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WO2019086008A1 - Crystal form of benzotriazole derivative and preparation method and use thereof - Google Patents

Crystal form of benzotriazole derivative and preparation method and use thereof Download PDF

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Publication number
WO2019086008A1
WO2019086008A1 PCT/CN2018/113806 CN2018113806W WO2019086008A1 WO 2019086008 A1 WO2019086008 A1 WO 2019086008A1 CN 2018113806 W CN2018113806 W CN 2018113806W WO 2019086008 A1 WO2019086008 A1 WO 2019086008A1
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Prior art keywords
compound
formula
solvent
reaction
group
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French (fr)
Chinese (zh)
Inventor
邱关鹏
张晨
魏用刚
卢泳华
祝国智
高秋
楚洪柱
李瑶
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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a crystalline form of a benzotriazole derivative, a process for its preparation and its use 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 crystalline form of a benzotriazole derivative having a dual action of muscarinic receptor antagonism and ⁇ 2 -adrenergic agonism, a preparation method thereof and use thereof in medicine.
  • the crystallization of the compound of the formula (I) of the present invention has the following advantages such as ease of processing and crystallization, convenient handling, ease of purification, ease of industrialization, good stability, good fluidity, easy micronization, etc., which make them particularly suitable for Made into an inhalation preparation.
  • the present invention provides a crystal of a compound of the formula (I), which has a characteristic diffraction peak at the following 2 ⁇ position using Cu-K ⁇ radiation: 6.03° ⁇ 0.2°, 9.11° ⁇ 0.2°, 10.68 ° ⁇ 0.2°, 11.16° ⁇ 0.2°, 11.78° ⁇ 0.2°, 13.52° ⁇ 0.2°, 15.04° ⁇ 0.2°, 16.05° ⁇ 0.2°, 16.86° ⁇ 0.2°, 17.40° ⁇ 0.2°, 17.91° ⁇ 0.2°, 19.08° ⁇ 0.2°, 20.48° ⁇ 0.2°, 21.24° ⁇ 0.2°, 22.96° ⁇ 0.2°, 23.47° ⁇ 0.2°, 24.36° ⁇ 0.2°, 27.36° ⁇ 0.2°;
  • the crystallization of the compound of formula (I) uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.03° ⁇ 0.2°, 7.59° ⁇ 0.2 °, 9.11 ° ⁇ 0.2 °, 10.68 ° ⁇ 0.2 °, 11.16 ° ⁇ 0.2 °, 11.78 ° ⁇ 0.2 °, 12.64 ° ⁇ 0.2 °, 13.52 ° ⁇ 0.2 °, 15.04 ° ⁇ 0.2 °, 16.05 ° ⁇ 0.2 °, 16.86° ⁇ 0.2°, 17.40° ⁇ 0.2°, 17.91° ⁇ 0.2°, 19.08° ⁇ 0.2°, 19.87° ⁇ 0.2°, 20.21° ⁇ 0.2°, 20.48° ⁇ 0.2°, 21.24° ⁇ 0.2°, 22.03° ⁇ 0.2°, 22.96° ⁇ 0.2°, 23.47° ⁇ 0.2°, 24.36° ⁇ 0.2°, 25.55° ⁇ 0.2°
  • the crystallization of the compound of formula (I) uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.03° ⁇ 0.2°, 7.59° ⁇ 0.2 °, 9.11 ° ⁇ 0.2 °, 10.68 ° ⁇ 0.2 °, 11.16 ° ⁇ 0.2 °, 11.78 ° ⁇ 0.2 °, 12.64 ° ⁇ 0.2 °, 13.52 ° ⁇ 0.2 °, 15.04 ° ⁇ 0.2 °, 16.05 ° ⁇ 0.2 °, 16.86° ⁇ 0.2°, 17.40° ⁇ 0.2°, 17.91° ⁇ 0.2°, 19.08° ⁇ 0.2°, 19.87° ⁇ 0.2°, 20.21° ⁇ 0.2°, 20.48° ⁇ 0.2°, 21.24° ⁇ 0.2°, 22.03° ⁇ 0.2°, 22.96° ⁇ 0.2°, 23.47° ⁇ 0.2°, 24.36° ⁇ 0.2°, 25.04° ⁇ 0.2°
  • X-ray powder diffraction pattern of the compound of the formula (I) is substantially as shown in Fig. 1.
  • DSC differential scanning calorimetry curve
  • DSC differential scanning calorimetry curve
  • 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 crystalline compound of the present invention is characterized by a DSC pattern having a characteristic peak position having substantially the same properties as the DSC pattern provided in the drawings of the present invention with a margin of error of ⁇ 3 °C.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound crystal of the above formula (I), and a pharmaceutically acceptable carrier or excipient; preferably, the composition is formulated for inhalation administration Form; preferably, the inhaled administration form is selected from a dry powder inhalation formulation or an aerosol.
  • the present invention also provides the use of the compound crystal 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 obstructiveness Pulmonary disease or bronchitis.
  • an airway obstructive disease preferably, asthma, chronic obstructiveness Pulmonary disease or bronchitis.
  • the present invention also provides a method for treating an airway obstructive disease, which comprises administering a compound crystal of any one of the above formula (I) or a pharmaceutical composition thereof, wherein the airway obstructive disease is preferably asthma, chronic obstruction Sexual lung disease or bronchitis.
  • the present invention relates to a process for the preparation of a crystal of a compound of the formula (I), which comprises recrystallizing and/or beating a compound of the formula (I) in a solvent selected from the group consisting of C 6-10 aromatic hydrocarbon solvents , C 5-10 alkane solvent, C 1-6 halogenated alkane solvent, C 1-6 alcohol solvent, C 2-6 ester solvent, C 2-6 ether solvent, C 1-6 ketone solvent and One or more of the water; preferably the solvent is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, One or more of isopropyl acetate, acetone, diethyl ether, methyl tert-butyl ether, and water; preferably seed crystals are added upon recrystallization.
  • a solvent selected from
  • the solvent for recrystallization and/or beating is selected from the group consisting of toluene, n-heptane, n-hexane, methanol, ethanol, isopropanol, dichloromethane.
  • the present invention relates to an embodiment of the process for producing a crystal of the compound of the formula (I), wherein the temperature for recrystallization and/or beating is from 0 ° C to reflux; preferably from 0 to 80 ° C; more preferably from 20 to 60 ° C; further preferably 20 ⁇ 40 ° C.
  • the present invention relates to an embodiment of the preparation method of the crystal of the compound represented by the formula (I), wherein the solvent is selected from the group consisting of a mixed solvent of dichloromethane and isopropanol; and the volume ratio thereof is preferably 5:1 to 1:5; It is preferably 2:1 to 1:2; further preferably 1:1; the temperature for recrystallization and/or beating is preferably 20 to 60 ° C; more preferably 20 to 40 ° C.
  • the solvent is selected from the group consisting of a mixed solvent of dichloromethane and isopropanol; and the volume ratio thereof is preferably 5:1 to 1:5; It is preferably 2:1 to 1:2; further preferably 1:1; the temperature for recrystallization and/or beating is preferably 20 to 60 ° C; more preferably 20 to 40 ° C.
  • the present invention provides a method for preparing a compound represented by the formula (I),
  • a desilicon ether reagent preferably tetrabutylammonium fluoride or a hydrate thereof, triethylamine Trihydrofluoride or pyridine hydrofluoride.
  • the present invention relates to an embodiment of the process for the preparation of the compound of the formula (I), 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 desilicon ether reagent is selected from the group consisting of tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridinium hydrogen Fluorate.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (I), wherein the C 1-6 alcohol solvent is one or more selected from the group consisting of methanol, ethanol and isopropanol; and the reaction temperature is preferably 0 to 60. °C; more preferably 20 to 60 ° C; more preferably 20 to 50 ° C.
  • the silyl ether reagent is preferably triethylamine trihydrofluoride; the temperature of the reaction is preferably 0 to 60 ° C; more preferably 20 to 60 ° C; more preferably 20 to 50 ° C.
  • the invention also relates to a method for preparing a compound represented by the formula (II),
  • the compound of the formula (III) and the compound of the formula (VI) are carried out in the presence of a reducing agent;
  • HA is selected from organic or inorganic acids; preferably HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
  • 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 solvent of the reaction is selected from the group consisting of polar solvents; 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;
  • the reaction is optionally carried out in the presence of a molecular sieve, a dehydrating agent or a water separation vessel;
  • the dehydrating agent is preferably a molecular sieve, sodium sulfate or magnesium sulfate;
  • the reaction is optionally carried out in the presence of an acidic catalyst; preferably the acid catalyst is one or more of formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and zinc chloride. .
  • the acid catalyst is one or more of formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and zinc chloride.
  • the present invention relates to a method for preparing the compound of the formula (II), the molar ratio of the reducing agent to the compound of the formula (III) is 1:1 to 1:3; preferably 1:1 to 1:2;
  • the reducing agent is preferably sodium tris(acetoxy)borohydride;
  • the temperature of the reaction is preferably 0 to 60 ° C; more preferably 0 to 40 ° C;
  • the reaction optionally in the molecular sieve and acetic acid is carried out in the presence.
  • reaction is carried out in the presence of a metal catalyst and triethylsilane;
  • HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (IV), wherein the solvent in the reaction is selected from a C 1-6 alcohol solvent; preferably methanol or ethanol;
  • the metal catalyst is selected from the group consisting of palladium black, palladium/carbon, palladium hydroxide/carbon, palladium chloride/carbon, Raney nickel, platinum/carbon or platinum oxide;
  • the temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 0 to 40 ° C;
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (IV). After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated to obtain a concentrate. The concentrate is dissolved in an organic solvent, and HA is added to form a formula (IV).
  • the organic solvent is preferably a polar solvent; preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl uncle
  • a polar solvent preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl uncle
  • butyl ether, methanol, ethanol, isopropanol acetamide, N,N-dimethylacetamide, N,N-dimethylformamide, and dimethyl sulfoxide.
  • the mass ratio of the metal catalyst (preferably palladium/carbon) to the compound of the formula (IV) is preferably from 1:1 to 1:100; more preferably 1:1 to 1:10; more preferably 1:1 to 1:5;
  • the molar ratio of triethylsilane to the compound of the formula (IV) is preferably from 20:1 to 1:1; more preferably from 10:1 to 1:1; more preferably from 5:1 to 1:1;
  • the temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 0 ° C to 40 ° C.
  • the compound of formula (IV) is purified by recrystallization; the solvent for recrystallization is preferably 2-methyltetrahydrofuran or/and tetrahydrofuran.
  • the product obtained after recrystallization has high purity, simple purification and easy industrialization.
  • the present invention relates to a process for the preparation of a compound of formula (V),
  • the compound of the formula (VI) is reacted in the presence of an alkaline reagent.
  • the present invention relates to an embodiment of the preparation method of the compound represented by the formula (V), wherein the alkaline agent is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium acetate, potassium fluoride, cesium fluoride, One or more of cesium carbonate, potassium carbonate, potassium acetate, and 1,8-diazabicycloundec-7-ene;
  • the alkaline agent is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium acetate, potassium fluoride, cesium fluoride, One or more of cesium carbonate, potassium carbonate, potassium acetate, and 1,8-diazabicycloundec-7-ene;
  • the solvent to be reacted is selected from the group consisting of a C 1-6 halogenated alkane solvent, a C 1-6 alcohol solvent, a C 2-6 ester solvent, a C 2-6 ether solvent, a C 1-6 ketone solvent, N, N- One or more of dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and water; preferably dichloromethane, chloroform, 1,2-dichloromethane, methanol, ethanol, iso Propyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetone, N,N-dimethylformamide, N,N-dimethylacetamide And one or more of the water;
  • the temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 20 ° C to 80 ° C.
  • the invention provides a preparation method of the compound represented by the formula (I), which comprises the following steps:
  • HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
  • a compound of the formula (VI) is formed in the presence of an alkaline reagent to form a compound of the formula (V), and the solvent to be reacted is selected from the group consisting of a mixture of N,N-dimethylformamide and one or two of water.
  • the alkaline agent is selected from lithium hydroxide; the temperature of the reaction is preferably from 20 ° C to 80 ° C;
  • the solvent of the reaction is selected from ethanol; the reaction temperature is preferably 0 ⁇ 40 ° C;
  • a compound of the formula (IV) is reacted with a compound of the formula (III) in the presence of sodium tris(acetoxy)borohydride to form a compound of the formula (II), and the solvent of the reaction is selected from the group consisting of dimethyl a mixture of one or more of sulfone, dichloromethane, isopropanol, acetonitrile and acetamide.
  • the solvent of the reaction is selected from the group consisting of dimethyl a mixture of one or more of sulfone, dichloromethane, isopropanol, acetonitrile and acetamide.
  • a molecular sieve is added to the reaction.
  • one or two of acetic acid and zinc chloride are added to the reaction. Mixing; the temperature of the reaction is preferably 0 to 40 ° C;
  • the solvent of the reaction is selected from ethanol; the reaction temperature is preferably 0 to 60 ° C;
  • the present invention provides a compound of the formula (IV):
  • HA is selected from HF, HBr, HCl, methanesulfonic acid or p-toluenesulfonic acid.
  • Figure 1 X-ray powder diffraction pattern of Compound 1 crystals.
  • Figure 2 Differential scanning calorimetry curve of compound 1 crystals.
  • Figure 3 Amorphous X-ray powder diffraction pattern of Compound 1.
  • Figure 4 X-ray powder diffraction pattern of Compound 1 seed crystals.
  • 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.
  • 1D (70 g, 176 mmol) was added to 250 mL of DMSO and 200 mL of isopropanol
  • 1E (70 g, 117 mmol, synthesized with reference to WO2017012489A1), 4A molecular sieve 70 g, and acetic acid (3.5 g, 58.5 mmol) were added with stirring, and stirred for 2 hours after the addition.
  • Sodium triacetoxyborohydride (70 g, 330 mmol) was added portionwise, and stirred at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was poured into 3 kg of ice water, extracted with 2 L of dichloromethane, and extracted with 1 L of dichloromethane.
  • Step 5 [7-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)) Ethyl]amino]methyl]benzotriazol-1-yl]propyl]-7-azaspiro[3.5]non-2-yl]2-hydroxy-2,2-bis(2-thienyl) Acetate (compound 1)
  • the compound 1 obtained by this method was subjected to a PXRD test, and the drawing is shown in Fig. 3.
  • the test methods and conditions were in agreement with the crystal of Compound 1 in Example 2.
  • Compound 1 obtained at this time was amorphous.
  • Method 2 Weigh about 15 mg of Compound 1 (prepared from Example 1) in a 3 ml vial, add 0.5 ml of isopropanol, magnetically stir at 500 ° C for 2 h at 50 ° C, and filter with a 0.45 ⁇ m PTFE filter. The supernatant. The obtained supernatant was cooled from 50 ° C to 5 ° C at a rate of 0.1 ° C / min and kept at a constant temperature of 5 ° C, and the precipitated solid was collected, which was a seed crystal of Compound 1.
  • Method 3 Weigh 1.0 g of Compound 1 (prepared from Example 1) in a 10 ml single-mouth bottle, add 1:1 (v/v) dichloromethane: isopropanol (1.8 mL), and warm to 40 ° C. The raw material was not completely dissolved. The mixture was stirred at this temperature for 8 hours, then allowed to stand for 3 days, the solution became cloudy, 3 ml of dichloromethane was added, stirred, filtered, and the filter cake was washed with 1 ml of dichloromethane to obtain a solid 1: light red. Solid 10 mg.
  • the filter cake was dried under vacuum at 50 ° C for 1 hour, then pulverized into a powder, and dried under vacuum at 70 ° C for 40 hours to give a crystalline compound 1 as a white solid (36 g, yield 53.7%, HPLC: 99.3%).
  • the crystal of Compound 1 and the seed crystal of Compound 1 were subjected to X-ray powder diffraction test as follows.
  • the crystal of Compound 1 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 of the crystal of Compound 1 is shown in Figure 2.

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Abstract

The present invention relates to a crystal form of a compound shown in formula (I) and a preparation method and medical use thereof. (I)

Description

一种苯并三氮唑衍生物的晶型及其制备方法和用途Crystal form of benzotriazole derivative, preparation method and use thereof 技术领域Technical field

本发明涉及一种苯并三氮唑衍生物的晶型及其制备方法和在医药上的用途。The present invention relates to a crystalline form of a benzotriazole derivative, a process for its preparation and its use in medicine.

背景技术Background technique

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。 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.

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。 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.

发明内容Summary of the invention

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苯并三氮唑衍生物晶型及其制备方法和在医药上的用途。 The present invention provides a crystalline form of a benzotriazole derivative having a dual action of muscarinic receptor antagonism and β 2 -adrenergic agonism, a preparation method thereof and use thereof in medicine.

本发明式(I)所示的化合物的结晶具有以下优点，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。The crystallization of the compound of the formula (I) of the present invention has the following advantages such as ease of processing and crystallization, convenient handling, ease of purification, ease of industrialization, good stability, good fluidity, easy micronization, etc., which make them particularly suitable for Made into an inhalation preparation.

本发明提供一种式(I)所示化合物的结晶，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：6.03°±0.2°、9.11°±0.2°、10.68°±0.2°、11.16°±0.2°、11.78°±0.2°、13.52°±0.2°、15.04°±0.2°、16.05°±0.2°、16.86°±0.2°、17.40°±0.2°、17.91°±0.2°、19.08°±0.2°、20.48°±0.2°、21.24°±0.2°、22.96°±0.2°、23.47°±0.2°、24.36°±0.2°、27.36°±0.2°；The present invention provides a crystal of a compound of the formula (I), which has a characteristic diffraction peak at the following 2θ position using Cu-Kα radiation: 6.03°±0.2°, 9.11°±0.2°, 10.68 °±0.2°, 11.16°±0.2°, 11.78°±0.2°, 13.52°±0.2°, 15.04°±0.2°, 16.05°±0.2°, 16.86°±0.2°, 17.40°±0.2°, 17.91°± 0.2°, 19.08°±0.2°, 20.48°±0.2°, 21.24°±0.2°, 22.96°±0.2°, 23.47°±0.2°, 24.36°±0.2°, 27.36°±0.2°;

Figure PCTCN2018113806-appb-000001
Figure PCTCN2018113806-appb-000001

本发明的一种实施方案，式(I)所示的化合物的结晶使用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：6.03°±0.2°、7.59°±0.2°、9.11°±0.2°、10.68°±0.2°、11.16°±0.2°、11.78°±0.2°、12.64°±0.2°、13.52°±0.2°、15.04°±0.2°、16.05°±0.2°、16.86°±0.2°、17.40°±0.2°、17.91°±0.2°、19.08°±0.2°、19.87°±0.2°、20.21°±0.2°、20.48°±0.2°、21.24°±0.2°、22.03°±0.2°、22.96°±0.2°、23.47°±0.2°、24.36°±0.2°、25.55°±0.2°、27.36°±0.2°、28.75°±0.2°、29.60°±0.2°、31.27°±0.2°、37.00°±0.2°。In one embodiment of the invention, the crystallization of the compound of formula (I) uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.03°±0.2°, 7.59°±0.2 °, 9.11 ° ± 0.2 °, 10.68 ° ± 0.2 °, 11.16 ° ± 0.2 °, 11.78 ° ± 0.2 °, 12.64 ° ± 0.2 °, 13.52 ° ± 0.2 °, 15.04 ° ± 0.2 °, 16.05 ° ± 0.2 °, 16.86°±0.2°, 17.40°±0.2°, 17.91°±0.2°, 19.08°±0.2°, 19.87°±0.2°, 20.21°±0.2°, 20.48°±0.2°, 21.24°±0.2°, 22.03° ±0.2°, 22.96°±0.2°, 23.47°±0.2°, 24.36°±0.2°, 25.55°±0.2°, 27.36°±0.2°, 28.75°±0.2°, 29.60°±0.2°, 31.27°±0.2 °, 37.00 ° ± 0.2 °.

本发明的一种实施方案，式(I)所示的化合物的结晶使用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：6.03°±0.2°、7.59°±0.2°、9.11°±0.2°、10.68°±0.2°、11.16°±0.2°、11.78°±0.2°、12.64°±0.2°、13.52°±0.2°、15.04°±0.2°、16.05°±0.2°、16.86°±0.2°、17.40°±0.2°、17.91°±0.2°、19.08°±0.2°、19.87°±0.2°、20.21°±0.2°、20.48°±0.2°、21.24°±0.2°、22.03°±0.2°、22.96°±0.2°、23.47°±0.2°、24.36°±0.2°、25.04°±0.2°、25.55°±0.2°、25.85°±0.2°、26.67°±0.2°、27.36°±0.2°、27.93°±0.2°、28.75°±0.2°、29.07°±0.2°、29.60°±0.2°、30.76°±0.2°、31.27°±0.2°、33.24°±0.2°、37.00°±0.2°。In one embodiment of the invention, the crystallization of the compound of formula (I) uses Cu-Kα radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.03°±0.2°, 7.59°±0.2 °, 9.11 ° ± 0.2 °, 10.68 ° ± 0.2 °, 11.16 ° ± 0.2 °, 11.78 ° ± 0.2 °, 12.64 ° ± 0.2 °, 13.52 ° ± 0.2 °, 15.04 ° ± 0.2 °, 16.05 ° ± 0.2 °, 16.86°±0.2°, 17.40°±0.2°, 17.91°±0.2°, 19.08°±0.2°, 19.87°±0.2°, 20.21°±0.2°, 20.48°±0.2°, 21.24°±0.2°, 22.03° ±0.2°, 22.96°±0.2°, 23.47°±0.2°, 24.36°±0.2°, 25.04°±0.2°, 25.55°±0.2°, 25.85°±0.2°, 26.67°±0.2°, 27.36°±0.2 °, 27.93 ° ± 0.2 °, 28.75 ° ± 0.2 °, 29.07 ° ± 0.2 °, 29.60 ° ± 0.2 °, 30.76 ° ± 0.2 °, 31.27 ° ± 0.2 °, 33.24 ° ± 0.2 °, 37.00 ° ± 0.2 °.

更进一步，式(I)所示的化合物结晶的X-射线粉末衍射图谱基本如附图1所示。Further, the X-ray powder diffraction pattern of the compound of the formula (I) is substantially as shown in Fig. 1.

本发明所述的式(I)所示的化合物结晶的差示扫描量热分析曲线(DSC)如附图2所示。A differential scanning calorimetry curve (DSC) of the crystal of the compound of the formula (I) according to the present invention is shown in Fig. 2.

式(I)所示的化合物的结晶，其差示扫描量热分析曲线(DSC)显示，其中T 开始＝166.9±3℃，T 峰＝171.3±3℃，其中，熔点温度为171.3±5℃。 The crystal of the compound of formula (I) has a differential scanning calorimetry curve (DSC) showing T start = 166.9 ± 3 ° C, T peak = 171.3 ± 3 ° C, wherein the melting point temperature is 171.3 ± 5 ° C .

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。因此，在一些实施方案中，本发明的结晶化合物的特征在于具有特征峰位置的DSC图，具有与本发明附图中提供的DSC图实质上相同的性质，误差容限为±3℃。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. Thus, in some embodiments, the crystalline compound of the present invention is characterized by a DSC pattern having a characteristic peak position having substantially the same properties as the DSC pattern provided in the drawings of the present invention with a margin of error of ±3 °C.

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

本发明提供一种药物组合物，包含治疗有效量的上述式(I)所示的化合物结晶，以及药学上可接受的载体或赋形剂；优选地，所述组合物被配制成吸入给药形式；优选地，所述的吸入给药形式选自干粉吸入制剂或气雾剂。The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound crystal of the above formula (I), and a pharmaceutically acceptable carrier or excipient; preferably, the composition is formulated for inhalation administration Form; preferably, the inhaled administration form is selected from a dry powder inhalation formulation or an aerosol.

本发明同时提供一种上述任一项式(I)所示的化合物结晶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。The present invention also provides the use of the compound crystal 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 obstructiveness Pulmonary disease or bronchitis.

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)所示的化合物结晶或其药物组合物，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。The present invention also provides a method for treating an airway obstructive disease, which comprises administering a compound crystal of any one of the above formula (I) or a pharmaceutical composition thereof, wherein the airway obstructive disease is preferably asthma, chronic obstruction Sexual lung disease or bronchitis.

本发明涉及式(I)所示化合物结晶的制备方法，所述方法为将式(I)所示化合物在溶剂中重结晶和/或打浆，所述的溶剂选自C 6-10芳烃类溶剂、C 5-10烷烃类溶剂、C 1-6卤代烷烃类溶剂、C 1-6醇类溶剂、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；优选所述的溶剂选自甲醇、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、乙酸乙酯、乙酸异丙酯、丙酮、乙醚、甲基叔丁基醚和水中的一种或多种；优选地重结晶时加入晶种。 The present invention relates to a process for the preparation of a crystal of a compound of the formula (I), which comprises recrystallizing and/or beating a compound of the formula (I) in a solvent selected from the group consisting of C 6-10 aromatic hydrocarbon solvents , C 5-10 alkane solvent, C 1-6 halogenated alkane solvent, C 1-6 alcohol solvent, C 2-6 ester solvent, C 2-6 ether solvent, C 1-6 ketone solvent and One or more of the water; preferably the solvent is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, One or more of isopropyl acetate, acetone, diethyl ether, methyl tert-butyl ether, and water; preferably seed crystals are added upon recrystallization.

本发明关于式(I)所示化合物结晶的制备方法的一种实施方案，重结晶和/或打浆的溶剂选自甲苯、正庚烷、正己烷、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、乙酸乙酯、乙酸异丙酯、丙酮、乙醚、甲基叔丁基醚和水中的一种或多种。According to one embodiment of the process for the preparation of the crystallization of the compound of the formula (I), the solvent for recrystallization and/or beating is selected from the group consisting of toluene, n-heptane, n-hexane, methanol, ethanol, isopropanol, dichloromethane. One or more of 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, diethyl ether, methyl tert-butyl ether and water.

本发明关于式(I)所示化合物结晶的制备方法的一种实施方案，重结晶和/或打浆的温度为0℃～回流；优选0～80℃；更优选20～60℃；进一步优选20～40℃。The present invention relates to an embodiment of the process for producing a crystal of the compound of the formula (I), wherein the temperature for recrystallization and/or beating is from 0 ° C to reflux; preferably from 0 to 80 ° C; more preferably from 20 to 60 ° C; further preferably 20 ~40 ° C.

本发明关于式(I)所示化合物结晶的制备方法的一种实施方案，所述的溶剂选自二氯甲烷和异丙醇的混合溶剂；其体积比优选5:1～1:5；更优选2:1～1:2；进一步优选1:1；重结晶和/或打浆的温度优选20～60℃；更优选20～40℃。The present invention relates to an embodiment of the preparation method of the crystal of the compound represented by the formula (I), wherein the solvent is selected from the group consisting of a mixed solvent of dichloromethane and isopropanol; and the volume ratio thereof is preferably 5:1 to 1:5; It is preferably 2:1 to 1:2; further preferably 1:1; the temperature for recrystallization and/or beating is preferably 20 to 60 ° C; more preferably 20 to 40 ° C.

本发明提供一种式(I)所示化合物的制备方法，The present invention provides a method for preparing a compound represented by the formula (I),

Figure PCTCN2018113806-appb-000002
Figure PCTCN2018113806-appb-000002

将式(II)所示化合物溶于C 1-6醇类溶剂中，在脱硅醚试剂存在下反应，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。 Dissolving the compound of the formula (II) in a C 1-6 alcohol solvent and reacting in the presence of a desilicon ether reagent, preferably tetrabutylammonium fluoride or a hydrate thereof, triethylamine Trihydrofluoride or pyridine hydrofluoride.

本发明关于式(I)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。The present invention relates to an embodiment of the process for the preparation of the compound of the formula (I), wherein the desilicon ether reagent is selected from the group consisting of tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridinium hydrogen Fluorate.

本发明关于式(I)所示化合物的制备方法的一种实施方案，C 1-6醇类溶剂选自甲醇、乙醇和异丙醇中的一种或多种；反应的温度优选0～60℃；更优选20～60℃；更优选20～50℃。 The present invention relates to an embodiment of the preparation method of the compound of the formula (I), wherein the C 1-6 alcohol solvent is one or more selected from the group consisting of methanol, ethanol and isopropanol; and the reaction temperature is preferably 0 to 60. °C; more preferably 20 to 60 ° C; more preferably 20 to 50 ° C.

本发明关于式(I)所示化合物的制备方法的一种实施方案，脱硅醚试剂与式(II)所示化合 物的摩尔比0.8:1～1:2；优选1:1；所述脱硅醚试剂优选三乙胺三氢氟酸盐；反应的温度优选0～60℃；更优选20～60℃；更优选20～50℃。An embodiment of the method for preparing a compound of the formula (I), wherein the molar ratio of the desilicon ether reagent to the compound of the formula (II) is from 0.8:1 to 1:2; preferably 1:1; The silyl ether reagent is preferably triethylamine trihydrofluoride; the temperature of the reaction is preferably 0 to 60 ° C; more preferably 20 to 60 ° C; more preferably 20 to 50 ° C.

本发明还涉及一种式(II)所示化合物的制备方法，The invention also relates to a method for preparing a compound represented by the formula (II),

Figure PCTCN2018113806-appb-000003
Figure PCTCN2018113806-appb-000003

式(III)所示化合物与式(VI)所示化合物在还原剂存在下进行；The compound of the formula (III) and the compound of the formula (VI) are carried out in the presence of a reducing agent;

HA选自有机酸或无机酸；优选HF、HBr、HCl、CH 3COOH、苯磺酸或对甲基苯磺酸。 HA is selected from organic or inorganic acids; preferably HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.

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。In one embodiment of the process of the invention for the preparation of a 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.

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℃；In one embodiment of the process for the preparation of the compound of formula (II), the solvent of the reaction is selected from the group consisting of polar solvents; 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;

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

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。Alternatively, the reaction is optionally carried out in the presence of an acidic catalyst; preferably the acid catalyst is one or more of formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and zinc chloride. .

本发明关于式(II)所示化合物的制备方法的一种实施方案，还原剂与式(III)所示化合物的摩尔比为1:1～1:3；优选1:1～1:2；还原剂优选三(乙酰氧基)硼氢化钠；反应的温度优选0～60℃；更优选0～40℃；反应任选地在分子筛和乙酸(与式(III)所示化合物的摩尔比为0.2:1～0.5:1)存在下进行。The present invention relates to a method for preparing the compound of the formula (II), the molar ratio of the reducing agent to the compound of the formula (III) is 1:1 to 1:3; preferably 1:1 to 1:2; The reducing agent is preferably sodium tris(acetoxy)borohydride; the temperature of the reaction is preferably 0 to 60 ° C; more preferably 0 to 40 ° C; the reaction optionally in the molecular sieve and acetic acid (the molar ratio of the compound represented by the formula (III) is 0.2:1 to 0.5:1) is carried out in the presence.

一种式(IV)所示化合物的制备方法，a method for preparing a compound of the formula (IV),

Figure PCTCN2018113806-appb-000004
Figure PCTCN2018113806-appb-000004

反应在金属催化剂和三乙基硅烷存在下进行；The reaction is carried out in the presence of a metal catalyst and triethylsilane;

HA选自HF、HBr、HCl、CH 3COOH、苯磺酸或对甲基苯磺酸。 HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.

本发明关于式(IV)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； The present invention relates to an embodiment of the preparation method of the compound of the formula (IV), wherein the solvent in the reaction is selected from a C 1-6 alcohol solvent; preferably methanol or ethanol;

所述的金属催化剂选自钯黑、钯/碳、氢氧化钯/碳、氯化钯/碳、兰尼镍、铂/碳或氧化铂；The metal catalyst is selected from the group consisting of palladium black, palladium/carbon, palladium hydroxide/carbon, palladium chloride/carbon, Raney nickel, platinum/carbon or platinum oxide;

反应的温度优选0℃至回流；更优选0～40℃；。The temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 0 to 40 ° C;

本发明关于式(IV)所示化合物的制备方法的一种实施方案，反应结束后，反应液过滤，滤液浓缩得到浓缩物，浓缩物溶于有机溶剂中，加入HA，生成式(IV)所示化合物；所述有机溶剂优选极性溶剂；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。The present invention relates to an embodiment of the preparation method of the compound of the formula (IV). After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated to obtain a concentrate. The concentrate is dissolved in an organic solvent, and HA is added to form a formula (IV). a compound; the organic solvent is preferably a polar solvent; preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl uncle One or more of butyl ether, methanol, ethanol, isopropanol, acetamide, N,N-dimethylacetamide, N,N-dimethylformamide, and dimethyl sulfoxide.

本发明关于式(IV)所示化合物的制备方法的一种实施方案，金属催化剂(优选钯/碳)与式(IV)所示化合物的质量比优选为1:1～1:100；更优选1:1～1:10；更优选1:1～1:5；In one embodiment of the process for the preparation of the compound of the formula (IV), the mass ratio of the metal catalyst (preferably palladium/carbon) to the compound of the formula (IV) is preferably from 1:1 to 1:100; more preferably 1:1 to 1:10; more preferably 1:1 to 1:5;

三乙基硅烷与式(IV)所示化合物的摩尔比优选为20:1～1:1；更优选10:1～1:1；更优选5:1～1:1；The molar ratio of triethylsilane to the compound of the formula (IV) is preferably from 20:1 to 1:1; more preferably from 10:1 to 1:1; more preferably from 5:1 to 1:1;

反应的温度优选0℃～回流；更优选0℃～40℃。The temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 0 ° C to 40 ° C.

本发明的一种实施方案，式(IV)所示化合物通过重结晶纯化；重结晶的溶剂优选2-甲基四氢呋喃或/和四氢呋喃。重结晶后得到的产品纯度高，纯化简单，易于工业化。In one embodiment of the invention, the compound of formula (IV) is purified by recrystallization; the solvent for recrystallization is preferably 2-methyltetrahydrofuran or/and tetrahydrofuran. The product obtained after recrystallization has high purity, simple purification and easy industrialization.

本发明涉及一种制备式(V)所示化合物的方法，The present invention relates to a process for the preparation of a compound of formula (V),

Figure PCTCN2018113806-appb-000005
Figure PCTCN2018113806-appb-000005

式(VI)所示化合物在碱性试剂存在下反应。The compound of the formula (VI) is reacted in the presence of an alkaline reagent.

本发明关于式(V)所示化合物的制备方法的一种实施方案，所述的碱性试剂选自氢氧化钾、氢氧化钠、氢氧化锂、乙酸锂、氟化钾、氟化铯、碳酸铯、碳酸钾、乙酸钾和1,8-二氮杂二环十一碳-7-烯中的一种或多种；The present invention relates to an embodiment of the preparation method of the compound represented by the formula (V), wherein the alkaline agent is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium acetate, potassium fluoride, cesium fluoride, One or more of cesium carbonate, potassium carbonate, potassium acetate, and 1,8-diazabicycloundec-7-ene;

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 2-6酯类溶剂、C 2-6醚类溶剂、C 1-6酮类溶剂、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜和水中的一种或多种；优选二氯甲烷、氯仿、1,2-二氯甲烷、甲醇、乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、乙醚、甲基叔丁基醚、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和水中的一种或多种； The solvent to be reacted is selected from the group consisting of a C 1-6 halogenated alkane solvent, a C 1-6 alcohol solvent, a C 2-6 ester solvent, a C 2-6 ether solvent, a C 1-6 ketone solvent, N, N- One or more of dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and water; preferably dichloromethane, chloroform, 1,2-dichloromethane, methanol, ethanol, iso Propyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetone, N,N-dimethylformamide, N,N-dimethylacetamide And one or more of the water;

反应的温度优选0℃～回流；更优选20℃～80℃。The temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 20 ° C to 80 ° C.

本发明提供一种式(I)所示化合物的制备方法，该方法包括如下步骤：The invention provides a preparation method of the compound represented by the formula (I), which comprises the following steps:

Figure PCTCN2018113806-appb-000006
Figure PCTCN2018113806-appb-000006

其中：among them:

HA选自HF、HBr、HCl、CH 3COOH、苯磺酸或对甲基苯磺酸。 HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.

(1)、式(VI)所示化合物在碱性试剂存在下生成式(V)所示化合物，反应的溶剂选自N,N-二甲基甲酰胺和水中的一种或两种的混合，所述的碱性试剂选自氢氧化锂；反应的温度优选20℃～80℃；(1) A compound of the formula (VI) is formed in the presence of an alkaline reagent to form a compound of the formula (V), and the solvent to be reacted is selected from the group consisting of a mixture of N,N-dimethylformamide and one or two of water. The alkaline agent is selected from lithium hydroxide; the temperature of the reaction is preferably from 20 ° C to 80 ° C;

(2)、式(V)所示化合物在钯/碳和三乙基硅烷存在下生成式(IV)所示化合物，反应的溶剂选自乙醇；反应的温度优选0～40℃；(2), the compound of the formula (V) in the presence of palladium / carbon and triethyl silane to form a compound of formula (IV), the solvent of the reaction is selected from ethanol; the reaction temperature is preferably 0 ~ 40 ° C;

(3)、式(IV)所示化合物与式(III)所示化合物在三(乙酰氧基)硼氢化钠存在下反应生成式(II)所示化合物，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的混合，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的混合；反应的温度优选0～40℃；(3) A compound of the formula (IV) is reacted with a compound of the formula (III) in the presence of sodium tris(acetoxy)borohydride to form a compound of the formula (II), and the solvent of the reaction is selected from the group consisting of dimethyl a mixture of one or more of sulfone, dichloromethane, isopropanol, acetonitrile and acetamide. Alternatively, a molecular sieve is added to the reaction. Alternatively, one or two of acetic acid and zinc chloride are added to the reaction. Mixing; the temperature of the reaction is preferably 0 to 40 ° C;

(4)、式(II)所示化合物在三乙胺三氢氟酸盐存在下生成式(I)所示化合物，反应的溶剂选自乙醇；反应的温度优选0～60℃；(4), the compound of the formula (II) in the presence of triethylamine trihydrofluoride to form a compound of the formula (I), the solvent of the reaction is selected from ethanol; the reaction temperature is preferably 0 to 60 ° C;

本发明提供一种式(IV)所示化合物：The present invention provides a compound of the formula (IV):

Figure PCTCN2018113806-appb-000007
Figure PCTCN2018113806-appb-000007

HA选自HF、HBr、HCl、甲磺酸或对甲苯磺酸。HA is selected from HF, HBr, HCl, methanesulfonic acid or p-toluenesulfonic acid.

附图说明DRAWINGS

图1：化合物1结晶的X-射线粉末衍射图谱。Figure 1: X-ray powder diffraction pattern of Compound 1 crystals.

图2：化合物1结晶的差示扫描量热分析曲线图谱。Figure 2: Differential scanning calorimetry curve of compound 1 crystals.

图3：化合物1无定形的X-射线粉末衍射图谱。Figure 3: Amorphous X-ray powder diffraction pattern of Compound 1.

图4：化合物1晶种的X-射线粉末衍射图谱。Figure 4: X-ray powder diffraction pattern of Compound 1 seed crystals.

具体实施方式Detailed ways

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。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.

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)。 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).

MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。The measurement of MS was carried out (Agilent 6120B (ESI) and 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)。The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).

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。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.

实施例中无特殊说明，溶液是指水溶液。Unless otherwise stated in the examples, the solution means an aqueous solution.

实施例中无特殊说明，室温为20℃～30℃。There is no particular description in the examples, and the room temperature is 20 ° C to 30 ° C.

实施例1：化合物1的制备Example 1: Preparation of Compound 1

Figure PCTCN2018113806-appb-000008
Figure PCTCN2018113806-appb-000008

Figure PCTCN2018113806-appb-000009
Figure PCTCN2018113806-appb-000009

第一步：7-[(1R)-2-叠氮基-1-[叔丁基(二甲基)甲硅烷基]氧基乙基]-4-[叔丁基(二甲基)甲硅烷基]氧基-3H-1,3-苯并噻唑-2-酮(1B)First step: 7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)-methyl Silyl]oxy-3H-1,3-benzothiazol-2-one (1B)

7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- One

将1A(100g,396.82mmol，参考WO2009098448A1制备得到)溶于N,N-二甲基甲酰胺(1L)中，加入咪唑(215.87g,3.174mol)，再分批加入叔丁基二甲基氯硅烷(239.3g,1.59mol)，加完后65℃反应2小时。将反应冷却至室温，倒入4L冰水中，并用乙酸乙酯萃取(3L×2)，合并有机相,有机相用水洗涤两次(4L×2)，饱和食盐水溶液(2L)洗涤一次，无水硫酸钠干燥，减压浓缩，残留物用石油醚500mL打浆一次，过滤后固体用红外灯干燥后即得1B，白色固体(175g,产率:92％)。1A (100 g, 396.82 mmol, prepared according to WO2009098448A1) was dissolved in N,N-dimethylformamide (1 L), imidazole (215.87 g, 3.174 mol) was added, and t-butyldimethyl chloride was added in portions. Silane (239.3 g, 1.59 mol) was reacted at 65 ° C for 2 hours after the addition. The reaction was cooled to room temperature, poured into 4 L of ice water, and extracted with ethyl acetate (3L×2). The organic phase was combined, the organic phase was washed twice with water (4L×2), and brine (2L) The organic layer was dried over sodium sulfate, and evaporated, evaporated, evaporated, evaporated.

1H NMR(400MHz,CDCl 3)δ8.22(s,1H),6.92(d,1H),6.71(d,1H),4.79–4.75(m,1H),3.44–3.38(m,1H),3.27–3.22(m,1H),1.04(s,9H),0.91(s,9H),0.29(d,6H),0.12(d,3H),-0.04(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.22 (s, 1H), 6.92 (d, 1H), 6.71 (d, 1H), 4.79-4.75 (m, 1H), 3.44-3.38 (m, 1H), 3.27–3.22 (m, 1H), 1.04 (s, 9H), 0.91 (s, 9H), 0.29 (d, 6H), 0.12 (d, 3H), -0.04 (d, 3H).

第二步：7-[(1R)-2-叠氮基-1-[叔丁基(二甲基)甲硅烷基]氧基乙基]-4-羟基-3H-1,3-苯并噻唑-2-酮(1C)Second step: 7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-hydroxy-3H-1,3-benzo Thiazol-2-one (1C)

7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one

将1B(175g,364.58mmol)溶于N,N-二甲基甲酰胺(875mL)和水(175mL)中，加入氢氧化锂(87.5g,3.645mol)，65℃反应2小时。将反应液冷却至室温，并缓慢倒入4L冰水中，加入柠檬酸一水合物调节至pH为3～4，用乙酸乙酯萃取(2L×2)，合并有机相，有机相依次用水、饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到1C，白色固 体(100g,74.94％)。1B (175 g, 364.58 mmol) was dissolved in N,N-dimethylformamide (875 mL) and water (175 mL), and lithium hydroxide (87.5 g, 3.645 mol) was added and reacted at 65 ° C for 2 hours. The reaction solution was cooled to room temperature, and slowly poured into 4 L of ice water, adjusted to pH 3-4 by adding citric acid monohydrate, extracted with ethyl acetate (2 L × 2), and the organic phase was combined, and the organic phase was sequentially washed with water and saturated. The organic layer was washed with EtOAc (EtOAc m.

1H NMR(400MHz,CDCl 3)δ10.11(s,1H),6.99(d,1H),6.89(d,1H),4.85–4.81(m,1H),3.47–3.39(m,1H),3.31–3.24(m,1H),0.94(s,9H),0.15(s,3H),0.01(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ10.11 (s, 1H), 6.99 (d, 1H), 6.89 (d, 1H), 4.85-4.81 (m, 1H), 3.47-3.39 (m, 1H), 3.31–3.24 (m, 1H), 0.94 (s, 9H), 0.15 (s, 3H), 0.01 (s, 3H).

LC-MS m/z＝367.2[M+1]。LC-MS m/z = 367.2 [M + 1].

第三步：7-[(1R)-2-氨基-1-[叔丁基(二甲基)甲硅烷基]氧基乙基]-4-羟基-3H-1,3-苯并噻唑-2-酮，乙酸盐(1D)Third step: 7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-hydroxy-3H-1,3-benzothiazole- 2-ketone, acetate (1D)

7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one,acetic acid7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one,acetic acid

将1C(100g,273.22mmol)溶于乙醇1L中，加入50％(w/w)钯碳50g，0℃氮气保护下缓慢滴加三乙基硅烷(95.31g,819.67mmol)，滴完后升至室温反应1.5小时。反应液用硅藻土过滤，并用乙醇300mL洗涤固体残留物，滤液减压浓缩，后残留物用四氢呋喃600mL溶解，并加入乙酸(49.18g,819.67mmol)，室温反应30min。将甲基叔丁基醚2.5L缓慢倒入反应液，析出大量固体，过滤，滤饼用2-甲基四氢呋喃800mL和四氢呋喃200mL溶解，85℃回流反应1小时，缓慢冷却至室温，并放置过夜，过滤析出的固体，固体用红外灯干燥后即得1D，灰色固体(75g，产率71.49％，HPLC 99.36％)。1C (100g, 273.22mmol) was dissolved in 1L of ethanol, 50% (w/w) palladium carbon 50g was added, and triethylsilane (95.31g, 819.67mmol) was slowly added dropwise under the protection of nitrogen at 0 °C. The reaction was allowed to reach room temperature for 1.5 hours. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc.EtOAc. 2.5 L of methyl tert-butyl ether was slowly poured into the reaction solution, a large amount of solid was precipitated, and the filter cake was dissolved in 800 mL of 2-methyltetrahydrofuran and 200 mL of tetrahydrofuran. The mixture was refluxed at 85 ° C for 1 hour, slowly cooled to room temperature, and left overnight. The precipitated solid was filtered, and the solid was dried with an infrared lamp to yield 1D, a gray solid (75 g, yield 71.49%, HPLC 99.36%).

1H NMR(400MHz,DMSO-d6)δ6.84(d,1H),6.69(d,1H),4.59–4.56(m,1H),2.76–2.71(m,1H),2.65-2.61(m,1H),1.88(s,3H),0.84(s,9H),0.04(s,3H),-0.12(s,3H)。 1 H NMR (400MHz, DMSO- d6) δ6.84 (d, 1H), 6.69 (d, 1H), 4.59-4.56 (m, 1H), 2.76-2.71 (m, 1H), 2.65-2.61 (m, 1H), 1.88 (s, 3H), 0.84 (s, 9H), 0.04 (s, 3H), -0.12 (s, 3H).

LC-MS m/z＝363.1[M+23]。LC-MS m/z = 363.1 [M+23].

第四步：7-[(1R)-2-叠氮基-1-[叔丁基(二甲基)甲硅烷基]氧基乙基]-4-[叔丁基(二甲基)甲硅烷基]氧基-3H-1,3-苯并噻唑-2-酮(1F)Fourth step: 7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)-methyl Silyl]oxy-3H-1,3-benzothiazol-2-one (1F)

7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- One

将1D(70g,176mmol)加入250mL DMSO和200mL异丙醇中，搅拌下加入1E(70g,117mmol,参考WO2017012489A1合成)、4A分子筛70g和乙酸(3.5g,58.5mmol)，加完后搅拌2小时。分批加入三乙酰氧基硼氢化钠(70g,330mmol)，加完后室温搅拌12小时。反应完毕后将反应液倒入3kg冰水中，2L二氯甲烷萃取一次，1L二氯甲烷萃取一次，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱色谱分离提纯(洗脱剂为甲醇：二氯甲烷(v:v)＝1％-2.5％)得化合物1F，淡黄色固体(90g,产率83.1％)。1D (70 g, 176 mmol) was added to 250 mL of DMSO and 200 mL of isopropanol, and 1E (70 g, 117 mmol, synthesized with reference to WO2017012489A1), 4A molecular sieve 70 g, and acetic acid (3.5 g, 58.5 mmol) were added with stirring, and stirred for 2 hours after the addition. . Sodium triacetoxyborohydride (70 g, 330 mmol) was added portionwise, and stirred at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was poured into 3 kg of ice water, extracted with 2 L of dichloromethane, and extracted with 1 L of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. Purification (eluent: methanol: methylene chloride (v: v) = 1% to 2.%) gave Compound 1F as pale yellow solid (90 g, yield 83.1%).

1H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.74(d,1H),7.50–7.40(m,3H),7.25(s,1H),7.11–7.04(m,2H),7.02–6.93(m,2H),6.87(d,1H),6.69(d,1H),5.01(quint,1H),4.73(dd,1H),4.67(t,2H),3.84(s,2H),2.82–2.56(m,2H),2.29–1.95(m,10H),1.76–1.63(m,2H),1.52–1.36(m,4H),0.82(s,9H),0.02(s,3H),-0.13(s,3H)。 1 H NMR (400MHz, DMSO- d6) δ7.84 (s, 1H), 7.74 (d, 1H), 7.50-7.40 (m, 3H), 7.25 (s, 1H), 7.11-7.04 (m, 2H) , 7.02–6.93 (m, 2H), 6.87 (d, 1H), 6.69 (d, 1H), 5.01 (quint, 1H), 4.73 (dd, 1H), 4.67 (t, 2H), 3.84 (s, 2H) ), 2.82–2.56 (m, 2H), 2.29–1.95 (m, 10H), 1.76–1.63 (m, 2H), 1.52–1.36 (m, 4H), 0.82 (s, 9H), 0.02 (s, 3H) ), -0.13 (s, 3H).

LCMS m/z＝438.2[(M+2)/2]。LCMS m/z = 438.2 [(M+2)/2].

第五步：[7-[3-[5-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]苯并三唑-1-基]丙基]-7-氮杂螺[3.5]壬-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物1)Step 5: [7-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)) Ethyl]amino]methyl]benzotriazol-1-yl]propyl]-7-azaspiro[3.5]non-2-yl]2-hydroxy-2,2-bis(2-thienyl) Acetate (compound 1)

[7-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]benzotriazol-1-yl]propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]benzotriazol -1-yl]propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate

将1F(90g,103mmol)加入800mL无水乙醇中，然后加入三乙胺三氢氟酸盐(240g,103mmol)，加完后升温至40℃搅拌6小时。搅拌下，将反应液倒入2L的无水乙醇中，加入2L石油醚，过滤析出的固体。向固体中加入1L乙醇，搅拌打浆1小时，过滤得微黄色固体。向所得固体中加入300mL二甲基亚砜，加热到40℃溶解得到溶液1。在另一容器中加入300mL饱和碳酸氢钠水溶液和2L水，冷却<10℃，搅拌下缓慢加入溶液1，搅拌30分钟，过滤。将滤饼用3L 15％甲醇/二氯甲烷(v/v)溶解，用1L水洗涤两次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。将浓缩物用1000mL二氯甲烷溶解，搅拌下缓慢加入1000mL甲基叔丁基醚，加完后继续搅拌30分钟，过滤得化合物1，浅黄色固体(60g，产率76.6％)。1F (90 g, 103 mmol) was added to 800 mL of absolute ethanol, and then triethylamine trihydrofluoric acid salt (240 g, 103 mmol) was added. After the addition, the mixture was warmed to 40 ° C and stirred for 6 hours. The mixture was poured into 2 L of absolute ethanol with stirring, 2 L of petroleum ether was added, and the precipitated solid was filtered. 1 L of ethanol was added to the solid, and the mixture was stirred for 1 hour, and filtered to give a pale yellow solid. To the obtained solid, 300 mL of dimethyl sulfoxide was added, and the mixture was heated to 40 ° C to dissolve to obtain a solution 1. In a separate vessel, 300 mL of a saturated aqueous solution of sodium hydrogencarbonate and 2 L of water were added, and the mixture was cooled <10 ° C, and the solution 1 was slowly added with stirring, stirred for 30 minutes, and filtered. The filter cake was dissolved with 3 L of 15% methanol / dichloromethane (v / v). The concentrate was dissolved in 1000 mL of dichloromethane, and 1000 mL of methyl tert-butyl ether was slowly added with stirring. After the addition was completed, stirring was continued for 30 minutes, and the compound 1 was obtained as a pale yellow solid (60 g, yield 76.6%).

1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.76(d,1H),7.49(dd,1H),7.46(dd,2H),7.25(s,1H),7.11–7.03(m,2H),7.00–6.95(m,2H),6.86(d,1H),6.68(d,1H),5.01(quint,1H),4.72–4.58(m,3H),3.87(s,2H),3.08(s,2H),2.74–2.57(m,2H),2.26–2.08(m,8H),2.08–1.98(m,2H),1.76–1.64(m,2H),1.53–1.35(m,4H)。 1 H NMR (400MHz, DMSO- d6) δ7.90 (s, 1H), 7.76 (d, 1H), 7.49 (dd, 1H), 7.46 (dd, 2H), 7.25 (s, 1H), 7.11-7.03 (m, 2H), 7.00–6.95 (m, 2H), 6.86 (d, 1H), 6.68 (d, 1H), 5.01 (quint, 1H), 4.72–4.58 (m, 3H), 3.87 (s, 2H) ), 3.08(s, 2H), 2.74–2.57 (m, 2H), 2.26–2.08 (m, 8H), 2.08–1.98 (m, 2H), 1.76–1.64 (m, 2H), 1.53–1.35 (m) , 4H).

LCMS m/z＝381.1[(M+2)/2]。LCMS m/z = 381.1 [(M+2)/2].

将由此方法得到的化合物1进行PXRD测试，其附图如图3所示。测试方法与条件与实施例2中化合物1结晶一致。此时得到的化合物1为无定型。The compound 1 obtained by this method was subjected to a PXRD test, and the drawing is shown in Fig. 3. The test methods and conditions were in agreement with the crystal of Compound 1 in Example 2. Compound 1 obtained at this time was amorphous.

实施例2：化合物1结晶的制备Example 2: Preparation of Compound 1 Crystallization

化合物1晶种的制备方法：Preparation method of compound 1 seed crystal:

方法1：称量约20mg的化合物1(由实施例1制备得到)至1.5ml玻璃小瓶中，分别加入0.3ml的甲苯/四氢呋喃(v/v＝1:1)，得到悬浮液，室温搅拌5天后，离心收集得到固体，即为化合物1的晶种。Method 1: About 20 mg of Compound 1 (prepared from Example 1) was weighed into a 1.5 ml glass vial, and 0.3 ml of toluene/tetrahydrofuran (v/v = 1:1) was added thereto to obtain a suspension, which was stirred at room temperature. After the day, the solid was collected by centrifugation, which was the seed crystal of Compound 1.

方法2：称取约15mg的化合物1(由实施例1制备得到)于3ml小瓶中，加入0.5ml异丙醇，在50℃下以500RPM的速度磁力搅拌2h，用0.45微米PTFE滤头过滤取上清液。将所得上清液以0.1℃/min速度从50℃降温至5℃并在5℃恒温，收集析出的固体，即为化合物1的晶种。Method 2: Weigh about 15 mg of Compound 1 (prepared from Example 1) in a 3 ml vial, add 0.5 ml of isopropanol, magnetically stir at 500 ° C for 2 h at 50 ° C, and filter with a 0.45 μm PTFE filter. The supernatant. The obtained supernatant was cooled from 50 ° C to 5 ° C at a rate of 0.1 ° C / min and kept at a constant temperature of 5 ° C, and the precipitated solid was collected, which was a seed crystal of Compound 1.

方法3：称取1.0g的化合物1(由实施例1制备得到)于10ml单口瓶中，加入1:1(v/v)的二氯甲烷：异丙醇(1.8mL)，升温到40℃，原料没有完全溶清，该温度下搅拌8小时，然后静置3天，溶液变浑浊，加入3ml的二氯甲烷，搅拌，过滤，滤饼用1ml二氯甲烷洗 涤，得到固体1：浅红固体10mg。另取1.0g化合物1于10ml单口瓶中，加入1:1(v/v)的二氯甲烷：异丙醇(2.5mL)，升温到40℃，搅拌10分钟左右，样品完全溶清，加入固体15mg，保持40℃搅拌8小时，静置过夜，加入2ml二氯甲烷，升温到40℃，搅拌2小时，过滤，滤饼用3ml x 2的二氯甲烷洗涤，把所得滤饼50℃真空干燥1小时，得到类白色固体150mg，即为化合物1的晶种。Method 3: Weigh 1.0 g of Compound 1 (prepared from Example 1) in a 10 ml single-mouth bottle, add 1:1 (v/v) dichloromethane: isopropanol (1.8 mL), and warm to 40 ° C. The raw material was not completely dissolved. The mixture was stirred at this temperature for 8 hours, then allowed to stand for 3 days, the solution became cloudy, 3 ml of dichloromethane was added, stirred, filtered, and the filter cake was washed with 1 ml of dichloromethane to obtain a solid 1: light red. Solid 10 mg. Another 1.0 g of Compound 1 was placed in a 10 ml single-mouth bottle, and 1:1 (v/v) dichloromethane: isopropyl alcohol (2.5 mL) was added, the temperature was raised to 40 ° C, and the mixture was stirred for about 10 minutes. The sample was completely dissolved and added. 15 mg of solid, kept at 40 ° C for 8 hours, allowed to stand overnight, added 2 ml of dichloromethane, warmed to 40 ° C, stirred for 2 hours, filtered, and the filter cake was washed with 3 ml of x 2 dichloromethane, and the resulting cake was vacuumed at 50 ° C. After drying for 1 hour, 150 mg of an off-white solid was obtained, which was a seed crystal of Compound 1.

化合物1结晶的制备方法Method for preparing crystal of compound 1

将化合物1(67g)加入二氯甲烷与异丙醇的混合溶剂中(150mL,v/v＝1:1)，升温到40℃，搅拌30分钟左右至完全溶清，加入晶种1克，40℃搅拌10小时，然后静置过夜，加入30ml的二氯甲烷溶液，升温40℃，再搅拌5小时，过滤，滤饼用二氯甲烷(50ml x 2)洗涤。滤饼50℃真空干燥1小时，然后磨碎成粉状，70℃真空干燥40小时，得到有晶型化合物1，类白固体(36g，产率53.7％，HPLC:99.3％)。Compound 1 (67 g) was added to a mixed solvent of dichloromethane and isopropyl alcohol (150 mL, v/v = 1:1), and the temperature was raised to 40 ° C, stirred for about 30 minutes to completely dissolve, and 1 g of seed crystal was added. After stirring at 40 ° C for 10 hours, it was allowed to stand overnight, 30 ml of a dichloromethane solution was added, the temperature was raised to 40 ° C, stirred for 5 hours, filtered, and the filter cake was washed with dichloromethane (50 ml x 2). The filter cake was dried under vacuum at 50 ° C for 1 hour, then pulverized into a powder, and dried under vacuum at 70 ° C for 40 hours to give a crystalline compound 1 as a white solid (36 g, yield 53.7%, HPLC: 99.3%).

将化合物1结晶和化合物1的晶种按照如下方法进行X-射线粉末衍射测试The crystal of Compound 1 and the seed crystal of Compound 1 were subjected to X-ray powder diffraction test as follows.

用PANalytical X射线衍射仪X’pertpowder型(PANalytical B.V.，荷兰)，使用Cu Kα辐射，在

Figure PCTCN2018113806-appb-000010
(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。将接受时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铺平表面以用于测试。该仪器每周用仪器自带的硅质标准样品片标定，至±0.02°的2θ角的偏差范围内。 Using a PANalytical X-ray diffractometer X'pertpowder type (PANalytical BV, The Netherlands), using Cu Ka radiation,
Figure PCTCN2018113806-appb-000010
(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. Samples that were ground to a fine powder as received were lightly loaded onto a grooved custom glass sample plate and the surface was flattened for testing. The instrument is calibrated weekly with a standard silicon sample sample that comes with the instrument to within ±200° of the 2θ angle.

化合物1结晶的X-射线粉末衍射图谱附图1所示。峰值如表1所示。The X-ray powder diffraction pattern of Compound 1 crystal is shown in Figure 1. The peak value is shown in Table 1.

表1Table 1

Figure PCTCN2018113806-appb-000011
Figure PCTCN2018113806-appb-000011

Figure PCTCN2018113806-appb-000012
Figure PCTCN2018113806-appb-000012

将化合物1结晶按照如下方法进行差示扫描量热分析测试The crystal of Compound 1 was subjected to differential scanning calorimetry analysis as follows.

使用NETZSCH DSC 214Polyma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℃。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.

化合物1结晶的DSC(差示扫描量热分析曲线)图谱图2所示。The DSC (differential scanning calorimetry curve) of the crystal of Compound 1 is shown in Figure 2.

化合物1结晶，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＝166.9℃，T 峰＝171.3℃。 Compound 1 crystallized and its differential scanning calorimetry curve (DSC) showed an endothermic curve with T start = 166.9 ° C and T peak = 171.3 ° C.

实施例3：化合物1结晶的稳定性试验Example 3: Stability test of Compound 1 crystal

样品放置：Sample placement:

取化合物1的无定形(实施例1制备得到)和化合物1结晶(使用与实施例2相同方法制备得到的另一批次)，分别按下表2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2。The amorphous form of Compound 1 (prepared in Example 1) and the crystal of Compound 1 (using another batch prepared in the same manner as in Example 2) were examined by inspecting the conditions and sampling time points of Table 2, respectively. The results of the investigation are shown in Table 2 below.

表2稳定性实验条件表Table 2 stability experimental conditions table

Figure PCTCN2018113806-appb-000013
Figure PCTCN2018113806-appb-000013

取样品适量，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0.25mg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；按下表3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。供试品溶液色谱图中如有杂质峰(扣除溶剂峰)，按峰面积归一化法计算。结果见表4。Take the appropriate amount of the sample, add the diluent [phosphate buffer (take sodium dihydrogen phosphate dihydrate 3.12g, add water 1000ml dissolved, adjust the pH value to 3.0 with phosphoric acid) - acetonitrile (80:20)] dissolved and diluted A solution containing about 0.25 mg per 1 ml was used 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; linear gradient elution as shown in Table 3 below 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. If there is an impurity peak (excluding the solvent peak) in the chromatogram of the test solution, it is calculated according to the peak area normalization method. The results are shown in Table 4.

表3化合物1结晶与无定形稳定性试验HPLC条件Table 3 Crystallographic and amorphous stability test of compound 1 HPLC conditions

Figure PCTCN2018113806-appb-000014
Figure PCTCN2018113806-appb-000014

表4化合物1结晶与无定形稳定性结果Table 4 Crystallization and amorphous stability results of Compound 1

Figure PCTCN2018113806-appb-000015
Figure PCTCN2018113806-appb-000015

结论：化合物1的结晶具有良好的稳定性。Conclusion: The crystal of Compound 1 has good stability.

Claims (26)

一种式(I)所示化合物的结晶，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：6.03°±0.2°、9.11°±0.2°、10.68°±0.2°、11.16°±0.2°、11.78°±0.2°、13.52°±0.2°、15.04°±0.2°、16.05°±0.2°、16.86°±0.2°、17.40°±0.2°、17.91°±0.2°、19.08°±0.2°、20.48°±0.2°、21.24°±0.2°、22.96°±0.2°、23.47°±0.2°、24.36°±0.2°、27.36°±0.2°A crystal of a compound of the formula (I), using Cu-Kα radiation, having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions: 6.03°±0.2°, 9.11°±0.2°, 10.68°±0.2 °, 11.16 ° ± 0.2 °, 11.78 ° ± 0.2 °, 13.52 ° ± 0.2 °, 15.04 ° ± 0.2 °, 16.05 ° ± 0.2 °, 16.86 ° ± 0.2 °, 17.40 ° ± 0.2 °, 17.91 ° ± 0.2 °, 19.08°±0.2°, 20.48°±0.2°, 21.24°±0.2°, 22.96°±0.2°, 23.47°±0.2°, 24.36°±0.2°, 27.36°±0.2°
Figure PCTCN2018113806-appb-100001
Figure PCTCN2018113806-appb-100001
 根据权利要求1所述的结晶，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：6.03°±0.2°、7.59°±0.2°、9.11°±0.2°、10.68°±0.2°、11.16°±0.2°、11.78°±0.2°、12.64°±0.2°、13.52°±0.2°、15.04°±0.2°、16.05°±0.2°、16.86°±0.2°、17.40°±0.2°、17.91°±0.2°、19.08°±0.2°、19.87°±0.2°、20.21°±0.2°、20.48°±0.2°、21.24°±0.2°、22.03°±0.2°、22.96°±0.2°、23.47°±0.2°、24.36°±0.2°、25.55°±0.2°、27.36°±0.2°、28.75°±0.2°、29.60°±0.2°、31.27°±0.2°、37.00°±0.2°。The crystal according to claim 1, wherein Cu-Kα radiation is used, and the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.03°±0.2°, 7.59°±0.2°, 9.11°±0.2°, 10.68. °±0.2°, 11.16°±0.2°, 11.78°±0.2°, 12.64°±0.2°, 13.52°±0.2°, 15.04°±0.2°, 16.05°±0.2°, 16.86°±0.2°, 17.40°± 0.2°, 17.91°±0.2°, 19.08°±0.2°, 19.87°±0.2°, 20.21°±0.2°, 20.48°±0.2°, 21.24°±0.2°, 22.03°±0.2°, 22.96°±0.2° 23.47°±0.2°, 24.36°±0.2°, 25.55°±0.2°, 27.36°±0.2°, 28.75°±0.2°, 29.60°±0.2°, 31.27°±0.2°, 37.00°±0.2°. 根据权利要求2所述的结晶，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：6.03°±0.2°、7.59°±0.2°、9.11°±0.2°、10.68°±0.2°、11.16°±0.2°、11.78°±0.2°、12.64°±0.2°、13.52°±0.2°、15.04°±0.2°、16.05°±0.2°、16.86°±0.2°、17.40°±0.2°、17.91°±0.2°、19.08°±0.2°、19.87°±0.2°、20.21°±0.2°、20.48°±0.2°、21.24°±0.2°、22.03°±0.2°、22.96°±0.2°、23.47°±0.2°、24.36°±0.2°、25.04°±0.2°、25.55°±0.2°、25.85°±0.2°、26.67°±0.2°、27.36°±0.2°、27.93°±0.2°、28.75°±0.2°、29.07°±0.2°、29.60°±0.2°、30.76°±0.2°、31.27°±0.2°、33.24°±0.2°、37.00°±0.2°。The crystallization according to claim 2, wherein Cu-Kα radiation is used, and the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.03°±0.2°, 7.59°±0.2°, 9.11°±0.2°, 10.68. °±0.2°, 11.16°±0.2°, 11.78°±0.2°, 12.64°±0.2°, 13.52°±0.2°, 15.04°±0.2°, 16.05°±0.2°, 16.86°±0.2°, 17.40°± 0.2°, 17.91°±0.2°, 19.08°±0.2°, 19.87°±0.2°, 20.21°±0.2°, 20.48°±0.2°, 21.24°±0.2°, 22.03°±0.2°, 22.96°±0.2° , 23.47 ° ± 0.2 °, 24.36 ° ± 0.2 °, 25.04 ° ± 0.2 °, 25.55 ° ± 0.2 °, 25.85 ° ± 0.2 °, 26.67 ° ± 0.2 °, 27.36 ° ± 0.2 °, 27.93 ° ± 0.2 °, 28.75 °±0.2°, 29.07°±0.2°, 29.60°±0.2°, 30.76°±0.2°, 31.27°±0.2°, 33.24°±0.2°, 37.00°±0.2°. 根据权利要求3所述的结晶，使用Cu-Kα辐射，其X-射线粉末衍射图谱如图1所示。The crystallization according to claim 3, using Cu-Kα radiation, the X-ray powder diffraction pattern of which is shown in Fig. 1. 根据权利要求1所述的结晶，所述结晶的差示扫描量热分析曲线如图2所示。The crystal according to claim 1, wherein the differential scanning calorimetry curve of the crystal is as shown in FIG. 一种药物组合物，包含治疗有效量的权利要求1～5中任一项所述的结晶，以及药学上可接受的载体或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of the crystal of any one of claims 1 to 5, and a pharmaceutically acceptable carrier or excipient. 根据权利要求6所述的药物组合物，其中所述组合物被配制成吸入给药形式，优选地，所述的吸入给药形式选自干粉吸入制剂或气雾剂。The pharmaceutical composition according to claim 6, wherein the composition is formulated into an inhaled administration form, preferably, the inhaled administration form is selected from a dry powder inhalation preparation or an aerosol. 权利要求1～5中任一项所述的结晶、或权利要求6～7中任一项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为哮喘、慢性阻塞性肺疾病或支气管炎。The use of the crystallization according to any one of claims 1 to 5, or the pharmaceutical composition according to any one of claims 6 to 7, for the preparation of a medicament for preventing and/or treating an airway obstructive disease, The airway obstructive disease is preferably asthma, chronic obstructive pulmonary disease or bronchitis. 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任意一项所述的结晶，或权利要求6～7中任一项所述的药物组合物；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。A method for treating an airway obstructive disease, the method comprising administering the crystal according to any one of claims 1 to 5, or the pharmaceutical composition according to any one of claims 6 to 7; the airway The obstructive disease is preferably asthma, chronic obstructive pulmonary disease or bronchitis. 一种如权利要求1所述的式(I)所示化合物结晶的制备方法，所述方法为将式(I)所示化合物在溶剂中重结晶和/或打浆，所述的溶剂选自C 6-10芳烃类溶剂、C 5-10烷烃类溶剂、C 1-6卤代烷烃类溶剂、C 1-6醇类溶剂、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的混合，任选地，重结晶时加入晶种。 A process for the preparation of a crystal of a compound of the formula (I) according to Claim 1 wherein the compound of the formula (I) is recrystallized and/or beaten in a solvent selected from the group consisting of C 6-10 aromatic hydrocarbon solvent, C 5-10 alkane solvent, C 1-6 halogenated alkane solvent, C 1-6 alcohol solvent, C 2-6 ester solvent, C 2-6 ether solvent, C 1 Mixing of -6 ketone solvent and one or more of water, optionally, seeding upon recrystallization. 根据权利要求10所述的制备方法，所述的溶剂选自甲苯、正庚烷、正己烷、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、乙酸乙酯、乙酸异丙酯、丙酮、乙醚、甲基叔丁基醚和水中的一种或多种的混合。The preparation method according to claim 10, wherein the solvent is selected from the group consisting of toluene, n-heptane, n-hexane, methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, Mixture of one or more of 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, diethyl ether, methyl tert-butyl ether, and water. 根据权利要求11所述的制备方法，重结晶和/或打浆的温度为0℃～回流，优选0～80℃，更优选20～60℃，进一步优选20～40℃。The process according to claim 11, wherein the temperature for recrystallization and/or beating is from 0 ° C to reflux, preferably from 0 to 80 ° C, more preferably from 20 to 60 ° C, still more preferably from 20 to 40 ° C. 一种式(I)所示化合物的制备方法，a method for preparing a compound of the formula (I),
Figure PCTCN2018113806-appb-100002
Figure PCTCN2018113806-appb-100002
 将式(II)所示化合物溶于C 1-6醇类溶剂中，在脱硅醚试剂存在下反应。 The compound of the formula (II) is dissolved in a C 1-6 alcohol solvent and reacted in the presence of a desilicon ether reagent. 根据权利要求13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。The process according to claim 13, wherein the desiliconized ether reagent is selected from the group consisting of tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridine hydrofluoride. 根据权利要求14所述的制备方法，C 1-6醇类溶剂选自甲醇、乙醇和异丙醇中的一种或多种的混合，反应的温度优选0～60℃。 The process according to claim 14, wherein the C 1-6 alcohol solvent is selected from the group consisting of methanol, ethanol and isopropanol, and the reaction temperature is preferably 0 to 60 ° C. 一种式(II)所示化合物的制备方法，a method for preparing a compound represented by the formula (II),
Figure PCTCN2018113806-appb-100003
Figure PCTCN2018113806-appb-100003
 式(III)所示化合物与式(VI)所示化合物在还原剂存在下进行；The compound of the formula (III) and the compound of the formula (VI) are carried out in the presence of a reducing agent; HA选自HF、HBr、HCl、CH 3COOH、苯磺酸或对甲基苯磺酸。 HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid. 根据权利要求16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。The process according to claim 16, 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. 根据权利要求17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的混合，反应的温度优选0～60℃；The process according to claim 17, 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 Mixing one or more kinds, the temperature of the reaction is preferably 0 to 60 ° C; 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；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; 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的混合。Alternatively, the reaction is optionally carried out in the presence of an acidic catalyst, preferably one or more of formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and zinc chloride. the mix of. 一种式(IV)所示化合物的制备方法，a method for preparing a compound of the formula (IV),
Figure PCTCN2018113806-appb-100004
Figure PCTCN2018113806-appb-100004
 反应在金属催化剂和三乙基硅烷存在下进行；The reaction is carried out in the presence of a metal catalyst and triethylsilane; HA选自HF、HBr、HCl、CH 3COOH、苯磺酸或对甲基苯磺酸。 HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid. 根据权利要求19所述的制备方法，所述的金属催化剂选自钯黑、钯/碳、氢氧化钯/碳、氯化钯/碳、兰尼镍、铂/碳或氧化铂；The method according to claim 19, wherein the metal catalyst is selected from the group consisting of palladium black, palladium/carbon, palladium hydroxide/carbon, palladium chloride/carbon, Raney nickel, platinum/carbon or platinum oxide; 反应的溶剂选自甲醇或乙醇；The solvent of the reaction is selected from methanol or ethanol; 反应的温度优选0℃至回流，更优选0～40℃。The temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 0 to 40 ° C. 根据权利要求19～20任一所述的制备方法，反应结束后，反应液过滤，滤液浓缩 得到浓缩物，浓缩物溶于有机溶剂中，加入HA，生成式(IV)所示化合物。The preparation method according to any one of claims 19 to 20, after the reaction is completed, the reaction liquid is filtered, and the filtrate is concentrated to obtain a concentrate. The concentrate is dissolved in an organic solvent, and HA is added to form a compound of the formula (IV). 根据权利要求21所述的制备方法，式(IV)所示化合物通过重结晶纯化，重结晶的溶剂优选2-甲基四氢呋喃或/和四氢呋喃。The process according to claim 21, wherein the compound of the formula (IV) is purified by recrystallization, and the solvent for recrystallization is preferably 2-methyltetrahydrofuran or/and tetrahydrofuran. 一种式(V)所示化合物的制备方法，a method for preparing a compound represented by the formula (V),
Figure PCTCN2018113806-appb-100005
Figure PCTCN2018113806-appb-100005
 式(VI)所示化合物在碱性试剂存在下反应。The compound of the formula (VI) is reacted in the presence of an alkaline reagent. 根据权利要求23所述的制备方法，所述的碱性试剂选自氢氧化钾、氢氧化钠、氢氧化锂、乙酸锂、氟化钾、氟化铯、碳酸铯、碳酸钾、乙酸钾和1,8-二氮杂二环十一碳-7-烯中的一种或多种的混合；The preparation method according to claim 23, wherein the alkaline agent is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium acetate, potassium fluoride, cesium fluoride, cesium carbonate, potassium carbonate, potassium acetate, and a mixture of one or more of 1,8-diazabicycloundec-7-ene; 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 2-6酯类溶剂、C 2-6醚类溶剂、C 1-6酮类溶剂、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜和水中的一种或多种的混合，优选二氯甲烷、氯仿、1,2-二氯甲烷、甲醇、乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃、乙醚、甲基叔丁基醚、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和水中的一种或多种的混合； The solvent to be reacted is selected from the group consisting of a C 1-6 halogenated alkane solvent, a C 1-6 alcohol solvent, a C 2-6 ester solvent, a C 2-6 ether solvent, a C 1-6 ketone solvent, N, N- Mixing one or more of dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and water, preferably dichloromethane, chloroform, 1,2-dichloromethane, methanol, ethanol , isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetone, N,N-dimethylformamide, N,N-dimethyl a mixture of acetamide and one or more of the water; 反应的温度优选0℃～回流，更优选20℃～80℃。The temperature of the reaction is preferably from 0 ° C to reflux, more preferably from 20 ° C to 80 ° C. 一种式(I)所示化合物的制备方法，该方法包括如下步骤：A method for preparing a compound of the formula (I), the method comprising the steps of:
Figure PCTCN2018113806-appb-100006
Figure PCTCN2018113806-appb-100006
Figure PCTCN2018113806-appb-100007
Figure PCTCN2018113806-appb-100007
 其中：among them: HA选自HF、HBr、HCl、CH 3COOH、苯磺酸或对甲基苯磺酸； HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid; (1)、式(VI)所示化合物在碱性试剂存在下生成式(V)所示化合物，反应的溶剂选自N,N-二甲基甲酰胺和水中的一种或两种的混合，所述的碱性试剂选自氢氧化锂，反应的温度优选20℃～80℃；(1) A compound of the formula (VI) is formed in the presence of an alkaline reagent to form a compound of the formula (V), and the solvent to be reacted is selected from the group consisting of a mixture of N,N-dimethylformamide and one or two of water. The alkaline reagent is selected from lithium hydroxide, and the reaction temperature is preferably 20 ° C to 80 ° C; (2)、式(V)所示化合物在钯/碳和三乙基硅烷存在下生成式(IV)所示化合物，反应的溶剂选自乙醇，反应的温度优选0～40℃；(2), the compound of the formula (V) in the presence of palladium / carbon and triethyl silane to form a compound of the formula (IV), the solvent of the reaction is selected from ethanol, the reaction temperature is preferably 0 ~ 40 ° C; (3)、式(IV)所示化合物与式(III)所示化合物在三(乙酰氧基)硼氢化钠存在下反应生成式(II)所示化合物，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的混合，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的混合，反应的温度优选0～40℃；(3) A compound of the formula (IV) is reacted with a compound of the formula (III) in the presence of sodium tris(acetoxy)borohydride to form a compound of the formula (II), and the solvent of the reaction is selected from the group consisting of dimethyl a mixture of one or more of sulfone, dichloromethane, isopropanol, acetonitrile and acetamide. Alternatively, a molecular sieve is added to the reaction. Alternatively, one or two of acetic acid and zinc chloride are added to the reaction. Mixing, the temperature of the reaction is preferably 0 to 40 ° C; (4)、式(II)所示化合物在三乙胺三氢氟酸盐存在下生成式(I)所示化合物，反应的溶剂选自乙醇，反应的温度优选0～60℃。(4) The compound of the formula (II) is formed into a compound of the formula (I) in the presence of triethylamine trihydrofluoride, and the solvent for the reaction is selected from the group consisting of ethanol, and the reaction temperature is preferably 0 to 60 °C. 一种(IV)所示化合物：a compound of the formula (IV):
Figure PCTCN2018113806-appb-100008
Figure PCTCN2018113806-appb-100008
 HA选自HF、HBr、HCl、甲磺酸或对甲苯磺酸。HA is selected from HF, HBr, HCl, methanesulfonic acid or p-toluenesulfonic acid.
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