WO2019015640A1

WO2019015640A1 - Salt of azacyclic amide derivative, crystal form thereof and preparation method therefor and use thereof

Info

Publication number: WO2019015640A1
Application number: PCT/CN2018/096250
Authority: WO
Inventors: 魏用刚; 邱关鹏; 卢泳华; 张晨; 严庞科; 郑伟
Original assignee: 四川海思科制药有限公司
Priority date: 2017-07-21
Filing date: 2018-07-19
Publication date: 2019-01-24

Abstract

The present invention relates to the salt of an azacyclic amide derivative, a crystal form thereof and a preparation method therefor and the medical use thereof. In particular, the salt of the azacyclic amide derivative is the compound as shown in formula (I).

Description

Salt of nitrogen heterocyclic amide derivative, crystal form thereof, preparation method and use thereof

Technical field

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.

Background technique

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 β 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.

In addition, drugs with dual effects of muscarinic receptor antagonism and β 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. In addition, compounds with muscarinic receptor antagonism and β ₂ -adrenergic agonistic dual action (MABA) 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.

Summary of the invention

The present invention provides a salt of a nitrogen heterocyclic amide derivative having a dual action of muscarinic receptor antagonism and β 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):

In one embodiment of the invention, the compound of formula (I) is in the form of a solid crystalline form.

In one embodiment of the present invention, the compound represented by the formula (I) is a crystal form of I, which uses Cu-Kα radiation, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 13.19 ° ± 0.2 °, 16.10°±0.2°, 18.23°±0.2°, 21.85°±0.2°, 24.33°±0.2°.

Further, 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 compound of the formula (I) is a crystal form of I, and its differential scanning calorimetry curve shows that T _starts = 165.4 ± 3 ° C, and T _peak = 172.5 ± 3 ° C, wherein the melting point temperature is 172.5 ± 5 ° C.

It will be appreciated that the melting peak height of the DSC curve, as is well known in the art of differential scanning calorimetry (DSC), depends on a number of factors associated with sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details.

It is also within the scope of the invention for the X-ray powder diffraction or DSC pattern disclosed herein to be substantially identical.

The present invention provides 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. Preferably, 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 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,

According to one embodiment of the process for the preparation of the compound of the formula (I), 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.

In one embodiment of the process for producing the compound of the formula (I), 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 One or more of 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.

In one embodiment of the process for the preparation of the crystalline form of the compound I represented by the formula (I), the molar ratio of citric acid to the compound of the formula (II) is from 1.5:1 to 0.8:1.

According to the demand for the purity of the product, 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. Preferably, 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. Preferably, 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.

According to one embodiment of the process for the preparation of the compound of formula (II), 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.

In one embodiment of the process for the preparation of the compound of formula (II), the temperature of the reaction is from 0 ° C to reflux, preferably from 0 to 60 ° C.

Alternatively, 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.

Alternatively, 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.

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 optionally carried out in the presence of an acidic catalyst, preferably formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and zinc chloride. One or more.

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.

According to one embodiment of the process for the preparation of the compound of the formula (III), 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. 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;

Alternatively, the 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.

In one embodiment of the process for the preparation of the compound of formula (III), 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:

Alternatively, the compound of the formula (VII) is involved in the reaction in the form of an organic amine salt, preferably a triethylamine salt.

According to one embodiment of the process for the preparation of the compound of formula (III), the reaction is carried out in the presence of a condensing agent and/or a condensing activator, preferably 1,3-(3-dimethylaminopropyl). 3-ethylcarbodiimide hydrochloride, dicycloethylcarbodiimide, diisopropylcarbodiimide, 2-(7-oxobenzotriazole)-N,N,N' , N'-tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3 ,3-tetramethylurea hexafluorophosphate (HCTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazole hexafluorophosphate 1-yl-oxytripyrrolidinyl (PyBOP), diphenylphosphinyl chloride or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-C1), preferably a condensation activator -hydroxybenzotriazole, 4-dimethylaminopyridine, 4-pyrrolidinopyridine or 1-hydroxy-7-azobenzotriazole;

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;

Optionally, 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:

among them:

(1) 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);

(2) 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. Alternatively, the formula (VII) The compound is shown to participate in the reaction in the form of a triethylamine salt;

(3), a compound of the formula (V) is reacted with a compound of the formula (VI) in the presence of diphenyl azide to form a compound of the formula (III);

(4), a compound of the formula (III) and a compound of the formula (IV) are reacted in the presence of a reducing agent to form a compound of the formula (II);

HA is selected from the group consisting of HF, HBr, HCl, CH ₃ COOH, benzenesulfonic acid or p-toluenesulfonic acid.

In one embodiment of the invention, a method of preparing a compound of formula (II), the method comprising the steps of:

(1) 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. One or more of the reaction; 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 triethylamine salt of the compound shown;

(2) 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. Alternatively, 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;

(3), 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;

(4) 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. , 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 One or more, alternatively, a molecular sieve is added to the reaction, and alternatively, one or both of acetic acid and zinc chloride are added to the reaction.

A process for the preparation of a compound of the formula (B) which comprises using the following reaction to give a compound of the formula (B):

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;

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) For the preparation, the reducing agent is preferably a combination of Pd/C and triethylsilane, and 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.

Terms used in the specification and claims have the following meanings unless stated to the contrary.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "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. Examples of 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).

It will be understood that the values described and claimed herein are approximate. Variations within the values may be due to equipment calibration, equipment errors, crystal purity, crystal size, sample size, and other factors.

It will be understood that the 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.

DRAWINGS

Figure 1: X-ray powder diffraction pattern of Compound 2I crystalline form.

Figure 2: Differential scanning calorimetry curve of Compound 2I crystal form.

Detailed ways

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) 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 measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

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.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the room temperature is 20 ° C to 30 ° C.

Example 1: Preparation of Compound 1

[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate (Compound 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

4-Piperidine N-(2-phenylphenyl)carbamate (1A) (1.54 kg, 5.19 mol) was added to 2-methyltetrahydrofuran (7 L), heated to 50 ° C, stirred and dissolved, then acrylic acid was added. (1B) (1.31kg, 18.2mol), the temperature was raised to 100 ° C for 3 hours, after the reaction was completed, cooled to room temperature, concentrated under reduced pressure to a volume of about 1/3 remaining, iced water bath, and triethylamine (1000 mL) was added with stirring. , 7.19 mol), stirring was continued for 2 h, then allowed to stand overnight, filtered to give a white solid, which was stirred with ethyl acetate and filtered to give [1-[3-[4-(hydroxymethyl)-1-piperidinyl]-3 -Oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate triethylamine salt (1C), white solid (1.4 kg, yield 57.4%, HPLC: 99.0 %).

LCMS m/z = 369.1 [M + 1].

^{1 H 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).

Second step: [1-[3-[4-(hydroxymethyl)-1-piperidinyl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl) Carbamate (1E)

[1-[3-[4-(hydroxymethyl)-1-piperidyl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-[4-(Hydroxymethyl)-1-piperidinyl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate The ester triethylamine salt (1C) (500 g, 1.36 mmol) and 4-hydroxymethylpiperidine (1D) (281 g, 2.44 mol) were added to dichloromethane (4 L), stirred for 30 min, and 1-hydroxybenzene was added. And triazole (275 g, 2.03 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (390 g, 2.03 mol) and triethylamine (206 g, 2.03 mol), The reaction was carried out for 3 hours at room temperature. 1.5 L of water was added to the reaction solution, and the mixture was stirred for 10 minutes, and the mixture was separated. The organic phase was washed with a saturated aqueous solution of sodium carbonate (1 L?) and aqueous sodium hydrogen sulfate (1L?), dried over anhydrous sodium sulfate, filtered and evaporated. , filtered to give a white solid. After the obtained solid was drained, 2 L of tetrahydrofuran was added, the temperature was raised to 55 ° C, and a lithium hydroxide aqueous solution (35 g / 350 mL of water) was added thereto, and the mixture was further stirred for 2 hours. After concentration under reduced pressure, 1 L of water and 2 L of dichloromethane were added, and the layers were separated and organic. The mixture was washed with a saturated aqueous solution of sodium carbonate (1 L, 2) and dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. [4-(Hydroxymethyl)-1-piperidinyl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (1E), white Solid (400 g, yield 63%, HPLC: 98.1%).

LCMS m/z = 466.1 [M + 1].

^{_{1 H 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).

Third step: [1-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-( 4-formylphenyl)carbamate (1G)

[1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-(4-formylphenyl)carbamate

[1-[3-[4-(Hydroxymethyl)-1-piperidinyl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate The acid ester (1E) (250 g, 0.54 mol) was added to toluene (2000 mL), followed by the addition of 4-formylbenzoic acid (1F) (96.7 g, 0.64 mol), triethylamine (135.8 g, 2.5 mol) and Diphenylphosphonium phosphate (177.3 g, 0.64 mol) was reacted at room temperature for 1 hour, and the reaction temperature was raised to reflux for 2 hours. To the 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. Add 1500 ml of petroleum ether to the organic phase, stir, viscous oil is precipitated, pour off the supernatant, dissolve the remaining oil with 1.5 L of dichloromethane, slowly add 1.5 L of petroleum ether, stir overnight, filter, filter The cake was beaten with 0.5 L of ethyl acetate, stirred for 1 hour, filtered, and the cake dried to give [1-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl Propionyl]-4-piperidinyl]methyl N-(4-formylphenyl)carbamate (1G), pale yellow solid (250 g, yield 76%, HPLC: 98.2%).

LCMS m/z = 613.2 [M + 1].

1H NMR (400MHz, CDCl3) δ 9.88 (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).

Fourth step: [1-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[ 4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate ( Compound 1)

[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[ [[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]- Phenyl]phenyl]carbamate (1G) (200 g, 0.32 mol) was dissolved in dimethyl sulfoxide (1200 mL), and 5-[(1R)-2-amino-1-hydroxy-ethyl]- 8-Hydroxy-1H-quinolin-2-one hydrofluoric acid salt (1H) (158 g, 0.64 mol), acetic acid (0.48 mol) molecular sieve 200 g, and reacted at room temperature for 3 hours. To the reaction liquid, 300 ml of anhydrous methanol was added. After cooling in an ice bath, sodium tris(acetoxy)borohydride (406.8 g, 1.92 mol) was slowly added, and the mixture was warmed to room temperature and stirred for 2 hours. The 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. Washed with 500 mL of saturated sodium chloride solution, then added 3 L of methyl tert-butyl ether, a large amount of solid precipitated, stirred for 30 minutes, filtered, and the filter cake was dried to give [1-[3-[4-[(2-phenyl) Phenyl)carbamoyloxy]-1-piperidinyl]propionyl]-4-piperidinyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxyl) 2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate (Compound 1), pale yellow solid (200 g, yield 76%, HPLC: 97.0% ).

LCMS m/z = 409.4 [(M+2)/2].

^{1 H 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) ).

Example 2: Preparation of citrate of Compound 1

[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate citrate (compound 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;

[1-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[ [[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate (Compound 1) (200g, 0.24mol) was dissolved in dichloromethane (1000mL), citric acid (47g, 0.24mol) was added, 2.0L of ethanol was slowly added, stirred at room temperature for 20 hours, filtered, and the filter cake was made with 3L of dichloromethane/ethanol = Beat 1:1 (v/v) for 30 minutes and filter. The filter cake was again beaten with 3 L of dichloromethane/ethanol = 1:1 (v/v) for 30 minutes, filtered and dried to give [1-[3-[4-[(2-phenylphenyl)carbamoyloxy) Iso-1-piperidinyl]propanoyl]-4-piperidinyl]methyl N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H) -Quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate citrate (Compound 2), pale yellow solid (191 g, yield 77%, HPLC: 98.3%).

Compound 2 was subjected to X-ray powder diffraction test as follows:

Using a PANalytical X-ray diffractometer X'pertpowder type (PANalytical BV, The Netherlands), using Cu Ka radiation,

(40kV, 40mA), powder X-ray diffraction pattern was obtained with PIXcel 1D detector, analysis software highscore 3.0e (3.0.5), acquisition software PANalytical Data Collector 4.2. The analysis is typically carried out at a scan rate of 0.1094°/s in a range of 2θ angles of 4° to 40° at a step of 0.013° per point. A sample ground to a fine powder was lightly loaded onto a grooved custom glass sample plate and the sample was plated on the surface of the glass sample plate for testing. The instrument was calibrated weekly with a standard silicon sample sample supplied with the instrument and the range of 2θ angles was kept within ±0.02°.

The X-ray powder diffraction pattern of Compound 2 is shown in Fig. 1, and the peak list is shown in Table 1.

Table 1

Compound 2 was subjected to differential scanning calorimetry analysis as follows:

Differential Scanning Calorimetry (DSC) 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.

The Form I of Compound 2, the differential scanning calorimetry curve (DSC) showed an endothermic curve with T _start = 165.4 ° C and T _peak = 172.5 ° C.

LCMS m/z = 409.4 [(M+2)/2].

^{1 H 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) ).

Example 3: Preparation of Compound 1H

5-[(1R)-2-Amino-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one hydrofluoric acid salt (1H)

5-[(1R)-2-amino-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one;hydrofluoride

First step: 5-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-8-hydroxy-1H-quinolin-2-one (3B)

5-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-8-hydroxy-1H-quinolin-2-one

5-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-8-benzyloxy-1H-quinolin-2-one (3A (900 g, 1997 mmol) dissolved in absolute ethanol (4500 ml), 50% (w/w) palladium on carbon (180 g) was added, triethylsilane (1161 g, 9987 mmol) was added dropwise under nitrogen, and the mixture was allowed to continue at room temperature. Stir for 30 minutes. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. EtOAc EtOAc (EtOAc) Oxyethyl]-8-hydroxy-1H-quinolin-2-one (3B), yellow-green solid (647 g, yield 96.84%).

_{1H NMR (400MHz, CD 3 OD} ) 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), -0.11 (s, 3H).

Second step: 5-[(1R)-2-Amino-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one hydrofluoric acid salt (1H)

5-[(1R)-2-amino-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one;hydrofluoride

5-[(1R)-2-Amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-8-hydroxy-1H-quinolin-2-one (3B) (700 g, 2093 mmol) was dissolved in absolute ethanol (3.5 L), triethylamine trihydrofluoride (1000 g, 6203 mmol) was added, and the temperature was raised to 80 ° C for 5 hours. The 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%).

1H NMR (400MHz, DMSO-d6) δ 8.15 (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).

Example 4: Conditional screening for the reaction of compound 1G with compound 1H to form compound 1

Table 2: Screening results of the reaction of the compound 1G with the compound 1H to form the compound 1

DMSO is dimethyl sulfoxide; eq is the molar equivalent ratio.

Example 5: Stability test of compound 2 I crystal form

Sample placement:

The compound 2 I crystal form was taken, and the influencing factors were investigated according to the conditions of the investigation and the sampling time points in Table 3, and the results are shown in Table 5 below.

Table 3 stability experimental conditions table

Each sample was added with a diluent [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. According to high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition four general rules 0512), using octadecylsilane bonded silica as a filler (Inertsil ODS-3, 4.6mm × 250mm, 5μm or equivalent performance of the column); Phosphate buffer (take 3.12 g of sodium dihydrogen phosphate dihydrate, dissolve in 1000 ml of water, adjust pH to 3.0 with phosphoric acid) to mobile phase A, and acetonitrile as mobile phase B; perform linear gradient elution according to Table 4; The detection wavelength was 210 nm, the column temperature was 40 ° C, and the flow rate was 1.0 ml per minute. 10 μl of the test solution 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.

Table 4 Compound 2 I crystal form stability test HPLC conditions

Table 5 Compound 2 I crystal form stability results

Conclusion: Compound 2 I crystal form has good stability.

Biological test case

Test Example 1: Methotrexate-induced inhibition of bronchoconstriction in rats

Eight-week-old whole male rats were purchased and placed in Vitalius (license number: SCXK (Beijing) 2012-0001), and the experiment was started after 3 days of adaptation. The positive compounds bafetenrol and compound 2 were first formulated into a stock solution with 87% absolute ethanol + 17% Tween 80, and the bafeftrol was diluted with water to the administered concentration. Prior to administration, animals were anesthetized with 5% isoflurane using a small animal anesthesia machine for an anesthesia time of 1.5-2 minutes. After the rats were anesthetized, the rats were fixed on an tracheal intubation operating platform and intratracheally administered using a rat liquid aerosol administration kit, and each rat was administered with a volume of 250 μl. Four hours after administration, 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

Conclusion: Compound 2 has good inhibitory activity against methacholine-induced bronchoconstriction in rats, which is superior to bafetentorol.

Claims

A compound of formula (I):
A compound according to claim 1 which is in the form of a solid crystal.
The compound according to claim 2, wherein the compound of the formula (I) is a crystal form of I, which uses Cu-Kα radiation, and its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 13.19 ° ± 0.2 ° , 16.10 ° ± 0.2 °, 18.23 ° ± 0.2 °, 21.85 ° ± 0.2 °, 24.33 ° ± 0.2 °.
The compound according to claim 3, wherein the compound of the formula (I) is irradiated with Cu-Kα, and an X-ray powder diffraction pattern thereof is shown in Fig. 1.
The compound of claim 3 wherein the differential scanning calorimetry curve is as shown in FIG.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 5, and a pharmaceutically acceptable carrier or excipient.
Use of the compound according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 6, for the preparation of a medicament for preventing and/or treating an airway obstructive disease, the airway obstructive disease Preferred is asthma, chronic obstructive pulmonary disease or bronchitis.
A method for treating an airway obstructive disease, the method comprising administering the compound according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 6; the airway obstructive disease is preferably asthma , chronic obstructive pulmonary disease or bronchitis.
A method for preparing a compound of the formula (I), which comprises contacting a compound of the formula (II) with citric acid,
A method for preparing a crystalline form of Compound I represented by formula (I), the method comprising the steps of:

The compound represented by the formula (II) is dissolved in a first solvent, and after adding citric acid, a second solvent is further added, stirred, crystals are precipitated, and crystals are collected.
The production method according to claim 10, wherein the first solvent is selected from the group consisting of a C 1-6 halogenated alkane solvent, a C 2-6 ester solvent, a C 2-6 ether solvent, and a C 1-6 ketone. One or more of the class of solvents;

The second solvent is selected from one or more of a C1-6 alcohol solvent, a C1-6 ether solvent, and water.
The production method according to claim 10, wherein the first solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, and isopropyl acetate. One or more of ester, acetone, diethyl ether and methyl tert-butyl ether;

The second solvent is selected from one or more of the group consisting of methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, and water.
The preparation method according to any one of claims 10 to 12, wherein the crystal is further recrystallized and/or beaten.
The process according to claim 13, wherein the recrystallization and/or the beating temperature is from 0 ° C to reflux, preferably from 0 to 80 ° C.
The process according to claim 13, wherein 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- One or more of methyl-2-pentanone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol and water Kind.
The preparation method according to claim 13, wherein the solvent for recrystallization and/or beating is one or two of dichloromethane and ethanol, and when the solvent is dichloromethane and ethanol, the volume ratio of the two is preferably 1:0 to 0:3, more preferably 1:1.
A method for preparing a compound of the formula (II) is obtained by the following reaction:

HA is selected from the group consisting of HF, HBr, HCl, CH3COOH, benzenesulfonic acid or p-toluenesulfonic acid;

The reaction is carried out under a reducing agent.
The process according to claim 17, wherein the reducing agent is selected from the group consisting of organoboron reducing agents, preferably sodium tris(acetoxy)borohydride, sodium borohydride, sodium cyanoborohydride or decane borane.
The process according to claim 18, wherein the solvent to be reacted is selected from the group consisting of polar solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-two. One of oxyhexacyclohexane, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetamide, N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl sulfoxide One or more kinds, the temperature of the reaction is preferably 0 to 60 ° C;

Alternatively, the reaction is optionally carried out in the presence of a molecular sieve, a dehydrating agent or a water-discharging vessel, preferably a molecular sieve, sodium sulfate or magnesium sulfate;

Alternatively, the reaction is optionally carried out in the presence of an acidic catalyst, preferably one of formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, zinc chloride and aluminum chloride. Kind or more.
A method for preparing a compound of the formula (III) is obtained by the following reaction:

The reaction is carried out in the presence of diphenylphosphoryl azide.
The preparation method according to claim 20, wherein the solvent to be reacted is selected from the group consisting of an aprotic solvent, preferably one or more of a C 6-10 aromatic hydrocarbon solvent, a C 1-6 halogenated alkane or a C 1-8 alkane solvent. 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;

Alternatively, the 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.
The process according to any one of claims 20 to 21, wherein the compound represented by the formula (VI) and the diphenylphosphoryl azide are in a molar ratio of from 1:1 to 1:5, and the compound represented by the formula (VI) The molar ratio to the compound represented by the formula (V) is from 1:0.5 to 1:1.
A method for preparing a compound of the formula (V) is obtained by the following reaction:

Alternatively, the compound of the formula (VII) is involved in the reaction in the form of an organic amine salt, preferably a triethylamine salt.
The process according to claim 23, wherein the reaction is carried out under a condensing agent and/or a condensing activator, and the condensing agent is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt. Acid salt, dicycloethylcarbodiimide, diisopropylcarbodiimide, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro Phosphate (HATU), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate Ester (HCTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrolidine hexafluorophosphate PyBOP, diphenylphosphinyl chloride or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-C1), the condensation activator is preferably 1-hydroxybenzotriazole, 4-di Methylaminopyridine, 4-pyrrolidinopyridine, 1-hydroxy-7-azobenzotriazole;

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 0 ° C to reflux, more preferably 0 ° C to 40 ° C;

Optionally, 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.
A process for the preparation of a compound of the formula (VII) is carried out 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 temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 20 ° C to reflux.
The process according to claim 25, which further comprises the step of purifying the compound of the formula (VII), wherein an organic amine is added to form a salt during the purification of the compound of the formula (VII), thereby obtaining a formula An organic amine salt of the compound of (VII), which is preferably triethylamine.
A method for preparing a compound of the formula (II), the method comprising the steps of:

among them:

(1) 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, and further comprises a step of purifying the compound of the formula (VII). In the process of the compound of the formula (VII), it is preferred to add an organic amine to form a salt thereof to obtain an organic amine salt of the compound of the formula (VII);

(2) 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. Alternatively, the formula (VII) The compound is shown to participate in the reaction in the form of a triethylamine salt;

(3), a compound of the formula (V) is reacted with a compound of the formula (VI) in the presence of diphenyl azide to form a compound of the formula (III);

(4), a compound of the formula (III) and a compound of the formula (IV) are reacted in the presence of a reducing agent to form a compound of the formula (II);

HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
The preparation method according to claim 27, wherein:

(1) 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. One or more of the reaction; the temperature of the reaction is selected from 0 ° C to reflux, preferably 20 ° C to reflux, in the process of purifying the compound of the formula (VII), preferably adding triethylamine and forming a salt thereof, thereby obtaining the formula (VII) a triethylamine salt of the compound shown;

(2) 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. Alternatively, 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;

(3), 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;

(4) 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. , 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 One or more, alternatively, a molecular sieve is added to the reaction, and alternatively, one or both of acetic acid and zinc chloride are added to the reaction.
A method for preparing a compound of the formula (B) is obtained by the following reaction:

The reaction is carried out in the presence of a reducing agent selected from the group consisting of Pd/C and triethylsilane.
The preparation method according to claim 29, 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 process according to claim 30, wherein the compound of the formula (B) is used for the preparation of the compound of the formula (IV), and the compound of the formula (B) is used to prepare the compound of the formula (IV) in the presence of a desilicon ether reagent. The desiliconized ether reagent is preferably tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridine hydrofluoride, and the solvent for the reaction is preferably tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or methanol. For one or more of ethanol, dichloromethane, chloroform, 1,2-dichloromethane and water, the temperature of the reaction is preferably from 0 ° C to reflux.
A process for the preparation of a compound of the formula (IV) is carried out 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 preparation method according to claim 32, wherein the desilicon ether reagent is selected from the group consisting of tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridine hydrofluoride;

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 temperature of the reaction is preferably from 0 ° C to reflux, preferably from 20 ° C to reflux.
a compound of the formula (V) and (IV):

HA is selected from HF, HBr, HCl, methanesulfonic acid or p-toluenesulfonic acid.