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WO2019015640A1 - 一种氮杂环酰胺衍生物的盐、其晶型及其制备方法和用途 - Google Patents

一种氮杂环酰胺衍生物的盐、其晶型及其制备方法和用途 Download PDF

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WO2019015640A1
WO2019015640A1 PCT/CN2018/096250 CN2018096250W WO2019015640A1 WO 2019015640 A1 WO2019015640 A1 WO 2019015640A1 CN 2018096250 W CN2018096250 W CN 2018096250W WO 2019015640 A1 WO2019015640 A1 WO 2019015640A1
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compound
formula
reaction
solvent
dichloromethane
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French (fr)
Inventor
魏用刚
邱关鹏
卢泳华
张晨
严庞科
郑伟
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a salt of a nitrogen heterocyclic amide derivative, a crystal form thereof, a process for the preparation thereof and use thereof in medicine.
  • Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • Bronchodilators in clinical use include widely muscarinic receptor antagonist and ⁇ 2 - adrenergic agonist.
  • a muscarinic receptor antagonist exerts potency in bronchodilation by reducing the level of vagal cholinergic energy in airway smooth muscle.
  • 2 2 -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine.
  • drugs with dual effects of muscarinic receptor antagonism and ⁇ 2 -adrenergic agonism are currently in clinical trials.
  • This bifunctional drug has the pharmaceutical advantages of a combination of two components, and has a single molecular drug. Generation dynamics. These compounds are administered as a single therapeutic agent and can provide bronchodilation by two different and possibly synergistic modes of action.
  • compounds with muscarinic receptor antagonism and ⁇ 2 -adrenergic agonistic dual action can also be combined with corticosteroid (ICS) anti-inflammatory drugs to form two therapeutic agents (MABA/ICS) to provide triple The therapeutic effect of the effect.
  • ICS corticosteroid
  • the present invention provides a salt of a nitrogen heterocyclic amide derivative having a dual action of muscarinic receptor antagonism and ⁇ 2 -adrenergic agonism, a crystal form thereof, a preparation method thereof, and use in medicine.
  • the compound represented by the formula (I) of the present invention has the following advantages such as easy processing and crystallization, convenient handling, easy purification, easy industrialization, good stability, good fluidity, easy micronization, etc., which makes them especially Suitable for inhalation preparations.
  • the present invention provides a compound of the formula (I):
  • the compound of formula (I) is in the form of a solid crystalline form.
  • the compound represented by the formula (I) is a crystal form of I, which uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 13.19 ° ⁇ 0.2 °, 16.10° ⁇ 0.2°, 18.23° ⁇ 0.2°, 21.85° ⁇ 0.2°, 24.33° ⁇ 0.2°.
  • the compound represented by the formula (I) is a crystalline form I, and its X-ray powder diffraction pattern is substantially as shown in Fig. 1.
  • the compound of the formula (I) according to the present invention is a crystal form of I, and its differential scanning calorimetry curve (DSC) is shown in Fig. 2.
  • the melting peak height of the DSC curve depends on a number of factors associated with sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the above formula (I), and a pharmaceutically acceptable carrier or excipient, preferably, the compound represented by the formula (I) is a crystal type.
  • the present invention also provides the use of the compound of the above formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for preventing and/or treating an airway obstructive disease, preferably asthma, chronic obstructive pulmonary disease Disease or bronchitis.
  • an airway obstructive disease preferably asthma, chronic obstructive pulmonary disease Disease or bronchitis.
  • the compound represented by the formula (I) is a crystalline form I.
  • the present invention also provides a method for treating an airway obstructive disease, the method comprising administering the compound of any one of the above formula (I) or a pharmaceutical composition thereof, wherein the airway obstructive disease is preferably asthma, chronic obstructive Pulmonary disease or bronchitis, preferably, the compound represented by the formula (I) is a crystalline form I.
  • the airway obstructive disease is preferably asthma, chronic obstructive Pulmonary disease or bronchitis, preferably, the compound represented by the formula (I) is a crystalline form I.
  • the present invention relates to a process for the preparation of a compound of the formula (I), which comprises contacting a compound of the formula (II) with citric acid,
  • the reaction is carried out in a solvent, preferably a C 1-6 alcohol solvent, a C 1-6 halogenated alkane solvent, C 2 - 6 ester solvent, C 2-6 ether solvent, C 1-6 ketone solvent and one or more of water, more preferably methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane Alkane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, 4-methyl-2-pentanone, butanone, acetone, diethyl ether, methyl uncle One or more of butyl ether and water.
  • a solvent preferably a C 1-6 alcohol solvent, a C 1-6 halogenated alkane solvent, C 2 - 6 ester solvent, C 2-6 ether solvent, C 1-6 ketone solvent and one or more of water, more preferably m
  • the reaction temperature is from 0 ° C to reflux, more preferably from 10 to 80 ° C, still more preferably from 10 to 50 ° C.
  • the present invention also includes a process for the preparation of the crystalline form of the compound I represented by the formula (I), which comprises the steps of dissolving the compound of the formula (II) in a first solvent, adding citric acid, and then adding a second The solvent was stirred, crystals were precipitated, and crystals were collected.
  • the present invention relates to an embodiment of the method for preparing the crystalline form of the compound I represented by the formula (I), wherein the first solvent is selected from the group consisting of a C 1-6 halogenated alkane solvent, a C 2-6 ester solvent, and a C 2-6 ether.
  • One or more solvents C 1-6 ketone solvents and water, preferably dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane
  • ethyl acetate isopropyl acetate, 4-methyl-2-pentanone, methyl ethyl ketone, acetone, diethyl ether and methyl tert-butyl ether;
  • the second solvent is selected from one or more of a C 1-6 alcohol solvent or a C 1-6 ether solvent, preferably methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl One or more of an ether and water.
  • the present invention relates to an embodiment of the method for producing the crystalline form of the compound I represented by the formula (I), wherein the reaction temperature is from 0 ° C to reflux, more preferably from 10 to 80 ° C, still more preferably from 10 to 50 ° C.
  • the molar ratio of citric acid to the compound of the formula (II) is from 1.5:1 to 0.8:1.
  • a higher purity crystal form of the compound I represented by the formula (I) is obtained, optionally by further recrystallization by a compound represented by the formula (I) or a crystal form thereof (such as a crystal form I). / or be prepared by beating.
  • the temperature for recrystallization and/or beating is from 0 ° C to reflux, preferably from 0 to 80 ° C, more preferably from 10 to 50 ° C.
  • the solvent for recrystallization and/or beating is selected from the group consisting of toluene, dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, isopropyl acetate, acetone, 4-methyl-2-pentanone , one or more of butanone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol and water, more preferably, heavy
  • the solvent for crystallization and/or beating is one or both of dichloromethane and ethanol, and the volume ratio of the two (dichloromethane to ethanol) is preferably from 1:0 to 0:3, more preferably 1:1. .
  • the invention also relates to a process for the preparation of a compound of formula (II), which is obtained using the following reaction:
  • HA is selected from organic or inorganic acids, preferably HF, HBr, HCl, CH3COOH, benzenesulfonic acid or p-toluenesulfonic acid;
  • the reaction is carried out under a reducing agent.
  • the reducing agent is selected from the group consisting of organoboron reducing agents, preferably sodium tris(acetoxy)borohydride, sodium borohydride, sodium cyanoborohydride or hydrazine. Borane.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (II), wherein the solvent for the reaction is selected from the group consisting of a polar solvent, preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2- Methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetamide, N,N-dimethylacetamide, N,N-dimethylformamide And one or more of dimethyl sulfoxide.
  • a polar solvent preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2- Methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol
  • the temperature of the reaction is from 0 ° C to reflux, preferably from 0 to 60 ° C.
  • the compound of the formula (III) and the compound of the formula (IV) may be optionally reacted in the presence of a molecular sieve, a dehydrating agent or a water-removing vessel, preferably a molecular sieve, sodium sulfate or magnesium sulfate.
  • the compound of the formula (III) and the compound of the formula (IV) are optionally reacted in the presence of an acidic catalyst, preferably formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, One or more of p-toluenesulfonic acid, zinc chloride, and aluminum chloride.
  • an acidic catalyst preferably formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, One or more of p-toluenesulfonic acid, zinc chloride, and aluminum chloride.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (II), wherein the solvent for the reaction is selected from the group consisting of a polar solvent, preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2- Methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetamide, N,N-dimethylacetamide, N,N-dimethylformamide And one or more of dimethyl sulfoxide, the temperature of the reaction is preferably 0 to 60 ° C, and optionally, the reaction is carried out in the presence of a molecular sieve, a dehydrating agent or a water separation vessel, and the dehydrating agent is preferably a molecular sieve, Sodium sulphate or magnesium sulphate; alternatively, the reaction is
  • the present invention relates to a process for the preparation of a compound of formula (III), which is obtained using the following reaction:
  • the reaction is carried out under diphenylphosphoryl azide.
  • the solvent of the reaction is selected from the group consisting of an aprotic solvent, preferably a C 6-10 aromatic hydrocarbon solvent, a C 1-6 halogenated alkane or a C 1-8 alkane hydrocarbon.
  • an aprotic solvent preferably a C 6-10 aromatic hydrocarbon solvent, a C 1-6 halogenated alkane or a C 1-8 alkane hydrocarbon.
  • One or more of the solvents more preferably one or more of toluene, benzene, dichloromethane, chloroform and 1,2-dichloroethane;
  • the temperature of the reaction is preferably from 0 ° C to reflux;
  • reaction is optionally carried out further in the presence of an acid-binding agent, preferably an organic amine, more preferably triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methyl One or more of morpholine and morpholine.
  • an acid-binding agent preferably an organic amine, more preferably triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methyl One or more of morpholine and morpholine.
  • the molar ratio of the compound of formula (VI) to diphenyl azide is from 1:1 to 1:5, formula (VI) The molar ratio of the compound shown to the compound of the formula (V) is from 1:0.5 to 1:1.
  • the present invention relates to a process for the preparation of a compound of formula (V) which is obtained using the following reaction:
  • the compound of the formula (VII) is involved in the reaction in the form of an organic amine salt, preferably a triethylamine salt.
  • the reaction is carried out in the presence of a condensing agent and/or a condensing activator, preferably 1,3-(3-dimethylaminopropyl).
  • the solvent to be reacted is selected from one or more of a C 1-6 halogenated alkane solvent, a C 2-6 ester solvent, N,N-dimethylformamide and N,N-dimethylacetamide, preferably One or more of dichloromethane, chloroform, 1,2-dichloromethane, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, and N,N-dimethylacetamide;
  • the reaction temperature is preferably from 0 ° C to reflux, more preferably from 0 ° C to 40 ° C;
  • an organic amine reagent is optionally further added to the reaction, and the organic amine reagent is preferably triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine or morpholine. One or more.
  • the present invention relates to a process for the preparation of a compound of formula (VII), which is obtained using the following reaction:
  • the solvent for the reaction is selected from the group consisting of C 2-6 ether solvents, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran and 1,2-dioxane;
  • the reaction temperature is preferably from 0 ° C to reflux, more preferably from 20 ° C to reflux.
  • the present invention relates to an embodiment of a process for the preparation of the compound of the formula (VII), which further comprises the step of purifying the compound of the formula (VII), in the process of purifying the compound of the formula (VII),
  • the organic amine forms a salt therewith to give an organic amine salt of the compound of the formula (VII), which is preferably triethylamine.
  • the invention relates to a method for preparing a compound of the formula (II), which comprises the following steps:
  • a compound of the formula (IX) is reacted with a compound of the formula (X) to give a compound of the formula (VII), and the solvent for the reaction is selected from a C 2-6 ether solvent, preferably tetrahydrofuran or 2-methyltetrahydrofuran. And one or more of 1,2-dioxane; the temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 20 ° C to reflux, during the purification of the compound of formula (VII), preferably organic amine is added. Forming a salt therewith to obtain an organic amine salt of the compound of formula (VII);
  • a compound of the formula (VII) is reacted with a compound of the formula (VIII) to form a compound of the formula (V), and the reaction is carried out under a condensing agent and/or a condensing activator.
  • the formula (VII) The compound is shown to participate in the reaction in the form of a triethylamine salt;
  • HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
  • a method of preparing a compound of formula (II), the method comprising the steps of:
  • a compound of the formula (IX) is reacted with a compound of the formula (X) to give a compound of the formula (VII), and the solvent of the reaction is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran and 1,2-dioxane.
  • the temperature of the reaction is selected from 0 ° C to reflux, preferably 20 ° C to reflux, and in the process of purifying the compound of the formula (VII), it is preferred to add triethylamine to form a salt thereof, thereby obtaining the formula (VII).
  • a compound of the formula (VII) is reacted with a compound of the formula (VIII) to form a compound of the formula (V), and the reaction is carried out under a condensing agent and/or a condensing activator.
  • the formula (VII) The compound is involved in the reaction in the form of a triethylamine salt selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, the condensation activator selected From 1-hydroxybenzotriazole, the solvent of the reaction is selected from one or more of dichloromethane, chloroform and 1,2-dichloromethane, and the temperature of the reaction is selected from 0 ° C to reflux, as an option, in the reaction.
  • Adding triethylamine is reacted with a compound of the formula (VIII) to form a compound of the formula (V), and the reaction is carried out under a condensing agent and/or a condens
  • the compound of the formula (V) and the compound of the formula (VI) are reacted in the presence of diphenyl azide to form a compound of the formula (III),
  • the solvent of the reaction is selected from toluene or benzene, and the temperature of the reaction It is selected from 0 ° C to reflux, and optionally, triethylamine is added to the reaction;
  • a compound of the formula (III) is reacted with a compound of the formula (IV) in the presence of a reducing agent to form a compound of the formula (II), the reducing agent being selected from sodium tris(acetoxy)borohydride.
  • a reducing agent being selected from sodium tris(acetoxy)borohydride.
  • sodium borohydride sodium cyanoborohydride or borane the temperature of the reaction is selected from 0 ° C to 60 ° C
  • the solvent of the reaction is selected from the group consisting of dimethyl sulfoxide, dichloromethane, isopropanol, acetonitrile and acetamide
  • a molecular sieve is added to the reaction, and alternatively, one or both of acetic acid and zinc chloride are added to the reaction.
  • the reaction is carried out in the presence of a reducing agent, preferably a combination of Pd/C and triethylsilane.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (B), wherein the solvent in the reaction is selected from a C 1-6 alcohol solvent, preferably methanol or ethanol;
  • the mass ratio of Pd/C to the compound represented by formula (A) is preferably from 1:1 to 1:100, more preferably from 1:1 to 1:10;
  • the molar ratio of triethylsilane to the compound of formula (A) is preferably from 20:1 to 1:1, more preferably from 10:1 to 1:1;
  • the temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 10 ° C to 40 ° C.
  • the compound of the formula (B) of the present invention is used for the preparation of the compound of the formula (IV), the compound of the formula (B) is prepared in the presence of a desilicon ether reagent to prepare a compound of the formula (IV), the desiliconized ether reagent Preferred is tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridine hydrofluoride, and the solvent for the reaction is preferably tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, dichloromethane, chloroform. One or more of 1,2-dichloromethane and water, the temperature of the reaction is preferably from 0 ° C to reflux.
  • the present invention relates to a process for the preparation of a compound of the formula (IV) which comprises obtaining a compound of the formula (IV) using the following reaction:
  • the reaction is carried out in the presence of a desilicon ether reagent
  • HA is selected from HF, HBr or HCl.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (IV), wherein the desilicon ether reagent is selected from the group consisting of tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridinium hydrogen Fluorate
  • the solvent to be reacted is selected from one or more of a C 1-6 halogenated alkane solvent, a C 1-6 alcohol solvent, a C 1-6 ether solvent, acetonitrile and water, preferably tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile. , one or more of methanol, ethanol, dichloromethane, chloroform, 1,2-dichloromethane and water;
  • the reaction temperature is preferably from 0 ° C to reflux, more preferably from 20 ° C to reflux.
  • An embodiment of the present invention relates to a process for the preparation of a compound of the formula (IV), which further comprises the preparation of a compound of the formula (B), wherein a reducing agent of the compound of the formula (A) is present to form a compound of the formula (B)
  • the reducing agent is preferably a combination of Pd/C and triethylsilane
  • the solvent in the reaction is selected from a C 1-6 alcohol solvent, preferably methanol or ethanol; Pd/C and the compound represented by formula (A)
  • the mass ratio is preferably from 1:1 to 1:100, more preferably from 1:1 to 1:10;
  • the molar ratio of triethylsilane to the compound of the formula (A) is preferably from 20:1 to 1:1, more preferably 10:1 to 1:1;
  • the temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 10 ° C to 40 ° C.
  • the present invention provides a compound of the formula (V) and (IV):
  • HA is selected from HF, HBr, HCl, methanesulfonic acid or p-toluenesulfonic acid.
  • alkyl group optionally substituted by F means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, with other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • IC50 refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • the crystalline structures of the present invention can 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 thermogravimetric analysis (Thermogravimetric). Analysis, TGA).
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • crystal form of the present invention is not limited to the feature maps identical to the feature maps described in the drawings disclosed in the present invention, such as XRD, DSC, TGA, which have substantially the same maps as those depicted in the drawings or Any crystal form of the substantially identical feature map is within the scope of the invention.
  • Figure 1 X-ray powder diffraction pattern of Compound 2I crystalline form.
  • Figure 2 Differential scanning calorimetry curve of Compound 2I crystal form.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the solution means an aqueous solution.
  • the room temperature is 20 ° C to 30 ° C.
  • reaction liquid 10 ml of t-butanol was added, stirred for 30 min, cooled to room temperature, and then 1500 ml of ethyl acetate was added, followed by washing with water, 2 L of sodium carbonate solution and 2 L of saturated sodium chloride.
  • reaction solution was poured into 2.6 L of ice water, filtered through Celite, washed with a mixture of 500 ml of dimethyl sulfoxide / water 1:1 (v / v), and the filtrate was extracted with ethyl acetate (2500 ml ⁇ 3), water
  • the layer was added to a stirred 7 L of saturated sodium bicarbonate solution, a large amount of solid was precipitated, filtered, and the solid was washed with water, then dissolved in 2 L of 30% methanol/dichloromethane, and the organic phase was sequentially treated with 1000 mL of saturated sodium hydrogen carbonate solution.
  • Fig. 1 The X-ray powder diffraction pattern of Compound 2 is shown in Fig. 1, and the peak list is shown in Table 1.
  • Compound 2 was subjected to differential scanning calorimetry analysis as follows:
  • DSC Differential Scanning Calorimetry testing was performed using the NETZSCH DSC 214 Polyma. About 1 mg of the sample was weighed into a pinhole-coated aluminum crucible, and nitrogen gas was used as a purge gas (flow rate: 60 ml/min), and the initial temperature was 35 ° C, and the temperature was raised to 200 ° C at a temperature increase rate of 10 ° C / min.
  • the DSC (differential scanning calorimetry curve) spectrum of Compound 2 is shown in Figure 2.
  • reaction solution was filtered, and the filter cake was beaten with 10% methanol/ethanol (2.5 L) at 60 ° C for 1 hour, filtered, and the filter cake was dried to give 5-(2-amino-1-hydroxy-ethyl)-8-hydroxy-1H- Quinoline-2-one hydrofluoric acid salt (1H), pale yellow solid (454 g, yield: 90.3%).
  • Example 4 Conditional screening for the reaction of compound 1G with compound 1H to form compound 1
  • DMSO dimethyl sulfoxide
  • eq is the molar equivalent ratio
  • phosphate buffer (3.12 g of sodium dihydrogen phosphate dihydrate, dissolved in 1000 ml of water, adjusted to pH 3.0 with phosphoric acid) - acetonitrile (80:20)] dissolved and diluted
  • a solution containing about 0.5 mg of sample per 1 ml was prepared as a test solution.
  • test solution 10 ⁇ l was accurately weighed and injected into a liquid chromatograph to record a chromatogram.
  • the chromatogram of the test solution (excluding the citrate peak and the solvent peak) was calculated by the peak area normalization method, and the results are shown in Table 4.
  • Test Example 1 Methotrexate-induced inhibition of bronchoconstriction in rats
  • rat PenH values were measured using a full volume oximeter. Aerosol was administered at 800 mg/ml Mch (acetylcholine) with an atomization time of 36 seconds and a recording time of 7 minutes. The PenH average was calculated and the results are shown in Table 6.
  • Table 6 shows the inhibitory effect of compound 2 on methacholine-induced rat bronchoconstriction
  • Compound 2 has good inhibitory activity against methacholine-induced bronchoconstriction in rats, which is superior to bafetentorol.

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Abstract

本发明涉及一种氮杂环酰胺衍生物的盐、其晶型及其制备方法和在医药上的用途，具体而言，氮杂环酰胺衍生物的盐即为式（I）所示化合物。

Description

一种氮杂环酰胺衍生物的盐、其晶型及其制备方法和用途 技术领域
本发明涉及一种氮杂环酰胺衍生物的盐、其晶型及其制备方法和在医药上的用途。
背景技术
支气管扩张剂对于呼吸疾病例如慢性阻塞性肺疾病(COPD)及哮喘等的治疗起重要作用。临床中广泛使用的支气管扩张剂包括蕈毒碱受体拮抗剂和β 2-肾上腺素能激动剂。蕈毒碱受体拮抗剂通过降低气道平滑肌的迷走神经胆碱能水平来发挥支气管扩张的效力。β 2-肾上腺素能激动剂通过刺激气道平滑肌的肾上腺素能受体而使支气管扩张，逆转支气管收缩剂对各种介质如乙酰胆碱的反应。
除此之外，具有蕈毒碱受体拮抗和β 2-肾上腺素能激动双重作用的药物目前处于临床试验中，这种双功能药物具有两种成分组合的药学优点，同时具备单一的分子药代动力学。这些化合物以单一治疗剂的形式给药，可以由两种不同且可能协同起效的作用模式提供支气管扩张作用。另外，具有蕈毒碱受体拮抗和β 2-肾上腺素能激动双重作用(MABA)的化合物还可以与皮质类固醇(ICS)消炎剂药物组合，形成两种治疗剂(MABA/ICS)而提供三重作用的治疗效果。
发明内容
本发明提供了具有蕈毒碱受体拮抗和β 2-肾上腺素能激动双重作用的氮杂环酰胺衍生物的盐、其晶型及其制备方法和在医药上的用途。
本发明式(I)所示的化合物为I晶型具有以下优点，诸如易于加工和结晶、方便处理、易于纯化，易于工业化、稳定性好、流动性好、易于微粉化等，这些使它们尤其适于制成吸入制剂。
本发明提供一种式(I)所示的化合物：
Figure PCTCN2018096250-appb-000001
本发明的一种实施方案，式(I)所示的化合物为固态晶体形式。
本发明的一种实施方案，式(I)所示的化合物为I晶型，其使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：13.19°±0.2°、16.10°±0.2°、18.23°±0.2°、21.85°±0.2°、24.33°±0.2°。
更进一步，式(I)所示的化合物为I晶型，其X-射线粉末衍射图谱基本如附图1所示。
本发明所述的式(I)所示的化合物为I晶型，其差示扫描量热分析曲线(DSC)如附图2所示。
式(I)所示的化合物为I晶型，其差示扫描量热分析曲线显示，其中T 开始＝165.4±3℃，T 峰＝172.5±3℃，其中，熔点温度为172.5±5℃。
可以理解的是，差示扫描量热(DSC)领域中所熟知的，DSC曲线的熔融峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。
本发明公开的X-射线粉末衍射或DSC图，与其实质上相同的也属于本发明的范围。
本发明提供一种药物组合物，包含治疗有效量的上述式(I)所示的化合物，以及药学上可接受的载体或赋形剂，优选地，式(I)所示的化合物为I晶型。
本发明同时提供一种上述任一项式(I)所示的化合物或其药物组合物在制备用于预防和/或治疗气道阻塞性疾病的药物中的应用，优选哮喘、慢性阻塞性肺疾病或支气管炎。优选地，式(I)所示的化合物为I晶型。
本发明同时提供治疗气道阻塞性疾病的方法，所述方法包括给予上述任一项式(I)所示的化合物或其药物组合物，所述的气道阻塞性疾病优选哮喘、慢性阻塞性肺疾病或支气管炎，优选地，式(I)所示的化合物为I晶型。
本发明涉及式(I)所示化合物的制备方法，该方法为使式(II)所示的化合物与柠檬酸接触，
Figure PCTCN2018096250-appb-000002
本发明关于式(I)所示化合物的制备方法的一种实施方案，反应在溶剂中进行，所述的溶剂优选C 1-6醇类溶剂、C 1-6卤代烷烃类溶剂、C 2-6酯类溶剂、C 2-6醚类溶剂、C 1-6酮类溶剂和水中的一种或多种，更优选甲醇、乙醇、异丙醇、二氯甲烷、1，2-二氯乙烷、氯仿、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、乙酸乙酯、乙酸异丙酯、4-甲基-2-戊酮、丁酮、丙酮、乙醚、甲基叔丁基醚和水中的一种或多种。
本发明关于式(I)所示化合物的制备方法的一种实施方案，反应的温度为0℃～回流，更优选为10～80℃，进一步优选为10～50℃。
本发明还包括式(I)所示的化合物I晶型的制备方法，该方法包括以下步骤：将式(II)所示的化合物溶于第一溶剂中，加入柠檬酸后，再加入第二溶剂，搅拌，析出晶体，收集晶体。
本发明关于式(I)所示化合物I晶型的制备方法的一种实施方案，第一溶剂选自C 1-6卤代烷烃类溶剂、C 2-6酯类溶剂、C 2-6醚类溶剂、C 1-6酮类溶剂和水中的一种或多种，优选二氯甲烷、1，2-二氯乙烷、氯仿、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、乙酸乙酯、乙酸异丙酯、4-甲基-2-戊酮、丁酮、丙酮、乙醚和甲基叔丁基醚中的一种或多种；
第二溶剂选自C 1-6醇类溶剂或C 1-6醚类溶剂的一种或多种，优选甲醇、乙醇、异丙醇、乙醚、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚和水中的一种或多种。
本发明关于式(I)所示化合物I晶型的制备方法的一种实施方案，反应的温度为0℃～回流，更优选为10～80℃，进一步优选为10～50℃。
本发明关于式(I)所示化合物I晶型的制备方法的一种实施方案，柠檬酸与式(II)所示的化合物的摩尔比为1.5∶1∶～0.8∶1。
根据对产品纯度的需求，欲得到更高纯度的式(I)所示化合物I晶型，任选进一步通过将式(I)所示化合物或者其晶型(如I晶型)通过重结晶和/或打浆制备得到。优选地，重结晶和/或打浆的温度为0℃～回流，优选0～80℃，更优选10～50℃。优选地，重结晶和/或打浆的溶剂选自甲苯、二氯甲烷、1，2-二氯乙烷、氯仿、乙酸乙酯、乙酸异丙酯、丙酮、4-甲基-2-戊酮、丁酮、乙醚、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、甲基叔 丁基醚、甲醇、乙醇、异丙醇和水中的一种或多种，更优选地，重结晶和/或打浆的溶剂为二氯甲烷和乙醇的中的一种或两种，两者(二氯甲烷与乙醇)的体积比优选为1∶0～0∶3，更优选为1∶1。
本发明还涉及一种式(II)所示化合物的制备方法，使用如下反应得到：
Figure PCTCN2018096250-appb-000003
HA选自有机酸或无机酸，优选HF、HBr、HCl、CH3COOH、苯磺酸或对甲基苯磺酸；
所述的反应在还原剂下进行。
本发明关于式(II)所示化合物的制备方法的一种实施方案，还原剂选自有机硼还原剂，优选三(乙酰氧基)硼氢化钠、硼氢化钠、氰基硼氢化钠或癸硼烷。
本发明关于式(II)所示化合物的制备方法的一种实施方案，反应的溶剂选自极性溶剂，优选二氯甲烷、氯仿、1，2-二氯乙烷、乙腈、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、甲基叔丁基醚、甲醇、乙醇、异丙醇、乙酰胺、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺和二甲基亚砜中的一种或多种。
本发明关于式(II)所示化合物的制备方法的一种实施方案，反应的温度为0℃～回流，优选为0～60℃。
作为选择，式(III)所示化合物与式(IV)所示化合物任选在分子筛、脱水剂或分水容器存在下进行反应，脱水剂优选分子筛、硫酸钠或硫酸镁。
作为选择，式(III)所示化合物与式(IV)所示化合物任选在酸性催化剂存在下进行反应，所述的酸性催化剂优选甲酸、三氟乙酸、乙酸、甲磺酸、苯磺酸、对甲苯磺酸、氯化锌和氯化铝中的一种或多种。
本发明关于式(II)所示化合物的制备方法的一种实施方案，反应的溶剂选自极性溶剂，优选二氯甲烷、氯仿、1，2-二氯乙烷、乙腈、四氢呋喃、2-甲基四氢呋喃、1，4-二氧 六环、甲基叔丁基醚、甲醇、乙醇、异丙醇、乙酰胺、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺和二甲基亚砜中的一种或多种，反应的温度优选0～60℃，作为选择，反应任选在分子筛、脱水剂或分水容器存在下进行，所述的脱水剂优选分子筛、硫酸钠或硫酸镁；作为选择，反应任选在酸性催化剂存在下进行，所述的酸性催化剂优选甲酸、三氟乙酸、乙酸、甲磺酸、苯磺酸、对甲苯磺酸和氯化锌中的一种或多种。
本发明涉及一种式(III)所示化合物的制备方法，使用如下反应得到：
Figure PCTCN2018096250-appb-000004
所述反应在叠氮磷酸二苯酯下进行。
本发明关于式(III)所示化合物的制备方法的一种实施方案，反应的溶剂选自非质子溶剂，优选C 6-10芳烃类溶剂、C 1-6卤代烷烃或C 1-8烷烃类溶剂中的一种或多种，更优选甲苯、苯、二氯甲烷、氯仿和1，2-二氯乙烷中的一种或多种；
反应的温度优选为0℃至回流；
作为选择，反应任选进一步在缚酸剂存在下进行，所述的缚酸剂优选有机胺，更优选三乙胺、二异丙基乙基胺、4-二甲氨基吡啶、N-甲基吗啉和吗啉中的一种或多种。
本发明关于式(III)所示化合物的制备方法的一种实施方案，式(VI)所示的化合物与叠氮磷酸二苯酯的摩尔比为1∶1～1∶5，式(VI)所示的化合物与式(V)所示的化合物的摩尔比为1∶0.5～1∶1。
本发明涉及一种式(V)所示化合物的制备方法，使用如下反应得到：
Figure PCTCN2018096250-appb-000005
作为选择，式(VII)所示化合物以有机胺盐的形式参与反应，所述的有机胺盐优选三 乙胺盐。
本发明关于式(III)所示化合物的制备方法的一种实施方案，反应在缩合剂和/或缩合活化剂存在下进行，所述的缩合剂优选1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、二环乙基碳二亚胺、二异丙基碳二亚胺、2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(HATU)、O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)、6-氯苯并三氮唑-1，1，3，3-四甲基脲六氟磷酸酯(HCTU)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBOP)、二苯基次膦酰氯或双(2-氧代-3-恶唑烷基)次磷酰氯(BOP-C1)，缩合活化剂优选1-羟基苯并三唑、4-二甲氨基吡啶、4-吡咯烷基吡啶或1-羟基-7-偶氮苯并三氮唑；
反应的溶剂选自C 1-6卤代烷烃类溶剂、C 2-6酯类溶剂、N，N-二甲基甲酰胺和N，N-二甲基乙酰胺中的一种或多种，优选二氯甲烷、氯仿、1，2-二氯甲烷、乙酸乙酯、乙酸异丙酯、N，N-二甲基甲酰胺和N，N-二甲基乙酰胺中的一种或多种；
反应的温度优选为0℃～回流，更优选为0℃～40℃；
作为选择，反应中任选进一步加入有机胺试剂，所述的有机胺试剂优选三乙胺、二异丙基乙基胺、4-二甲氨基吡啶、N-甲基吗啉或吗啉中的一种或多种。
本发明涉及式(VII)所示化合物的制备方法，使用如下反应得到：
Figure PCTCN2018096250-appb-000006
反应的溶剂选自C 2-6醚类溶剂，优选四氢呋喃、2-甲基四氢呋喃和1，2-二氧六环中的一种或多种；
反应的温度优选为0℃～回流，更优选为20℃～回流。
本发明关于式(VII)所示化合物的制备方法的一种实施方案，所述方法还包括对式(VII)所示化合物进行精制的步骤，在精制式(VII)所示化合物过程中，加入有机胺与其形成盐，从而得到式(VII)所示化合物的有机胺盐，所述的有机胺优选三乙胺。
本发明关于一种式(II)所示化合物的制备方法，该方法包括如下步骤：
Figure PCTCN2018096250-appb-000007
其中：
(1)、式(IX)所示化合物与式(X)所示化合物反应生成式(VII)所示化合物，反应的溶剂选自C 2-6醚类溶剂，优选四氢呋喃、2-甲基四氢呋喃和1，2-二氧六环中的一种或多种；反应的温度优选为0℃～回流，更优选为20℃～回流，精制式(VII)所示化合物过程中，优选加入有机胺与其形成盐，从而得到式(VII)所示化合物的有机胺盐；
(2)、式(VII)所示化合物与式(VIII)所示化合物反应生成式(V)所示化合物，反应在缩合剂和/或缩合活化剂下进行，作为选择，式(VII)所示化合物以三乙胺盐的形式参与反应；
(3)、式(V)所示化合物与式(VI)所示化合物在叠氮磷酸二苯酯存在下反应生成式(III)所示化合物；
(4)、式(III)所示化合物与式(IV)所示化合物在还原剂存在下反应生成式(II)所示化合物；
HA选自HF、HBr、HCl、CH 3COOH、苯磺酸或对甲基苯磺酸。
本发明的一种实施方案，一种式(II)所示化合物的制备方法，该方法包括如下步骤：
(1)、式(IX)所示化合物与式(X)所示化合物反应生成式(VII)所示化合物，反应的溶剂选自四氢呋喃、2-甲基四氢呋喃和1，2-二氧六环中的一种或多种；反应的温度选自0℃～回流，优选为20℃～回流，精制式(VII)所示化合物过程中，优选加入三乙胺与其形成盐，从而得到式(VII)所示化合物的三乙胺盐；
(2)、式(VII)所示化合物与式(VIII)所示化合物反应生成式(V)所示化合物，反应在缩 合剂和/或缩合活化剂下进行，作为选择，式(VII)所示化合物以三乙胺盐的形式参与反应，所述的缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，所述的缩合活化剂选自1-羟基苯并三唑，反应的溶剂选自二氯甲烷、氯仿和1，2-二氯甲烷中的一种或多种，反应的温度选自0℃～回流，作为选择，反应中加入三乙胺；
(3)、式(V)所示化合物与式(VI)所示化合物在叠氮磷酸二苯酯存在下反应生成式(III)所示化合物，反应的溶剂选自甲苯或苯，反应的温度选自0℃～回流，作为选择，反应中加入三乙胺；
(4)、式(III)所示化合物与式(IV)所示化合物在还原剂存在下反应生成式(II)所示化合物，所述的还原剂选自三(乙酰氧基)硼氢化钠、硼氢化钠氰基硼氢化钠或癸硼烷，反应的温度选自0℃～60℃，反应的溶剂选自二甲基亚砜、二氯甲烷、异丙醇、乙腈和乙酰胺中的一种或多种，作为选择，反应中加入分子筛，作为选择，反应中加入乙酸和氯化锌中的一种或两种。
一种式(B)所示化合物的制备方法，所述方法包括使用如下反应得到式(B)所示化合物：
Figure PCTCN2018096250-appb-000008
反应在还原剂存在下进行，所述的还原剂优选Pd/C和三乙基硅烷的组合。
本发明关于式(B)所示化合物的制备方法的一种实施方案，反应中的溶剂选自C 1-6醇类溶剂，优选甲醇或乙醇；
Pd/C与式(A)所示化合物的质量比优选为1∶1～1∶100，更优选1∶1～1∶10；
三乙基硅烷与式(A)所示化合物的摩尔比优选为20∶1～1∶1，更优选10∶1～1∶1；
反应的温度优选为0℃～回流，更优选为10℃～40℃。
本发明式(B)所示化合物用于制备式(IV)所示化合物，式(B)所示化合物在脱硅醚试剂存在下制备式(IV)所示化合物，所述的脱硅醚试剂优选四丁基氟化铵或其水合物、三乙胺三氢氟酸盐或吡啶氢氟酸盐，反应的溶剂优选四氢呋喃、2-甲基四氢呋喃、乙腈、甲醇、乙醇、二氯甲烷、氯仿、1，2-二氯甲烷和水中的一种或多种，反应的温度优选为0℃～回流。
本发明涉及一种制备式(IV)所示化合物的方法，所述方法包括使用如下反应得到式 (IV)所示化合物：
Figure PCTCN2018096250-appb-000009
反应在脱硅醚试剂存在下进行；
HA选自HF、HBr或HCl。
本发明关于式(IV)所示化合物的制备方法的一种实施方案，所述的脱硅醚试剂选自四丁基氟化铵或其水合物、三乙胺三氢氟酸盐或吡啶氢氟酸盐；
反应的溶剂选自C 1-6卤代烷烃类溶剂、C 1-6醇类溶剂、C 1-6醚类溶剂、乙腈和水中的一种或多种，优选四氢呋喃、2-甲基四氢呋喃、乙腈、甲醇、乙醇、二氯甲烷、氯仿、1，2-二氯甲烷和水中的一种或多种；
反应的温度优选为0℃～回流，更优选为20℃～回流。
本发明关于式(IV)所示化合物的制备方法的一种实施方案，其进一步包括式(B)所示化合物的制备，式(A)所示化合物还原剂存在生成式(B)所示化合物的制备，所述的还原剂优选Pd/C和三乙基硅烷的组合，反应中的溶剂选自C 1-6醇类溶剂，优选甲醇或乙醇；Pd/C与式(A)所示化合物的质量比优选为1∶1～1∶100，更优选1∶1～1∶10；三乙基硅烷与式(A)所示化合物的摩尔比优选为20∶1～1∶1，更优选10∶1～1∶1；反应的温度优选为0℃～回流，更优选为10℃～40℃。
本发明提供一种式(V)和(IV)所示化合物：
Figure PCTCN2018096250-appb-000010
HA选自HF、HBr、HCl、甲磺酸或对甲苯磺酸。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物，其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“有效剂量”指引起组织、系统或受试者生理或医学翻译的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
本发明晶型结构可以使用本领域普通技术人员已知的各种分析技术分析，包括但不限于，X-射线粉末衍射(XRD)、示差扫描热法(DSC)和/或热重分析(Thermogravimetric Analysis，TGA)。
可以理解的是，本发明描述的和保护的数值为近似值。数值内的变化可能归因于设备的校准、设备误差、晶体的纯度、晶体大小、样本大小以及其他因素。
可以理解的是，本发明的晶型不限于与本发明公开的附图中描述的特征图谱完全相同的特征图谱，比如XRD、DSC、TGA，具有与附图中描述的哪些图谱基本上相同或本质上相同的特征图谱的任何晶型均落入本发明的范围内。
附图说明
图1：化合物2I晶型的X-射线粉末衍射图谱。
图2：化合物2I晶型的差示扫描量热分析曲线图谱。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker  Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，室温为20℃～30℃。
实施例1：化合物1的制备
[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(化合物1)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate
Figure PCTCN2018096250-appb-000011
将4-哌啶N-(2-苯基苯基)氨基甲酸酯(1A)(1.54kg，5.19mol)加入2-甲基四氢呋喃(7L)中，升温到50℃搅拌溶解，然后加入丙烯酸(1B)(1.31kg，18.2mol)，升温到100℃反应3小时，反应完毕后，冷却至室温，减压浓缩至剩余约1/3的体积，冰水浴，搅拌下加入三乙胺(1000mL，7.19mol)，继续搅拌2h，放置过夜，过滤得白色固体，用乙酸乙 酯搅拌打浆，过滤，得到[1-[3-[4-(羟基甲基)-1-哌啶基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯三乙胺盐(1C)，白色固体(1.4kg，产率57.4％，HPLC：99.0％)。
LCMS m/z＝369.1[M+1]。
1H NMR(400MHz，DMSO-d6)δ8.63(m，1H)，7.35(m，9H)，4.46(m，1H)，3.00(q，3H)，2.63(s，2H)，2.56(t，2H)，2.35(t，2H)，2.23(t，2H)，1.71(s，2H)，1.43(d，2H)，1.16(m，3H)。
第二步：[1-[3-[4-(羟基甲基)-1-哌啶基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(1E)
[1-[3-[4-(hydroxymethyl)-1-piperidyl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate
Figure PCTCN2018096250-appb-000012
将[1-[3-[4-(羟基甲基)-1-哌啶基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯三乙胺盐(1C)(500g，1.36mmol)和4-羟甲基哌啶(1D)(281g，2.44mol)加入二氯甲烷(4L)中，搅拌30分钟，加入1-羟基苯并三唑(275g，2.03mol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(390g，2.03mol)和三乙胺(206g，2.03mol)，室温反应3小时。向反应液加入1.5L水，搅拌10min，分液。有机相依次用饱和碳酸钠水溶液(1L×2)和磷酸二氢钠水溶液(1L×1)洗涤，无水硫酸钠干燥，过滤，浓缩，向残留物中加入1.6L乙酸乙酯，搅拌20分钟，过滤，得到白色固体。所得固体抽干后，加入2L四氢呋喃，升温到55℃，加入氢氧化锂水溶液(35g/350mL水)，继续搅拌2h，减压浓缩后，加1L水和2L二氯甲烷，萃取分层，有机相用饱和碳酸钠水溶液洗涤(1L×2)、无水硫酸钠干燥，过滤，滤液减压浓缩，向残留物中加入2L乙酸乙酯打浆，过滤，滤饼干燥，得到[1-[3-[4-(羟基甲基)-1-哌啶基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(1E)，白色固体(400g，产率63％，HPLC：98.1％)。
LCMS m/z＝466.1[M+1]。
1H NMR(400MHz，CDCl 3)δ8.08(d，1H)，7.49(m，2H)，7.41(m，1H)，7.35(td，3H)，7.22(dd，1H)，7.13(td，1H)，6.59(s，1H)，4.74(m，1H)，4.63(d，1H)，3.89(d，1H)，3.49(p，2H)，3.01(td，1H)，2.71(m，4H)，2.55(m，3H)，2.32(s，2H)，1.94(s，2H)，1.73(m，6H)，1.16(m，2H)。
第三步：[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-(4-甲酰基苯基)氨基甲酸酯(1G)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-(4-formylphenyl)carbamate
Figure PCTCN2018096250-appb-000013
将[1-[3-[4-(羟基甲基)-1-哌啶基]-3-氧代-丙基]-4-哌啶基]N-(2-苯基苯基)氨基甲酸酯(1E)(250g，0.54mol)加到甲苯(2000mL)中，依次加入4-甲酰基苯甲酸(1F)(96.7g，0.64mol)、三乙胺(135.8g，2.5mol)和叠氮磷酸二苯酯(177.3g，0.64mol)，室温反应1小时后，反应温度升至回流2小时。向反应液加入10ml叔丁醇，搅拌30min，冷却到室温，加入1500ml乙酸乙酯，然后依次用水、2L碳酸钠溶液和2L饱和氯化钠洗涤。向有机相加入1500ml的石油醚，搅拌，有粘稠状的油析出，倾倒掉上层清液，用1.5L二氯甲烷溶解剩余的油状物，缓慢加入1.5L石油醚，搅拌过夜，过滤，滤饼用0.5L乙酸乙酯打浆，搅拌1小时，过滤，滤饼干燥，得到[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-(4-甲酰基苯基)氨基甲酸酯(1G)，浅黄色固体(250g，产率76％，HPLC：98.2％)。
LCMS m/z＝613.2[M+1]。
1H NMR(400MHz，CDCl3)δ9.88(s，1H)，7.96(d，1H)，7.85(m，2H)，7.68(m，3H)，7.52(m，2H)，7.43(m，4H)，7.23(dd，1H)，7.20(m，1H)，6.75(s，1H)，4.90(s，1H)，4.57(d，1H)，4.06(d，2H)，3.86(d，1H)，3.28(m，10H)，2.82(m，1H)，2.64-2.51(m，1H)，2.18-2.06(m，2H)，2.00-1.85(m，3H)，1.73(t，2H)。
第四步：[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(化合物1)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate
Figure PCTCN2018096250-appb-000014
将[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(1G)(200g，0.32mol)溶于二甲基亚砜(1200mL)中，加入5-[(1R)-2-氨基-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮氢氟酸盐(1H)(158g，0.64mol)，乙酸(0.48mol)分子筛200g，室温反应3小时。向反应液加入300ml的无水甲醇。冰浴冷却，慢慢加入三(乙酰氧基)硼氢化钠(406.8g，1.92mol)，升至室温，搅拌2小时。将反应液加入2.6L冰水中，硅藻土过滤，用500ml二甲基亚砜/水＝1∶1(v/v)的混合溶液洗涤，滤液用乙酸乙酯(2500ml×3)萃取，水层加入到搅拌中的7L饱和碳酸氢钠溶液中，有大量固体析出，过滤，固体用水洗涤，然后用2L 30％甲醇/二氯甲烷溶解，分层，有机相依次用1000mL饱和碳酸氢钠溶液和500mL饱和氯化钠溶液洗涤，然后加入3L甲基叔丁基醚，有大量固体析出，搅拌30分钟，过滤，滤饼干燥，得到[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(化合物1)，浅黄色固体(200g，产率76％，HPLC：97.0％)。
LCMS m/z＝409.4[(M+2)/2]。
1H NMR(400MHz，DMSO-d6)δ9.53(s，1H)，8.59(s，1H)，8.08(d，1H)，7.33(m，11H)，7.20(d，2H)，7.05(d，1H)，6.90(d，1H)，6.45(d，1H)，5.03(dd，1H)，4.42(m，2H)，3.92(dd，3H)，3.66(m，2H)，2.99(t，1H)，2.63(m，4H)，2.46(m，4H)，2.13(t，2H)，1.89(s，1H)，1.70(s，4H)，1.41(d，2H)，1.13(m，2H)。
实施例2：化合物1的柠檬酸盐的制备
[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯柠檬酸盐(化合物2)
[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate citric acid；
Figure PCTCN2018096250-appb-000015
将[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯(化合物1)(200g，0.24mol)溶于二氯甲烷(1000mL)中，加入柠檬酸(47g，0.24mol)，慢慢加入乙醇2.0L，室温搅拌20小时，过滤，滤饼用3L二氯甲烷/乙醇＝1∶1(v/v)打浆30分钟，过滤。滤饼再次用3L二氯甲烷/乙醇＝1∶1(v/v)打浆30分钟，过滤，干燥，得到[1-[3-[4-[(2-苯基苯基)氨基甲酰氧基]-1-哌啶基]丙酰基]-4-哌啶基]甲基N-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酸酯柠檬酸盐(化合物2)，浅黄色固体(191g，产率77％，HPLC：98.3％)。
将化合物2按照如下方法进行X-射线粉末衍射测试：
用PANalytical X射线衍射仪X’pertpowder型(PANalytical B.V.，荷兰)，使用Cu Kα辐射，在
Figure PCTCN2018096250-appb-000016
(40kV，40mA)，用PIXcel 1D detector探测器获得粉末X射线衍射图，分析软件highscore 3.0e(3.0.5)，采集软件PANalytical Data Collector 4.2。分析典型地在扫描速率0.1094°/s、在4°到40°的2θ角范围内以每点0.013°步长进行。将研磨至细粉末的样品轻轻的装到带凹槽的定制玻璃样品板上，并将样品铺平在玻璃样品板表面上以用于测试。每周用仪器自带的硅质标准样品片标定该仪器，并将2θ角的偏差范围保持在±0.02°的范围内。
化合物2的X-射线粉末衍射图谱如图1所示，峰列表如表1所示。
表1
Figure PCTCN2018096250-appb-000017
将化合物2按照如下方法进行差示扫描量热分析测试：
使用NETZSCH DSC 214 Polyma进行差示扫描量热法(DSC)测试。称取样品约 1mg至针孔式加盖的铝坩埚中，氮气作为吹扫气(流速60ml/min)，初始温度35℃，以10℃/min的升温速率升温至200℃。
化合物2的DSC(差示扫描量热分析曲线)图谱如图2所示。
化合物2的I晶型，其差示扫描量热分析曲线(DSC)显示一条吸热曲线，其中T 开始＝165.4℃，T 峰＝172.5℃。
LCMS m/z＝409.4[(M+2)/2]。
1H NMR(400MHz，DMSO-d6)δ9.72(s，1H)，8.63(s，1H)，8.07(d，1H)，7.35(m，12H)，7.10(d，1H)，6.96(d，1H)，6.54(d，1H)，5.26(s，1H)，4.49(s，1H)，4.40(d，1H)，3.96(m，5H)，2.97(m，3H)，2.66(m，4H)，2.56(s，2H)，2.53(s，2H)，2.34(s，2H)，1.91(s，1H)，1.72(m，4H)，1.48(s，2H)，1.11(m，2H)。
实施例3：化合物1H的制备
5-[(1R)-2-氨基-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮氢氟酸盐(1H)
5-[(1R)-2-amino-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one；hydrofluoride
Figure PCTCN2018096250-appb-000018
第一步：5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-8-羟基-1H-喹啉-2-酮(3B)
5-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-8-hydroxy-1H-quinolin-2-one
Figure PCTCN2018096250-appb-000019
将5-[(1R)-2-叠氮基-1-[叔丁基(二甲基)硅基]氧基乙基]-8-苄氧基-1H-喹啉-2-酮(3A)(900g，1997mmol)溶解在无水乙醇(4500ml)中，加入50％(w/w)钯碳(180g)，氮气保护下滴加三乙基硅烷(1161g，9987mmol)，滴完后继续室温搅拌30分钟。反应液直接过滤，滤液减压浓缩所得粗品用10L乙酸乙酯打浆，过滤，收集滤饼干燥得5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-8-羟基-1H-喹啉-2-酮(3B)，黄绿色固体(647g，收率96.84％)。
1H NMR(400MHz，CD 3OD)δ8.42(d，1H)，7.25(d，1H)，7.06(d，1H)，6.72(d，1H)，5.45-5.42(m，1H)，3.26(m，2H)，0.92(s，9H)，0.15(s，3H)，-0.10(s，3H)。
第二步：5-[(1R)-2-氨基-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮氢氟酸盐(1H)
5-[(1R)-2-amino-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one；hydrofluoride
Figure PCTCN2018096250-appb-000020
将5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-8-羟基-1H-喹啉-2-酮(3B)(700g，2093mmol)溶解在无水乙醇(3.5L)中，加入三乙胺三氢氟酸盐(1000g，6203mmol)，温度升至80℃反应5小时。反应液过滤，滤饼用10％甲醇/乙醇(2.5L)在60℃打浆1小时，过滤，滤饼干燥得5-(2-氨基-1-羟基-乙基)-8-羟基-1H-喹啉-2-酮氢氟酸盐(1H)，浅黄色固体(454g，收率90.3％)。
1H NMR(400MHz，DMSO-d6)δ8.15(d，1H)，7.10(d，1H)，6.93(d，1H)，6.50(d，1H)，5.15(d，1H)，2.92(d，1H)，2.87-2.78(t，1H)。
实施例4：由化合物1G与化合物1H反应生成化合物1的条件筛选
Figure PCTCN2018096250-appb-000021
表2：合物1G与化合物1H反应生成化合物1的条件筛选结果
Figure PCTCN2018096250-appb-000022
Figure PCTCN2018096250-appb-000023
DMSO为二甲基亚砜；eq为摩尔当量比。
实施例5：化合物2 I晶型的稳定性试验
样品放置：
取化合物2 I晶型，按下表3的考察条件及取样时间点进行影响因素考察，考察结果见下表5。
表3稳定性实验条件表
Figure PCTCN2018096250-appb-000024
Figure PCTCN2018096250-appb-000025
将每次取样的样品加稀释剂[磷酸盐缓冲液(取磷酸二氢钠二水合物3.12g，加水1000ml溶解后，用磷酸调节pH值至3.0)-乙腈(80∶20)]溶解并稀释制成每1ml中约含0.5mg样品的溶液，作为供试品溶液。按照高效液相色谱法(中国药典2015年版四部通则0512)测定，用十八烷基硅烷键合硅胶为填充剂(Inertsil ODS-3，4.6mm×250mm，5μm或效能相当的色谱柱)；以磷酸盐缓冲液(取磷酸二氢钠二水合物3.12g，加水1000ml溶解后，用磷酸调节pH值至3.0)为流动相A，以乙腈为流动相B；按表4进行线性梯度洗脱；检测波长为210nm，柱温为40℃，流速为每分钟1.0ml。精密量取供试品溶液10μl，注入液相色谱仪，记录色谱图。供试品溶液色谱图(扣除枸橼酸峰和溶剂峰)按峰面积归一化法计算，结果见表4。
表4化合物2 I晶型稳定性试验HPLC条件
Figure PCTCN2018096250-appb-000026
表5化合物2 I晶型稳定性结果
Figure PCTCN2018096250-appb-000027
结论：化合物2 I晶型具有良好的稳定性。
生物测试例
测试例1：乙酰甲胆碱诱导的大鼠支气管收缩抑制作用
8周龄全雄大鼠购置于维通利华(许可证号：SCXK(京)2012-0001)，适应3天后开始实验。阳性化合物batefenterol和化合物2先用87％无水乙醇+17％吐温80分别配制成储备液，再用水将batefentrol稀释为给药浓度。给药前，使用小动物麻醉机给予5％异氟烷麻醉动物，麻醉时间为1.5-2分钟。待大鼠麻醉后，将大鼠固定于气管插管操作平台上，使用大鼠液体气溶胶给药套装气管内给药，每只大鼠给药体积250μl。给药后4小时，使用全体积描计仪测量大鼠PenH值。雾化给予800mg/ml Mch(乙酰甲胆碱)，雾化时间36秒，记录时间7分钟。计算PenH平均值，结果见表6。
表6化合物2对乙酰甲胆碱诱导的大鼠支气管收缩抑制作用结果
Figure PCTCN2018096250-appb-000028
结论：化合物2对乙酰甲胆碱诱导的大鼠支气管收缩具有较好的抑制活性，优于batefenterol。

Claims (34)

  1. 一种式(I)所示的化合物：
    Figure PCTCN2018096250-appb-100001
  2. 根据权利要求1所述的化合物，其为固态晶体形式。
  3. 根据权利要求2所述的化合物，式(I)所示的化合物为I晶型，其使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：13.19°±0.2°、16.10°±0.2°、18.23°±0.2°、21.85°±0.2°、24.33°±0.2°。
  4. 根据权利要求3所述的化合物，式(I)所示的化合物使用Cu-Kα辐射，其X-射线粉末衍射图谱如图1所示。
  5. 根据权利要求3所述的化合物，其特征在于，其差示扫描量热分析曲线如图2所示。
  6. 一种药物组合物，包含治疗有效量的权利要求1～5中任一项所述化合物，以及药学上可接受的载体或赋形剂。
  7. 权利要求1～5中任一项所述化合物，或权利要求6所述的药物组合物在制备用于预防和/或治疗气道阻塞性疾病的药物中的应用，所述气道阻塞性疾病优选哮喘、慢性阻塞性肺疾病或支气管炎。
  8. 一种治疗气道阻塞性疾病的方法，所述方法包括给予权利要求1～5任意一项所述的化合物，或权利要求6所述的药物组合物；所述气道阻塞性疾病优选为哮喘、慢性阻塞性肺疾病或支气管炎。
  9. 一种式(I)所示化合物的制备方法，该方法为使式(II)所示的化合物与柠檬酸接触，
    Figure PCTCN2018096250-appb-100002
  10. 一种式(I)所示的化合物I晶型的制备方法，该方法包括以下步骤：
    将式(II)所示的化合物溶于第一溶剂中，加入柠檬酸后，再加入第二溶剂，搅拌，析出晶体，收集晶体。
  11. 根据权利要求10所述的制备方法，其中，所述的第一溶剂选自C 1-6卤代烷烃类溶剂、C 2-6酯类溶剂、C 2-6醚类溶剂和C 1-6酮类溶剂中的一种或多种；
    第二溶剂选自C1-6醇类溶剂、C1-6醚类溶剂和水中的一种或多种。
  12. 根据权利要求10所述的制备方法，其中，所述的第一溶剂选自二氯甲烷、1，2-二氯乙烷、氯仿、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、乙酸异丙酯、丙酮、乙醚和甲基叔丁基醚的一种或多种；
    第二溶剂选自甲醇、乙醇、异丙醇、乙醚、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、甲基叔丁基醚和水中的一种或多种。
  13. 根据权利要求10～12任一所述的制备方法，将所述的晶体进一步重结晶和/或打浆。
  14. 根据权利要求13所述的制备方法，重结晶和/或打浆温度为0℃～回流，优选0～80℃。
  15. 根据权利要求13所述的制备方法，重结晶和/或打浆的溶剂选自甲苯、二氯甲烷、1，2-二氯乙烷、氯仿、乙酸乙酯、乙酸异丙酯、丙酮、4-甲基-2-戊酮、丁酮、乙醚、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、甲基叔丁基醚、甲醇、乙醇、异丙醇和水中的一种或多种。
  16. 根据权利要求13所述的制备方法，重结晶和/或打浆的溶剂为二氯甲烷和乙醇的中的一种或两种，当溶剂为二氯甲烷和乙醇时，两者的体积比优选为1∶0～0∶3，更优选为1∶1。
  17. 一种式(II)所示化合物的制备方法，使用如下反应得到：
    Figure PCTCN2018096250-appb-100003
    HA选自HF、HBr、HCl、CH3COOH、苯磺酸或对甲基苯磺酸；
    反应在还原剂下进行。
  18. 根据权利要求17所述的制备方法，所述的还原剂选自有机硼还原剂，优选三(乙酰氧基)硼氢化钠、硼氢化钠、氰基硼氢化钠或癸硼烷。
  19. 根据权利要求18所述的制备方法，反应的溶剂选自极性溶剂，优选二氯甲烷、氯仿、1，2-二氯乙烷、乙腈、四氢呋喃、2-甲基四氢呋喃、1，4-二氧六环、甲基叔丁基醚、甲醇、乙醇、异丙醇、乙酰胺、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺和二甲基亚砜中的一种或多种，反应的温度优选0～60℃；
    作为选择，反应任选在分子筛、脱水剂或分水容器存在下进行，所述的脱水剂优选分子筛、硫酸钠或硫酸镁；
    作为选择，反应任选在酸性催化剂存在下进行，所述的酸性催化剂优选甲酸、三氟乙酸、乙酸、甲磺酸、苯磺酸、对甲苯磺酸、氯化锌和氯化铝中的一种或多种。
  20. 一种式(III)所示化合物的制备方法，使用如下反应得到：
    Figure PCTCN2018096250-appb-100004
    所述反应在叠氮磷酸二苯酯存在下进行。
  21. 根据权利要求20所述的制备方法，反应的溶剂选自非质子溶剂，优选C 6-10芳烃类溶剂、C 1-6卤代烷烃或C 1-8烷烃类溶剂中的一种或多种，更优选甲苯、苯、二氯甲烷、氯仿和1，2-二氯乙烷中的一种或多种；
    反应的温度优选0℃至回流；
    作为选择，反应任选进一步在缚酸剂存在下进行，所述的缚酸剂优选有机胺，更优选三乙胺、二异丙基乙基胺、4-二甲氨基吡啶、N-甲基吗啉和吗啉中的一种或多种。
  22. 根据权利要求20-21任一项所述的制备方法，式(VI)所示的化合物与叠氮磷酸二苯酯的摩尔比为1∶1～1∶5，式(VI)所示的化合物与式(V)所示的化合物的摩尔比为1∶0.5～1∶1。
  23. 一种式(V)所示化合物的制备方法，使用如下反应得到：
    Figure PCTCN2018096250-appb-100005
    作为选择，式(VII)所示化合物以有机胺盐的形式参与反应，所述的有机胺盐优选三乙胺盐。
  24. 根据权利要求23所述的制备方法，反应在缩合剂和/或缩合活化剂下进行，所述的缩合剂优选1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、二环乙基碳二亚胺、二异丙基碳二亚胺、2-(7-氧化苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(HATU)、O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)、6-氯苯并三氮唑-1，1，3，3-四甲基脲六氟磷酸酯(HCTU)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBOP)、二苯基次膦酰氯或双(2-氧代-3-恶唑烷基)次磷酰氯(BOP-C1)，缩合活化剂优选1-羟基苯并三唑、4-二甲氨基吡啶、4-吡咯烷基吡啶、1-羟基-7-偶氮苯并三氮唑；
    反应的溶剂选自C 1-6卤代烷烃类溶剂、C 2-6酯类溶剂、N，N-二甲基甲酰胺和N，N-二甲基乙酰胺中的一种或多种，优选二氯甲烷、氯仿、1，2-二氯甲烷、乙酸乙酯、乙酸异丙酯、N，N-二甲基甲酰胺和N，N-二甲基乙酰胺中的一种或多种；
    反应的温度优选0℃～回流，更优选0℃～40℃；
    作为选择，反应中任选进一步加入有机胺试剂，所述的有机胺试剂优选三乙胺、二异丙基乙基胺、4-二甲氨基吡啶、N-甲基吗啉或吗啉中的一种或多种。
  25. 一种式(VII)所示化合物的制备方法，使用如下反应得到：
    Figure PCTCN2018096250-appb-100006
    反应的溶剂选自C 2-6醚类溶剂，优选四氢呋喃、2-甲基四氢呋喃和1，2-二氧六环中的一种或多种；
    反应的温度优选0℃～回流，更优选20℃～回流。
  26. 根据权利要求25所述的制备方法，所述方法还包括对式(VII)所示化合物进行精制的步骤，在精制式(VII)所示化合物过程中，加入有机胺与其形成盐，从而得到式(VII)所示化合物的有机胺盐，所述的有机胺优选三乙胺。
  27. 一种式(II)所示化合物的制备方法，该方法包括如下步骤：
    Figure PCTCN2018096250-appb-100007
    其中：
    (1)、式(IX)所示化合物与式(X)所示化合物反应生成式(VII)所示化合物，反应的溶剂选自C 2-6醚类溶剂，优选四氢呋喃、2-甲基四氢呋喃和1，2-二氧六环中的一种或多 种；反应的温度优选0℃～回流，更优选20℃～回流，还包括对式(VII)所示化合物进行精制的步骤，在精制式(VII)所示化合物过程中，优选加入有机胺与其形成盐，从而得到式(VII)所示化合物的有机胺盐；
    (2)、式(VII)所示化合物与式(VIII)所示化合物反应生成式(V)所示化合物，反应在缩合剂和/或缩合活化剂下进行，作为选择，式(VII)所示化合物以三乙胺盐的形式参与反应；
    (3)、式(V)所示化合物与式(VI)所示化合物在叠氮磷酸二苯酯存在下反应生成式(III)所示化合物；
    (4)、式(III)所示化合物与式(IV)所示化合物在还原剂存在下反应生成式(II)所示化合物；
    HA选自HF、HBr、HCl、CH 3COOH、苯磺酸或对甲基苯磺酸。
  28. 根据权利要求27所述的制备方法，其中：
    (1)、式(IX)所示化合物与式(X)所示化合物反应生成式(VII)所示化合物，反应的溶剂选自四氢呋喃、2-甲基四氢呋喃和1，2-二氧六环中的一种或多种；反应的温度选自0℃～回流，优选20℃～回流，精制式(VII)所示化合物过程中，优选加入三乙胺与其形成盐，从而得到式(VII)所示化合物的三乙胺盐；
    (2)、式(VII)所示化合物与式(VIII)所示化合物反应生成式(V)所示化合物，反应在缩合剂和/或缩合活化剂下进行，作为选择，式(VII)所示化合物以三乙胺盐的形式参与反应，所述的缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，所述的缩合活化剂选自1-羟基苯并三唑，反应的溶剂选自二氯甲烷、氯仿和1，2-二氯甲烷中的一种或多种，反应的温度选自0℃～回流，作为选择，反应中加入三乙胺；
    (3)、式(V)所示化合物与式(VI)所示化合物在叠氮磷酸二苯酯存在下反应生成式(III)所示化合物，反应的溶剂选自甲苯或苯，反应的温度选自0℃～回流，作为选择，反应中加入三乙胺；
    (4)、式(III)所示化合物与式(IV)所示化合物在还原剂存在下反应生成式(II)所示化合物，所述的还原剂选自三(乙酰氧基)硼氢化钠、硼氢化钠氰基硼氢化钠或癸硼烷，反应的温度选自0℃～60℃，反应的溶剂选自二甲基亚砜、二氯甲烷、异丙醇、乙腈和乙酰胺中的一种或多种，作为选择，反应中加入分子筛，作为选择，反应中加入乙酸和氯化锌中的一种或两种。
  29. 一种式(B)所示化合物的制备方法，使用如下反应得到：
    Figure PCTCN2018096250-appb-100008
    反应在还原剂存在下进行，所述的还原剂选Pd/C和三乙基硅烷的组合。
  30. 根据权利要求29所述的制备方法，反应中的溶剂选自C 1-6醇类溶剂，优选甲醇或乙醇；
    Pd/C与式(A)所示化合物的质量比优选为1∶1～1∶100，更优选1∶1～1∶10；
    三乙基硅烷与式(A)所示化合物的摩尔比优选为20∶1～1∶1，更优选10∶1～1∶1；
    反应的温度优选0℃～回流，更优选10℃～40℃。
  31. 根据权利要求30所述的制备方法，式(B)所示化合物用于制备式(IV)所示化合物，式(B)所示化合物在脱硅醚试剂存在下制备式(IV)所示化合物，所述的脱硅醚试剂优选四丁基氟化铵或其水合物、三乙胺三氢氟酸盐或吡啶氢氟酸盐，反应的溶剂优选四氢呋喃、2-甲基四氢呋喃、乙腈、甲醇、乙醇、二氯甲烷、氯仿、1，2-二氯甲烷和水中的一种或多种，反应的温度优选0℃～回流。
  32. 一种式(IV)所示化合物的制备方法，使用如下反应得到：
    Figure PCTCN2018096250-appb-100009
    反应在脱硅醚试剂存在下进行；
    HA选自HF、HBr或HCl。
  33. 根据权利要求32所述的制备方法，所述的脱硅醚试剂选自四丁基氟化铵或其水合物、三乙胺三氢氟酸盐或吡啶氢氟酸盐；
    反应的溶剂选自C 1-6卤代烷烃类溶剂、C 1-6醇类溶剂、C 1-6醚类溶剂、乙腈和水中的一种或多种，优选四氢呋喃、2-甲基四氢呋喃、乙腈、甲醇、乙醇、二氯甲烷、氯仿、1，2-二氯甲烷和水中的一种或多种；
    反应的温度优选0℃～回流，优选20℃～回流。
  34. 一种式(V)和(IV)所示化合物：
    Figure PCTCN2018096250-appb-100010
    HA选自HF、HBr、HCl、甲磺酸或对甲苯磺酸。
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