN 116730851 A CN116730851 A CN 116730851A CN 202310202214 A CN202310202214 A CN 202310202214A CN 116730851 A CN116730851 A CN 116730851A
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compound
acid
formula
solvent
ray powder
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Inventor
张轩邈
窦赢
毛华
范江
邓士豪
宫正
周洋
宋航
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/124—Acids containing four carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention provides a novel vilanafloc salt compound. The novel vilanafloc salt compound can be stably prepared, has the advantages of good water solubility, low hygroscopicity, storage stability and the like, and is easy to prepare a crystal form with high crystallinity. The novel salt is particularly suitable for preparing preparations such as inhalation solution, soft fog agent and the like, has excellent physical and chemical stability and has excellent pharmacokinetic characteristics.

Description

Violet salt type compound and preparation method and application thereof
Technical Field
The invention relates to a salt type compound, a preparation method and medical application thereof, in particular to a vilan salt type compound, a preparation method thereof and application thereof in preparing medicines for treating chronic obstructive pulmonary disease or asthma, and belongs to the technical field of medicinal chemistry.
Background
Veland is a novel long-acting beta 2-receptor agonist (LABA), developed by the company gelan smith, approved by the FDA in the united states for marketing in 2013, approved by the national drug administration in china for 7 months in 2018. The domestic market varieties are dual or triple compound preparations containing the vilanaterol, and are dry powder inhalation preparations (DPI).
Administration of dry powder inhalation requires the patient to learn the inhalation method and requires the patient to have better lung function to inhale the drug. However, most patients suffering from chronic obstructive pulmonary disease and asthma are old patients, the operation and use methods of the DPI device are difficult to understand and fully master, the operation error rate is higher, the teaching difficulty is also higher, and the use ability of the patients needs to be comprehensively considered when selecting the inhalation device for special people, especially the old people and severe patients. Patient preference, understanding ability, inhalation skills, etc. of the inhalation device can affect patient satisfaction and compliance with the treatment. In addition, for some patients with severe chronic obstructive pulmonary disease and asthma, the lung function is poor, the inhalation airflow required by inhalation of the powder aerosol cannot be achieved, and the medicine cannot be effectively delivered to the lung or the inhaled dosage is insufficient, so that the curative effect of the medicine is reduced. However, with aerosol inhalation administration, patients do not need special training, and particularly for patients with severe chronic obstructive pulmonary disease and asthma, a sufficient dose of the drug can be inhaled by adopting a normal breathing mode, so that development of an inhalation solution of vilanabro is necessary to meet the clinical demands of such patients. The existing powder foggers containing the vilantro on the market are vilantro triphenyl acetate, the solubility of the vilantro in water is low, clear and transparent solution can not be obtained, and therefore the vilantro-triphenyl acetate can not be prepared into inhalation solution. Therefore, development of a salt-type compound of valirome, which can be used in inhalation solution formulations, to meet clinical demands is a problem to be solved in the art.
The prior vilantro triphenyl acetate can not obtain clear and transparent solution in the use concentration meeting the drug effect requirement in the solution with the pH value of 3.0-8.0. In order to develop inhalation solutions at concentrations meeting clinical requirements, the inventors have conducted studies from various aspects, such as adjusting the formulation prescription process, hopefully to find a viable means to increase the water solubility of vilantel triton acetate, but have not been achieved. Therefore, in turn, a study on various salt forms of vilanaflounder was conducted, and a study on the vilanaflounder salt forms corresponding to tens of acids in total was conducted, and unexpectedly, it was found that only a few salt forms of vilanaflounder could be prepared, satisfying the requirements of inhalation solution formulations in terms of drug solubility, stability and the like, thereby completing the present invention.
Disclosure of Invention
In order to solve the problems in the prior art as described above for the preparation of a vilantro drug, the present invention provides a vilantro salt type compound which is vilantro dimethyl acetate, 2-phenylpropionate, 2-dimethylbutyrate and/or 2-phenylisobutyrate; 2-phenylisobutyrate is preferred.
The invention provides a vilantriol salt type compound shown in a formula (I):
wherein, the liquid crystal display device comprises a liquid crystal display device,
HA is selected from dimethyl acetic acid and n is selected from 0.5-2, for example 0.5, 1, 1.5 or 2; or (b)
HA is selected from 2-phenylpropionic acid and n is selected from 0.5-2, for example 0.5, 1, 1.5 or 2; or (b)
HA is selected from 2, 2-dimethylbutyric acid, n is selected from 0.5-2, for example 0.5, 1, 1.5 or 2; or (b)
HA is selected from 2-phenylisobutyric acid and n is selected from 0.5-2, for example 0.5, 1, 1.5 or 2;
the compound is in solid crystalline or amorphous form.
In one embodiment, HA in formula (I) is dimethyl acetic acid, n is 1, which is crystalline form I, using Cu-ka radiation, the X-ray powder diffraction pattern of which HAs characteristic diffraction peaks at the following 2θ positions: 3.51 ° ± 0.2 °, 6.91 ° ± 0.2 °, 14.12 ° ± 0.2 °, 16.61 ° ± 0.2 °, 24.77 ° ± 0.2 °, 27.84 ° ± 0.2 °.
Further, in formula (I), HA is dimethyl acetic acid, n is 1, which is crystalline form I, using Cu-ka radiation, which HAs an X-ray powder diffraction pattern substantially as shown in figure 1.
In one embodiment, HA in formula (I) is dimethyl acetic acid, n is 1, which is crystalline form I, which HAs no distinct endothermic peak in differential scanning calorimetry, and which HAs a melting point of 72±2 ℃.
Further, HA in formula (I) is dimethyl acetic acid, n is 1, which is form I, having a differential scanning calorimetric profile as shown in fig. 6.
In one embodiment, HA in formula (I) is dimethyl acetic acid and n is 1, which is form I, having a thermogravimetric profile as shown in fig. 11.
In one embodiment, HA in formula (I) is 2-phenylpropionic acid, n is 1, which is crystalline form I, and the X-ray powder diffraction pattern thereof HAs characteristic diffraction peaks at the following 2θ positions using Cu-ka radiation: 3.36 ° ± 0.2 °, 6.54 ° ± 0.2 °, 9.71 ° ± 0.2 °, 14.87 ° ± 0.2 °, 16.07 ° ± 0.2 °.
Further, the X-ray powder diffraction pattern thereof also has characteristic diffraction peaks at the following 2 theta positions: 21.02 ° ± 0.2 °, 22.09 ° ± 0.2 °, 22.84 ° ± 0.2 °, 26.48 ° ± 0.2 °.
Further, the X-ray powder diffraction pattern thereof also has characteristic diffraction peaks at the following 2 theta positions: 16.68 ° ± 0.2 °, 20.45 ° ± 0.2 °, 33.06 ° ± 0.2 °.
Still further, in formula (I), HA is 2-phenylpropionic acid, n is 1, which is crystalline form I, and Cu-K alpha radiation is used, which HAs an X-ray powder diffraction pattern substantially as shown in FIG. 2.
In one embodiment, HA in formula (I) is 2-phenylpropionic acid, n is 1, which is crystalline form I, which HAs no distinct endothermic peak in differential scanning calorimetry, and which HAs a melting point of 65±2 ℃.
Further, HA in formula (I) is 2-phenylpropionic acid, n is 1, which is crystalline form I, having a differential scanning calorimetry trace pattern as shown in fig. 7.
In one embodiment, HA in formula (I) is 2-phenylpropionic acid and n is 1, which is form I, having a thermogravimetric profile as shown in fig. 12.
In one embodiment, HA in formula (I) is 2, 2-dimethylbutyric acid, n is 1, which is crystalline form I, using Cu-ka radiation, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ positions: 7.30 ° ± 0.2 °, 10.86 ° ± 0.2 °, 15.02 ° ± 0.2 °, 15.48 ° ± 0.2 °, 18.03 ° ± 0.2 ° 22.02 ° ± 0.2 °, 24.69 ° ± 0.2 ° and 25.73 ° ± 0.2 °.
Further, the X-ray powder diffraction pattern thereof also has characteristic diffraction peaks at the following 2 theta positions: 18.56 ° ± 0.2 °, 18.85 ° ± 0.2 °, 19.95 ° ± 0.2 °, 24.13 ° ± 0.2 °, 28.63 ° ± 0.2 °, 29.17 ° ± 0.2 °, 32.56 ° ± 0.2 °, 33.63 ° ± 0.2 °.
Further, the X-ray powder diffraction pattern thereof also has characteristic diffraction peaks at the following 2 theta positions: 17.00 DEG+ -0.2 DEG, 19.31 DEG+ -0.2 DEG, 20.23 DEG+ -0.2 DEG, 21.61 DEG+ -0.2 DEG, 25.21 DEG+ -0.2 DEG, 28.24 DEG+ -0.2 DEG, 34.64 DEG+ -0.2 DEG, 35.31 DEG+ -0.2 DEG, a first phase-change material having a second phase-change material having a first phase with a second phase-change material having a first phase-change material having a second phase with the first phase-change material having a first phase with the first phase of the first phase-change material having the first phase of the first phase,
39.01°±0.2°。
Still further, in formula (I), HA is 2, 2-dimethylbutyric acid, n is 1, which is in crystalline form I, using Cu-K alpha radiation, having an X-ray powder diffraction pattern substantially as shown in FIG. 4.
In one embodiment, HA in formula (I) is 2, 2-dimethylbutyric acid, n is 1, which is form I, having a characteristic endothermic peak at 33-48 ℃ and a melting point of 73±2 ℃ in a differential scanning calorimetric analysis.
Further, HA in formula (I) is 2, 2-dimethylbutyric acid, n is 1, which is form I, having a differential scanning calorimetry trace pattern as shown in figure 9.
In one embodiment, HA in formula (I) is 2, 2-dimethylbutyric acid, n is 1, which is form I, having a thermogravimetric profile as shown in fig. 14.
In one embodiment, HA in formula (I) is 2, 2-dimethylbutyric acid, n is 1, which is amorphous.
Further, in formula (I), HA is 2, 2-dimethylbutyric acid, n is 1, which is amorphous, and Cu-K alpha radiation is used, which HAs an X-ray powder diffraction pattern as shown in FIG. 10.
In one embodiment, HA in formula (I) is 2, 2-dimethylbutyric acid, n is 1, which is amorphous, having a characteristic endothermic peak at 35-42 ℃ and a melting point of 73±2 ℃ in a differential scanning calorimetric analysis.
Further, in the formula (I), HA is 2, 2-dimethylbutyric acid, n is 1, and the HA is amorphous, and the HA HAs a differential scanning calorimetric analysis curve pattern shown in figure 8.
In one embodiment, HA in formula (I) is 2, 2-dimethylbutyric acid, n is 1, which is amorphous, having a thermogravimetric profile as shown in fig. 13.
In one embodiment, HA in formula (I) is 2-phenylisobutyric acid, n is 1, which is crystalline form I, using Cu-ka radiation, the X-ray powder diffraction pattern of which HAs characteristic diffraction peaks at the following 2θ positions: 4.94 ° ± 0.2 °, 9.89 ° ± 0.2 °, 10.50 ° ± 0.2 °, 10.84 ° ± 0.2 °, 12.66 ° ± 0.2 °, 13.84 ° ± 0.2 °, 14.90 ° ± 0.2 °, 18.72 ° ± 0.2 °, 19.74 ° ± 0.2 °, 21.37 ° ± 0.2 °, 22.36 ° ± 0.2 °, 23.75 ° ± 0.2 °, 25.74 ° ± 0.2 °, 27.52 ° ± 0.2 °.
Further, the X-ray powder diffraction pattern thereof also has characteristic diffraction peaks at the following 2 theta positions: 13.16 ° ± 0.2 °, 16.29 ° ± 0.2 °, 18.06 ° ± 0.2 °, 19.05 ° ± 0.2 °, 20.15 ° ± 0.2 °, 21.68 ° ± 0.2 °, 24.60 ° ± 0.2 °, 24.88 ° ± 0.2 °
26.50°±0.2°、31.43°±0.2°。
Further, the X-ray powder diffraction pattern thereof also has characteristic diffraction peaks at the following 2 theta positions: 11.34 ° ± 0.2 °, 16.04 ° ± 0.2 °, 22.61 ° ± 0.2 °, 23.26 ° ± 0.2 °, 24.15 ° ± 0.2 °, 25.46 ° ± 0.2 °, 27.12 ° ± 0.2 °, 27.87 ° ± 0.2 °
28.66°±0.2°、30.10°±0.2°、30.41°±0.2°、31.81°±0.2°、35.67°±0.2°。
Still further, in formula (I), HA is 2-phenylisobutyric acid, n is 1, which is crystalline form I, using Cu-K alpha radiation, having an X-ray powder diffraction pattern substantially as shown in FIG. 5.
In one embodiment, HA in formula (I) is 2-phenylisobutyric acid, n is 1, which is form I, which HAs no distinct endothermic peak in differential scanning calorimetry, and HAs a melting point of 94±2 ℃.
Further, in formula (I), HA is 2-phenylisobutyric acid, n is 1, and the compound is crystal form I, and the compound HAs a differential scanning calorimetric analysis curve chart shown in figure 10.
In one embodiment, HA in formula (I) is 2-phenylisobutyric acid, n is 1, which is form I, having a thermogravimetric profile as shown in fig. 15.
The structural formula of the acid radical and CAS number are shown in Table 1
The preparation method of the invention
The invention provides a preparation method of a compound shown in a formula (I), which comprises the following steps:
dissolving a compound shown in a formula (II) in a first solvent at room temperature, adding a second solvent in which HA is dissolved, stirring, separating out a solid, and collecting the solid; wherein HA is selected from dimethyl acetic acid, 2-phenylpropionic acid, 2-dimethylbutyric acid or 2-phenylisobutyric acid, n is selected from 0-5, for example 0.5, 1, 1.5 or 2;
in one embodiment, n is 1 and the molar ratio of the compound of formula (II) to HA is 1:1 to 1.5; further, the molar ratio of the compound shown in the formula (II) to HA is 1:1-1.2; further, the molar ratio of the compound of formula (II) to HA was 1:1.
In some embodiments, the first solvent or the second solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, acetonitrile, isopropyl acetate, acetone, n-heptane.
Further, the first solvent or the second solvent is selected from ethyl acetate, acetonitrile or n-heptane.
In any of the embodiments of the invention, when HA is selected from the group consisting of dimethyl acetic acid, 2-phenylpropionic acid, n is 1, the solid produced is in amorphous or crystalline form, respectively, such as crystalline form I of vilantro Luo Er methylacetate, crystalline form I of vilantro 2-phenylpropionate.
In any of the embodiments of the present invention, there is provided a process for the preparation of amorphous and crystalline form I of a vilanaterol 2, 2-dimethylbutyrate compound (n is selected from 0-5, for example 0.5, 1, 1.5 or 2), comprising the steps of:
dissolving a compound shown in a formula (II) in a first solvent at room temperature, adding a second solvent in which 2, 2-dimethylbutyric acid is dissolved, stirring, separating out a solid, and collecting the solid to obtain an amorphous compound shown in a formula (I); placing the amorphous form at room temperature under 80% -90% RH for 1-3 days to obtain a crystal form I of the compound shown in the formula (I);
wherein the first solvent or the second solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, acetonitrile, isopropyl acetate, acetone and n-heptane, preferably selected from ethyl acetate, acetonitrile or n-heptane.
In any of the embodiments of the present invention, there is provided a process for the preparation of a vilanaterol 2-phenylisobutyrate compound (n is selected from 0-5, e.g. 0.5, 1, 1.5 or 2), comprising the steps of:
dispersing a compound shown in a formula (II) in a solvent at room temperature to obtain a solution 1; adding 2-phenylisobutyric acid and dissolving in the solution 1, stirring, adding n-heptane, stirring at 2-8deg.C, separating out solid or obtaining suspension, centrifuging the suspension, and collecting solid to obtain vilanafloc 2-phenylisobutyrate solid;
wherein the solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, isopropyl acetate and acetone, preferably ethyl acetate.
The present invention provides a process for the preparation of crystalline form I of viland-terol 2-phenylisobutyrate (n is selected from 0-5, e.g. 0.5, 1, 1.5 or 2), comprising the steps of:
dispersing a compound shown in a formula (II) in a first solvent at room temperature to obtain a solution 1; adding 2-phenylisobutyric acid and dissolving in the solution 1, stirring, adding n-heptane, stirring at 2-8deg.C, separating out solid or obtaining suspension, centrifuging the suspension, and collecting solid to obtain compound (2-phenylisobutyrate) of formula (I); wherein the first solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, isopropyl acetate and acetone, preferably ethyl acetate.
Optionally, dissolving a compound of formula (II) in a second solvent at 40±5 ℃; adding 2-phenylisobutyric acid, reacting at 33+/-2 ℃ until the reaction is completed, adding the solid of the compound of the formula (I) obtained in the previous step, preserving the temperature at 30+/-5 ℃ for 30-60 min, stirring for 10-24 h at 20+/-5 ℃, and collecting the precipitated solid to obtain the crystal form I of the 2-phenylisobutyrate of the vilantrum; wherein the second solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, isopropyl acetate and acetone, preferably ethyl acetate.
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the above formula (I) or a hydrate, solvate or crystal thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is preferably an inhalation formulation composition, such as an inhalation solution, inhalation suspension, aerosol, soft mist, or the like.
The invention also provides application of the compound shown in the formula (I) and hydrates, solvates and crystal forms thereof in preparing medicines for treating chronic obstructive pulmonary disease or asthma.
The present invention also provides a method of treating chronic obstructive pulmonary disease or asthma comprising administering a compound of formula (I) as described above, or a hydrate, solvate and crystalline form thereof, or a pharmaceutical composition as described above. For the treatment of respiratory diseases, it is preferred that the compounds of the invention are administered by inhalation.
Inhalable formulations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations. For this purpose, it may be administered directly as a powder (preferably in micronized form), or via a spray solution or suspension containing them.
Excipients or carriers may be added to the powder compounds of the invention, which are generally non-toxic and chemically inert to the compounds of the invention, such as lactose or any other additive suitable for improving the respirable fraction.
Inhalation aerosols comprising a gaseous propellant, such as a hydrofluoroalkane, may comprise the compounds of the invention in solution or dispersion form. Propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
Propellant-free inhalable formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be delivered by jet, vibrating screen or ultrasonic nebulizers known in the art, or by soft-mist nebulizers (soft-mist nebulizers).
The "therapeutically effective amount" of the present invention refers to that amount of a compound that causes physiological or medical translation of a tissue, system or subject, which amount is sought, including an amount of the compound that is sufficient to prevent or reduce to some extent one or more symptoms of the condition or disorder being treated when administered to a subject. For example, the therapeutically effective amount may be from 0.01 μg/kg to 100 μg/kg.
The crystalline structure of the present invention may be analyzed using various analytical techniques known to those of ordinary skill in the art, including, but not limited to, X-ray powder diffraction (XRD), differential Scanning Calorimetry (DSC), and/or Thermogravimetry (TG). Thermogravimetric analysis (Thermogravi metric Analysis, TGA), also known as Thermogravimetry (TG).
Technical effects of the invention
Unlike the water-soluble vilantro triphenyl acetate, the novel salt compound of the vilantro has good water solubility, low hygroscopicity, storage stability and the like, is suitable for being developed into preparations such as inhalation solution, soft fog agent and the like, the inhalation preparation is not required to be inhaled by a patient actively, the patient can inhale enough medicine through spontaneous breathing, and the compound is more convenient to use and has better drug effect than powder fog formulation for chronic obstructive pulmonary diseases and asthma patients who cannot grasp the using skill and inhalation ability of the powder fog agent and cannot reach the optimal inhalation flow rate of the powder fog agent. The novel salt has excellent physical and chemical stability and excellent pharmacokinetic properties.
Drawings
Fig. 1 is: an X-ray powder diffraction pattern of the crystal form I when HA in the formula (I) is dimethyl acetic acid and n is 1;
fig. 2 is: an X-ray powder diffraction pattern of the crystal form I when HA in the formula (I) is 2-phenylpropionic acid and n is 1;
fig. 3 is: an amorphous X-ray powder diffraction pattern when HA is 2, 2-dimethylbutyric acid and n is 1 in formula (I);
fig. 4 is: an X-ray powder diffraction pattern of the crystal form I when HA in the formula (I) is 2, 2-dimethylbutyric acid and n is 1;
fig. 5 is: x-ray powder diffraction pattern of crystal form I when HA is 2-phenylisobutyric acid and n is 1 in the formula (I);
fig. 6 is: a differential scanning calorimetric analysis (DSC) curve for form I when HA is dimethyl acetic acid and n is 1 in formula (I);
fig. 7 is: a Differential Scanning Calorimetric (DSC) curve for form I when HA is 2-phenylpropionic acid and n is 1 in formula (I);
fig. 8 is: an amorphous differential scanning calorimetric curve when HA is 2, 2-dimethylbutyric acid and n is 1 in formula (I);
fig. 9 is: a Differential Scanning Calorimetric (DSC) curve for form I when HA is 2, 2-dimethylbutyric acid and n is 1 in formula (I);
fig. 10 is: a Differential Scanning Calorimetric (DSC) profile for form I when HA is 2-phenylisobutyric acid and n is 1 in formula (I);
fig. 11 is: thermogravimetric analysis (TGA) profile for form I when HA is dimethyl acetic acid and n is 1 in formula (I);
fig. 12 is: thermogravimetric analysis (TGA) profile for form I when HA is 2-phenylpropionic acid, 1 in formula (I);
fig. 13 is: an amorphous thermogravimetric analysis (TGA) curve for HA of formula (I) 2, 2-dimethylbutyric acid, n being 1;
fig. 14 is: thermogravimetric analysis (TGA) profile for form I when HA is 2, 2-dimethylbutyric acid and n is 1 in formula (I);
fig. 15 is: thermogravimetric analysis (TGA) profile for form I when HA is 2-phenylisobutyric acid and n is 1 in formula (I);
fig. 16 is: in the formula (I), when HA is dimethyl acetic acid and n is 1, the crystal form I 1 H-NMR spectrum;
fig. 17 is: in the formula (I), when HA is 2-phenylpropionic acid and n is 1, the crystal form I 1 H-NMR spectrum;
fig. 18 is: in the formula (I), HA is 2, 2-dimethylbutyric acid, n is 1, amorphous 1 H-NMR spectrum;
fig. 19 is: in the formula (I), when HA is 2-phenylisobutyric acid and n is 1, the crystal form I 1 H-NMR spectrum.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are included in the present disclosure, are intended to be within the scope of the present invention.
EXAMPLE 1 Wilantetrol salification test
In the salt formation studies of vilantro, the inventors tried several tens of organic and inorganic acids to form salts with vilantro, including arginine, isoleucine, pyroglutamic acid, glycolic acid, propionic acid, orotic acid, nicotinic acid, terephthalic acid, mucic acid, alpha-ketoglutaric acid, hippuric acid, citric acid, maleic acid, 2-ethylsuccinic acid, L-malic acid, diethyl acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc., and all of them were found to be not successful in salt formation by using ethanol, isopropanol, acetone, ethyl acetate, butanone, tetrahydrofuran, acetonitrile, methylene chloride, toluene, etc.; the inventors have found that other acids than triphenylacetic acid, which form salts with vilantro smoothly, are only dimethyl acetic acid, 2-phenylpropionic acid, 2-dimethylbutyric acid, 2-phenylisobutyric acid, which form salts with vilantro. The partial information excerpts are as follows:
TABLE 2 salt formation studies of Violet
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EXAMPLE 2 preparation of Violet dimethyl acetate
Step 1: about 150mg of Violet is taken, 1.0mL of ethyl acetate is added, and ultrasonic clearing is carried out, so as to obtain solution 1; step 2: about 30mg of dimethylacetic acid was dissolved in 0.5mL of ethyl acetate at room temperature to obtain solution 2;
step 3: slowly dripping the solution 2 into the solution 1 under stirring at room temperature, stirring overnight at 4 ℃ without turbidity, and precipitating solid to obtain suspension;
step 4: the suspension was centrifuged and the resulting solid was dried at room temperature under vacuum overnight and then dried at 40 ℃ under vacuum for 4 hours to give vilantt Luo Er methylacetate. Is the crystal form I of the vilanterol dimethyl acetate.
EXAMPLE 3 preparation of Violet terol 2-phenylpropionate
Step 1: about 150mg of Violet is taken, 1.0mL of ethyl acetate is added, and ultrasonic clearing is carried out, so as to obtain solution 1;
step 2: about 50mg of dimethylacetic acid was dissolved in 0.3mL of ethyl acetate at room temperature to obtain solution 2;
step 3: slowly dripping the solution 2 into the solution 1 under stirring at room temperature, stirring overnight at 4 ℃ without turbidity, and precipitating solid to obtain suspension;
step 4: the suspension was centrifuged and the resulting solid was dried under vacuum overnight at room temperature to give valatide 2-phenylpropionate. Is the crystal form I of the viland tersweet 2-phenylpropionate.
EXAMPLE 4 preparation of Violet terol 2, 2-dimethylbutyrate
Step 1: about 150mg of Violet is taken, 1.0mL of ethyl acetate is added, and ultrasonic clearing is carried out, so as to obtain solution 1;
step 2: about 40mg of 2, 2-dimethylbutyric acid was dissolved in 0.7mL of ethyl acetate at room temperature to give solution 2;
step 3: slowly dripping the solution 2 into the solution 1 under stirring at room temperature, stirring overnight at 4 ℃ without turbidity, and precipitating solid to obtain suspension;
step 4: the suspension was centrifuged and the resulting solid was dried overnight at room temperature under vacuum and at 40℃for about 6 hours to give vilantro 2, 2-dimethylbutyrate. It was determined to be in amorphous form.
Step 5: taking a proper amount of viland tersweet 2, 2-dimethylbutyrate amorphous, and placing the amorphous product in a humidity device with 85% RH for 1 day at room temperature to obtain the 2, 2-dimethylbutyrate crystal form I.
EXAMPLE 5 preparation of Violet terol 2-phenylisobutyrate
Step 1: about 150mg of Violet is taken, 1.0mL of ethyl acetate is added, and ultrasonic clearing is carried out, so as to obtain solution 1;
step 2: adding 56mg of 2-phenylisobutyric acid solid into the solution 1 under stirring at room temperature, dissolving, and stirring at 4 ℃ overnight without separating out the solid;
step 3: about 20mL of n-heptane was added to precipitate a solid, which was stirred overnight at 4℃to give a suspension;
step 4: the suspension was centrifuged to give a solid which was dried overnight at room temperature under vacuum to give the vilantro 2-phenylisobutyrate solid.
EXAMPLE 6 preparation of Violet 2-phenylisobutyrate
10.0g of velamer and 60ml of ethyl acetate are added into a 100ml single-mouth bottle, the temperature is raised to 40+/-5 ℃, and the mixture is stirred until the mixture is dissolved; adding 4.7g of 2-phenylisobutyric acid, and preserving the temperature for 10-20 min; cooling to 33+/-2 ℃, adding 10mg of viland terlo 2-phenyl isobutyl acid salt solid (prepared by the method in the embodiment 5), continuously cooling to 30+/-5 ℃, and preserving heat for 30-40 min; continuously cooling to 20+/-5 ℃, stirring for 10-12 hours, filtering, washing the filter cake twice with 10ml of ethyl acetate, and vacuum drying for 10-12 hours at 35+/-5 ℃ to obtain the vilantro 2-phenyl isobutyl acid salt crystal form I.
Test 1 dissolution characteristics study of Violet triphenylacetate, triphenylacetic acid under different pH conditions
10mg of Violet Luo San phenylacetate raw material medicine is added into 10mL of buffer solution with pH value of 3.0-8.0 (the preparation method of the buffer solution with pH value of 3.0-6.0 comprises the steps of preparing 5mM citric acid solution, regulating the pH value to be corresponding to that of the buffer solution with 0.05mol/L sodium hydroxide solution, the preparation method of the buffer solution with pH value of 7.0-8.0 comprises the steps of weighing 0.68g of monopotassium phosphate, weighing 29.1mL of 0.1mol/L sodium hydroxide solution, diluting to 100mL with water, regulating the pH value to be corresponding to that of the buffer solution with 0.05mol/L sodium hydroxide solution), stirring and dissolving for 48 hours, and observing the properties of the solution. The property results show that the solutions all have white floaters, the concentration of the velamer in the filtrate is measured after the solutions are filtered, and the detection results are shown in the following table.
TABLE 3 detection of the concentration of Violet in the filtrate
The results in the above table show that: the lower the pH, the higher the concentration of vilantro in the filtrate, and the concentration of vilantro in the filtrate after the pH is raised is significantly reduced.
The white floats which did not pass through the filter membrane were examined and analyzed, and it was found that in the solutions of pH3.0 and pH 4.0, the white floats were mostly triphenylacetic acid. The white float of the pH5.0 solution had both vilanterol triphenylacetate and more triphenylacetic acid. In the solution with pH of 6.0-8.0, the white floater is mainly vilantt Luo San phenylacetate.
The solubility of triphenylacetic acid in aqueous solutions of different pH was tested and the results were as follows:
table 4 triphenylacetic acid solubility assay
As can be seen from the table above: the solubility of triphenylacetic acid is extremely low in low pH solutions and higher in high pH solutions. Since the dissolution properties of vilanabro are precisely opposite to those of triphenylacetic acid: the valbuterol has good solubility in low pH solution, and the solubility decreases after the pH is raised. In conclusion, the solubility difference of the vilantro and the triphenylacetic acid in the solution with the same pH value is huge, so that the vilantro triphenylacetate can not be prepared into a clear and transparent solution all the time under the planned effective concentration of the preparation, and the vilantro triphenylacetate is unfavorable to be developed into a solution for inhalation.
Because the valbuterol molecule has a long chain structure, salification is difficult. The glazin is prepared by using triphenylacetic acid as a counter ion, and the glazin is not easy to form salt, but the salt is poor in water solubility, cannot be prepared into clear and transparent solution, and is only suitable for being developed into powder fog agent.
Test 2 solubility study of 4 salts of vilanaflo in aqueous solutions of different pH
The preparation method of the buffer solution comprises the steps of taking 4 salt forms of the Violet obtained in the examples 2-6, adding the salt forms into 100mL of aqueous solutions with different pH values (buffer solution with the pH value of 3.0-8.0) (the preparation method of the buffer solution with the pH value of 3.0-6.0 comprises the steps of preparing 5mM citric acid solution, adjusting the pH value to the corresponding pH value by using 0.05mol/L sodium hydroxide solution, the preparation method of the buffer solution with the pH value of 7.0-8.0 comprises the steps of weighing 0.68g of monopotassium phosphate, weighing 29.1mL of 0.1mol/L sodium hydroxide solution, diluting the solution with water to 100mL, adjusting the pH value to the corresponding pH value by using 0.05mol/L sodium hydroxide solution), and measuring the content of Violet in the aqueous solution after stirring for 48 hours.
TABLE 5 New salt solubility test
From the above table, the above 4 new vilantro salt forms have better solubility in aqueous solution, and the amount of the drug dissolved in the aqueous solution is far higher than Yu Weilan t Luo San phenylacetate, which meets the requirement of inhalation solution preparation on the water solubility of the drug.
Experimental study of influence factor of 4 salts of 3 Violet
Sample: the compound of example 2, the compound of example Luo Er, the compound of example 3, the compound of example 2, the compound of example 3, the compound of example 4, the compound of example 2, 2-dimethylbutyrate, the compound of example 6, the compound of example 2, and the compound of example 6.
Experiment: the stability of each sample under high temperature, light and high humidity conditions was examined, and the experimental results are shown in the following table.
Test conditions: the purity conditions for HPLC detection are:
chromatographic column: octadecyl bonded silica gel as filler (XBridge C18, 250 x 4.6mm,5 μm or other column with comparable potency)
Column temperature: 40 DEG C
Detection wavelength: 220nm
Mobile phase: mobile phase a:10mM potassium dihydrogen phosphate (pH adjusted to 3.0 with phosphoric acid); mobile phase B: acetonitrile
The elution procedure is shown in the following table:
the flow rate was 1.0ml/min.
The test results are shown in Table 6
TABLE 6 influence factor test
Conclusion: the salt-type compounds of examples 2-4 increased slightly faster in impurity under high temperature and light conditions. The salt form of the compound of example 6 (vilanaterol 2-phenylisobutyrate) is most stable.
Test 4-Violet-4 salt-type hygroscopicity study
Sample: the compound of example 2, the compound of example Luo Er, the compound of example 3, the compound of example 2, the compound of example 3, the compound of example 4, the compound of example 2, 2-dimethylbutyrate, the compound of example 6, the compound of example 2, and the compound of example 6.
The experimental method comprises the following steps: the test was carried out according to the 2020 edition "Chinese pharmacopoeia" item four 9103, and the results are shown in Table 7.
Table 7 hygroscopicity results
The table above shows: the 4 salts of viland have low hygroscopicity, and particularly, the 2-phenylisobutyrate has almost no hygroscopicity.
Test 5 Violet Tide 4 salt crystallinity study
Sample: the compound of example 2, the compound of example Luo Er, the compound of example 3, the compound of example 2, the compound of example 3, the compound of example 4, the compound of example 2, 2-dimethylbutyrate, the compound of example 6, the compound of example 2, and the compound of example 6.
The test method comprises the following steps: XRPD detection is carried out on the prepared 4 salt forms respectively, and detection patterns are shown in fig. 1-5. And simultaneously, the appearance properties of different salt forms are observed through a polarizing microscope, and the test results are shown in table 8.
TABLE 8 crystallinity results
The test results show that the XRPD pattern diffraction peaks of the viland-terol 2-phenylisobutyric acid salt have the highest peak intensity in the XRPD patterns of the 4 salt forms, which shows that the crystallization degree is the best; in addition, the appearance of different salt forms is observed under a polarizing microscope, and the properties of the vilanterol 2-phenylisobutyrate are optimal, and the vilanterol 2-phenylisobutyrate is fine crystalline particles. Other salt forms are all sticky agglomerated solids.
Test long-term and accelerated stability study of 6-Violet 2-phenylisobutyrate
Long-term and accelerated stability tests were carried out on the valterol 2-phenylisobutyrate prepared in example 6, and the test results are shown in Table 9:
table 9 stability test
The test results show that: the vilantro 2-phenyl isobutyrate is placed under the conditions of long term and acceleration, impurities are slowly increased, and the stability is good.

Claims (44)

1. A vilantriol salt compound: which is vilantel dimethyl acetate, 2-phenylpropionate, 2-dimethylbutyrate and/or 2-phenylisobutyrate; preferably 2-phenylisobutyrate; preferably, it is as shown in formula (I):
wherein HA is selected from dimethyl acetic acid, 2-phenylpropionic acid, 2-dimethylbutyric acid or 2-phenylisobutyric acid; 2-phenylisobutyric acid is preferred.
2. The compound of claim 1, which is in solid crystalline form or amorphous form.
3. A compound according to claim 1 or 2, n being selected from 0.5-2, such as 0.5, 1, 1.5 or 2.
4. A compound according to claim 3, HA being dimethyl acetic acid, n being 1, which is crystalline form i, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 3.51 ° ± 0.2 °, 6.91 ° ± 0.2 °, 14.12 ° ± 0.2 °, 16.61 ° ± 0.2 °, 24.77 ° ± 0.2 °, 27.84 ° ± 0.2 °.
5. The compound of claim 4, using Cu-ka radiation, having an X-ray powder diffraction pattern substantially as shown in figure 1.
6. The compound of any one of claims 4-5, which has no distinct endothermic peak in a differential scanning calorimetric analysis and has a melting point of 72±2 ℃.
7. The compound of claim 6 having a differential scanning calorimetric profile as shown in figure 6.
8. The compound of claims 4-5 having a thermogravimetric profile as shown in figure 11.
9. A compound according to claim 3, HA is 2-phenylpropionic acid, n is 1, which is crystalline form i, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 3.36 ° ± 0.2 °, 6.54 ° ± 0.2 °, 9.71 ° ± 0.2 °, 14.87 ° ± 0.2 °, 16.07 ° ± 0.2 °.
10. The compound of claim 9, having an X-ray powder diffraction pattern further having characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 21.02 ° ± 0.2 °, 22.09 ° ± 0.2 °, 22.84 ° ± 0.2 °, 26.48 ° ± 0.2 °.
11. The compound of claim 10, having an X-ray powder diffraction pattern further having characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 16.68 ° ± 0.2 °, 20.45 ° ± 0.2 °, 33.06 ° ± 0.2 °.
12. The compound of any one of claims 9-11, using Cu-ka radiation, having an X-ray powder diffraction pattern substantially as shown in figure 2.
13. The compound of any one of claims 9-12, which has no distinct endothermic peak in a differential scanning calorimetric analysis and has a melting point of 65±2 ℃.
14. The compound of claim 13 having a differential scanning calorimetric profile as shown in figure 7.
15. The compound of any one of claims 9-12 having a thermogravimetric analysis profile as shown in figure 12.
16. A compound according to claim 3, HA is 2, 2-dimethylbutyric acid, n is 1, which is crystalline form i, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 7.30 ° ± 0.2 °, 10.86 ° ± 0.2 °, 15.02 ° ± 0.2 °, 15.48 ° ± 0.2 °, 18.03 ° ± 0.2 °, 22.02 ° ± 0.2 °, 24.69 ° ± 0.2 °, 25.73 ° ± 0.2 °,.
17. The compound of claim 16, having an X-ray powder diffraction pattern further having characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 18.56 ° ± 0.2 °, 18.85 ° ± 0.2 °, 19.95 ° ± 0.2 °, 24.13 ° ± 0.2 °, 28.63 ° ± 0.2 °, 29.17 ° ± 0.2 °, 32.56 ° ± 0.2 °, 33.63 ° ± 0.2 °.
18. The compound of claim 17, having an X-ray powder diffraction pattern further having characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 17.00 ° ± 0.2 °, 19.31 ° ± 0.2 °, 20.23 ° ± 0.2 °, 21.61 ° ± 0.2 °, 25.21 ° ± 0.2 °, 28.24 ° ± 0.2 °, 34.64 ° ± 0.2 °, 35.31 ° ± 0.2 ° and 39.01 ° ± 0.2 °.
19. The compound of any one of claims 16-18, using Cu-ka radiation, having an X-ray powder diffraction pattern substantially as shown in figure 4.
20. The compound of any one of claims 16-19, having a characteristic endothermic peak at 33-48 ℃ and a melting point of 73±2 ℃ in a differential scanning calorimetric analysis.
21. The compound of claim 20 having a differential scanning calorimetric profile as shown in figure 9.
22. The compound of any one of claims 16-19, having a thermogravimetric analysis profile as shown in figure 14.
23. A compound according to claim 3, HA is 2, 2-dimethylbutyric acid, n is 1, which is amorphous.
24. The compound of claim 23, using Cu-ka radiation having an X-ray powder diffraction pattern substantially as shown in figure 3.
25. The compound of claim 23, having a characteristic endothermic peak at 35-42 ℃ and a melting point of 73±2 ℃ in a differential scanning calorimetric analysis.
26. The compound of claim 25 having a differential scanning calorimetric profile as shown in figure 8.
27. The compound of claims 23-24 having a thermogravimetric analysis profile as shown in figure 13.
28. A compound according to claim 3, HA is 2-phenylisobutyric acid, n is 1, which is crystalline form i, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 4.94 ° ± 0.2 °, 9.89 ° ± 0.2 °, 10.50 ° ± 0.2 °, 10.84 ° ± 0.2 °, 12.66 ° ± 0.2 °, 13.84 ° ± 0.2 °, 14.90 ° ± 0.2 °, 18.72 ° ± 0.2 °, 19.74 ° ± 0.2 °, 21.37 ° ± 0.2 °, 22.36 ° ± 0.2 °, 23.75 ° ± 0.2 °, 25.74 ° ± 0.2 °, 27.52 ° ± 0.2 °.
29. The compound of claim 28, having an X-ray powder diffraction pattern further having characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 13.16 ° ± 0.2 °, 16.29 ° ± 0.2 °, 18.06 ° ± 0.2 °, 19.05 ° ± 0.2 °, 20.15 ° ± 0.2 °, 21.68 ° ± 0.2 °, 24.60 ° ± 0.2 °, 24.88 ° ± 0.2 °, 26.50 ° ± 0.2 °, 31.43 ° ± 0.2 °.
30. The compound of claim 29, having an X-ray powder diffraction pattern further having characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 11.34 ° ± 0.2 °, 16.04 ° ± 0.2 °, 22.61 ° ± 0.2 °, 23.26 ° ± 0.2 °, 24.15 ° ± 0.2 °, 25.46 ° ± 0.2 °, 27.12 ° ± 0.2 °, 27.87 ° ± 0.2 °, 28.66 ° ± 0.2 °, 30.10 ° ± 0.2 °, 30.41 ° ± 0.2 °, 31.81 ° ± 0.2 °, 35.67 ° ± 0.2 °.
31. The compound of any one of claims 28-30, using Cu-ka radiation, having an X-ray powder diffraction pattern substantially as shown in figure 5.
32. The compound of any one of claims 28-31, which has no distinct endothermic peak in a differential scanning calorimetric analysis and has a melting point of 94±2 ℃.
33. The compound of claim 32 having a differential scanning calorimetric profile as shown in figure 10.
34. The compound of any one of claims 28-31, having a thermogravimetric analysis profile as shown in figure 15.
35. A process for the preparation of a compound of formula (I) wherein HA is selected from the group consisting of dimethyl acetic acid, 2-phenylpropionic acid, 2-dimethylbutyric acid, 2-phenylisobutyric acid, n=0.5-2, for example 0.5, 1, 1.5 or 2, comprising the steps of:
and (3) dissolving the compound shown in the formula (II) in a first solvent at room temperature, adding a second solvent in which HA is dissolved, stirring, separating out solids, and collecting the solids.
36. The process according to claim 35, wherein the first solvent or the second solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, acetonitrile, isopropyl acetate, acetone, and n-heptane.
37. The process of claim 36, wherein the first solvent or the second solvent is selected from ethyl acetate, acetonitrile or n-heptane.
38. The process according to any one of claims 35 to 37, wherein HA is selected from the group consisting of dimethyl acetic acid, 2-phenylpropionic acid, n is 1, and the solids produced are respectively velamer Luo Er methylacetate, velamer 2-phenylpropionate, velamer 2, 2-dimethylbutyrate, velamer 2-phenylisobutyrate.
39. A process for the preparation of a compound of formula (I) wherein HA is selected from 2, 2-dimethylbutyric acid, n=0.5-2, for example 0.5, 1, 1.5 or 2, comprising the steps of:
dissolving a compound shown in a formula (II) in a first solvent at room temperature, adding a second solvent in which 2, 2-dimethylbutyric acid is dissolved, stirring, separating out a solid, and collecting the solid to obtain vilanaterol 2, 2-dimethylbutyrate; optionally, standing the obtained solid at room temperature under 80% -90% RH for 1-3 days to obtain a crystal form I of the compound shown in the formula (I);
wherein the first solvent or the second solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, acetonitrile, isopropyl acetate, acetone and n-heptane, preferably selected from ethyl acetate, acetonitrile or n-heptane.
40. A process for the preparation of a compound of formula (I) wherein HA is selected from 2-phenylisobutyric acid, n=0.5-2, e.g. 0.5, 1, 1.5 or 2, comprising the steps of:
dispersing a compound shown in a formula (II) in a solvent at room temperature to obtain a solution 1; adding 2-phenylisobutyric acid and dissolving in the solution 1, stirring, adding n-heptane, stirring at 2-8deg.C, separating out solid or obtaining suspension, centrifuging the suspension, and collecting solid to obtain vilanafloc 2-phenylisobutyrate solid;
wherein the solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, isopropyl acetate and acetone, preferably ethyl acetate.
41. A process for the preparation of a compound of formula (I) wherein HA is selected from 2-phenylisobutyric acid, n=0.5-2, e.g. 0.5, 1, 1.5 or 2, comprising the steps of:
dispersing a compound shown in a formula (II) in a first solvent at room temperature to obtain a solution 1; adding 2-phenylisobutyric acid and dissolving in the solution 1, stirring, adding n-heptane, stirring at 2-8deg.C, separating out solid or obtaining suspension, centrifuging the suspension, and collecting solid to obtain compound (2-phenylisobutyrate) of formula (I); wherein the first solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, isopropyl acetate and acetone, preferably ethyl acetate.
Optionally, dissolving a compound of formula (II) in a second solvent at 40±5 ℃; adding 2-phenylisobutyric acid, reacting at 33+/-2 ℃ until the reaction is completed, adding the solid of the compound of the formula (I) obtained in the previous step, preserving the temperature at 30+/-5 ℃ for 30-60 min, stirring for 10-24 h at 20+/-5 ℃, and collecting the precipitated solid to obtain the crystal form I of the 2-phenylisobutyrate of the vilantrum; wherein the second solvent is selected from one or more of ethyl acetate, ethanol, isopropanol, isopropyl acetate and acetone, preferably ethyl acetate.
42. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-34, or a hydrate, solvate, crystalline form thereof, and a pharmaceutically acceptable carrier and excipient; preferably, the pharmaceutical composition is an inhalation formulation composition, such as an inhalation solution, an inhalation suspension, an aerosol, a soft mist.
43. Use of a compound according to any one of claims 1 to 34, as well as hydrates, solvates and crystal forms thereof or a composition according to claim 42, for the preparation of a medicament for the treatment of chronic obstructive pulmonary disease or asthma.
44. A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering a compound of any one of claims 1 to 34, or a hydrate, solvate, crystalline form thereof, or a pharmaceutical composition of claim 42.
CN202310202214.6A 2022-03-08 2023-03-06 Violet salt type compound and preparation method and application thereof Pending CN116730851A (en)

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