WO2019237957A1 - 膦酰胺酯化合物及其盐和相关晶体形式、制备方法和用途 - Google Patents

膦酰胺酯化合物及其盐和相关晶体形式、制备方法和用途 Download PDF

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WO2019237957A1
WO2019237957A1 PCT/CN2019/089744 CN2019089744W WO2019237957A1 WO 2019237957 A1 WO2019237957 A1 WO 2019237957A1 CN 2019089744 W CN2019089744 W CN 2019089744W WO 2019237957 A1 WO2019237957 A1 WO 2019237957A1
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formula
compound
crystal
salt
fumarate
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PCT/CN2019/089744
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English (en)
French (fr)
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田强
王天明
刘伟
张保磊
赵明亮
梁玉峰
蔡家强
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to US17/047,000 priority Critical patent/US11186599B2/en
Priority to JP2020555846A priority patent/JP2021528363A/ja
Priority to CN201980025223.4A priority patent/CN111989335B/zh
Priority to EP19819653.7A priority patent/EP3808752A4/en
Publication of WO2019237957A1 publication Critical patent/WO2019237957A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/025—Purification; Separation; Stabilisation; Desodorisation of organo-phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to (S) -P-(((((R) -1- (6-amino-9H-purine-9-yl) prop-2-yl) oxy) methyl) -phenoxy-N- (2- (benzyloxy) ethyl) -phosphonamide (hereinafter referred to as "the compound of formula (I)”) and (R) -P-(((((R) -1- (6-amino-9H -Purine-9-yl) prop-2-yl) oxy) methyl) -phenoxy-N- (2- (benzyloxy) ethyl) -phosphonamide (hereinafter referred to as "Formula (II) Compound "), its chiral synthesis and chiral separation method, and also relates to a" compound of formula (I) "and its crystal form and preparation method, a pharmaceutical composition containing the same, and its preparation for prevention or treatment Use in medicines for viral infectious diseases such as hepatitis B.
  • Hepatitis B virus is a DNA virus belonging to the family Hepadnaviridae, and its DNA synthesis depends on the hepatitis B virus DNA polymerase.
  • the use of DNA polymerase inhibitors as anti-HBV drugs has become a very competitive option.
  • Tenofovir (PMPA) is a nucleotide DNA polymerase and reverse transcriptase inhibitor with anti-HBV and HIV activity. Its phosphonate derivative, tenofovir dipyrfurate ( TDF) and phosphonate ester derivatives tenofovir alafenamide (TAF) have been approved by the FDA for the treatment of human immunodeficiency syndrome and hepatitis B virus. TAF overcomes the disadvantage of poor TDF plasma stability.
  • TAF mainly generates adenosine triphosphate analogs in liver cells by esterase hydrolysis and phosphorylation, which inserts newly generated DNA strands, thereby blocking DNA polymerase-catalyzed DNA synthesis and inhibiting viral replication (WO2013025788A1; Nucleosides Nucleotides, Nucleic Acids, 2001, 20, 1085-1090).
  • ALT rehabilitation rate ⁇ 80%
  • BMD spinal bone density
  • Another aspect of the present invention provides a method for the synthesis of a racemate of a compound of formula (I) and formula (II) as shown in the following reaction scheme and a method for chiral separation thereof:
  • Another aspect of the present invention provides a chiral synthesis method of a compound of formula (I) as shown in the following reaction scheme:
  • Chiral synthesis of a compound of formula (I) uses tenofovir monophenyl ester as a raw material, and a compound of formula (I) having a diastereomeric purity of greater than 90% is prepared through a chlorination reaction and a substitution reaction.
  • the compound of formula (I) and its salt provided by the present invention have the following advantages: as a prodrug, it can be rapidly metabolized into active ingredients in animals, and then inhibit HBV virus reverse transcriptase and DNA polymerase, thereby achieving the effect of inhibiting HBV DNA replication .
  • the salt of the compound of the formula (I) provided by the present invention has good manufacturability (easy to prepare), and the solvent residue in the crystal form of various salts is low.
  • the acid used for salt formation in the present invention has high safety and does not cause undesired toxicity.
  • the salt of the compound of formula (I) provided by the present invention has good safety in animal tests, has no significant effect on liver, kidney, bone metabolism, etc., and is expected to reduce side effects caused by long-term medication of patients, including abnormal liver function, glomeruli Pain and osteoporosis caused by reduced filtration rate and reduced bone density.
  • the various salts and crystal forms of the present invention are easier to prepare in large quantities in high purity, and are therefore more suitable for the preparation of pharmaceutical preparations, and may also exhibit other advantageous physical properties (such as good solubility, low hygroscopicity (hygroscopicity) ) And good solid-state stability, etc.) and pharmacokinetic properties (such as different lattices can increase the dissolution rate and bioavailability).
  • Another aspect of the present invention provides a method for preparing a salt of a compound of formula (I), which comprises reacting a compound of formula (I) in any solid form with an inorganic or organic acid to precipitate a solid, and then separating the precipitated solid and dry.
  • the method for precipitating solids includes, but is not limited to, a gas-solid permeation method, an anti-solvent crystallization method, a room-temperature suspension stirring method, a high-temperature suspension stirring method, a gas-liquid permeation method, a room-temperature slow volatilization method, and a slow cooling method.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a salt of a compound of formula (I) described above (eg, a fumarate, citrate, tartrate or phosphate salt of a compound of formula (I), in particular formula ( 1) a fumarate crystal, a citrate crystal, a tartrate crystal or a phosphate crystal of a compound of the compound, more particularly a fumarate crystal of a compound of formula (I)) or any combination thereof, and one or more A pharmaceutically acceptable carrier.
  • a salt of a compound of formula (I) described above eg, a fumarate, citrate, tartrate or phosphate salt of a compound of formula (I), in particular formula ( 1) a fumarate crystal, a citrate crystal, a tartrate crystal or a phosphate crystal of a compound of the compound, more particularly a fumarate crystal of a compound of formula (I)) or any combination thereof, and one or more A pharmaceutically acceptable carrier.
  • Another aspect of the present invention provides a method for treating a viral infectious disease such as hepatitis B in an individual, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the above formula (I) or a salt thereof (e.g., formula A fumarate, citrate, tartrate or phosphate of a compound of (I), in particular a fumarate crystal, citrate crystal, tartrate crystal or phosphate crystal of a compound of formula (I), more Especially a fumarate crystal of a compound of formula (I)), or any combination thereof.
  • a compound of the above formula (I) or a salt thereof e.g., formula A fumarate, citrate, tartrate or phosphate of a compound of (I), in particular a fumarate crystal, citrate crystal, tartrate crystal or phosphate crystal of a compound of formula (I), more Especially a fumarate crystal of a compound of formula (I)
  • Another aspect of the present invention provides a compound of formula (I) or a salt thereof (e.g., a fumarate, citrate, tartrate or phosphate of a compound of formula (I), in particular a compound of formula (I) Fumarate crystals, citrate crystals, tartrate crystals or phosphate crystals, more particularly fumarate crystals of a compound of formula (I)), or any combination thereof, for use in the treatment of a viral infectious disease in an individual Such as hepatitis B.
  • a compound of formula (I) or a salt thereof e.g., a fumarate, citrate, tartrate or phosphate of a compound of formula (I), in particular a compound of formula (I) Fumarate crystals, citrate crystals, tartrate crystals or phosphate crystals, more particularly fumarate crystals of a compound of formula (I)
  • Another aspect of the present invention provides a compound of formula (I) or a salt thereof (e.g., a fumarate, citrate, tartrate or phosphate of a compound of formula (I), in particular a compound of formula (I) Fumarate crystals, citrate crystals, tartrate crystals or phosphate crystals, and more particularly fumarate crystals of a compound of formula (I)) or any combination thereof in the preparation of a virus infectious disease for use in the treatment of an individual Uses in medicines such as hepatitis B.
  • a compound of formula (I) or a salt thereof e.g., a fumarate, citrate, tartrate or phosphate of a compound of formula (I)
  • the crystal of a salt of a compound of formula (I) of the present invention has one or more of the following advantageous properties:
  • Excellent physical and chemical stability including but not limited to light stability, thermal stability, high humidity resistance, etc.
  • good light stability can ensure the reliability of the crystals during storage and transportation, thereby ensuring the safety of the formulation; so that the crystals do not need to be treated with special packaging to prevent the effects of light, thereby reducing costs;
  • the crystal will not be degraded due to the influence of light, thereby improving the safety of the preparation and the effectiveness after long-term storage; and the patient taking the crystal will not worry about the photosensitive reaction of the preparation due to exposure to sunlight.
  • the good thermal stability enables the crystals to remain stable for a long time and is suitable for standard formulation production processes.
  • Good physical and chemical stability makes the crystals easier to prepare and more suitable for the preparation of formulations.
  • Figure 1 shows an XRPD pattern of a fumarate crystal A of a compound of formula (I).
  • Figure 2 shows a DSC spectrum of a fumarate crystal A of a compound of formula (I).
  • FIG. 3 shows the TGA pattern of the fumarate crystal A of the compound of formula (I).
  • Figure 4 shows an XRPD pattern of the fumarate crystal B of the compound of formula (I).
  • Figure 5 shows an XRPD pattern of the fumarate crystal C of the compound of formula (I).
  • Figure 6 shows an XRPD pattern of citrate crystal A of a compound of formula (I).
  • Figure 7 shows a DSC pattern of citrate crystal A of a compound of formula (I).
  • Figure 8 shows the TGA pattern of citrate crystal A of a compound of formula (I).
  • FIG. 9 shows an XRPD pattern of tartrate crystal A of a compound of formula (I).
  • FIG. 10 shows an XRPD pattern of tartrate crystal B of a compound of formula (I).
  • FIG. 11 shows a DSC pattern of tartrate crystal B of a compound of formula (I).
  • Figure 12 shows a TGA pattern of the tartrate crystal B of the compound of formula (I).
  • FIG. 13 shows an XRPD pattern of phosphate crystal A of a compound of formula (I).
  • FIG. 14 shows a DSC pattern of phosphate crystal A of a compound of formula (I).
  • FIG. 15 shows a TGA pattern of phosphate crystal A of a compound of formula (I).
  • FIG. 16 shows an XRPD pattern of phosphate crystal B of a compound of formula (I).
  • FIG. 17 shows a single crystal molecular structure of a fumarate crystal A of a compound of formula (I).
  • the word "about” means that one of ordinary skill in the art believes that the value is within an acceptable standard error, such as ⁇ 0.05, ⁇ 0.1, ⁇ 0.2, ⁇ 0.3, ⁇ 1, ⁇ 2, or ⁇ 3 and so on.
  • salt of a compound of formula (I) includes an inorganic or organic acid salt of a compound of formula (I), such as, but not limited to, a fumarate salt, a citric acid of a compound of formula (I) Salt, tartrate, maleate, succinate, malate, adipate, lactate, glycolate, mucate, gentisate, oxalate, malonate, horse Urate, nicotinate, nicotinamide, phosphate, hydrochloride, sulfate, ethanesulfonate, naphthalene disulfonate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, Camphor sulfonate, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine Acid salt
  • solid form includes all solid forms, such as crystalline or amorphous forms, of compounds of formula (I) and salts of compounds of formula (I).
  • amorphous refers to any solid matter that is unordered in three dimensions.
  • amorphous solids can be characterized by known techniques including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques.
  • ssNMR solid-state nuclear magnetic resonance
  • crystalline form or “crystal” as used herein refers to any solid matter exhibiting a three-dimensional ordering, as opposed to an amorphous solid matter, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern refers to a diffraction pattern experimentally observed or a parameter derived therefrom. XRPD patterns are usually characterized by peak position (abscissa) and / or peak intensity (ordinate).
  • 2 ⁇ refers to a peak position in degrees based on an experimental setting of an X-ray diffraction experiment, and is generally an abscissa unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms a ⁇ angle with a lattice plane, the experimental setup needs to record the reflected beam at a 2 ⁇ angle. It should be understood that the specific 2 ⁇ value of the specific crystal form mentioned herein is intended to represent the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • thermogravimetric analysis (TGA) pattern refers to a curve recorded by a thermogravimetric analyzer.
  • DSC differential scanning calorimetry
  • nuclear magnetic resonance (1 H-NMR) spectrum refers to a signal peak from the NMR spectrometer to record.
  • the term "substantially the same" for X-ray diffraction peak positions means taking into account representative peak positions and intensity variations. For example, those skilled in the art will understand that the peak position (2 ⁇ ) will show some changes, usually up to 0.1-0.2 degrees, and the instrument used to measure diffraction will also show some changes. In addition, those skilled in the art will understand that relative peak intensities will show changes between instruments and changes due to the degree of crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to those skilled in the art, and should be considered as only It is a qualitative measurement.
  • DSC patterns and TGA patterns are also intended to encompass variations known to those skilled in the art in relation to these analytical techniques.
  • the differential scanning calorimetry will usually have variations of up to ⁇ 0.2 ° C, and even broad peaks (eg up to ⁇ 1 ° C).
  • good solvent means a solvent for dissolving the (I) compound or the (I) compound salt of the present invention.
  • anti-solvent means a solvent for reducing the solubility of a substance to be crystallized in a good solvent.
  • anti-solvent crystallization method means a method of using a good solvent in combination with an anti-solvent, thereby reducing the solubility of a substance to be crystallized in the good solvent.
  • antisolvent crystallization methods can be divided into antisolvent addition methods and antiantisolvent addition methods.
  • the anti-solvent addition method is a method of dissolving a substance to be crystallized in a good solvent, and then adding an anti-solvent thereto to crystallize, and the anti-anti-solvent method is to dissolve the substance to be crystallized in a good solvent, and then adding the obtained solution A method of crystallization into an anti-solvent.
  • hydrocarbons as used herein preferably means hydrocarbons having from 1 to 10 carbon atoms, including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics, including but not limited to dichloromethane , Chloroform (chloroform), n-hexane, n-heptane and toluene.
  • alcohol as used herein preferably means an alcohol having 1 to 10 carbon atoms, including, but not limited to, methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropyl Alcohol), 1-butanol, 2-butanol, and tert-butanol.
  • ethers as used herein preferably means ethers having 2 to 6 carbon atoms, which include chain ethers and cyclic ethers (e.g. furans (including tetrahydrofurans) and dioxane) ), Including but not limited to ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole, and dimethoxyethyl alkyl.
  • chain ethers and cyclic ethers e.g. furans (including tetrahydrofurans) and dioxane
  • nitrile as used herein preferably means a nitrile having 2-6 carbon atoms, which includes but is not limited to acetonitrile and propionitrile.
  • ketones as used herein preferably means ketones having 2 to 6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone.
  • esters as used herein preferably means an ester having 3 to 10 carbon atoms, including but not limited to ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropylate, dicarbonate Methyl ester and butyl acetate.
  • organic acid as used herein preferably means an organic acid having 1 to 10 carbon atoms, which includes but is not limited to formic acid and acetic acid.
  • sulfones as used herein preferably means a sulfone or sulfoxide having 2 to 10 carbon atoms, which includes, but is not limited to, dimethylsulfoxide.
  • amides as used herein preferably means amides having from 1 to 10 carbon atoms, including but not limited to dimethylformamide or dimethylacetamide.
  • nitrogen heterocycle preferably means a nitrogen-containing heterocycle having 3-10 carbon atoms and at least one nitrogen atom, which includes, but is not limited to, N-methylpyrrolidone.
  • a numerical range (such as “1-10") and its sub-ranges (such as “2-10", “2-6", “3-10"), etc., as used herein, cover the numerical range Any of (for example 1, 2, 3, 4, 5, 5, 6, 7, 8, 9 or 10) and is not limited to an integer.
  • Solid lines can be used in this article Wavy line Solid wedge Virtual wedge
  • the chemical bonds of the compounds of the invention are depicted.
  • the use of a solid line to depict a bond to an asymmetric atom indicates that all possible stereoisomers at that atom are included (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of wavy lines to depict a bond to an asymmetric atom indicates that the bond is a real wedge Virtual wedge Either of the keys.
  • the use of real or imaginary wedges to depict bonds to asymmetric atoms indicates the presence of the stereoisomers shown. When present in a racemic mixture, real and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • DSC patterns For example, a Mettler Toledo DSC1 differential scanning calorimeter can be used to determine the DSC spectrum.
  • the term "substantially the same" for DSC patterns takes into account representative characteristic peak positions. For example, those skilled in the art will understand that the characteristic peak positions will show some changes, typically up to 5 ° C.
  • the temperature increase rate of DSC test has a greater effect on the DSC spectrum. At a faster temperature rise rate, the thermal hysteresis effect of the instrument is obvious, and the high melting point solid crystal form is too late to recrystallize.
  • the DSC spectrum often only shows the melting endothermic peak of the low melting point crystal form.
  • the DSC spectrum shows two peaks: a low-melting crystalline melting endothermic peak and a high-melting crystalline melting endothermic peak; and only at lower heating rates, the instrument's thermal hysteresis is weak. Then three peaks will appear: the melting peak of the low melting point crystal form-the recrystallization exothermic peak-the melting endothermic peak of the high melting point crystal.
  • the skilled person will understand that the determination of the heating rate range corresponding to the different DSC patterns mentioned above will vary depending on the weight, morphology, particle size and distribution of the test product (Reference: Giron D. Thermal analysis and calorimetric methods the characterisation of polymorphs and solves [J]. Thermochimica Acta, 1995, 248: 1-59.).
  • the solid form of a compound of formula (I), a salt of a compound of formula (I), or a crystalline form thereof may be passed through decantation, centrifugation, evaporation, gravity filtration, suction filtration, or under pressure or under reduced pressure. Any other methods for solids recovery.
  • the recovered solid may be optionally dried.
  • the "drying" in the present invention is performed under reduced pressure (preferably under vacuum) until the content of the residual solvent is reduced to the International Conference on Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines Within range.
  • the residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm.
  • the drying can be performed in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a quick dryer, etc. get on.
  • the drying can be at a temperature of less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 50 ° C, less than about 30 ° C, or any other suitable temperature, at atmospheric pressure or reduced pressure ( Vacuum is preferred) for any desired time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours, or overnight) to achieve the desired result, as long as the quality of the product does not deteriorate.
  • the drying can be performed any desired number of times until the desired product quality is achieved.
  • the dried product may optionally be subjected to a pulverization operation to produce a desired particle size.
  • the product may be ground or micronized before or after drying. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller milling, and hammer milling, as well as jet milling.
  • amorphous form as used herein preferably means a crystalline form in which water molecules are not contained as a structural element.
  • An object of the present invention is to provide compounds of formula (I) and formula (II) shown below and a method for preparing the same,
  • the present invention provides a method for the synthesis of a racemate of a compound of formula (I) and formula (II) as shown in the following reaction scheme and a method for chiral separation thereof:
  • the intermediate tenofovir monophenyl ester phosphonochloride was prepared by reacting with tenofovir monophenyl ester.
  • the chlorinating reagent includes, but is not limited to, dichlorosulfoxide, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, and the like.
  • the tenofovir monophenyl ester phosphonochloride obtained in step 1 is reacted with 2- (benzyloxy) ethylamine to obtain a phosphonamide racemate product.
  • the compounds of formula (I) and formula (II) are prepared by separating the phosphoamidate racemate obtained in step 2 by chiral chromatography.
  • the present invention provides a chiral preparation method of a compound of formula (I) as shown in the following reaction scheme:
  • step one includes: in a solvent such as toluene, xylene, anisole, acetonitrile, etc., at 50-120 ° C (preferably 80-110 ° C, more preferably 90-100) °C), (((1R) -2- (6-amino-9H-purin-9-yl) -1-methylethoxy) methyl) phosphonic acid monophenyl ester (tenofovir Monophenyl ester) is reacted with chlorinating reagents such as dichlorosulfoxide, phosphorus oxychloride, phosphorus pentachloride, and oxalyl chloride to prepare an intermediate (((R) -1- (6-amino-9H-purine -9-yl) -1-methyl-ethoxy) methyl) phenoxyphosphonochloride; step two includes: using the intermediate obtained in step one ((((R) -1- (6-amino-
  • n is 1 or 1/2, preferably 1.
  • the molar ratio of the compound of formula (I) to fumaric acid is 1: 1 or 1: 1/2, preferably 1: 1.
  • the present invention provides a fumarate crystal A of a compound of formula (I), wherein the molar ratio of the compound of formula (I) to fumaric acid is 1: 1.
  • the XRPD pattern of the fumarate crystal A of the compound of formula (I) includes diffraction angles (2 ⁇ ) at 5.1 ⁇ 0.2 °, 6.4 ⁇ 0.2 °, 16.3 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, 28.2 ⁇ 0.2 ° Characteristic peaks.
  • the XRPD pattern of the fumarate crystal A of the compound of formula (I) includes at 5.1 ⁇ 0.2 °, 6.4 ⁇ 0.2 °, 14.7 ⁇ 0.2 °, 15.3 ⁇ 0.2 °, 16.3 ⁇ 0.2 Characteristic peaks at diffraction angles (2 ⁇ ) of °, 18.0 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, 19.2 ⁇ 0.2 °, 28.2 ⁇ 0.2 °, and 29.6 ⁇ 0.2 °.
  • the XRPD pattern of the fumarate crystal A of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the fumarate crystal A of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the fumarate crystal A of the compound of formula (I) includes a peak at a diffraction angle (2 ⁇ ) substantially the same as shown in FIG.
  • the XRPD peak position of the fumarate crystal A of the compound of formula (I) is substantially the same as that shown in FIG. 1.
  • the DSC pattern of the fumarate crystal A of the compound of formula (I) of the present invention comprises at about 125 ⁇ 5 ° C (starting temperature), preferably about 125 ⁇ 2 ° C (starting temperature)
  • the characteristic peak at about 125 ⁇ 0.2 ° C (starting temperature) is more preferable.
  • the DSC pattern of the fumarate crystal A of the compound of formula (I) includes a characteristic peak at substantially the same temperature as shown in FIG. 2.
  • the characteristic peak positions of the DSC pattern of the fumarate crystal A of the compound of formula (I) are substantially the same as those shown in FIG. 2.
  • the fumarate crystal A of the compound of formula (I) of the present invention is an unsolvate. In a more preferred embodiment, the fumarate crystal A of the compound of formula (I) of the present invention is an crystalline form.
  • the fumarate crystal A of the compound of formula (I) of the present invention has the following unit cell parameters:
  • the present invention provides a fumarate crystal B of a compound of formula (I), wherein the molar ratio of the compound of formula (I) to fumaric acid is 1: 1.
  • the XRPD pattern of the fumarate crystal B of the compound of formula (I) includes diffraction angles (2 ⁇ ) at 10.2 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 17.1 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 21.7 ⁇ 0.2 ° Characteristic peaks.
  • the XRPD pattern of the fumarate crystal B of the compound of formula (I) includes 9.7 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 14.7 ⁇ 0.2 °, 17.1 ⁇ 0.2 Characteristic peaks at diffraction angles (2 ⁇ ) of °, 18.1 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 19.2 ⁇ 0.2 °, 20.6 ⁇ 0.2 °, and 21.7 ⁇ 0.2 °.
  • the XRPD pattern of the fumarate crystal B of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the fumarate crystal B of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the fumarate crystal B of the compound of formula (I) includes a peak at a diffraction angle (2 ⁇ ) that is substantially the same as that shown in FIG. 4.
  • the XRPD peak position of the fumarate crystal B of the compound of formula (I) is substantially the same as that shown in FIG. 4.
  • the present invention provides a fumarate crystal C of a compound of formula (I), wherein the molar ratio of the compound of formula (I) to fumaric acid is 1: 1.
  • the XRPD pattern of the fumarate crystal C of the compound of formula (I) includes diffraction angles (2 ⁇ ) at 4.3 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 14.3 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 27.9 ⁇ 0.2 ° Characteristic peaks.
  • the XRPD pattern of the fumarate crystal C of the compound of formula (I) includes at 4.3 ⁇ 0.2 °, 6.6 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 14.3 ⁇ 0.2 °, 16.6 ⁇ 0.2 Characteristic peaks at diffraction angles (2 ⁇ ) of °, 18.5 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 19.2 ⁇ 0.2 °, 27.6 ⁇ 0.2 °, and 27.9 ⁇ 0.2 °.
  • the XRPD pattern of the fumarate crystal C of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the fumarate crystal C of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the fumarate crystal C of the compound of formula (I) includes a peak at a diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 5.
  • the XRPD peak position of the fumarate crystal C of the compound of formula (I) is substantially the same as that shown in FIG. 5.
  • n is 1 or 1/2 or 1/3, preferably 1.
  • the molar ratio of the compound of formula (I) to citric acid is 1: 1 or 1: 1/2 or 1: 1/3, preferably 1: 1.
  • the present invention provides a citrate crystal A of a compound of formula (I), wherein the molar ratio of the compound of formula (I) to citric acid is 1: 1.
  • the XRPD pattern of the citrate crystal A of the compound of formula (I) includes diffraction angles (2 ⁇ ) at 7.6 ⁇ 0.2 °, 14.1 ⁇ 0.2 °, 15.5 ⁇ 0.2 °, 16.0 ⁇ 0.2 °, 20.7 ⁇ 0.2 ° Characteristic peak.
  • the XRPD pattern of the citrate crystal A of the compound of formula (I) includes 7.6 ⁇ 0.2 °, 14.1 ⁇ 0.2 °, 14.9 ⁇ 0.2 °, 15.5 ⁇ 0.2 °, 16.0 ⁇ 0.2 ° Characteristic peaks at diffraction angles (2 ⁇ ) of 19.6 ⁇ 0.2 °, 20.7 ⁇ 0.2 °, 21.4 ⁇ 0.2 °, 22.5 ⁇ 0.2 °, and 24.5 ⁇ 0.2 °.
  • the XRPD pattern of the citrate crystal A of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the citrate crystal A of the compound of formula (I) includes a peak at a diffraction angle (2 ⁇ ) that is substantially the same as that shown in FIG. 6.
  • the XRPD peak position of the citrate crystal A of the compound of formula (I) is substantially the same as that shown in FIG. 6.
  • the DSC pattern of the citrate crystal A of the compound of formula (I) of the present invention includes at about 115 ⁇ 5 ° C (starting temperature), preferably about 115 ⁇ 2 ° C (starting temperature), The characteristic peak at about 115 ⁇ 0.2 ° C (starting temperature) is more preferable.
  • the DSC pattern of the citrate crystal A of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. 7.
  • the characteristic peak positions of the DSC pattern of the crystal A of the citrate of the compound of formula (I) are substantially the same as those shown in FIG. 7.
  • the citrate crystal A of the compound of formula (I) of the present invention is an unsolvate. In a more preferred embodiment, the citrate crystal A of the compound of formula (I) of the present invention is an crystalline form.
  • An object of the present invention is to provide a tartrate salt of a compound of formula (I) as shown below:
  • n is 1 or 1/2, preferably 1.
  • the molar ratio of the compound of the formula (I) to the tartaric acid is 1: 1 or 1: 1/2, preferably 1: 1.
  • the present invention provides a tartrate crystal A of a compound of formula (I), wherein the molar ratio of the compound of formula (I) to tartaric acid is 1: 1.
  • the XRPD pattern of the tartrate crystal A of the compound of formula (I) includes diffraction angles (2 ⁇ ) at 16.9 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, 19.2 ⁇ 0.2 °, 21.9 ⁇ 0.2 ° Characteristic peaks.
  • the XRPD pattern of the tartrate crystal A of the compound of formula (I) includes at 4.5 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 10.9 ⁇ 0.2 °, 16.9 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, Characteristic peaks at diffraction angles (2 ⁇ ) of 17.9 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 19.2 ⁇ 0.2 °, and 21.9 ⁇ 0.2 °.
  • the XRPD pattern of the tartrate crystal A of the compound of formula (I) comprises 3.9 ⁇ 0.2 °, 4.5 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 7.3 ⁇ 0.2 °, 9.1 ⁇ 0.2 ° , 10.2 ⁇ 0.2 °, 10.9 ⁇ 0.2 °, 14.2 ⁇ 0.2 °, 16.4 ⁇ 0.2 °, 16.9 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 17.9 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 19.2 ⁇ 0.2 ° Characteristic peaks at diffraction angles (2 ⁇ ) of 21.9 ⁇ 0.2 °, 22.8 ⁇ 0.2 °, 25.7 ⁇ 0.2 °, 27.6 ⁇ 0.2 °.
  • the XRPD pattern of the tartrate crystal A of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ )
  • the XRPD pattern of the tartrate crystal A of the compound of formula (I) includes a peak at a diffraction angle (2 ⁇ ) that is substantially the same as that shown in FIG. 9.
  • the XRPD peak position of the tartrate crystal A of the compound of formula (I) is substantially the same as that shown in FIG. 9.
  • the present invention provides a tartrate crystal B of a compound of formula (I), wherein the molar ratio of the compound of formula (I) to tartaric acid is 1: 1.
  • the XRPD pattern of the tartrate crystal B of the compound of formula (I) includes diffraction angles (2 ⁇ ) at 7.3 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 17.8 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 19.2 ⁇ 0.2 ° Characteristic peaks.
  • the XRPD pattern of the tartrate crystal B of the compound of formula (I) includes 7.3 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 17.8 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 18.5 ⁇ 0.2 °, Characteristic peaks at diffraction angles (2 ⁇ ) of 18.8 ⁇ 0.2 °, 19.2 ⁇ 0.2 °, 19.6 ⁇ 0.2 °, 20.0 ⁇ 0.2 °, and 21.9 ⁇ 0.2 °.
  • the XRPD pattern of the tartrate crystal B of the compound of formula (I) comprises 3.9 ⁇ 0.2 °, 7.3 ⁇ 0.2 °, 7.8 ⁇ 0.2 °, 8.4 ⁇ 0.2 °, 9.8 ⁇ 0.2 ° , 14.6 ⁇ 0.2 °, 15.6 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 17.5 ⁇ 0.2 °, 17.8 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 18.5 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 19.2 ⁇ 0.2 °, 19.6 ⁇ 0.2 ° Characteristic peaks at diffraction angles (2 ⁇ ) of 20.0 ⁇ 0.2 °, 20.6 ⁇ 0.2 °, 21.9 ⁇ 0.2 °, 22.3 ⁇ 0.2 °, and 23.7 ⁇ 0.2 °.
  • the XRPD pattern of the tartrate crystal B of the compound of formula (I) includes peaks at the
  • the XRPD pattern of the tartrate crystal B of the compound of formula (I) includes a peak at a diffraction angle (2 ⁇ ) substantially the same as that shown in FIG.
  • the XRPD peak position of the tartrate crystal B of the compound of formula (I) is substantially the same as that shown in FIG. 10.
  • the DSC pattern of the tartrate crystal B of the compound of formula (I) according to the present invention comprises at about 143 ⁇ 5 ° C (starting temperature), preferably about 143 ⁇ 2 ° C (starting temperature), more The characteristic peak at about 143 ⁇ 0.2 ° C (starting temperature) is preferred.
  • the DSC spectrum of the tartrate crystal B of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. 11.
  • the characteristic peak positions of the DSC pattern of the tartrate crystal B of the compound of formula (I) are substantially the same as those shown in FIG. 11.
  • the tartrate crystal B of the compound of formula (I) according to the invention is an unsolvate.
  • the tartrate crystal B of the compound of formula (I) of the present invention is an amorphous form.
  • n is 1 or 1/2 or 1/3, preferably 1.
  • the molar ratio of the compound of formula (I) to phosphoric acid is 1: 1 or 1: 1/2 or 1: 1/3, preferably 1: 1.
  • the invention provides a phosphate crystal A of a compound of formula (I).
  • the XRPD pattern of the phosphate crystal A of the compound of formula (I) includes diffraction angles (2 ⁇ ) at 5.3 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 17.3 ⁇ 0.2 °, 18.6 ⁇ 0.2 °, 19.5 ⁇ 0.2 ° Characteristic peaks.
  • the XRPD pattern of the phosphate crystal A of the compound of formula (I) includes 5.3 ⁇ 0.2 °, 7.9 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 16.3 ⁇ 0.2 °, 17.3 ⁇ 0.2 °, Characteristic peaks at diffraction angles (2 ⁇ ) of 18.6 ⁇ 0.2 °, 19.5 ⁇ 0.2 °, 20.4 ⁇ 0.2 °, 20.7 ⁇ 0.2 °, and 23.1 ⁇ 0.2 °.
  • the XRPD pattern of the phosphate crystal A of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the phosphate crystal A of the compound of formula (I) includes a peak at a diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 13.
  • the XRPD peak position of the phosphate crystal A of the compound of formula (I) is substantially the same as that shown in FIG. 13.
  • the DSC pattern of phosphate crystal A of a compound of formula (I) of the present invention includes a characteristic peak at about 142 ⁇ 5 ° C, preferably about 142 ⁇ 2 ° C, and more preferably about 142 ⁇ 0.2 ° C .
  • the DSC pattern of the phosphate crystal A of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. 14.
  • the characteristic peak positions of the DSC pattern of the phosphate crystal A of the compound of formula (I) are substantially the same as those shown in FIG. 14.
  • the phosphate crystal A of the compound of formula (I) of the present invention is an unsolvate. In a more preferred embodiment, the phosphate crystal A of the compound of formula (I) of the present invention is an crystalline form.
  • the present invention provides a phosphate crystal B of a compound of formula (I).
  • the XRPD pattern of the phosphate crystal B of the compound of formula (I) includes diffraction angles (2 ⁇ ) at 7.9 ⁇ 0.2 °, 15.9 ⁇ 0.2 °, 16.3 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 24.2 ⁇ 0.2 ° Characteristic peaks.
  • the XRPD pattern of the phosphate crystal B of the compound of formula (I) includes 7.9 ⁇ 0.2 °, 10.4 ⁇ 0.2 °, 12.2 ⁇ 0.2 °, 15.9 ⁇ 0.2 °, 16.3 ⁇ 0.2 °, Characteristic peaks at diffraction angles (2 ⁇ ) of 18.8 ⁇ 0.2 °, 19.4 ⁇ 0.2 °, 20.0 ⁇ 0.2 °, 24.2 ⁇ 0.2 °, 24.7 ⁇ 0.2 °.
  • the XRPD pattern of the phosphate crystal B of the compound of formula (I) includes peaks at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the phosphate crystal B of the compound of formula (I) includes a peak at a diffraction angle (2 ⁇ ) that is substantially the same as that shown in FIG. 16.
  • the XRPD peak position of the phosphate crystal B of the compound of formula (I) is substantially the same as that shown in FIG. 16.
  • Another object of the present invention is to provide a method for preparing a salt (including but not limited to fumarate, citrate, tartrate and hydrochloride) of the compound of the above formula (I) and various crystal forms thereof, including:
  • the compound of formula (I) in any solid form is reacted with the inorganic acid or the organic acid to precipitate a solid, and the precipitated solid is then separated and dried.
  • the method for precipitating solids includes, but is not limited to, a gas-solid penetration method, an anti-solvent addition method, a room temperature suspension stirring method, a high-temperature suspension stirring method, a gas-liquid permeation method, a room temperature slow volatilization method, a slow cooling method, and an anti-anti-solvent addition method Wait.
  • the various crystal forms of the fumarate, citrate, tartrate and hydrochloride of the compound of the formula (I) of the present invention described above can be suspended and stirred by a gas-solid permeation method, an anti-solvent addition method, and room temperature. It is prepared by the method of high-temperature suspension stirring method, gas-liquid permeation method, room temperature slow volatilization method, slow cooling method or anti-anti-solvent addition method.
  • crystals are prepared using a gas-solid infiltration method, the method comprising placing a first container containing a salt of a compound of formula (I) in a second container containing a solvent, wherein the solid state
  • the salt of the compound of formula (I) in the form is not in direct contact with the solvent, the second container is sealed, and crystals are obtained after standing.
  • the solvents include, but are not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., alcohols, amides, sulfones, ketones, hydrocarbons (including alkanes) , Halogenated alkanes, olefins, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane)), nitriles and Esters such as methanol, ethanol, isopropanol, chloroform, acetone, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, N, N-dimethyl Formamide, dimethyl sulfoxide, ethyl acetate, etc.).
  • organic solvents e.g., alcohols, amides,
  • the weight-volume ratio (mg / mL) of the salt of the compound of formula (I) to the solvent is about (1-20): 1, preferably (2-10 ):1.
  • the placing and crystallization includes static or stirring crystallization, preferably static crystallization.
  • crystals are prepared using an anti-solvent addition method, which includes, but is not limited to, dissolving a salt of a compound of formula (I) in a good solvent to form a clear solution (the solution may be filtered as necessary to A clear solution is obtained), and then an antisolvent is added to the clear solution, and the mixture is stirred (the stirring may be at room temperature or cooling conditions (for example, cooling to 0-20 ° C, preferably 0-10 ° C, such as 0 ° C, 5 ° C, or The crystals are precipitated at 10 ° C, or are left to stand (for example, at room temperature) (preferably while slowly evaporating the solvent) to precipitate the crystals.
  • an anti-solvent addition method includes, but is not limited to, dissolving a salt of a compound of formula (I) in a good solvent to form a clear solution (the solution may be filtered as necessary to A clear solution is obtained), and then an antisolvent is added to the clear solution, and the mixture is stirred (the stirring
  • the good solvent includes But not limited to organic solvents, such as alcohols, ketones, nitriles, hydrocarbons (selected from halogenated alkanes, aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) ) And dioxanes)), sulfones, esters, amides and organic acids, such as methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, dimethylsulfoxide, N, N-dimethylacetamide, N-methylpyrrolidone, methylethyl , Ethyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, anisole, toluene, dichloromethane, etc.
  • organic solvents such as alcohols, ketones, nitriles, hydrocarbons (selected from halogenated alkanes, aromatics), ether
  • the anti-solvent includes, but is not limited to Inorganic solvents (such as water) and organic solvents (such as hydrocarbons (selected from alkanes, olefins, alkynes), such as n-hexane, n-heptane, cyclohexane, etc.).
  • the volume ratio of the good solvent to the anti-solvent is 1: (1-60), preferably 1: (1-40).
  • the salt of the compound of formula (I) The weight-volume ratio (mg / mL) to the good solvent is (1-80): 1, and preferably (1-40): 1.
  • various crystal forms of fumarate, citrate, tartrate, phosphate of a compound of formula (I) are prepared by the following method: For example, crystalline or amorphous) the compound of formula (I) is reacted with fumaric acid, citric acid, tartaric acid or phosphoric acid in a good solvent.
  • an antisolvent is added thereto, and the mixture is stirred (the stirring may be at room temperature or Precipitation of crystals under cooling conditions (for example, cooling to 0-20 ° C, preferably 0-10 ° C, such as 0 ° C, 5 ° C, or 10 ° C), or standing (for example, at room temperature) (preferably slow evaporation at the same time) Solvent) to thereby precipitate crystals, and the precipitated crystals were then separated and dried.
  • the volume ratio of the good solvent to the anti-solvent is 1: (1-60), preferably 1: (1-40).
  • the weight-volume ratio (mg / mL) of the salt of the compound of formula (I) to the good solvent is (1-80): 1, preferably (10-40): 1.
  • crystals are prepared by a suspension stirring method at room temperature, which includes, but is not limited to, adding a salt of a compound of formula (I) to a solvent to obtain a suspension, stirring at room temperature, and then separating the crystals.
  • the solvents include, but are not limited to, inorganic solvents (such as water) and organic solvents (such as alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, olefins) Types, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane)), esters, nitriles, amides and Organic acids, such as methyl tert-butyl ether, isopropyl alcohol, isobutyl acetate, methanol, acetone, tetrahydrofuran, acetonitrile, dimethylsulfoxide, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, toluene, etc.
  • inorganic solvents such as water
  • organic solvents such as alcohols, ketones, hydrocarbons (including alkanes,
  • the weight-volume ratio (mg / mL) of the salt of the compound of formula (I) to the solvent is (1-80): 1, preferably (1-50) :1.
  • crystals are prepared using a high temperature suspension stirring method, which includes, but is not limited to, adding a salt of a compound of formula (I) to a solvent to obtain a suspension, and the suspension is heated (e.g., heated) To 40-100 ° C, preferably 40-80 ° C, such as 45 ° C, 50 ° C, 55 ° C, 60 ° C, 65 ° C or 70 ° C), and then separated to obtain crystals.
  • a high temperature suspension stirring method includes, but is not limited to, adding a salt of a compound of formula (I) to a solvent to obtain a suspension, and the suspension is heated (e.g., heated) To 40-100 ° C, preferably 40-80 ° C, such as 45 ° C, 50 ° C, 55 ° C, 60 ° C, 65 ° C or 70 ° C), and then separated to obtain crystals.
  • the solvents include, but are not limited to, inorganic solvents (such as water) and organic solvents (such as alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, olefins) Types, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane)), esters, nitriles, sulfones, Amides and nitrogen heterocycles, such as methyl ethyl ketone, isobutanol, isobutyl acetate, methanol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, 2-methyltetrahydrofuran, chloroform, ethyl acetate , Toluene, n-hexane, etc.), or a mixed solvents (such as water) and organic solvents (such as
  • crystals are prepared using a gas-liquid permeation method, which includes dissolving a salt of a compound of formula (I) in a good solvent in a first container to form a clear solution (the solution may be filtered if necessary To obtain a clear solution), a second container was charged with an antisolvent, the first container was opened in the second container, the second container was sealed and left to stand, and the precipitated solid was filtered to obtain crystals.
  • a gas-liquid permeation method which includes dissolving a salt of a compound of formula (I) in a good solvent in a first container to form a clear solution (the solution may be filtered if necessary
  • a second container was charged with an antisolvent, the first container was opened in the second container, the second container was sealed and left to stand, and the precipitated solid was filtered to obtain crystals.
  • the good solvent includes, but is not limited to, organic solvents, such as hydrocarbons (selected from halogenated alkanes and aromatics), alcohols, ketones, ethers (including chain Ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane)), esters, nitriles, sulfones, amides, and nitrogen heterocyclics, etc., such as methanol, ethanol, Acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, isopropanol, methyl isobutyl ketone, isopropyl acetate, methyl tert-butyl ether, 1,4-dioxane, anisole, cyclopentyl Methyl ether, toluene, chloroform, or a mixed solvent formed of two or more of the organic solvents, such as hydrocarbons (selected from halogenated alkan
  • the anti-solvent includes, but is not limited to, inorganic solvents (such as water) and organic solvents (such as hydrocarbons (selected from alkane, olefin, and alkyne), such as N-hexane, n-heptane, cyclohexane, etc.), or a mixed solvent formed of two or more of the aforementioned solvents.
  • the weight-volume ratio (mg / mL) of the salt of the compound of formula (I) to the good solvent is about (1-80): 1, preferably (10- 60): 1.
  • the volume ratio of the anti-solvent to the good solvent is 1: (1-20), preferably 1: (1-10).
  • the sealing and standing of the second container may be performed at room temperature.
  • crystals are prepared using a slow evaporation method at room temperature, the method comprising dissolving a salt of a compound of formula (I) in a solvent in a container to form a clear solution (the solution may be filtered to obtain a clear solution if necessary Solution), the container is sealed (for example, using a parafilm), small holes or gaps are left at the seal, and the clear solution is left to evaporate the solvent to obtain crystals.
  • the solvents include, but are not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., alcohols, amides, hydrocarbons (including alkanes, halogenated alkanes, alkenes) Types, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxanes)), ketones, nitriles or esters, Specific examples include isopropanol, methyl ethyl ketone, isopropyl acetate, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methanol, acetone, acetonitrile, ethyl acetate, n-hexane, tetrahydrofuran, dichloromethane, etc.), Or a mixed solvent formed
  • the weight-volume ratio (mg / mL) of the salt of the compound of formula (I) to the solvent is (1-50): 1, preferably (1-30) :1.
  • the placing may be performed at room temperature.
  • various crystal forms of fumarate, citrate, tartrate, phosphate of a compound of formula (I) are prepared by: (E.g., crystalline or amorphous), the compound of formula (I) is dissolved and reacted with fumaric acid, citric acid, tartaric acid or phosphoric acid in a solvent. After the reaction, the compound is slowly volatilized at room temperature to precipitate crystals, and the precipitated crystals are then separated. And dry.
  • the weight-volume ratio (mg / mL) of the salt of the compound of formula (I) to the solvent is (1-50): 1, preferably (1-30): 1.
  • crystals are prepared by a slow cooling method, which comprises adding a salt of a compound of formula (I) to a solvent, heating and stirring to dissolve it, and dissolving the resulting clear solution (the solution may be performed as needed) It was filtered to obtain a clear solution) and left to cool slowly to obtain crystals.
  • a slow cooling method which comprises adding a salt of a compound of formula (I) to a solvent, heating and stirring to dissolve it, and dissolving the resulting clear solution (the solution may be performed as needed) It was filtered to obtain a clear solution) and left to cool slowly to obtain crystals.
  • the solvents include, but are not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes) , Alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane)), nitriles, amides and esters, specifically (E.g., inorganic solvents (e.g., water) and organic solvents (e.g., alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes) , Alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane)), nitriles, amides and esters, specifically (E.g.
  • the cooling rate of the slow cooling is 0.1-0.5 ° C / minute, preferably 0.1-0.3 ° C / minute, and more preferably 0.1 ° C / minute.
  • the heating temperature is 30-80 ° C, preferably 40-70 ° C, such as 45 ° C, 50 ° C, 55 ° C, or 60 ° C.
  • the temperature at the end of the cooling is room temperature or 0-10 ° C, such as 3 ° C, 5 ° C, or 7 ° C.
  • the weight-volume ratio (mg / mL) of the salt of the compound of formula (I) to the solvent is (2-100): 1, preferably (10-80): 1.
  • crystals are prepared by an anti-anti-solvent addition method, which includes, but is not limited to, dissolving a salt of a compound of formula (I) in a good solvent to form a clear solution (the solution may be filtered if necessary To obtain a clear solution), and then the clear solution is added to the antisolvent and stirred (the stirring may be at room temperature or under heating conditions (for example, heated to 30-100 ° C, preferably 30-80 ° C, more preferably 35-65) (For example, at 45 ° C, 50 ° C, 55 ° C, or 60 ° C)), or the crystals are precipitated by standing (for example, at room temperature) (preferably while slowly evaporating the solvent).
  • an anti-anti-solvent addition method includes, but is not limited to, dissolving a salt of a compound of formula (I) in a good solvent to form a clear solution (the solution may be filtered if necessary To obtain a clear solution), and then the clear solution is added to the antisolvent and stirred (
  • the good solvent includes, but is not limited to, organic solvents such as alcohols, ketones, hydrocarbons (selected from halogenated alkanes and aromatics), ethers (including Chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxane)), sulfones, amides and organic acids, such as N-methylpyrrolidone, ethanol, acetone, acetonitrile, Tetrahydrofuran, dichloromethane, methyl isobutyl ketone, ethyl acetate, 2-methyltetrahydrofuran, toluene, and the like.
  • organic solvents such as alcohols, ketones, hydrocarbons (selected from halogenated alkanes and aromatics), ethers (including Chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxane)), sulfones, amide
  • the anti-solvent includes, but is not limited to, inorganic solvents (such as water) and organic solvents (such as hydrocarbons (selected from alkane, olefin, and alkyne), For example, cyclohexane, n-hexane, n-heptane, etc.
  • the volume ratio of the good solvent to the antisolvent is (1-20): 1, preferably ( 1-10): 1.
  • the weight-volume ratio (mg / mL) of the salt of the compound of formula (I) to the good solvent is (1-80): 1, preferably (1-50 ):1.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • a salt of a compound of formula (I) of the present invention such as a compound of formula (I), a fumarate, citrate, tartrate or phosphate, in particular a compound of formula (I), Solid forms of citrate, tartrate or phosphate, more particularly fumarate crystals of a compound of formula (I), tartrate crystals of a compound of formula (I), citrate of a compound of formula (I) Crystals or phosphate crystals of compounds of formula (I), more particularly fumarate crystals A, B or C of compounds of formula (I), tartrate crystals A or B of compounds of formula (I), formula ( Citrate crystal A of a compound of compound A or phosphate crystal A or B of a compound of formula (I); and
  • Another object of the present invention is to provide a method for treating a viral infectious disease such as hepatitis B in an individual, which comprises administering to a subject in need thereof a therapeutically effective amount of a salt of a compound of formula (I) of the present invention ,
  • a salt of a compound of formula (I) of the present invention Such as a fumarate, citrate, tartrate or phosphate of a compound of formula (I), especially a solid form of a fumarate, citrate, tartrate or phosphate of a compound of formula (I) , More particularly a fumarate crystal of a compound of formula (I), a tartrate crystal of a compound of formula (I), a citrate crystal of a compound of formula (I) or a phosphate crystal of a compound of formula (I) , More particularly a fumarate crystal A, B or C of a compound of formula (I), a tartrate crystal A or B of a compound of formula (I), a citrate crystal A or a
  • Another object of the present invention is to provide a salt of a compound of formula (I) (for example, a fumarate, citrate, tartrate or phosphate of a compound of formula (I), particularly a compound of formula (I) Solid form of a fumarate, citrate, tartrate or phosphate of a compound, more particularly a fumarate crystal of a compound of formula (I), a tartrate crystal of a compound of formula (I), formula (I ) Or citrate crystals of a compound of formula (I) or phosphate crystals of a compound of formula (I), and more particularly fumarate crystals of a compound of formula (I) A, B or C, tartrate of a compound of formula (I) Crystal A or B, citrate crystal A of a compound of formula (I) or phosphate crystal A or B of a compound of formula (I)), or any combination thereof, for use in treating a viral infection such as hepatitis B in an individual sexually transmitted diseases.
  • Another object of the present invention is to provide a salt of a compound of formula (I) (for example, a fumarate, citrate, tartrate or phosphate of a compound of formula (I), particularly a compound of formula (I) Solid form of a fumarate, citrate, tartrate or phosphate of a compound, more particularly a fumarate crystal of a compound of formula (I), a tartrate crystal of a compound of formula (I), formula (I ) Crystals of a compound of citrate or phosphate crystals of a compound of formula (I), more particularly fumarate crystals of a compound of formula (I) A, B or C, tartaric acid of a compound of formula (I) Salt crystals A or B, citrate crystals A of a compound of formula (I) or phosphate crystals A or B of a compound of formula (I)) or any combination thereof in the preparation of a virus such as hepatitis B for use in treating an individual Use in medicine for infectious diseases.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient, or vehicle administered with a therapeutic agent and is suitable for contact within the scope of sound medical judgment Human and / or other animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications corresponding to a reasonable benefit / risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals Oil, sesame oil, etc.
  • sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals Oil, sesame oil, etc.
  • water is an exemplary carrier.
  • Physiological saline and dextrose and glycerol aqueous solutions can also be used as liquid carriers, especially for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, Ethanol and so on.
  • the composition may further contain a small amount of a wetting agent, an emulsifying agent, or a pH buffering agent, as necessary.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • the pharmaceutical composition of the present invention may act systemically and / or locally.
  • they can be administered by a suitable route, such as by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal; orally, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • composition of the present invention can be administered in a suitable dosage form.
  • the dosage form may be a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation, including but not limited to tablets, capsules, powders, granules, lozenges, hard candy, powders, sprays, creams, ointments , Suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.
  • the pharmaceutical composition of the present invention can be prepared by any method well known in the art, for example, by mixing, dissolving, granulating, sugar coating, milling, emulsifying, lyophilizing, and the like.
  • terapéuticaally effective amount refers to the amount of a compound that, after administration, will to some extent alleviate one or more symptoms of the condition being treated.
  • the dosing regimen can be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is to be noted that the dose value may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time based on the individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of a compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 50 mg per kg of body weight per day, such as about 0.01 to about 10 mg / kg / day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg / day to about 3500 mg / day, such as about 0.7 mg / day to about 700 mg / day.
  • a dosage level that is not higher than the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses for administration throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg and 25mg.
  • treating means reversing, alleviating, inhibiting the condition or condition to which such term is applied or the progression of one or more symptoms of such condition or condition, or preventing such A disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals with a disease, such as the diseases described herein.
  • “non-human animals” include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and / or domesticated animals (such as sheep, dogs, etc.). , Cat, cow, pig, etc.).
  • Anode material Cu Palladium
  • Test method 35 ° C ⁇ 200 ° C; 10K / min; perforation on the roof.
  • DSC data was collected on a Mettler-Toledo DSC1 differential scanning calorimeter.
  • Test method 35 °C ⁇ 500 °C; 10K / min.
  • TGA data were collected on a Mettler-Toledo TGA thermogravimetric analyzer.
  • Step 1 Preparation of (((((R) -1- (6-amino-9H-purin-9-yl) -1-methyl-ethoxy) methyl) phenoxyphosphonochloride
  • Step 2 (2S)-((((1R) -2- (6-amino-9H-purine-9-yl) -1-methyl-ethoxy) methyl-phenoxy-phosphoryl) amino ) -3- (2-methylbenzyloxy) -propane
  • Step 3 (S) -P-((((R) -1- (6-amino-9H-purine-9-yl) prop-2-yl) oxy) methyl) -phenoxy-N- (2- (benzyloxy) ethyl) -phosphonamide (compound of formula (I)) and (R) -P-((((R) -1- (6-amino-9H-purine-9-yl ) Prop-2-yl) oxy) methyl) -phenoxy-N- (2- (benzyloxy) ethyl) -phosphonamide (compound of formula (II))
  • Step 1 Preparation of (((((R) -1- (6-amino-9H-purin-9-yl) -1-methyl-ethoxy) methyl) phenoxyphosphonochloride
  • Step 2 (2S)-((((1R) -2- (6-amino-9H-purine-9-yl) -1-methyl-ethoxy) methyl-phenoxy-phosphoryl) amino ) -3- (2-methylbenzyloxy) -propane
  • Method 1 XRPD analysis was performed on the obtained crystals to obtain three fumarate crystals A, B, and C.
  • the XRPD patterns of the crystals are shown in Figures 1, 4, and 5, respectively.
  • the XRPD pattern and DSC pattern of the obtained solid are shown in Figs. 1 and 2, respectively, indicating that the crystal types obtained by the above antisolvent method are all fumarate crystals A of the compound of formula (I).
  • the XRPD pattern and DSC pattern of the obtained solid are substantially the same as the XRPD pattern and DSC pattern in Example 4.2, indicating that the crystal types obtained by the above high-temperature suspension stirring method are all the fumarate crystals A of the compound of formula (I).
  • the free base (120 mg) of the compound of formula (I) was weighed and placed in a 5 ml EP tube. A 0.1 M solution of fumaric acid in methanol (2.4 ml) was added thereto, and completely dissolved until clear. Stir at room temperature for 2 h and dry the solvent under vacuum. Take half of the samples in an EP tube, add acetonitrile (1 ml), and stir at room temperature overnight. Filtered, collected solids and dried under vacuum for 5h.
  • the DSC / TGA analysis chart is shown in Figure 2/3: the sample had no weight loss before decomposition; the sample had no desolvation endothermic peak before melting point, and a sharp endothermic peak at 125 ° C (initial temperature), which is the sample melting point.
  • the molar ratio of acid to base in the sample was determined by 1 H-NMR, and no solvent remained.
  • the fumarate crystal A of the compound of formula (I) has good crystallinity, a single simple thermal signal (the baseline in the DSC spectrum is flat, the peak is narrow, single and sharp), and the melting point exceeds 100 ° C.
  • the DSC / TGA analysis chart shown in Figure 7/8 shows that the sample has a weight loss of 7.7% at about 115 ° C (starting temperature) and a broad, sharp endothermic peak at 115 ° C (starting temperature), which is the melting point of the sample.
  • the acid-base molar ratio in the sample was determined to be 1 by 1 H-NMR.
  • the DSC / TGA analysis chart is shown in Figure 11/12: the sample has no weight loss before decomposition, and the sample has no desolvation endothermic peak before melting point. There is a broad and gentle endothermic peak at 120 ° C (starting temperature). 143 ° C (starting temperature) has a broad and sharp endothermic peak, which is presumed to be a mixed crystal.
  • the molar ratio of acid to base in the sample was determined by 1 H-NMR, and no solvent remained.
  • the samples were tested by XRPD, TGA / DSC.
  • the DSC / TGA analysis spectrum is shown in Figure 14/15: the sample had a weight loss of 1.9% before 99 ° C, and there was a significant desolvation endothermic peak before the melting point on DSC, and a broader peak at 142 ° C (initial temperature) 2. The sharp endothermic peak is the melting point of the sample.
  • the fumarate crystal A of the compound of the formula (I) of the present invention has good solubility in both the water environment and the fasting intestinal fluid. And after administration, it can be quickly dissolved in the body, which is conducive to the absorption of the drug.
  • the fumarate crystal A of the compound of formula (I) has a mass change (%) of less than 0.2% under 80% and 90% humidity conditions, and has almost no hygroscopicity. Conducive to storage stability after preparation.
  • the fumarate crystals of the compound of formula (I) were filled into capsules and administered to Beagle dogs, and the doses of crystal A and crystal C were 2.5 mg / kg. Venous blood was collected at different times after administration, and the free base precursor of the compound of formula (I) and its metabolite tenofovir (TFV) were detected separately.
  • the test results are shown in Table 9-10 below:

Abstract

本发明涉及式(I)和式(II)的化合物、其手性合成及手性分离方法，还涉及式(I)的化合物的盐及其晶体形式和制备方法、包含其的药物组合物以及其在制备用于治疗诸如乙型肝炎的病毒感染性疾病的药物中的用途。

Description

膦酰胺酯化合物及其盐和相关晶体形式、制备方法和用途
相关申请的交叉引用
本申请要求2018年6月12日提交的中国专利申请201810600569.X的优先权，所述申请的公开内容以其整体援引加入本文。
发明领域
本发明涉及(S)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(在下文中称作“式(I)的化合物”)和(R)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(在下文中称作“式(II)的化合物”)、其手性合成及手性分离方法，还涉及“式(I)的化合物”的盐及其晶体形式和制备方法、包含其的药物组合物以及其在制备用于预防或治疗诸如乙型肝炎的病毒感染性疾病的药物中的用途。
发明背景
乙型肝炎病毒是一种DNA病毒，属于嗜肝DNA病毒科，其DNA的合成依赖于乙肝病毒DNA聚合酶。利用DNA聚合酶抑制剂作为抗乙肝病毒药物已经成为一个极具竞争力的选择。替诺福韦(tenofovir，PMPA)是一种核苷酸类DNA聚合酶和逆转录酶抑制剂，具有抗HBV和HIV的活性，其膦酸酯类衍生物替诺福韦二吡呋酯(TDF)和膦酰胺酯类衍生物替诺福韦艾拉酚胺(TAF)已被FDA批准用于治疗人类免疫缺陷综合征和乙型病毒肝炎。TAF克服了TDF血浆稳定性较差的缺点。TAF主要在肝细胞内通过酯酶水解、磷酸化等作用生成腺苷三磷酸类似物，后者插入新产生的DNA链，从而阻断DNA聚合酶催化的DNA合成，抑制病毒复制(WO2013025788A1；Nucleosides Nucleotides Nucleic Acids,2001,20,1085-1090)。然而，在临床III期试验中，尽管TAF比TDF在丙氨酸转氨酶(ALT)复常、骨代谢和肾脏功能等方面改善明显，但仍存在诸如以下的问题：ALT复常率<80％；10％以上患者的脊柱骨密度(BMD)降低>5％；10％以上患者肾小球滤过率降低>25％。这些问题即是未满足的临床需求，因而迫切需要新一代的更有效且更安全的治疗药物。
在申请人提交的第PCT/CN2017/117126号国际专利申请中，披露了结构新颖的膦酰胺酯类化合物，该类化合物作为替诺福韦前药，可以迅速代谢为替诺福韦，具有良好的体内外药代和药效性质。
发明概述
本发明的一个方面提供如下所示的式(I)和式(II)的化合物：
Figure PCTCN2019089744-appb-000001
本发明的另一个方面提供如以下反应路线所示的式(I)和式(II)的化合物的外消旋体的合成及其手性分离方法：
Figure PCTCN2019089744-appb-000002
本发明的另一个方面提供如以下反应路线所示的式(I)的化合物的手性合成方法：
Figure PCTCN2019089744-appb-000003
式(I)的化合物的手性合成以替诺福韦单苯酯为原料，经过氯代反应和取代反应制得非对映异构体纯度大于90％的式(I)的化合物。
本发明的另一方面提供式(I)的化合物的盐，包括式(I)的化合物的有机酸盐或无机酸盐，例如式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐、马来酸盐、琥珀酸盐、苹果酸盐、已二酸盐、乳酸盐、乙醇酸盐、黏酸盐、龙胆酸盐、草酸盐、丙二酸盐、马尿酸盐、烟酸盐、烟酰胺盐、磷酸盐、盐酸盐、硫酸盐、乙二磺酸盐、萘二磺酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、樟脑磺酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、脯氨酸盐、色氨酸盐、丝氨酸盐、酪氨酸盐、半胱氨酸盐、蛋氨酸盐、苏氨酸盐、天冬氨酸盐、谷氨酸盐、赖氨酸盐、精氨酸盐和组氨酸盐，特别是式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐和磷酸盐，更特别是式(I)的化合物的富马酸盐晶体、柠檬酸盐晶体、酒石酸盐晶体和磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体A、B和C、柠檬酸盐晶体A、酒石酸盐晶体A和B以及磷酸盐晶体A和B。优选地，在所述式(I)的化合物的盐中，式(I)的化合物与所述无机酸或所述有机酸的摩尔比为1:1或1:1/2或1:1/3，特别优选为1:1。
本发明所提供的式(I)的化合物及其盐具有以下优点：作为前药可以在动物体内迅速代谢为活性成分，进而抑制HBV病毒逆转录酶和DNA聚合酶，达到抑制HBV DNA复制的效果。本发明所提供的式(I)的化合物的盐具有很好的可制备性(便于制备)，各种盐的晶体形式中的溶剂残留较低。本发明中成盐所利用的酸具有较高的安全性，不会引起不期望的毒性。本发明所提供的式(I)的化合物的盐在动物试验中安全性良好，对肝、肾、骨代谢等无明显影响，有望减少患者长期用药造成的副作用，包括肝功能异常、肾小球滤过率降低、骨密度降低造成的疼痛和骨质疏松等问题。此外，本发明的各种盐及其晶体形式更容易以高纯度大量制备，从而更适合用于制备药物制剂，而且还可表现其它有利的物理性质(例如良好的溶解性、低引湿性(吸湿性)和良好的固态稳定性等)以及药物代谢动力学性质(例如不同的晶格能提高溶出速率以及生物利用度)等。
本发明的另一方面提供制备式(I)的化合物的盐的方法，其包括使任意固体形式的式(I)的化合物与无机酸或有机酸反应，析出固体，随后将析出的固体分离并干燥。所述析出固体的方法包括但不限于气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法、缓慢降温法等。
本发明的另一方面提供药物组合物，其包含上述式(I)的化合物的盐(例如式(I)的化合物的富马酸 盐、柠檬酸盐、酒石酸盐或磷酸盐，特别是式(I)的化合物的富马酸盐晶体、柠檬酸盐晶体、酒石酸盐晶体或磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体)或其任意组合，以及一种或多种药学上可接受的载体。
本发明的另一方面提供用于治疗个体的病毒感染性疾病如乙型肝炎的方法，其包括向有此需要的个体给药治疗有效量的上述式(I)的化合物或其盐(例如式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐，特别是式(I)的化合物的富马酸盐晶体、柠檬酸盐晶体、酒石酸盐晶体或磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体)，或其任意组合。
本发明的另一方面提供上述式(I)的化合物或其盐(例如式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐，特别是式(I)的化合物的富马酸盐晶体、柠檬酸盐晶体、酒石酸盐晶体或磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体)或其任意组合，其用于治疗个体的病毒感染性疾病如乙型肝炎。
本发明的另一方面提供上述式(I)的化合物或其盐(例如式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐，特别是式(I)的化合物的富马酸盐晶体、柠檬酸盐晶体、酒石酸盐晶体或磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体)或其任意组合在制备用于治疗个体的病毒感染性疾病如乙型肝炎的药物中的用途。
本发明的式(I)的化合物的盐的晶体具有一种或多种以下有利性质：
i)高溶解度、高溶出率、低吸湿性、高流动性或明显改善的粘黏性。
ii)优良的物理化学稳定性，包括但不限于光稳定性、热稳定性、耐高湿性等。例如，良好的光稳定性可保证所述晶体在储存和运输时的可靠性，从而保证制剂的安全性；使得所述晶体不需要为防止受光照影响而采取特殊包装处理，从而降低了成本；使得所述晶体不会因光照影响产生降解，从而提高了制剂的安全性和长期贮藏后的有效性；并且使得服用所述晶体的患者不会担忧制剂因暴露于日光下而产生光敏反应。良好的热稳定性使得所述晶体能够保持长时间稳定，且适用于标准的制剂生产过程。良好的物理化学稳定性使所述晶体易于制备并且更适合用于制剂的制备。
iii)改善的代谢、提高的生物利用度、降低的毒性或提高的安全性。
iv)适合和便于大量制备，节约成本。
附图说明
图1显示式(I)的化合物的富马酸盐晶体A的XRPD图谱。
图2显示式(I)的化合物的富马酸盐晶体A的DSC图谱。
图3显示式(I)的化合物的富马酸盐晶体A的TGA图谱。
图4显示式(I)的化合物的富马酸盐晶体B的XRPD图谱。
图5显示式(I)的化合物的富马酸盐晶体C的XRPD图谱。
图6显示式(I)的化合物的柠檬酸盐晶体A的XRPD图谱。
图7显示式(I)的化合物的柠檬酸盐晶体A的DSC图谱。
图8显示式(I)的化合物的柠檬酸盐晶体A的TGA图谱。
图9显示式(I)的化合物的酒石酸盐晶体A的XRPD图谱。
图10显示式(I)的化合物的酒石酸盐晶体B的XRPD图谱。
图11显示式(I)的化合物的酒石酸盐晶体B的DSC图谱。
图12显示式(I)的化合物的酒石酸盐晶体B的TGA图谱。
图13显示式(I)的化合物的磷酸盐晶体A的XRPD图谱。
图14显示式(I)的化合物的磷酸盐晶体A的DSC图谱。
图15显示式(I)的化合物的磷酸盐晶体A的TGA图谱。
图16显示式(I)的化合物的磷酸盐晶体B的XRPD图谱。
图17显示式(I)的化合物的富马酸盐晶体A的单晶分子立体结构图谱。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领 域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用的词语“约”是指本领域的普通技术人员认为在所述值的可接受的标准误差内，例如±0.05、±0.1、±0.2、±0.3、±1、±2或±3等。
本发明所使用的术语“式(I)的化合物的盐”包括式(I)的化合物的无机酸盐或有机酸盐，例如但不限于式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐、马来酸盐、琥珀酸盐、苹果酸盐、已二酸盐、乳酸盐、乙醇酸盐、黏酸盐、龙胆酸盐、草酸盐、丙二酸盐、马尿酸盐、烟酸盐、烟酰胺盐、磷酸盐、盐酸盐、硫酸盐、乙二磺酸盐、萘二磺酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、樟脑磺酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、脯氨酸盐、色氨酸盐、丝氨酸盐、酪氨酸盐、半胱氨酸盐、蛋氨酸盐、苏氨酸盐、天冬氨酸盐、谷氨酸盐、赖氨酸盐、精氨酸盐和组氨酸盐。
本发明所使用的术语“固体形式”包括式(I)的化合物和式(I)的化合物的盐的所有固态形式，例如晶体形式或无定形形式。
如本文中所使用的术语“无定形”是指三维上无排序的任意固体物质。在一些情况中，无定形固体可通过已知技术表征，所述技术包括XRPD晶体学、固态核磁共振(ssNMR)波谱学、DSC或这些技术的一些组合。如以下所说明，无定形固体产生弥散的XRPD图谱，其通常包括一个或两个宽峰(即具有约5°2θ或更大的基宽的峰)。
如本文中所使用的术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定形固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。
如本文中所使用的术语“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。
如本文中所使用的术语“2θ”是指基于X射线衍射实验的实验设置的以度数表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果当入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶体形式的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。
如本文中所使用的术语“热重分析(TGA)图谱”是指由热重分析仪记录到的曲线。
如本文中所使用的术语“差示扫描量热(DSC)图谱”是指由差示扫描量热仪记录到的曲线。
如本文中所使用的术语“核磁共振( 1H-NMR)图谱”是指由核磁共振仪记录到的信号峰。
如本文中所使用的，对于X射线衍射峰位的术语“基本上相同”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1-0.2度，并且用于测量衍射的仪器也会显示一些变化。另外，本领域技术人员会理解相对峰强度会显示仪器间的变化以及由于结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素的变化，并应将其看作仅为定性测量。相似地，如本文中所使用，对于DSC图谱和TGA图谱的“基本上相同”也意图涵盖本领域技术人员已知的与这些分析技术有关的变化。例如，对于边界清楚的峰，在差示扫描量热图谱通常会具有多达±0.2℃的变化，对于宽峰甚至更大(例如多达±1℃)。
如本文中所使用的术语“良溶剂”意指用于溶解本发明的(I)化合物或者(I)化合物盐的溶剂。
如本文中所使用的术语“反溶剂”意指用于降低待结晶物在良溶剂中的溶解性的溶剂。
如本文中所使用的术语“反溶剂结晶法”意指将良溶剂与反溶剂结合使用，从而降低待结晶物在良溶剂中的溶解性的方法。按照溶剂的添加顺序，反溶剂结晶法可分为反溶剂添加法和反反溶剂添加法。反溶剂添加法是将待结晶物溶解于良溶剂中，然后向其中添加反溶剂从而析晶的方法，而反反溶剂添加法则是将待结晶物溶解于良溶剂中，然后将所得的溶液加入到反溶剂中从而析晶的方法。
如本文中所使用的术语“烃类”优选意指具有1-10个碳原子的烃，其包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类，包括但不限于二氯甲烷、三氯甲烷(氯仿)、正己烷、正庚烷和甲苯。
如本文中所使用的术语“醇类”优选意指具有1-10个碳原子的醇，其包括但不限于甲醇、乙醇、1-丙醇(正丙醇)、2-丙醇(异丙醇)、1-丁醇、2-丁醇和叔丁醇。
如本文中所使用的术语“醚类”优选意指具有2-6个碳原子的醚，其包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类)，具体包括但不限于乙醚、二异丙基醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、二氧六环、环戊基甲醚、苯甲醚和二甲氧基乙烷。
如本文中所使用的术语“腈类”优选意指具有2-6个碳原子的腈，其包括但不限于乙腈和丙腈。
如本文中所使用的术语“酮类”优选意指具有2-6个碳原子的酮，其包括但不限于丙酮、丁酮、甲基乙基酮、甲基异丁基酮和二乙基酮。
如本文中所使用的术语“酯类”优选意指具有3-10个碳原子的酯，其包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、异丙酸乙酯、碳酸二甲酯和乙酸丁酯。
如本文中所使用的术语“有机酸类”优选意指具有1-10个碳原子的有机酸，其包括但不限于甲酸和乙酸。
如本文中所使用的术语“砜类”优选意指具有2-10个碳原子的砜或亚砜，其包括但不限于二甲基亚砜。
如本文中所使用的术语“酰胺类”优选意指具有1-10个碳原子的酰胺，其包括但不限于二甲基甲酰胺或二甲基乙酰胺。
如本文中所使用的术语“氮杂环类”优选意指具有3-10个碳原子和至少一个氮原子的含氮杂环，其包括但不限于N-甲基吡咯烷酮。
如本文中所使用的数值范围(如“1-10个”)及其子范围(如“2-10个”、“2-6个”、“3-10个”)等涵盖所述数值范围中的任意个(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个)，且不限于整数。
本文中可使用实线
Figure PCTCN2019089744-appb-000004
波浪线
Figure PCTCN2019089744-appb-000005
实楔形
Figure PCTCN2019089744-appb-000006
或虚楔形
Figure PCTCN2019089744-appb-000007
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称原子的键欲表明，包括该原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用波浪线以描绘键连至不对称原子的键欲表明，该键为实楔形
Figure PCTCN2019089744-appb-000008
或虚楔形
Figure PCTCN2019089744-appb-000009
键中的任意一种。使用实或虚楔形以描绘键连至不对称原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。
应当理解用不同类型设备或用不同的测试条件可能会给出略有差异的DSC图谱。例如可以使用Mettler Toledo DSC1差示扫描量热仪测定DSC图谱。如本文中所使用的，对于DSC图谱的术语“基本上相同”会将代表性特征峰位考虑在内。例如，本领域技术人员会理解特征峰位会显示一些变化，通常多达5℃。对于存在多晶型的固体样品来说，DSC测试的升温速率对DSC图谱的影响较大。在较快的升温速率下，仪器热滞后效应明显，高熔点固体晶型来不及重结晶，因此，DSC图谱往往仅仅出现低熔点晶型的熔化吸热峰。在中等升温速率下，DSC图谱则显示两个峰：低熔点晶型熔化吸热峰和高熔点晶型熔化吸热峰；而只有在较低的升温速率下，仪器热滞后效应较弱的情况下，才会出现三个峰：低熔点晶型的熔化峰-重结晶放热峰-高熔点晶体的熔化吸热峰。本技术人员会理解，上述不同DSC图谱所对应的升温速率范围的确定，会因测试品的重量、形态、粒度大小及分布的不同而存在差异(参考文献:Giron D.Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates[J].Thermochimica Acta,1995,248:1-59.)。
可将制备的式(I)的化合物的固体形式、式(I)的化合物的盐或其晶体形式通过包括倾析、离心、蒸发、重力过滤、抽滤或者在加压下或在减压下的任何其它用于固体回收的技术在内的方法进行回收。可将回收的固体任选地进行干燥。本发明中的“干燥”是在减压(优选真空)下进行直到残留溶剂的含量降低至International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(“ICH”)指南所给出的限度的范围内。残留溶剂含量取决于溶剂的类型，但不超过约5000ppm、或优选约4000ppm、或更优选约3000ppm。所述干燥可以在盘式干燥器、真空烘箱、空气烘箱、锥形真空干燥器(cone vacuum dryer)、旋转式真空干燥器、流化床干燥器、旋转闪蒸干燥器、快速干燥器等中进行。所述干燥可以在低于约100℃、低于约80℃、低于约60℃、低于约50℃、低于约30℃的温度或任何其它合适的温度下，在大气压或减压(优选真空)下在能够实现期望的结果的任何期望的时间内(如约1、2、3、5、10、15、20、24小时或者过夜)进行，只要产物的品质不劣化。所述干燥可以进行任何期望的次数，直到实现所需的产物品质。干燥的产物可以任选地经历粉碎操作，以产生期望的粒度。可在产物的干燥前或干燥完成后进行研磨或微粉化。可用于减小粒度的技术包括但不限于球磨、辊磨和锤磨，以及喷射研磨(jet milling)。
如本文中所使用的术语“无水晶型”优选意指其中不含有水分子作为结构要素的晶型。
式(I)和式(II)的化合物及其制备方法：
本发明的一个目的在于提供以下所示的式(I)和式(II)的化合物及其制备方法，
Figure PCTCN2019089744-appb-000010
根据本发明的一个实施方案，本发明提供如以下反应路线所示的式(I)和式(II)的化合物的外消旋体的合成及其手性分离方法：
Figure PCTCN2019089744-appb-000011
步骤一：
以替诺福韦单苯酯为原料，经与氯代试剂反应，制得中间体替诺福韦单苯酯膦酰氯。所述氯代试剂包括但不限于二氯亚砜、三氯氧磷、五氯化磷、草酰氯等。
步骤二：
使步骤一中获得的替诺福韦单苯酯膦酰氯与2-(苄氧基)乙胺反应，制得膦酰胺酯外消旋体产物。
步骤三：
通过将步骤二中获得的膦酰胺酯外消旋体经手性色谱法分离制得式(I)和式(II)的化合物。
根据本发明的另一实施方案，本发明提供如以下反应路线所示的式(I)的化合物的手性制备方法：
Figure PCTCN2019089744-appb-000012
在所述手性制备方法的优选实施方案中，步骤一包括：在诸如甲苯、二甲苯、苯甲醚、乙腈等溶剂中，在50-120℃(优选80-110℃，更优选90-100℃)的温度下，使(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基)甲基)膦酸单苯酯(替诺福韦单苯酯)与诸如二氯亚砜、三氯氧磷、五氯化磷、草酰氯的氯代试剂反应，制得中间体((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基膦酰氯；步骤二包括：使步骤一中获得的中间体((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基膦酰氯与2-(苄氧基)乙胺反应，制得非对映异构体纯度大于90％的式(I)的化合物。
式(Ia)的化合物的盐及其晶体和制备方法
式(I)的化合物的富马酸盐
本发明的一个目的在于提供如下所示的式(I)的化合物的富马酸盐：
Figure PCTCN2019089744-appb-000013
其中n为1或1/2，优选为1。换言之，在式(I)的化合物的富马酸盐中，式(I)的化合物与富马酸的摩尔比为1:1或1:1/2，优选为1:1。
根据本发明的一个实施方案，本发明提供式(I)的化合物的富马酸盐晶体A，其中式(I)的化合物与富马酸的摩尔比为1:1。所述式(I)的化合物的富马酸盐晶体A的XRPD图谱包括在5.1±0.2°、6.4±0.2°、16.3±0.2°、18.7±0.2°、28.2±0.2°的衍射角(2θ)处的特征峰。在优选的实施方案中，所述式(I)的化合物的富马酸盐晶体A的XRPD图谱包括在5.1±0.2°、6.4±0.2°、14.7±0.2°、15.3±0.2°、16.3±0.2°、18.0±0.2°、18.7±0.2°、19.2±0.2°、28.2±0.2°、29.6±0.2°的衍射角(2θ)处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 2θ(°)±0.2°
5.1 20.0
6.4 20.7
12.9 22.2
14.7 24.0
15.3 24.9
16.3 25.3
18.0 27.8
18.7 28.2
18.9 29.6
19.2 -
在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.1 59.1 20.0 11.4
6.4 100.0 20.7 11.2
12.9 17.8 22.2 11.3
14.7 45.0 24.0 13.5
15.3 32.4 24.9 12.7
16.3 39.9 25.3 17.6
18.0 25.6 27.8 18.8
18.7 31.8 28.2 73.8
18.9 19.4 29.6 21.2
19.2 29.1 - -
在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体A的XRPD图谱包括与图1所示基本上相同的衍射角(2θ)处的峰。在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体A的XRPD峰位与图1所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的富马酸盐晶体A的DSC图谱包括在约125±5℃(起始温度)、优选约125±2℃(起始温度)、更优选约125±0.2℃(起始温度)处的特征峰。在进一步优选的实施方案中，所述式(I)的化合物的富马酸盐晶体A的DSC图谱包括与图2所示基本上相同的温度处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体A的DSC图谱的特征峰位与图2所示基本上相同。
在特别优选实施方案中，本发明的式(I)的化合物的富马酸盐晶体A为非溶剂合物。在更优选的实施方案中，本发明的式(I)的化合物的富马酸盐晶体A为无水晶型。
在优选的实施方案中，本发明的式(I)的化合物的富马酸盐晶体A具有如下的晶胞参数：
晶胞尺寸：
Figure PCTCN2019089744-appb-000014
Figure PCTCN2019089744-appb-000015
Figure PCTCN2019089744-appb-000016
α/°＝90
β/°＝96.113(6)
γ/°＝90
晶胞体积：
Figure PCTCN2019089744-appb-000017
晶系：单斜晶系
空间群：P2 1
分子内不对称单位数Z＝2。
根据本发明的另一实施方案，本发明提供式(I)的化合物的富马酸盐晶体B，其中式(I)的化合物与富马酸的摩尔比为1:1。所述式(I)的化合物的富马酸盐晶体B的XRPD图谱包括在10.2±0.2°、10.8±0.2°、17.1±0.2°、18.8±0.2°、21.7±0.2°的衍射角(2θ)处的特征峰。在优选的实施方案中，所述式(I)的化合物的富马酸盐晶体B的XRPD图谱包括在9.7±0.2°、10.2±0.2°、10.8±0.2°、14.7±0.2°、17.1±0.2°、18.1±0.2°、18.8±0.2°、19.2±0.2°、20.6±0.2°、21.7±0.2°的衍射角(2θ)处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体B的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 2θ(°)±0.2°
9.7 18.8
10.2 19.2
10.8 20.6
11.8 21.7
13.2 22.3
13.8 23.8
14.7 26.7
16.1 27.0
17.1 27.5
18.1 29.3
在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体B的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
9.7 33.0 18.8 53.2
10.2 100.0 19.2 28.7
10.8 72.1 20.6 36.0
11.8 10.2 21.7 39.1
13.2 12.6 22.3 16.6
13.8 17.9 23.8 10.2
14.7 18.7 26.7 18.1
16.1 18.5 27.0 14.4
17.1 47.9 27.5 10.8
18.1 33.4 29.3 12.1
在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体B的XRPD图谱包括与图4所示基本上相同的衍射角(2θ)处的峰。在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体B的XRPD峰位与图4所示基本上相同。
根据本发明的另一实施方案，本发明提供式(I)的化合物的富马酸盐晶体C，其中式(I)的化合物与富马酸的摩尔比为1:1。所述式(I)的化合物的富马酸盐晶体C的XRPD图谱包括在4.3±0.2°、6.8±0.2°、14.3±0.2°、18.8±0.2°、27.9±0.2°的衍射角(2θ)处的特征峰。在优选的实施方案中，所述式(I)的化合物的富马酸盐晶体C的XRPD图谱包括在4.3±0.2°、6.6±0.2°、6.8±0.2°、14.3±0.2°、16.6±0.2°、18.5±0.2°、18.8±0.2°、19.2±0.2°、27.6±0.2°、27.9±0.2°的衍射角(2θ)处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体C的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 2θ(°)±0.2°
4.3 18.5
6.6 18.8
6.8 19.2
13.0 20.1
14.3 22.6
15.3 23.3
15.8 25.8
16.2 26.2
16.6 27.6
17.3 27.9
在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体C的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
4.3 100.0 18.5 22.5
6.6 20.4 18.8 47.5
6.8 32.1 19.2 27.3
13.0 11.2 20.1 11.8
14.3 31.0 22.6 13.8
15.3 12.2 23.3 11.0
15.8 15.4 25.8 15.4
16.2 20.2 26.2 11.8
16.6 26.4 27.6 27.5
17.3 10.4 27.9 33.6
在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体C的XRPD图谱包括与图5所示基本上相同的衍射角(2θ)处的峰。在特别优选的实施方案中，所述式(I)的化合物的富马酸盐晶体C的XRPD峰位与图5所示基本上相同。
式(I)的化合物的柠檬酸盐
本发明的一个目的在于提供如下所示的式(I)的化合物的柠檬酸盐：
Figure PCTCN2019089744-appb-000018
其中n为1或1/2或1/3，优选为1。换言之，在式(I)的化合物的柠檬酸盐中，式(I)的化合物与柠檬酸的摩尔比为1:1或1:1/2或1:1/3，优选为1:1。
根据本发明的一个实施方案，本发明提供式(I)的化合物的柠檬酸盐晶体A，其中式(I)的化合物与柠檬酸的摩尔比为1:1。所述式(I)的化合物的柠檬酸盐晶体A的XRPD图谱包括在7.6±0.2°、14.1±0.2°、15.5±0.2°、16.0±0.2°、20.7±0.2°的衍射角(2θ)处的特征峰。在优选的实施方案中，所述式(I)的化合物的柠檬酸盐晶体A的XRPD图谱包括在7.6±0.2°、14.1±0.2°、14.9±0.2°、15.5±0.2°、16.0±0.2°、19.6±0.2°、20.7±0.2°、21.4±0.2°、22.5±0.2°、24.5±0.2°的衍射角(2θ)处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的柠檬酸盐晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
7.6 35.7 20.7 63.5
14.1 38.6 21.4 20.5
14.9 23.8 22.5 26.3
15.5 57.3 24.5 22.9
16.0 100.0 28.5 6.3
19.6 13.3 - -
在特别优选的实施方案中，所述式(I)的化合物的柠檬酸盐晶体A的XRPD图谱包括与图6所示基本上相同的衍射角(2θ)处的峰。在特别优选的实施方案中，所述式(I)的化合物的柠檬酸盐晶体A 的XRPD峰位与图6所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的柠檬酸盐晶体A的DSC图谱包括在约115±5℃(起始温度)、优选约115±2℃(起始温度)、更优选约115±0.2℃(起始温度)处的特征峰。在进一步优选的实施方案中，所述式(I)的化合物的柠檬酸盐晶体A的DSC图谱包括与图7所示基本上相同的温度处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的柠檬酸盐的晶体A的DSC图谱的特征峰位与图7所示基本上相同。
在特别优选实施方案中，本发明的式(I)的化合物的柠檬酸盐晶体A为非溶剂合物。在更优选的实施方案中，本发明的式(I)的化合物的柠檬酸盐晶体A为无水晶型。
式(I)的化合物的酒石酸盐
本发明的一个目的在于提供如下所示的式(I)的化合物的酒石酸盐：
Figure PCTCN2019089744-appb-000019
其中n为1或1/2，优选为1。换言之，在式(I)的化合物的酒石酸盐中，式(I)的化合物与酒石酸的摩尔比为1:1或1:1/2，优选为1:1。
根据本发明的一个实施方案，本发明提供式(I)的化合物的酒石酸盐晶体A，其中式(I)的化合物与酒石酸的摩尔比为1:1。所述式(I)的化合物的酒石酸盐晶体A的XRPD图谱包括在16.9±0.2°、17.2±0.2°、18.7±0.2°、19.2±0.2°、21.9±0.2°的衍射角(2θ)处的特征峰。在优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体A的XRPD图谱包括在4.5±0.2°、6.8±0.2°、10.9±0.2°、16.9±0.2°、17.2±0.2°、17.9±0.2°、18.7±0.2°、19.1±0.2°、19.2±0.2°、21.9±0.2°的衍射角(2θ)处的特征峰。在更优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体A的XRPD图谱包括在3.9±0.2°、4.5±0.2°、6.8±0.2°、7.3±0.2°、9.1±0.2°、10.2±0.2°、10.9±0.2°、14.2±0.2°、16.4±0.2°、16.9±0.2°、17.2±0.2°、17.9±0.2°、18.7±0.2°、19.1±0.2°、19.2±0.2°、21.9±0.2°、22.8±0.2°、25.7±0.2°、27.6±0.2°的衍射角(2θ)处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
3.9 16.7 16.9 100.0
4.5 26.5 17.2 45.3
6.8 22.5 17.9 21.2
7.3 11.5 18.7 55.4
9.1 10.6 19.1 30.3
10.2 11.0 19.2 38.9
10.9 18.8 21.9 34.7
11.5 7.1 22.8 8.9
13.7 6.4 25.7 16.6
14.2 10.3 27.6 8.9
16.4 10.6 - -
在特别优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体A的XRPD图谱包括与图9所示基本上相同的衍射角(2θ)处的峰。在特别优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体A的XRPD峰位与图9所示基本上相同。
根据本发明的另一实施方案，本发明提供式(I)的化合物的酒石酸盐晶体B，其中式(I)的化合物与酒石酸的摩尔比为1:1。所述式(I)的化合物的酒石酸盐晶体B的XRPD图谱包括在7.3±0.2°、17.2±0.2°、17.8±0.2°、18.2±0.2°、19.2±0.2°的衍射角(2θ)处的特征峰。在优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体B的XRPD图谱包括在7.3±0.2°、17.2±0.2°、17.8±0.2°、18.2±0.2°、18.5±0.2°、18.8±0.2°、19.2±0.2°、19.6±0.2°、20.0±0.2°、21.9±0.2°的衍射角(2θ)处的特征峰。在更优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体B的XRPD图谱包括在3.9±0.2°、7.3± 0.2°、7.8±0.2°、8.4±0.2°、9.8±0.2°、14.6±0.2°、15.6±0.2°、17.2±0.2°、17.5±0.2°、17.8±0.2°、18.2±0.2°、18.5±0.2°、18.8±0.2°、19.2±0.2°、19.6±0.2°、20.0±0.2°、20.6±0.2°、21.9±0.2°、22.3±0.2°、23.7±0.2°的衍射角(2θ)处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体B的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
3.9 20.0 18.5 63.1
7.3 100.0 18.8 63.5
7.8 29.9 19.2 87.8
8.4 18.5 19.6 63.7
8.8 15.3 20.0 54.6
9.8 21.1 20.6 24.4
14.6 35.4 21.9 46.4
15.6 20.0 22.3 21.1
16.2 13.3 23.7 23.1
17.2 87.6 25.1 11.4
17.5 44.4 25.8 10.2
17.8 65.8 28.3 9.9
18.2 65.3 29.7 10.9
在特别优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体B的XRPD图谱包括与图10所示基本上相同的衍射角(2θ)处的峰。在特别优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体B的XRPD峰位与图10所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的酒石酸盐晶体B的DSC图谱包括在约143±5℃(起始温度)、优选约143±2℃(起始温度)、更优选约143±0.2℃(起始温度)处的特征峰。在进一步优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体B的DSC图谱包括与图11所示基本上相同的温度处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的酒石酸盐晶体B的DSC图谱的特征峰位与图11所示基本上相同。
在特别优选实施方案中，本发明的式(I)的化合物的酒石酸盐晶体B为非溶剂合物。在更优选的实施方案中，本发明的式(I)的化合物的酒石酸盐晶体B为无水晶型。
式(I)的化合物的磷酸盐
本发明的一个目的在于提供如下所示的式(I)的化合物的磷酸盐：
Figure PCTCN2019089744-appb-000020
其中n为1或1/2或1/3，优选为1。换言之，在式(I)的化合物的磷酸盐中，式(I)的化合物与磷酸的摩尔比为1:1或1:1/2或1:1/3，优选为1:1。
根据本发明的一个实施方案，本发明提供式(I)的化合物的磷酸盐晶体A。所述式(I)的化合物的磷酸盐晶体A的XRPD图谱包括在5.3±0.2°、14.5±0.2°、17.3±0.2°、18.6±0.2°、19.5±0.2°的衍射角(2θ)处的特征峰。在优选的实施方案中，所述式(I)的化合物的磷酸盐晶体A的XRPD图谱包括在5.3±0.2°、7.9±0.2°、14.5±0.2°、16.3±0.2°、17.3±0.2°、18.6±0.2°、19.5±0.2°、20.4±0.2°、20.7±0.2°、23.1±0.2°的衍射角(2θ)处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的磷酸盐晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.3 100.0 19.5 41.7
7.9 13.0 20.4 16.5
14.5 26.0 20.7 11.9
16.3 16.0 23.1 10.6
17.3 30.3 27.0 6.9
18.6 19.4 32.5 7.5
在特别优选的实施方案中，所述式(I)的化合物的磷酸盐晶体A的XRPD图谱包括与图13所示基本上相同的衍射角(2θ)处的峰。在特别优选的实施方案中，所述式(I)的化合物的磷酸盐晶体A的XRPD峰位与图13所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的磷酸盐晶体A的DSC图谱包括在约142±5℃、优选约142±2℃、更优选约142±0.2℃处的特征峰。在进一步优选的实施方案中，所述式(I)的化合物的磷酸盐晶体A的DSC图谱包括与图14所示基本上相同的温度处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的磷酸盐晶体A的DSC图谱的特征峰位与图14所示基本上相同。
在特别优选实施方案中，本发明的式(I)的化合物的磷酸盐晶体A为非溶剂合物。在更优选的实施方案中，本发明的式(I)的化合物的磷酸盐晶体A为无水晶型。
根据本发明的另一个实施方案，本发明提供式(I)的化合物的磷酸盐晶体B。所述式(I)的化合物的磷酸盐晶体B的XRPD图谱包括在7.9±0.2°、15.9±0.2°、16.3±0.2°、18.8±0.2°、24.2±0.2°的衍射角(2θ)处的特征峰。在优选的实施方案中，所述式(I)的化合物的磷酸盐晶体B的XRPD图谱包括在7.9±0.2°、10.4±0.2°、12.2±0.2°、15.9±0.2°、16.3±0.2°、18.8±0.2°、19.4±0.2°、20.0±0.2°、24.2±0.2°、24.7±0.2°的衍射角(2θ)处的特征峰。在特别优选的实施方案中，所述式(I)的化合物的磷酸盐晶体B的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
7.9 84.2 20.0 21.0
10.4 21.9 21.9 13.3
11.8 12.7 23.1 10.1
12.2 18.6 24.2 36.1
15.9 69.1 24.7 20.5
16.3 50.3 26.2 13.9
18.8 100.0 27.8 15.0
19.4 24.9    
在特别优选的实施方案中，所述式(I)的化合物的磷酸盐晶体B的XRPD图谱包括与图16所示基本上相同的衍射角(2θ)处的峰。在特别优选的实施方案中，所述式(I)的化合物的磷酸盐晶体B的XRPD峰位与图16所示基本上相同。
本发明的另一目的在于提供制备上述式(I)的化合物的盐(包括但不限于富马酸盐、柠檬酸盐、酒石酸盐和盐酸盐)及其各种晶体形式的方法，其包括使任意固体形式的式(I)的化合物与所述无机酸或所述有机酸反应，析出固体，随后将析出的固体分离并干燥。所述析出固体的方法包括但不限于：气固渗透法、反溶剂添加法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法、缓慢降温法、反反溶剂添加法等。也就是说，上述本发明的式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐和盐酸盐的各种晶体形式可通过气固渗透法、反溶剂添加法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法、缓慢降温法或反反溶剂添加法进行制备。
根据本发明的一些实施方案，采用气固渗透法制备晶体，所述方法包括将装有式(I)的化合物的盐的第一容器放置于装有溶剂的第二容器中，其中所述固态形式的式(I)的化合物的盐与所述溶剂不直接接触，将第二容器密封，放置后得到晶体。在采用气固渗透法制备晶体的一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)和有机溶剂(例如醇类、酰胺类、砜类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、腈类和酯类，例如甲醇、乙醇、异丙醇、三氯甲烷、丙酮、乙酸异丙酯、甲基叔丁基醚、四氢呋喃、二氧六环、乙腈、二氯甲烷、N,N-二甲基甲酰胺、二甲亚砜、乙酸乙酯等)。在采用气固渗透法制备晶体的一些实施方案中，所述式(I)的化合物的盐与溶剂的重量体积比(mg/mL)为约(1-20):1，优选(2-10):1。在采用气固渗透法制备晶体的一些实施方案中，所述放置析晶包括静置或搅拌析晶，优选静置析晶。
根据本发明的一些实施方案，采用反溶剂添加法制备晶体，所述方法包括但不限于将式(I)的化合物的盐在良溶剂中溶解，形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，然后向所述澄清溶液中添加反溶剂，在搅拌(所述搅拌可在室温或者降温条件(例如降温至0-20℃，优选0-10℃，例如0℃、5℃或10℃下进行)下析出晶体，或者静置(例如于室温下放置)(优选同时缓慢地挥发溶剂)从而析出晶体。在采用反溶剂添加法制备晶体的一些实施方案中，所述良溶剂包括但不限于有机溶剂，例如醇类、酮类、腈类、烃类(选自卤代烷烃类、芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、砜类、酯类、酰胺类和有机酸类，例如甲醇、乙醇、丙酮、乙腈、四氢呋喃、二甲基亚砜、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、甲基乙基酮、乙酸乙酯、2-甲基四氢呋喃、环戊基甲醚、苯甲醚、甲苯、二氯甲烷等。在采用反溶剂添加法制备晶体的一些实施方案中，所述反溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如烃类(选自烷烃类、烯烃类、炔烃类)，例如正己烷、正庚烷、环己烷等)。在采用反溶剂添加法制备晶体的一些实施方案中，所述良溶剂与反溶剂的体积比为1:(1-60)，优选为1:(1-40)。在一些实施方案中，所述式(I)的化合物的盐与良溶剂的重量体积比(mg/mL)为(1-80):1，优选为(1-40):1。
在通过反溶剂添加法析出固体的一些实施方案中，通过以下方法制备式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐、磷酸盐的各种晶体形式：使任意固体形式(例如晶型或无定形)的式(I)的化合物与富马酸、柠檬酸、酒石酸或磷酸在良溶剂中反应，反应结束后向其中添加反溶剂，在搅拌(所述搅拌可在室温或者降温条件(例如降温至0-20℃，优选0-10℃，例如0℃、5℃或10℃)下进行)下析出晶体，或者静置(例如于室温下放置)(优选同时缓慢地挥发溶剂)从而析出晶体，随后将析出的晶体分离并干燥。所述良溶剂与反溶剂的体积比为1:(1-60)，优选为1:(1-40)。所述式(I)的化合物的盐与良溶剂的重量体积比(mg/mL)为(1-80):1，优选为(10-40):1。
根据本发明的一些实施方案，采用室温悬浮搅拌法制备晶体，所述方法包括但不限于将式(I)的化合物的盐加入溶剂中得到悬浮液，于室温搅拌，然后分离得到晶体。在采用室温悬浮搅拌法制备晶体的一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(如醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类、腈类、酰胺类和有机酸类，例如甲基叔丁基醚、异丙醇、乙酸异丁酯、甲醇、丙酮、四氢呋喃、乙腈、二甲亚砜、2-甲基四氢呋喃、二氯甲烷、乙酸乙酯、甲苯等)，或者选自上述溶剂中的两种或更多种的混合溶剂。在采用室温悬浮搅拌法制备晶体的一些实施方案中，所述式(I)的化合物的盐与溶剂的重量体积比(mg/mL)为(1-80):1，优选(1-50):1。
根据本发明的一些实施方案，采用高温悬浮搅拌法制备晶体，所述方法包括但不限于将式(I)的化合物的盐加入至溶剂中，得到悬浮液，将所述悬浮液加热(例如加热至40-100℃，优选40-80℃，例如45℃、50℃、55℃、60℃、65℃或70℃)搅拌，然后分离得到晶体。在采用高温悬浮搅拌法制备晶体的一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(如醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类、腈类、砜类、酰胺类以及氮杂环类，例如甲基乙基酮、异丁醇、乙酸异丁酯、甲醇、丙酮、四氢呋喃、乙腈、二甲亚砜、2-甲基四氢呋喃、三氯甲烷、乙酸乙酯、甲苯、正己烷等)，或者选自上述溶剂中的两种或更多种的混合溶剂。在采用高温悬浮搅拌法制备晶体的一些实施方案中，所述式(I)的化合物的盐与溶剂的重量体积比(mg/mL)为(1-80):1，优选(5-60):1。
根据本发明的一些实施方案，采用气液渗透法制备晶体，所述方法包括将式(I)的化合物的盐在第一容器的良溶剂中溶解以形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，向第二容器中装入反溶剂，将第一容器敞口放置于第二容器中，将第二容器密封并静置，将析出的固体过滤得到晶体。在采用气液渗透法制备晶体的一些实施方案中，所述良溶剂包括但不限于有机溶剂，例如烃类(选自卤代烷烃类和芳烃类)、醇类、酮类、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类、腈类、砜类、酰胺类以及氮杂环类等，具体例如甲醇、乙醇、丙酮、四氢呋喃、乙腈、二甲亚砜、异丙醇、甲基异丁基酮、乙酸异丙酯、甲基叔丁基醚、1,4-二氧六环、苯甲醚、环戊基甲醚、甲苯、三氯甲烷，或者由上述溶剂中的两种或更多种形成的混合溶剂。在采用气液渗透法制备晶体的一些实施方案中，所述反溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如烃类(选自烷烃类、烯烃类、炔烃类)，例如正己烷、正庚烷、环己烷等)，或者由上述溶剂中的 两种或更多种形成的混合溶剂。在采用气液渗透法制备晶体的一些实施方案中，所述式(I)的化合物的盐与良溶剂的重量体积比(mg/mL)为约(1-80):1，优选(10-60):1。在一些实施方案中，所述反溶剂与良溶剂的体积比为1:(1-20)，优选1:(1-10)。在一些实施方案中，所述将第二容器密封并静置可在室温下进行。
根据本发明的一些实施方案，采用室温缓慢挥发法制备晶体，所述方法包括将式(I)的化合物的盐在容器中的溶剂中溶解形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，将容器密封(例如使用封口膜)，在封口处留小孔或缝隙，将所述澄清溶液放置，使溶剂挥发，得到晶体。在采用室温缓慢挥发法制备晶体的一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如醇类、酰胺类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酮类、腈类或酯类，具体例如异丙醇、甲基乙基酮、乙酸异丙酯、2-甲基四氢呋喃、环戊基甲醚、甲醇、丙酮、乙腈、乙酸乙酯、正己烷、四氢呋喃、二氯甲烷等)，或者由上述溶剂中的两种或更多种形成的混合溶剂。在采用室温缓慢挥发法制备晶体的一些实施方案中，所述式(I)的化合物的盐与溶剂的重量体积比(mg/mL)为(1-50):1，优选(1-30):1。在一些实施方案中，所述放置可在室温下进行。
在通过室温缓慢挥发法析出固体的一些实施方案中，通过以下方法制备式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐、磷酸盐的各种晶体形式：使任意固体形式(例如晶型或无定形)的式(I)的化合物与富马酸、柠檬酸、酒石酸或磷酸在溶剂中溶解并反应，反应结束后于室温下缓慢挥发以析出晶体，随后将析出的晶体分离并干燥。所述式(I)的化合物的盐与溶剂的重量体积比(mg/mL)为(1-50):1，优选(1-30):1。
根据本发明的一些实施方案，采用缓慢降温法制备晶体，所述方法包括将式(I)的化合物的盐加入至溶剂中，加热搅拌使其溶解，将所得澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)放置，缓慢降温，得到晶体。在采用缓慢降温法制备晶体的一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、腈类、酰胺类和酯类，具体例如甲基异丁基酮、异丁醇、乙酸异丁酯、甲醇、四氢呋喃、乙醇、2-甲基四氢呋喃、正己烷等)，或者由上述溶剂中的两种或更多种形成的混合溶剂。在采用缓慢降温法制备晶体的一些实施方案中，所述缓慢降温的降温速度为0.1-0.5℃/分钟，优选0.1-0.3℃/分钟，更优选0.1℃/分钟。在一些实施方案中，加热温度为30-80℃，优选40-70℃，例如45℃、50℃、55℃或60℃。在一些实施方案中，所述降温结束时的温度为室温或0-10℃，例如3℃、5℃或7℃。在采用缓慢降温法制备晶体的一些实施方案中，所述式(I)的化合物的盐与溶剂的重量体积比(mg/mL)为(2-100):1，优选(10-80):1。
根据本发明的一些实施方案，采用反反溶剂添加法制备晶体，所述方法包括但不限于将式(I)的化合物的盐在良溶剂中溶解，形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，然后将所述澄清溶液添加至反溶剂中，在搅拌(所述搅拌可在室温或者加热条件(例如加热至30-100℃，优选30-80℃，更优选35-65℃，例如45℃、50℃、55℃或60℃)下进行)下析出晶体，或者静置(例如于室温下放置)(优选同时缓慢地挥发溶剂)从而析出晶体。在采用反反溶剂添加法制备晶体的一些实施方案中，所述良溶剂包括但不限于有机溶剂，如醇类、酮类、烃类(选自卤代烷烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、砜类、酰胺类和有机酸类，例如N-甲基吡咯烷酮、乙醇、丙酮、乙腈、四氢呋喃、二氯甲烷、甲基异丁基酮、乙酸乙酯、2-甲基四氢呋喃、甲苯等。在采用反反溶剂添加法制备晶体的一些实施方案中，所述反溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如烃类(选自烷烃类、烯烃类、炔烃类)，例如环己烷、正己烷、正庚烷等。在采用反反溶剂添加法制备晶体的一些实施方案中，所述良溶剂与反溶剂的体积比为(1-20):1，优选为(1-10):1。在一些实施方案中，所述式(I)的化合物的盐与良溶剂的重量体积比(mg/mL)为(1-80):1，优选为(1-50):1。
药物组合物和用途
本发明的另一目的在于提供一种药物组合物，其包含：
i)本发明的式(I)的化合物的盐，例如式(I)的化合物富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐，特别是式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐的固体形式，更特别是式(I)的化合物的富马酸盐晶体、式(I)的化合物的酒石酸盐晶体、式(I)的化合物的柠檬酸盐晶体或式(I)的化合物的磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体A、B或C、式(I)的化合物的酒石酸盐晶体A或B、式(I)的化合物的柠檬酸盐晶体A或式(I)的化合物的磷酸盐晶体A或B；以及
ii)一种或多种药学上可接受的载体。
本发明的另一目的在于提供用于治疗个体的诸如乙型肝炎的病毒感染性疾病的方法，其包括向有此需要的个体给药治疗有效量的本发明的式(I)的化合物的盐，例如式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐，特别是式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐的固体形式，更特别是式(I)的化合物的富马酸盐晶体、式(I)的化合物的酒石酸盐晶体、式(I)的化合物的柠檬酸盐晶体或式(I)的化合物的磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体A、B或C、式(I)的化合物的酒石酸盐晶体A或B、式(I)的化合物的柠檬酸盐晶体A或式(I)的化合物的磷酸盐晶体A或B，或其任意组合。
本发明的另一目的在于提供本发明的式(I)的化合物的盐(例如式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐，特别是式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐的固体形式，更特别是式(I)的化合物的富马酸盐晶体、式(I)的化合物的酒石酸盐晶体、式(I)的化合物的柠檬酸盐晶体或式(I)的化合物的磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体A、B或C、式(I)的化合物的酒石酸盐晶体A或B、式(I)的化合物的柠檬酸盐晶体A或式(I)的化合物的磷酸盐晶体A或B)或其任意组合，其用于治疗个体的诸如乙型肝炎的病毒感染性疾病。
本发明的另一目的在于提供本发明的式(I)的化合物的盐(例如式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐，特别是式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐或磷酸盐的固体形式，更特别是式(I)的化合物的富马酸盐晶体、式(I)的化合物的酒石酸盐晶体、式(I)的化合物的柠檬酸盐的晶体或式(I)的化合物的磷酸盐晶体，更特别是式(I)的化合物的富马酸盐晶体A、B或C、式(I)的化合物的酒石酸盐晶体A或B、式(I)的化合物的柠檬酸盐晶体A或式(I)的化合物的磷酸盐晶体A或B)或其任意组合在制备用于治疗个体的诸如乙型肝炎的病毒感染性疾病的药物中的用途。
如本文中所使用的术语“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的组合物。
所述剂型可为固体制剂、半固体制剂、液体制剂或气态制剂，包括但不限于片剂、胶囊剂、散剂、颗粒剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、混悬剂、酏剂、糖浆剂。
本发明所述的药物组合物可以通过本领域熟知的任何方法来制备，例如通过混合、溶解、制粒、糖包衣、碾磨、乳化、冻干等处理来制备。
如本文中所使用的术语“治疗有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日， 例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg和25mg等。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
实施例
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非用于限定本发明的范围，本领域技术人员可进行一些非本质的改进和调整，仍属于本发明的保护范围。
实验所用的测试仪器信息和方法：
方法1、X射线粉末衍射(XRPD)
设备信息
仪器名称：Xpert 3 Powder
阳极材料：Cu钯
样品载体：透射薄膜
试验条件：
Figure PCTCN2019089744-appb-000021
方法2、差示扫描量热分析(DSC)
设备信息：Mettler-Toledo DSC1
试验方法：35℃～200℃；10K/min；盖顶扎孔。
在Mettler-Toledo DSC1差示扫描量热仪上采集DSC数据。
方法3、热重分析(TGA)
设备信息：Mettler-Toledo TGA
试验方法：35℃～500℃；10K/min。
在Mettler-Toledo TGA热重分析仪上采集TGA数据。
方法4、 1H-NMR
由Bruker 400MHz核磁共振仪采集 1H-NMR数据。
方法5、晶胞参数测定
使用Xcalibur Eos衍射仪测定晶胞参数；并使用OLEX2软件进行单晶结构解析。
实施例1
(S)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(式(I)的化合物)和(R)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(式(II)的化合物)的外消旋体的制备及其手性分离
Figure PCTCN2019089744-appb-000022
步骤一：((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基膦酰氯的制备
室温下，将(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)磷酸单苯酯(3.0g，8.3mmol)溶于乙腈(3mL)中，加入二氯亚砜(90mL)。滴加完毕后，将反应液升温至70℃，反应3h后，将反应液浓缩，得到标题化合物(3.29g)，未经进一步纯化直接用于下一步反应。
ESI-MS(m/z)：378.1[M+H] +。
步骤二：(2S)-((((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基-苯氧基-磷酰基)氨基)-3-(2-甲基苄氧基)-丙烷的制备
室温下，将((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基膦酰氯(3.29g，8.3mmol)溶于干燥二氯甲烷(66mL)中。将反应液降温至-20℃，加入2-(苄氧基)乙胺(1.9g，12.3mmol)，并滴加三乙胺(9.6mL)。滴加完毕后在-20℃下反应1h后，将反应液倒入水中终止反应。用二氯甲烷萃取，合并有机相并用水洗涤，干燥，浓缩得到粗品化合物。经制备高效液相色谱纯化得到标题膦酰胺酯外消旋体(1.4g)。其结构表征如下： 1H NMR(400MHz,DMSO-d 6)δ8.15-8.12(m,2H),7.34-7.26(m,8H),7.14-7.03(m,3H),5.22-5.12(m,1H),4.39-4.24(m,3H),3.95-3.68(m,3H),3.36-3.28(m,1H),3.05-2.95(m,1H),1.29-1.16(m,2H),1.05-0.95(m,3H).ESI-MS(m/z)：497.2[M+H] +。
步骤三：(S)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(式(I)的化合物)和(R)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(式(II)的化合物)的制备
将步骤二中获得的膦酰胺酯外消旋体(400mg)通过手性色谱法分离，分离条件如下：分离柱CHIRALPAK OD-H 0.46cm I.D.×15cm L，流动相：己烷/IPA/TEA＝70/30/0.1(V/V/V)，流速1.0ml/min，波长UV 254nm，温度35℃，分离得到标题两种立体异构体化合物。
异构体(I)：(S)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(式(I)的化合物)
R t＝5.846min，198mg，ee％＝98.5％，其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.10(s,1H),7.37-7.18(m,9H),7.17-7.10(m,1H),7.05(dt,J＝8.5,1.2Hz,2H),5.16(dt,J＝11.9,6.9Hz,1H),4.40(s,2H),4.26(dd,J＝14.4,3.7Hz,1H),4.14(dd,J＝14.4,6.6Hz,1H),4.02-3.81(m,2H),3.75(dd,J＝13.5,9.2Hz,1H),3.28(d,J＝5.7Hz,2H),3.05-2.93(m,2H),1.06(d,J＝6.2Hz,3H).ESI-MS(m/z)：497.2[M+H] +。
异构体(II)：(R)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(式(II)的化合物)
R t＝7.345min，166mg，ee％＝98.3％，其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.10(s,1H),7.35-7.21(m,9H),7.13(t,J＝7.3Hz,1H),7.05(dt,J＝8.5,1.2Hz,2H),5.16(dt,J＝11.8,6.9Hz,1H),4.40(s,2H),4.26(dd,J＝14.4,3.7Hz,1H),4.14(dd,J＝14.4,6.6Hz,1H),3.97-3.81(m,2H),3.75(dd,J＝13.5,9.2Hz,1H),3.30(d,J＝11.1Hz,2H),3.00(dq,J＝12.5,6.2Hz,2H),1.06(d,J＝6.2Hz,3H).ESI-MS(m/z)：497.2[M+H] +。
实施例2
(S)-P-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-膦酰胺(式(I)的化合物)的手性合成
Figure PCTCN2019089744-appb-000023
步骤一：((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基膦酰氯的制备
室温下，将(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基)甲基)膦酸单苯酯(25g，68.81mmol)溶于甲苯(250mL)中，加入二氯亚砜(28.65g，240.84mmol)。滴加完毕后，将反应液升温至95℃，反应48h。将反应液减压蒸馏，得到标题化合物(30g)。所得产物未经进一步纯化而直接用于下一步反应。
ESI-MS(m/z)：378.1[M+H] +。
步骤二：(2S)-((((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基-苯氧基-磷酰基)氨基)-3-(2-甲基苄氧基)-丙烷的制备
室温下，将2-(苄氧基)乙胺(46.82g，309.65mmol)溶于干燥的二氯甲烷(200mL)中，在氮气保护下降温至-35℃，加入步骤一所得的粗品(30g)的甲苯(200mL)溶液，控制温度小于-10℃。加毕，保持温度在-10℃，反应1h。加入15％的磷酸氢钾水溶液(400mL)，充分搅拌，静置，分层。将有机相依次用15％的磷酸氢钾(200mL×2)、去离子水(200mL×2)洗涤，干燥。滤除不溶物，将滤液浓缩得标题化合物(30g)。经手性HPLC检测，非对映异构体纯度为94.6％。 1H NMR数据与实施例1中异构体(I)的 1H NMR数据基本相同。
实施例3
式(I)的化合物的无定型形式的制备
称取约150mg式(I)的化合物，用4mL下表1所列的良性溶剂完全溶解至澄清。在搅拌下，缓慢将其滴加入装有20mL蒸馏水的玻璃瓶中。滴加完毕后在低温下冻结，冷冻干燥，收集固体。经XRPD检测确认为式(I)的化合物的无定型形式，实验结果如下表1所示。
表1
溶剂 固体类型
乙醇/水 无定型
丙酮/水 无定型
实施例4
式(I)的化合物的富马酸盐晶体的制备与表征
实施例4.1室温悬浮搅拌法
称取若干份式(I)的化合物的富马酸盐(每份15mg)，分别将其转移至5ml EP管中。然后加入下表2所列的不同溶剂将其悬浮。在室温下搅拌8h，收集固体。若完全溶解至澄清，则在室温下敞口放置至溶剂挥发完全。收集所得的固体，对其进行XRPD检测。结果如下表2所示：
表2
溶剂 收集方法 固体晶型
甲醇 自然挥发 富马酸盐晶型B
乙醇 自然挥发 富马酸盐晶型A
异丙醇 过滤 富马酸盐晶型A
正丁醇 过滤 富马酸盐晶型A
乙酸异丙酯 过滤 富马酸盐晶型A
乙酸异丁酯 过滤 富马酸盐晶型A
碳酸二甲酯 过滤 富马酸盐晶型A
四氢呋喃 自然挥发 富马酸盐晶型B
丁酮 过滤 富马酸盐晶型A
异丙醚 过滤 富马酸盐晶型A
苯甲醚 过滤 富马酸盐晶型C
正丙醇 自然挥发 富马酸盐晶型A
根据方法4，测得在所得的式(I)的化合物的富马酸盐晶体中，式(I)的化合物与富马酸的摩尔比为1:1。
根据方法1，对所获得的晶体分别进行XRPD分析，得到三种富马酸盐晶体A、B、C，其XRPD图谱分别如图1、4、5中所示。
实施例4.2反溶剂法
称取若干份式(I)的化合物的富马酸盐(每份40mg)，将其用乙醇或四氢呋喃完全溶解至澄清，然后在搅拌下向其中缓慢滴加下表3所列的不同的非良性溶剂。观察现象，并收集固体，对其进行XRPD检测。结果如下表3所示：
表3
Figure PCTCN2019089744-appb-000024
所得固体的XRPD图谱和DSC图谱分别如图1和图2所示，表明以上反溶剂法得到的晶体类型 均为式(I)的化合物的富马酸盐晶体A。
实施例4.3高温悬浮搅拌法
称取若干份式(I)的化合物的富马酸盐(每份30mg)，分别将其转移至20ml玻璃瓶中，然后加入下表4所列的不同溶剂将其悬浮。在60℃下搅拌6h，收集固体，对其进行XRPD检测。结果如下表4所示：
表4
溶剂 收集方法 固体晶型
甲叔醚 过滤 富马酸盐晶型A
石油醚 过滤 富马酸盐晶型A
异丙醚 过滤 富马酸盐晶型A
苯甲醚 过滤 富马酸盐晶型A
二氯甲烷 过滤 富马酸盐晶型A
正庚烷 过滤 富马酸盐晶型A
正己烷 过滤 富马酸盐晶型A
环己烷 过滤 富马酸盐晶型A
所得固体的XRPD图谱和DSC图谱与实施例4.2中的XRPD图谱和DSC图谱基本上相同，表明以上高温悬浮搅拌法得到的晶体类型均为式(I)的化合物的富马酸盐晶体A。
实施例5
式(I)的化合物的富马酸盐晶体A的制备与表征
称取式(I)的化合物的游离碱(120mg)，将其置于5ml的EP管中。向其中加入0.1M富马酸甲醇溶液(2.4ml)，完全溶解至澄清。在室温下搅拌2h，真空抽干溶剂。取其中一半样品置于EP管中，并加入乙腈(1ml)，在室温下搅拌过夜。过滤，收集固体，真空干燥5h。
对样品进行了XRPD、TGA/DSC、 1H-NMR及纯度测试。
XRPD结果显示成功制备得到式(I)的化合物的富马酸盐晶体A。
DSC/TGA分析图谱如图2/3显示：样品在分解前无失重；样品在熔点前无脱溶剂吸热峰，在125℃(起始温度)有尖锐的吸热峰，为样品熔点。通过 1H-NMR确定样品中的酸碱摩尔比为1，且无溶剂残留。
式(I)的化合物的富马酸盐晶体A的晶胞参数如下所示：
晶胞尺寸：
Figure PCTCN2019089744-appb-000025
Figure PCTCN2019089744-appb-000026
Figure PCTCN2019089744-appb-000027
α/°＝90
β/°＝96.113(6)
γ/°＝90
晶胞体积：
Figure PCTCN2019089744-appb-000028
晶系：单斜晶系
空间群：P2 1
分子内不对称单位数Z＝2。
式(I)的化合物的富马酸盐晶体A具有良好的结晶度、单一简单的热信号(DSC图谱中基线平整，峰窄、单一而尖锐)，且熔点超过100℃。
实施例6
式(I)的化合物的柠檬酸盐晶体A的制备与表征
称取式(I)的化合物的游离碱(63.4mg)，将其置于5ml的EP管中。向其中加入0.1M柠檬酸甲醇溶 液(1.3ml)，完全溶解至澄清。在室温下搅拌2h，真空抽干溶剂。向EP管中加入乙腈(1ml)，在室温下搅拌过夜。过滤，收集固体，真空干燥5h。
对样品进行了XRPD、TGA/DSC、 1H-NMR及纯度测试。
XRPD结果显示成功制备得到柠檬酸盐晶体A。
DSC/TGA分析图谱如图7/8显示：样品在约115℃(起始温度)有7.7％的失重，在115℃(起始温度)有较宽的、尖锐吸热峰，为样品熔点。
通过 1H-NMR确定样品中酸碱摩尔比为1。
实施例7
式(I)的化合物酒石酸盐晶体的制备与表征
称取式(I)的化合物的游离碱(300mg)，将其置于20ml瓶中。向其中加入0.1M的酒石酸甲醇溶液(6ml)，在密闭条件下室温反应2h后分装于EP管中。于30℃下减压除去溶剂，得到白色固体，然后分别向其中加入下表5所列的溶剂，静置转晶。48h后进行偏光显微镜(PLM)检测，然后搅拌48h，收集固体，对其进行XRPD检测。结果如下表5所示：
表5
溶剂 XRPD
甲醇 A
乙腈 A
EA B
DCM A
THF A
MTBE A
正己烷 A
甲苯 A
根据方法1，对所获得的晶体分别进行XRPD分析，证明得到两种酒石酸盐晶体A、B，其所得XRPD图谱分别如图9、10中所示。
实施例8
式(I)的化合物酒石酸盐晶体B的制备及表征
称取式(I)的化合物的游离碱(110mg)，将其置于5ml的EP管中。向其中加入0.1M酒石酸甲醇溶液(2.3ml)，完全溶解至澄清。在室温下搅拌2h，真空抽干溶剂。取其中一半样品于EP管中，并加入乙酸乙酯(1ml)，在室温下搅拌过夜。过滤，收集固体，真空干燥5h。
对样品进行了XRPD、TGA/DSC、 1H-NMR及纯度测试。
XRPD结果显示成功制备得到酒石酸盐晶体B。
DSC/TGA分析图谱如图11/12显示：样品在分解前无失重，样品在熔点前无脱溶剂吸热峰，在120℃(起始温度)有较宽的、平缓的吸热峰，在143℃(起始温度)有较宽的、尖锐的吸热峰，推测为混晶。
通过 1H-NMR确定样品中酸碱摩尔比为1，且无溶剂残留。
实施例9
式(I)的化合物的磷酸盐晶体的制备与表征
称取式(I)的化合物的游离碱(300mg)，将其置于20ml瓶中。向其中加入0.1M的磷酸甲醇溶液(6ml)并搅拌，在搅拌过程中有白色固体析出。在室温下搅拌60min后，旋转蒸发至干燥，得到白色固体(250mg)。将其分装于10个EP管中，然后加入下表6所列的不同溶剂(各1.5ml)，在磁力搅拌下结晶，在实验中不停观察现象。经偏光显微镜(PLM)检测后，在室温下搅拌24h，然后进行XRPD检测。结果如下表6所示：
表6
溶剂 XRPD
甲醇 A
乙腈 B
丙酮 A
EA A
DCM A
THF A
水 B
MTBE B
甲苯 B
正己烷 B
根据方法1，对所获得的晶体分别进行XRPD分析，证明得到两种磷酸盐晶体A、B，其所得XRPD图谱分别如图13、16中所示。
实施例10
式(I)的化合物的磷酸盐晶体A的制备及表征
称取式(I)的化合物的游离碱(110mg)，将其置于5ml的EP管中。向其中加入0.1M磷酸甲醇溶液(2.2ml)，完全溶解至澄清。在室温下搅拌2h，真空抽干溶剂。取其中2/3样品于EP管中，并加入乙腈(1.5ml ml)，在室温下搅拌过夜。过滤，收集固体，真空干燥5h。
对样品进行了XRPD、TGA/DSC检测。
XRPD结果显示成功制备得到磷酸盐晶体A。
DSC/TGA分析图谱如图14/15显示：样品在99℃前有1.9％的失重，且DSC上在熔点前有明显的脱溶剂吸热峰，在142℃(起始温度)有较宽的、尖锐吸热峰，为样品的熔点。
实验例
实验例1.式(I)的化合物的富马酸盐晶体A的理化性质
分别配制pH 2.0的水溶液(用适量盐酸调节pH)、pH 7.4的水溶液(用10mM磷酸二氢钾及适量NaOH调节pH)、以及模拟禁食状态肠液(FaSSIF)作为溶剂。各称取1mg供试品溶于1mL相应溶剂中，充分震荡后超声5min，观察是否达到过饱和，若没有，则继续加样直到达到过饱和。于恒温震荡水浴锅中振摇24h后，经0.45uM水系滤膜过滤，经HPLC测定溶解度。测定结果如下表7所示：
表7
Figure PCTCN2019089744-appb-000029
由上述结果可知：本发明的式(I)的化合物的富马酸盐晶体A在水环境及禁食状态肠液中均具有良好的溶解度。并且在给药后，在体内可快速溶解，有利于药物的吸收。
实验例2.引湿性测试
利用动态水份吸附仪(DVS)测定富马酸盐晶体A及晶体B的引湿性，采用DVS Intrinsic(SMS)，在25℃、cycle-DMDT模式下进行检测。检测结果如下表8所示：
表8.式(I)的化合物的富马酸盐晶体A引湿性测定结果
Figure PCTCN2019089744-appb-000030
Figure PCTCN2019089744-appb-000031
由上表可知，式(I)的化合物的富马酸盐晶体A在80％及90％的湿度条件下质量改变(％)均小于0.2％，几乎无引湿性。有利于成药后存储稳定性。
另外，由式(I)的化合物的富马酸盐晶体B的引湿性结果可知，该晶体在20％湿度条件下质量改变(％)为0.2％，改变幅度较小。
实验例3.物理化学稳定性测试
取适量的本发明的式(I)的化合物的富马酸盐晶体A，在以下条件下检测其物理化学稳定性：40℃/75％RH敞口放置14天。然后进行XRPD和LC-MS分析，以确定晶型和纯度变化。实验结果显示在40℃/75％RH放置14天相对纯度达到99％，无明显变化。
实验例4
本发明的式(I)的化合物的富马酸盐(酸碱摩尔比为1:1)的晶体A和晶体C的比格犬药代试验
将式(I)的化合物富马酸盐晶体装于胶囊中灌胃给予比格犬，晶体A和晶体C的给药量均为2.5mg/kg。给药后于不同时间采集静脉血，分别检测式(I)的化合物的游离碱原形物和其代谢产物替诺福韦(TFV)。检测结果如下表9-10所示：
表9 富马酸晶体A体内代谢情况
Figure PCTCN2019089744-appb-000032
表10 富马酸晶体C体内代谢情况
Figure PCTCN2019089744-appb-000033
由表9、10可知，在比格犬药代试验中，式(I)的化合物的富马酸盐晶体A和C均能迅速转化为TFV，以TFV计的半衰期约为10h，符合一天给药一次(QD)的用药频率需求。
上述具体实施方式对本发明作进一步的详细描述。但不应将此理解为本发明上述主题的范围仅限于所列的实施例，凡基于本发明内容所实施的技术方案均落入于本发明的范围。

Claims (26)

  1. 式(I)的化合物的盐：
    Figure PCTCN2019089744-appb-100001
    所述盐优选为式(I)的化合物的有机酸盐或无机酸盐，优选式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐、马来酸盐、琥珀酸盐、苹果酸盐、已二酸盐、乳酸盐、乙醇酸盐、黏酸盐、龙胆酸盐、草酸盐、丙二酸盐、马尿酸盐、烟酸盐、烟酰胺盐、磷酸盐、盐酸盐、硫酸盐、乙二磺酸盐、萘二磺酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、樟脑磺酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、脯氨酸盐、色氨酸盐、丝氨酸盐、酪氨酸盐、半胱氨酸盐、蛋氨酸盐、苏氨酸盐、天冬氨酸盐、谷氨酸盐、赖氨酸盐、精氨酸盐和组氨酸盐，更优选式(I)的化合物的富马酸盐、柠檬酸盐、酒石酸盐和磷酸盐。
  2. 权利要求1的式(I)的化合物的盐，其中式(I)的化合物与所述无机酸或所述有机酸的摩尔比为1:1或1:1/2或1:1/3，优选为1:1。
  3. 制备权利要求1的式(I)的化合物的盐的方法，其包括使任意固体形式的式(I)的化合物与所述无机酸或所述有机酸反应，析出固体，随后将析出的固体分离并干燥。
  4. 权利要求3的方法，其中式(I)的化合物是通过以下路线制备的：
    Figure PCTCN2019089744-appb-100002
    其中优选地，
    步骤一包括：在诸如甲苯、二甲苯、苯甲醚、乙腈的溶剂中，在50-120℃(优选80-110℃，更优选90-100℃)的温度下，使(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基)甲基)膦酸单苯酯与诸如二氯亚砜、三氯氧磷、五氯化磷、草酰氯的氯代试剂反应，制得中间体((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基膦酰氯；
    步骤二包括：使步骤1中获得的中间体((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基膦酰氯与2-(苄氧基)乙胺反应，制得式(I)的化合物。
  5. 如权利要求1中所示的式(I)的化合物的富马酸盐，其中式(I)的化合物与富马酸的摩尔比为1:1或1:1/2，优选为1:1。
  6. 如权利要求1中所示的式(I)的化合物的富马酸盐晶体A：
    所述式(I)的化合物的富马酸盐晶体A的XRPD图谱包括在5.1±0.2°、6.4±0.2°、16.3±0.2°、18.7±0.2°、28.2±0.2°的衍射角(2θ)处的特征峰，优选包括在5.1±0.2°、6.4±0.2°、14.7±0.2°、15.3±0.2°、16.3±0.2°、18.0±0.2°、18.7±0.2°、19.2±0.2°、28.2±0.2°、29.6±0.2°的衍射角(2θ)处的特征峰，更优选包括在5.1±0.2°、6.4±0.2°、12.9±0.2°、14.7±0.2°、15.3±0.2°、16.3±0.2°、18.0± 0.2°、18.7±0.2°、18.9±0.2°、19.2±0.2°、20.0±0.2°、20.7±0.2°、22.2±0.2°、24.0±0.2°、24.9±0.2°、25.3±0.2°、27.8±0.2°、28.2±0.2°、29.6±0.2°的衍射角(2θ)处的特征峰，最优选包括如图1所示的特征峰；
    特别优选地，所述式(I)的化合物的富马酸盐晶体A具有如下的晶胞参数：
    晶胞尺寸：
    Figure PCTCN2019089744-appb-100003
    Figure PCTCN2019089744-appb-100004
    Figure PCTCN2019089744-appb-100005
    α/°＝90
    β/°＝96.113(6)
    γ/°＝90
    晶胞体积：
    Figure PCTCN2019089744-appb-100006
    晶系：单斜晶系
    空间群：P2 1
    分子内不对称单位数Z＝2。
  7. 制备权利要求6的式(I)的化合物的富马酸盐晶体A的方法，其选自气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法和缓慢降温法。
  8. 如权利要求1中所示的式(I)的化合物的富马酸盐晶体B：
    所述式(I)的化合物的富马酸盐晶体B的XRPD图谱包括在10.2±0.2°、10.8±0.2°、17.1±0.2°、18.8±0.2°、21.7±0.2°的衍射角(2θ)处的特征峰，优选包括在9.7±0.2°、10.2±0.2°、10.8±0.2°、14.7±0.2°、17.1±0.2°、18.1±0.2°、18.8±0.2°、19.2±0.2°、20.6±0.2°、21.7±0.2°的衍射角(2θ)处的特征峰，更优选包括在9.7±0.2°、10.2±0.2°、10.8±0.2°、11.8±0.2°、13.2±0.2°、13.8±0.2°、14.7±0.2°、16.1±0.2°、17.1±0.2°、18.1±0.2°、18.8±0.2°、19.2±0.2°、20.6±0.2°、21.7±0.2°、22.3±0.2°、23.8±0.2°、26.7±0.2°、27.0±0.2°、27.5±0.2°、29.3±0.2°的衍射角(2θ)处的特征峰，最优选包括如图4所示的特征峰。
  9. 制备权利要求8的式(I)的化合物的富马酸盐晶体B的方法，其选自气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法和缓慢降温法。
  10. 如权利要求1中所示的式(I)的化合物的富马酸盐晶体C：
    所述式(I)的化合物的富马酸盐晶体C的XRPD图谱包括在4.3±0.2°、6.8±0.2°、14.3±0.2°、18.8±0.2°、27.9±0.2°的衍射角(2θ)处的特征峰，优选包括在4.3±0.2°、6.6±0.2°、6.8±0.2°、14.3±0.2°、16.6±0.2°、18.5±0.2°、18.8±0.2°、19.2±0.2°、27.6±0.2°、27.9±0.2°的衍射角(2θ)处的特征峰，更优选包括在4.3±0.2°、6.6±0.2°、6.8±0.2°、13.0±0.2°、14.3±0.2°、15.3±0.2°、15.8±0.2°、16.2±0.2°、16.6±0.2°、17.3±0.2°、18.5±0.2°、18.8±0.2°、19.2±0.2°、20.1±0.2°、22.6±0.2°、23.3±0.2°、25.8±0.2°、26.2±0.2°、27.6±0.2°、27.9±0.2°的衍射角(2θ)处的特征峰，最优选包括如图5所示的特征峰。
  11. 制备权利要求10的式(I)的化合物的富马酸盐晶体C的方法，其选自气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法和缓慢降温法。
  12. 如权利要求1中所示的式(I)的化合物的柠檬酸盐，其中式(I)的化合物与柠檬酸的摩尔比为1:1或1:1/2或1:1/3，优选为1:1。
  13. 如权利要求1中所示的式(I)的化合物的柠檬酸盐晶体A：
    所述式(I)的化合物的柠檬酸盐晶体A的XRPD图谱包括在7.6±0.2°、14.1±0.2°、15.5±0.2°、16.0±0.2°、20.7±0.2°的衍射角(2θ)处的特征峰，优选包括在7.6±0.2°、14.1±0.2°、14.9±0.2°、15.5±0.2°、16.0±0.2°、19.6±0.2°、20.7±0.2°、21.4±0.2°、22.5±0.2°、24.5±0.2°的衍射角(2θ)处的特征峰，更优选包括在7.6±0.2°、14.1±0.2°、14.9±0.2°、15.5±0.2°、16.0±0.2°、19.6±0.2°、20.7±0.2°、21.4±0.2°、22.5±0.2°、24.5±0.2°、28.5±0.2°的衍射角(2θ)处的特征峰，最优选包括如图6所示的特征峰。
  14. 制备权利要求13的式(I)的化合物的柠檬酸盐晶体A的方法，其选自气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法和缓慢降温法。
  15. 如权利要求1中所示的式(I)的化合物的酒石酸盐，其中式(I)的化合物与酒石酸的摩尔比为1:1或1:1/2，优选为1:1。
  16. 如权利要求1中所示的式(I)的化合物的酒石酸盐晶体A：
    所述式(I)的化合物的酒石酸盐晶体A的XRPD图谱包括在16.9±0.2°、17.2±0.2°、18.7±0.2°、19.2±0.2°、21.9±0.2°的衍射角(2θ)处的特征峰，优选包括在4.5±0.2°、6.8±0.2°、10.9±0.2°、16.9±0.2°、17.2±0.2°、17.9±0.2°、18.7±0.2°、19.1±0.2°、19.2±0.2°、21.9±0.2°的衍射角(2θ)处的特征峰，更优选包括在3.9±0.2°、4.5±0.2°、6.8±0.2°、7.3±0.2°、9.1±0.2°、10.2±0.2°、10.9±0.2°、14.2±0.2°、16.4±0.2°、16.9±0.2°、17.2±0.2°、17.9±0.2°、18.7±0.2°、19.1±0.2°、19.2±0.2°、21.9±0.2°、22.8±0.2°、25.7±0.2°、27.6±0.2°的衍射角(2θ)处的特征峰，特别优选包括在3.9±0.2°、4.5±0.2°、6.8±0.2°、7.3±0.2°、9.1±0.2°、10.2±0.2°、10.9±0.2°、11.5±0.2°、13.7±0.2°、14.2±0.2°、16.4±0.2°、16.9±0.2°、17.2±0.2°、17.9±0.2°、18.7±0.2°、19.1±0.2°、19.2±0.2°、21.9±0.2°、22.8±0.2°、25.7±0.2°、27.6±0.2°的衍射角(2θ)处的特征峰，最优选包括如图9所示的特征峰。
  17. 制备权利要求16的式(I)的化合物的酒石酸盐晶体A的方法，其选自气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法和缓慢降温法。
  18. 如权利要求1中所示的式(I)的化合物的酒石酸盐晶体B：
    所述式(I)的化合物的酒石酸盐晶体B的XRPD图谱包括在7.3±0.2°、17.2±0.2°、17.8±0.2°、18.2±0.2°、19.2±0.2°的衍射角(2θ)处的特征峰，优选包括在7.3±0.2°、17.2±0.2°、17.8±0.2°、18.2±0.2°、18.5±0.2°、18.8±0.2°、19.2±0.2°、19.6±0.2°、20.0±0.2°、21.9±0.2°的衍射角(2θ)处的特征峰，更优选包括在3.9±0.2°、7.3±0.2°、7.8±0.2°、8.4±0.2°、9.8±0.2°、14.6±0.2°、15.6±0.2°、17.2±0.2°、17.5±0.2°、17.8±0.2°、18.2±0.2°、18.5±0.2°、18.8±0.2°、19.2±0.2°、19.6±0.2°、20.0±0.2°、20.6±0.2°、21.9±0.2°、22.3±0.2°、23.7±0.2°的衍射角(2θ)处的特征峰，特别优选包括在3.9±0.2°、7.3±0.2°、7.8±0.2°、8.4±0.2°、8.8±0.2°、9.8±0.2°、14.6±0.2°、15.6±0.2°、16.2±0.2°、17.2±0.2°、17.5±0.2°、17.8±0.2°、18.2±0.2°、18.5±0.2°、18.8±0.2°、19.2±0.2°、19.6±0.2°、20.0±0.2°、20.6±0.2°、21.9±0.2°、22.3±0.2°、23.7±0.2°、25.1±0.2°、25.8±0.2°、28.3±0.2°、29.7±0.2°的衍射角(2θ)处的特征峰，最优选包括如图10所示的特征峰。
  19. 制备权利要求18的式(I)的化合物的酒石酸盐晶体B的方法，其选自气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法和缓慢降温法。
  20. 如权利要求1中所示的式(I)的化合物的磷酸盐，其中式(I)的化合物与磷酸的摩尔比为1:1或1:1/2或1:1/3，优选为1:1。
  21. 如权利要求1中所示的式(I)的化合物的磷酸盐晶体A：
    所述式(I)的化合物的磷酸盐晶体A的XRPD图谱包括在5.3±0.2°、14.5±0.2°、17.3±0.2°、18.6±0.2°、19.5±0.2°的衍射角(2θ)处的特征峰，优选包括在5.3±0.2°、7.9±0.2°、14.5±0.2°、16.3±0.2°、17.3±0.2°、18.6±0.2°、19.5±0.2°、20.4±0.2°、20.7±0.2°、23.1±0.2°的衍射角(2θ)处的特征峰，更优选包括在5.3±0.2°、7.9±0.2°、14.5±0.2°、16.3±0.2°、17.3±0.2°、18.6±0.2°、19.5±0.2°、20.4±0.2°、20.7±0.2°、23.1±0.2°、27.0±0.2°、32.5±0.2°的衍射角(2θ)处的特征峰，最优选包括如图13所示的特征峰。
  22. 制备权利要求20的式(I)的化合物的磷酸盐晶体A的方法，其选自气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法和缓慢降温法。
  23. 如权利要求1中所示的式(I)的化合物的磷酸盐晶体B：
    所述式(I)的化合物的磷酸盐晶体B的XRPD图谱包括在7.9±0.2°、15.9±0.2°、16.3±0.2°、18.8±0.2°、24.2±0.2°的衍射角(2θ)处的特征峰，优选包括在7.9±0.2°、10.4±0.2°、12.2±0.2°、15.9±0.2°、16.3±0.2°、18.8±0.2°、19.4±0.2°、20.0±0.2°、24.2±0.2°、24.7±0.2°的衍射角(2θ)处的特征峰，更优选包括在7.9±0.2°、10.4±0.2°、11.8±0.2°、12.2±0.2°、15.9±0.2°、16.3±0.2°、18.8±0.2°、19.4±0.2°、20.0±0.2°、21.9±0.2°、23.1±0.2°、24.2±0.2°、24.7±0.2°、26.2±0.2°、27.8±0.2°的衍射角(2θ)处的特征峰，最优选包括如图16所示的特征峰。
  24. 制备权利要求23的式(I)的化合物的磷酸盐晶体B的方法，其选自气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法和缓慢降温法。
  25. 药物组合物，其包含：
    i)以下物质中的任意一种或多种：
    权利要求1的式(I)化合物的盐；
    权利要求5的式(I)化合物的富马酸盐；
    权利要求6的式(I)化合物的富马酸盐晶体A；
    权利要求8的式(I)化合物的富马酸盐晶体B；
    权利要求10的式(I)化合物的富马酸盐晶体C；
    权利要求12的式(I)的化合物的柠檬酸盐；
    权利要求13的式(I)的化合物的柠檬酸盐晶体A；
    权利要求15的式(I)的化合物的酒石酸盐；
    权利要求16的式(I)的化合物的酒石酸盐晶体A；
    权利要求18的式(I)的化合物的酒石酸盐晶体B；
    权利要求20的式(I)的化合物的磷酸盐；
    权利要求21的式(I)的化合物的磷酸盐晶体A；
    或者
    权利要求23的式(I)的化合物的磷酸盐晶体B；以及
    ii)一种或多种药学上可接受的载体。
  26. 任意一种或多种以下物质在制备用于治疗诸如乙型肝炎的病毒感染性疾病的药物中的用途：
    权利要求1的式(I)化合物的盐；
    权利要求5的式(I)化合物的富马酸盐；
    权利要求6的式(I)化合物的富马酸盐晶体A；
    权利要求8的式(I)化合物的富马酸盐晶体B；
    权利要求10的式(I)化合物的富马酸盐晶体C；
    权利要求12的式(I)的化合物的柠檬酸盐；
    权利要求13的式(I)的化合物的柠檬酸盐晶体A；
    权利要求15的式(I)的化合物的酒石酸盐；
    权利要求16的式(I)的化合物的酒石酸盐晶体A；
    权利要求18的式(I)的化合物的酒石酸盐晶体B；
    权利要求20的式(I)的化合物的磷酸盐；
    权利要求21的式(I)的化合物的磷酸盐晶体A；
    或者
    权利要求23的式(I)的化合物的磷酸盐晶体B。
PCT/CN2019/089744 2018-06-12 2019-06-03 膦酰胺酯化合物及其盐和相关晶体形式、制备方法和用途 WO2019237957A1 (zh)

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