WO2024046175A1 - 一种多胺衍生物药用盐及其晶型和制备方法 - Google Patents

一种多胺衍生物药用盐及其晶型和制备方法 Download PDF

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WO2024046175A1
WO2024046175A1 PCT/CN2023/114282 CN2023114282W WO2024046175A1 WO 2024046175 A1 WO2024046175 A1 WO 2024046175A1 CN 2023114282 W CN2023114282 W CN 2023114282W WO 2024046175 A1 WO2024046175 A1 WO 2024046175A1
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aminopropyl
aminopropylamine
bis
dimethoxyphenylpropionyl
phosphate
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PCT/CN2023/114282
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English (en)
French (fr)
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刘宪波
张晓�
饶翔
刘欣
蔡超
李雷
李振武
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武汉武药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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 invention relates to the technical field of chemical industry and medicine, and specifically relates to a bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate and its Crystal form and preparation method.
  • Systemic inflammatory response syndrome and autoimmune disorder-related diseases are two types of diseases caused by the body's own excessive immune response. There is still a lack of effective treatments, and targeted prevention and treatment is Clinical focus and hot issues.
  • Sepsis refers to systemic inflammatory response syndrome (SIRS) mediated by infectious factors, with as many as 19 million cases worldwide each year. Although antibiotics and critical care medicine technology have made great progress, sepsis is still the main cause of death in infected patients, and there is still no ideal treatment drug. Research shows that the mechanism of sepsis is that the pathogen-associated molecular pattern (PAMP) released by pathogens such as bacteria, viruses, and fungi is recognized by the pattern recognition receptor (PRR) of the host's natural immune system. Mediates the activation of inflammatory response cells, thereby triggering a systemic excessive inflammatory response.
  • PAMP pathogen-associated molecular pattern
  • PRR pattern recognition receptor
  • PAMP molecules that cause sepsis mainly include bacterial lipopolysaccharide (LPS), bacterial genomic DNA (CpG DNA), peptidoglycan (PGN), and lipoteichoic acid (LTA). , viral RNA and zymosan.
  • LPS bacterial lipopolysaccharide
  • CpG DNA bacterial genomic DNA
  • PPN peptidoglycan
  • LTA lipoteichoic acid
  • Patent document CN105348137B discloses a pharmaceutical salt of a polyamine derivative, its preparation method and its use in treating sepsis.
  • the pharmaceutical salt of the polyamine derivative is bis((N-3-aminopropyl)-( N-(3,4-Dimethoxyphenylpropionyl))) Aminopropylamine hydrochloride with an acid-base ratio of 3.
  • the present invention provides a bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl) Base))) aminopropylamine phosphate and its crystal form and preparation method.
  • a first aspect of the invention provides a bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate.
  • the bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate has the following structure:
  • x represents the number of moles of phosphoric acid combined per mole of di((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropanoyl)))aminopropylamine, further, The , preferably, the x is 1.5 to 2.5, more preferably, the x is 1.9 to 2.1, and most preferably, the x is 2.0.
  • the phosphate is:
  • the phosphate is in crystalline, amorphous form, or a mixed form of crystalline and amorphous.
  • the second aspect of the present invention provides the preparation of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate described in the first aspect
  • a method comprising the step of mixing bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine and phosphoric acid.
  • the preparation method is:
  • the reaction solvent is selected from: ethyl acetate, dichloromethane, methanol, water, chloroform, ethanol, acetone, acetonitrile, butanol, dimethylformamide, dimethyl sulfoxide, methyl tert.
  • the reaction solvent is selected from: one or more of methanol, ethanol, ethyl acetate, acetone and dichloromethane, more
  • the reaction solvent is methanol or ethanol.
  • the temperature of the reaction is 0-30°C (such as 0°C, 5°C, 15°C, 20°C, 25°C, 30°C).
  • the temperature of the reaction is 0-15°C.
  • reaction time is 2 to 6h (such as 2h, 3h, 4h, 5h, 6h), preferably 3 to 5h, more preferably 4h.
  • seed crystals are added during the reaction.
  • the equivalent ratio of the bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine and phosphoric acid is 1:1 ⁇ 2.5 (such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1 , 1:2.2, 1:2.3, 1:2.4, 1:2.5), preferably, the equivalent ratio is 1:1 ⁇ 2, more preferably, the equivalent ratio is 1:1.8 ⁇ 2, the equivalent ratio Ratio is the ratio of moles.
  • the preparation method of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate also includes the step of isolating the product.
  • the separation includes filtration or centrifugation steps.
  • the filtration operation refers to filtering the reaction system obtained after the reaction to obtain a filter cake, and optionally washing the filter cake.
  • the solvent used for washing is selected from one of methanol, ethyl acetate, ethanol and isopropyl alcohol.
  • the washing solvent is methanol or ethyl acetate.
  • the preparation method of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate also includes a drying step.
  • drying step refers to drying the separated material under normal pressure or under reduced pressure.
  • the drying temperature is 0-35°C (such as 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C).
  • the drying temperature is 25-35°C.
  • the bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine can be produced in gram scale or kilogram scale according to any of several different methods. Preparation, for example, the preparation method described in patent document CN201510729318.8, which is incorporated herein by reference.
  • the preparation method of the bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate also includes bis(( Purification (refining) step of N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate.
  • the purification (refining) step includes recrystallization and/or washing.
  • the solvent for recrystallization is selected from one or a combination of two of methanol, ethanol and water, especially methanol-water, ethanol-water, water-methanol, and water-ethanol.
  • the solvent for washing is selected from one of methanol, ethanol, ethyl acetate and isopropyl alcohol.
  • the solvent for washing crystals is methanol or ethyl acetate.
  • the purification (refining) step includes adding seed crystals.
  • the third aspect of the present invention provides non-bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate described in the first aspect. Preparation method of crystalline form.
  • the preparation method is selected from one or more combinations of gas-liquid diffusion method, polymer induction method, slow volatilization method and slow cooling method.
  • the preparation method is selected from: One or a combination of one or more of gas-liquid diffusion method, polymer induction method and slow evaporation method.
  • the gas-liquid diffusion method includes: placing the target product in an open container and dissolving it with a positive solvent, then placing the open container in a sealed container filled with anti-solvent and letting it stand (at room temperature), and finally collecting it. solid.
  • the polymer induction method includes: dissolving the target product in a solvent, filtering through needle membrane, adding the polymer to the filtrate, and evaporating at room temperature to obtain a solid.
  • the slow volatilization method includes: dissolving the target product in a solvent and then drying to obtain a solid.
  • the slow cooling method includes: dissolving the target product in a solvent, heating at 40°C-60°C, stirring and balancing for 1-4 hours, filtering after the solution becomes clear, and slowly cooling the filtrate from 40°C-60°C to 0°C. °C-10°C, and still clarified after being placed at a constant temperature of -10 ⁇ 30°C (such as 10°C, 15°C, 20°C, 25°C, 30°C) for 3-8 days, and finally processed at 40 ⁇ 60°C (such as 40°C, 45°C °C, 50°C, 55°C, 60°C) volatilization treatment.
  • the amorphous form of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate is the slow evaporation method, which specifically refers to weighing 10 to 20 mg of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl))) in a 4mL glass bottle ) Aminopropylamine phosphate, add it to a mixed solution of DMSO and water with a volume ratio of 2:1 and dissolve it.
  • the fourth aspect of the present invention provides crystals of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate described in the first aspect.
  • Type A bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate described in the first aspect.
  • the XRPD pattern of the crystal form A has 2 ⁇ values of 6.4° ⁇ 0.2°, 9.7° ⁇ 0.2°, 16.2° ⁇ 0.2°, 19.5° ⁇ 0.2°, 22.9° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the XRPD pattern of the crystal form A has 2 ⁇ values of 6.4° ⁇ 0.2°, 9.7° ⁇ 0.2°, 11.80° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.8° ⁇ 0.2°, and 16.2° ⁇ 0.2°. , 19.5° ⁇ 0.2°, 22.9° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • characteristic peaks main characteristic diffraction peaks
  • the XRPD pattern of the crystal form A has 2 ⁇ values of 11.80° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.8° ⁇ 0.2°, 15.3° ⁇ 0.2°, 18.7° ⁇ 0.2°, and 20.8° ⁇ 0.2°.
  • characteristic peaks secondary characteristic diffraction peaks at at least three (at least four or all) of the positions of , 22.6° ⁇ 0.2° and 23.7° ⁇ 0.2°.
  • crystal form A has an XRPD pattern substantially as shown in Figure 1.
  • the DSC spectrum of the crystalline form A is at 175-195°C (such as 175°C, 180°C, 185°C, 190°C (near 195°C) has an endothermic peak.
  • the crystal form A has a DSC pattern substantially as shown in Figure 2.
  • the weight loss is about 3% (such as 1.5%, 2.0%, 2.5%, 3.0%).
  • the crystal form A has a TGA pattern basically as shown in Figure 2.
  • a fifth aspect of the present invention provides a method for preparing the crystalline form A described in the fourth aspect.
  • the preparation method is anti-solvent crystallization method and anti-anti-solvent crystallization method.
  • the anti-solvent crystallization method includes: dissolving the target product with a positive solvent, and then adding an anti-solvent to the system.
  • the anti-solvent cannot dissolve or can only slightly dissolve the substance to be crystallized, thus reducing the solubility of the crystallized substance, making it precipitate from the mixed solution.
  • the anti-anti-solvent crystallization method includes: after dissolving the solution of the target product with a positive solvent, adding one or several anti-solvents, and the product is in a slightly soluble state in the solution, thereby making the solution A method of precipitating crystals after reaching a supersaturated state.
  • the anti-solvent crystallization method specifically includes:
  • step (3) The solution obtained in step (2) is cooled and separated to obtain a wet product
  • step (3) Dry the wet product obtained in step (3) to obtain dry phosphate crystal A.
  • the positive solvent described in step (1) is selected from the group consisting of: the positive solvent is water, a mixture of methanol and water, or a mixture of ethanol and water; preferably, the positive solvent described in step (1) is methanol and water. Water mixture.
  • the antisolvent in step (1) is selected from one or more of methanol, ethanol, tetrahydrofuran, ethyl acetate or toluene.
  • the cooling treatment in step (3) refers to lowering the temperature to 0-15°C (such as 0°C, 5°C, 10°C, 15°C).
  • the cooling treatment in step (3) is Refers to lowering the temperature to 5°C.
  • the time of the cooling treatment in step (3) is 3 to 16h (such as 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h), preferably , the time of the cooling treatment in step (3) is 8-14h (such as 8h, 9h, 10h, 11h, 12h, 13h, 14h), and further preferably, the time of the cooling treatment in step (3) is 12h.
  • the separation method in step (3) includes centrifugation, filtration and/or suction filtration.
  • the centrifugation refers to centrifuging the mixed solution after the reaction to obtain a solid.
  • the drying temperature is 25-35°C (such as 25°C, 30°C, 35°C).
  • the drying temperature is 30°C.
  • the sixth aspect of the present invention provides a bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate and its crystal form A Application in the preparation of anti-PAMP drugs.
  • the PAMP is selected from: bacterial lipopolysaccharide (LPS), bacterial genomic DNA (CpG DNA), peptidoglycan (PGN), phosphoteichoic acid (lipoteichoic acid, LTA), viral RNA and yeast One or more polysaccharides.
  • the seventh aspect of the present invention provides a bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate and its crystal form
  • SIRS systemic inflammatory response syndrome
  • systemic inflammatory response syndrome is sepsis.
  • the eighth aspect of the present invention provides a bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate and its crystal form A Application in the preparation of drugs for the prevention and/or treatment of autoimmune diseases.
  • the autoimmune disease is selected from: organ-specific autoimmune disease, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective One or more of histopathies, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis.
  • the bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate described in the present application is relatively different from the bis((N-3- The free base and other salts of aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine have good stability and high dynamic solubility, which are beneficial to industrial production.
  • bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine diphosphate is compared with bis((N-3- Aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl))) aminopropylamine triphosphate has higher stability and is more conducive to drug safety; in bis((N-3-amino In the preparation process of propyl)-(N-(3,4-dimethoxyphenylpropionyl))) aminopropylamine phosphate, the phosphoric acid equivalent ratio described in this application is used, and the salt is easier to precipitate from the reaction system , salt can be separated from the system with a simple filtration operation, which is greatly beneficial to industrial large-scale production.
  • Figure 1 shows the XRPD pattern of phosphate crystal form A.
  • Figure 2 shows the TGA/DSC spectrum of phosphate crystal form A.
  • the term "crystalline form" is confirmed by characterization of X-ray powder diffraction patterns.
  • X-ray powder diffraction patterns often change with the conditions of the instrument. It is particularly important to point out that the relative intensity of X-ray powder diffraction patterns may also change with changes in experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown in this article are illustrative and not used for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less. The error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • due to the influence of experimental factors such as sample thickness there will be an overall shift in the peak angle, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of a crystalline form in the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein.
  • the XRPD pattern is the same as described herein does not mean It means absolutely the same, the same peak position can differ by ⁇ 0.2° and the peak intensity allows certain variability. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns falls within the scope of the present invention. Those skilled in the art can compare the spectrum listed in the present invention with the spectrum of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms. In some embodiments, Form A of the present invention is pure and unitary, with substantially no admixture of any other crystalline forms.
  • substantially no when used to refer to a new crystal form means that the crystal form contains less than 20% (weight) of other crystal forms, especially less than 10% (weight) of other crystal forms, and even less Less than 5% (weight) of other crystalline forms refers to less than 1% (weight) of other crystalline forms.
  • the diffraction pattern obtained from crystalline compounds is often characteristic of a specific crystalline form, in which the relative intensity of the bands (especially at low angles) may vary due to crystallization.
  • the dominant orientation effects vary due to differences in conditions, particle size, relative content of the mixture and other test conditions. Therefore, the relative intensity of the diffraction peak is not characteristic of the target crystal. When judging whether it is the same as a known crystal form, more attention should be paid to the position of the peak rather than their relative intensity.
  • the term "substantially as shown in Figure" refers to an XRPD pattern or a DSC pattern or a TGA pattern. At least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the spectrum are shown in its plot.
  • room temperature means that the temperature of the item is close to or the same as the temperature of the space (eg, the location of the fume hood in which the item is located). Typically, room temperature is about 20°C to about 30°C, or about 22°C to 27°C, or about 25°C.
  • the antisolvent crystallization (also known as antisolvent addition, precipitation crystallization, salting out or forced crystallization) method is usually performed by adding one or several antisolvents to a solution in which the target product is dissolved in a normal solvent, and the product is dissolved in the solution.
  • the solution is in a slightly soluble state, so that the solution reaches a supersaturated state and then crystallizes.
  • Anti-anti-solvent crystallization is usually performed by adding one or several anti-solvents to the solution of the target product after dissolving it with a positive solvent.
  • the product is in a slightly soluble state in the solution, so that the solution reaches a supersaturated state.
  • the method of precipitation and crystallization is usually performed by adding one or several antisolvents to a solution in which the target product is dissolved in a normal solvent, and the product is dissolved in the solution.
  • the solution is in a slightly soluble state, so that the solution reaches a supersaturated state
  • the ability of the antisolvent to dissolve the target product is worse than that of the positive solvent, for example, the difference is more than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%. Therefore, the antisolvent in the system is relatively .
  • the positive solvent and the anti-solvent can be polar solvents or non-polar solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (dimethyl sulfoxide), water, alcoholic solvents, ethers One or more solvents, ketone solvents, ester solvents, alkane solvents, aromatic hydrocarbon solvents, and nitrile solvents.
  • alcohol solvents include but are not limited to methanol, ethanol, propanol, isopropanol or 1,3-propanediol, 1,2-propanediol or chlorobutanol or combinations thereof;
  • ether solvents include but are not limited to tetrahydrofuran, Methyl tert-butyl ether or 1,4-dioxane or combinations thereof;
  • ketone solvents include but are not limited to acetone, methyl ethyl ketone or 4-methyl-2-pentanone or combinations thereof;
  • ester solvents include but are not limited to Ethyl acetate, isopropyl acetate, n-butyl acetate or tert-butyl acetate or combinations thereof;
  • alkane solvents include but are not limited to methylene chloride, chloroform, n-hexane, cyclohexane or pentane or n-heptane or their combinations
  • Anti-solvent crystallization, anti-anti-solvent crystallization can be operated by batch, semi-batch or continuous crystallization.
  • the antisolvent is added to the solution (antisolvent crystallization) or the product solution is added to the antisolvent (anti-antisolvent crystallization), either dropwise at a constant rate or slowly at the beginning and then gradually increasing the rate.
  • the X-ray powder diffractometer (XRPD) test conditions are: use Bruker D2 model X-ray powder diffractometer to collect X-ray powder diffraction data of the sample under ambient conditions, and the X-ray emitter power is 300W.
  • the X-ray tube uses Cu target (K ⁇ ), and the K ⁇ 2/K ⁇ 1 intensity ratio is
  • TGA Thermogravimetric Analysis
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric data for phosphates were collected using a TA Discovery series thermogravimeter (TGA). Take a few milligrams of the sample and put it into a Tzero aluminum pan, and heat it from room temperature to the target temperature under N2 protection, with a N2 flow rate of 25mL/min and a heating rate of 10°C/min. Thermal data of the samples was collected using a TA Discovery Series Differential Scanning Calorimeter (DSC). For crystalline samples, weigh a few milligrams of sample into a Tzero aluminum pan, seal it with a Tzero sealing cap, and heat under N2 protection with a N2 flow rate of 50mL/min and a heating rate of 10°C/min.
  • TGA thermogravimeter
  • DSC Differential Scanning Calorimeter
  • the modulation mode for testing For amorphous samples, set the modulation mode for testing: weigh about 10mg in a Tzero aluminum pan, seal it with a Tzero sealing cap, and heat under N2 protection, the N2 flow rate is 50mL/min, and the modulation temperature amplitude is ⁇ 1°C.
  • the modulation period is 40 seconds, the heating rate is 1°C/min, and the test temperature range is 25°C to 200°C.
  • hygroscopicity refers to the Chinese Pharmacopoeia 2015 edition of the guiding principles for drug hygroscopicity testing.
  • the specific test methods are as follows:
  • test sample Take an appropriate amount of the test sample and place it flatly in the above-mentioned weighing bottle.
  • the thickness of the test sample is generally about 1mm, and accurately weigh it (m2).
  • Weight gain percentage (m3-m2)/(m2-m1) ⁇ 100%
  • Deliquescence Absorption of sufficient water to form a liquid.
  • the weight gain by attracting moisture is not less than 15%.
  • the moisture-absorbing weight gain is less than 15% but not less than 2%.
  • weight gain due to moisture attraction is less than 2% but not less than 0.2%.
  • weight gain due to moisture absorption is less than 0.2%.
  • free base bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine free base (hereinafter referred to as free base) at room temperature
  • free base an acid solution with an acid-base molar ratio of 1:1 into an HPLC vial
  • acid solution of the free base add the ethanol solution of the free base, and stir magnetically at room temperature; after magnetic stirring at room temperature for 2 to 4 days, a small amount of the system obtained a turbid solid, and some systems observed sticky walls, The gelation phenomenon occurs, and the rest of the system is still clarified.
  • the subsequent processing steps are: 1) For the turbid system, centrifuge the solid; 2) For the sticky wall/gel-forming system, perform a 25°C ⁇ 50°C cyclic temperature rise and fall treatment (see Table 5 for the temperature rise and fall program), try to improve the apparent state/obtain Solid; 3) For a clear or slightly turbid system, stir magnetically at 5°C for about 5 hours and then let stand at -20°C overnight. Try to collect a sufficient amount of solid for subsequent characterization. If the amount of solid is still small, proceed to slow evaporation at room temperature. ; If the system is still clear in the end, add anti-solvent (n-heptane) or slowly evaporate at room temperature. The solid obtained above was separated by centrifugation. The test results are shown in Table 4.
  • the acid-base molar feeding ratio is 1:1.
  • the acid-base molar feeding ratio is 3:1.
  • the solid obtained by the reaction can be sealed and left at room temperature for 1 week to form a gel.
  • the above experimental data shows that among the five salt types, only the phosphate prepared with an acid-base ratio of 1 is relatively stable.
  • the phosphate solids prepared with an acid-base input ratio of 1 or 3 were sampled to measure the acid-base ratio.
  • the test method for phosphate ion content is shown in Table 2.
  • the test structure shows that the acid-base ratio of the phosphate prepared with an acid-base input ratio of 1 is 1.9. ;
  • the acid-base ratio of the phosphate prepared by setting the acid-base feeding ratio to 3 is 3.0.
  • test the dynamic solubility of phosphate in water and three kinds of biological solvents simulated gastric juice SGF, simulated fasting intestinal fluid FaSSIF, simulated eating intestinal fluid FeSSIF.
  • the specific method of solubility test is: weigh 4 30mg samples, Add 3 mL of water and 3 kinds of biological solvents respectively, shake at a constant temperature of 37°C (100 rpm); take 1.0 mL of suspension (or clear solution) at 1/4/24 hours, centrifuge the suspension for 3 minutes, and remove the supernatant/clear solution After filtration, it was used for solubility testing (HPLC) and pH determination (pH meter).
  • HPLC solubility testing
  • pH determination pH determination
  • the solubility of phosphate in water/SGF/FaSSIF/FeSSIF is >9mg/mL.
  • Use HPLC to measure the solubility of the sample. Specifically, use an Agilent 1260 high-performance liquid chromatograph (equipped with a DAD detector) to collect the purity and solubility data of the sample. The test method is shown in Table 1 above. The pH value does not change within 24 hours. Phosphate has good solubility in both water and simulated biological environments.
  • Bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine hydrochloride is extremely hygroscopic and will form a gel at room temperature. Samples with better solid state properties cannot be obtained without vacuum drying.
  • the sulfate prepared with an acid-base ratio of 1 can form a solid at room temperature, but the resulting salt has poor stability at room temperature and is highly hygroscopic; L-tartaric acid can form a solid at room temperature, but the resulting solid is It will form a gel after being sealed and placed at room temperature for 1 week; the phosphate prepared with a oxalate and acid-base ratio of 3 is extremely hygroscopic, has poor stability, and is extremely hygroscopic, resulting in varying degrees of wall sticking during the preparation process. Not conducive to industrial production.
  • the phosphoric acid produced with an acid-base input ratio of 1 is in a better state of suspension during the salt-forming process, and the salt is easier to precipitate and separate from the system, and the stability of the prepared phosphoric acid phosphate is better. After being left for two weeks, the properties and purity will not change. obvious changes, and the hygroscopicity is relatively low, extremely It is very conducive to industrial large-scale production.
  • Amount/molar weight of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropyl)))aminopropylamine that is, acid-base molar ratio, phosphate ion content
  • the test methods are shown in Table 2; test results The results are shown in Table 7.
  • the phosphate prepared by 3.05eq with an acid-base ratio of 3 is unstable.
  • the purity of the product obtained is relatively high. Compared with the raw materials, the purity has not decreased but has increased by 1%. That is to say, there is a greater elimination process in the salt formation process of free alkali and phosphoric acid. Mixed effects.
  • the reaction prepares bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropyl
  • the acid-base ratio of amine phosphate is 1.9-2.1; and during the preparation process, the salt is easier to precipitate from the reaction system.
  • a simple filtration operation can be used to separate the salt from the system, which is greatly beneficial to industrial large-scale production; and when phosphoric acid equivalent When it is 3.05eq, the reaction prepares bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate with an acid-base ratio of 3.0 ;Severe wall sticking phenomenon occurred during the reaction.
  • the phosphoric acid equivalent was 1.9eq, the reaction system was good and the solid produced was uniform; but when the phosphoric acid equivalent was 3.05eq, the mixture in the reaction system was obviously uneven and the bottom of the mixed system was white.
  • Example 4 prepare bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, and take the prepared bis( 3.27g of (N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate was added to 11.4g of purified water, and then slowly poured into the reaction vessel Add 13.3g methanol, adjust the temperature in the reaction vessel to 0-10°C, and then slowly add 193.0g methanol into the reaction vessel.
  • the phosphate crystal form A was characterized by TGA and DSC. The results are shown in Figure 2.
  • the TGA results show that the sample has a weight loss of 2.714% when heated from 22°C to 150°C. This part of the weight loss is the weight loss of desorbed water.
  • the DSC results show that the sample is 71.28%.
  • There is an endothermic peak at 185.64°C which is the peak of desorbed water from the sample.
  • the sample has an endothermic peak at 185.64°C, which is the peak corresponding to the crystalline transformation of the sample.
  • the signal from the start of DSC heating is presumed to be the instrument signal.
  • the prepared phosphate crystal form A has an acid-base ratio of 2.0, and the hygroscopicity classification is slightly hygroscopic; it has good stability under the conditions of 25°C/60%RH, light, 60°C, and 80°C. There was no change in the crystal form after being placed for 2 weeks.

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Abstract

本发明公开了一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐及其晶型和制备方法，相较于二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺的游离碱和其他盐来说，其具有较好的稳定性和较高的动态溶解度，更有利于用药安全和工业化生产。

Description

一种多胺衍生物药用盐及其晶型和制备方法 技术领域
本发明涉及化工医药技术领域，具体涉及一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐及其晶型和制备方法。
背景技术
全身炎症反应综合征和自身免疫紊乱相关疾病，如脓毒症和自身免疫性疾病，是由于机体自身过度免疫反应而引发的两类疾病，目前仍然缺乏有效治疗药物，对其的针对性防治是临床关注的焦点和热点问题。
脓毒症是指由感染因素介导的全身炎症反应综合征(systemic inflammatory response syndrome，SIRS)，全球每年发病人数高达1900万。尽管当前抗生素和重症医学技术已取得长足进展，但是脓毒症仍然是感染患者死亡的主要因素，至今没有理想的治疗药物。研究显示，脓毒症的发生机制在于细菌、病毒、真菌等病原体释放的病原体相关分子(pathogen-associated molecular pattern，PAMP)被宿主天然免疫系统的模式识别受体(pattern recognition receptor，PRR)识别，介导炎症反应细胞活化，从而引发全身性的过度炎症反应。流行病学调查显示，引发脓毒症的PAMP分子主要包括细菌脂多糖(lipopolysaccharide，LPS)、细菌基因组DNA(CpG DNA)、肽聚糖(peptidoglycan，PGN)、磷壁酸(lipoteichoic acid，LTA)、病毒RNA以及酵母多糖。
专利文件CN105348137B公开了一种多胺衍生物药用盐及其制备方法和治疗脓毒症的用途，所述的多胺衍生物药用盐为二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺酸碱比为3的盐酸盐。
但在实际生产中发现，现有技术中所公开的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺酸碱比为3的盐酸盐，生产制备过程中存在严重的粘壁现象，存在产品出料困难，不利于实际生产的可操作性差的缺点。
因此，研发一种适于工业化生产且稳定的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺药用盐显得非常有必要。
发明内容
为克服现有技术的不足，本发明提供了一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰 基)))氨基丙基胺磷酸盐及其晶型和制备方法。
本发明第一方面提供了一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐。
进一步地，所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐具有如下结构：
x表示每摩尔二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺结合的磷酸的摩尔数，进一步地，所述的x为1～3(如1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0)，优选地，所述的x为1.5～2.5，更优选地，所述的x为1.9～2.1，最优选的，所述的x为2.0。
优选地，所述磷酸盐为：
进一步地，所述磷酸盐为结晶、非结晶形式，或结晶与非结晶的混合形式。
本发明第二方面提供了第一方面所述二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的制备方法，其包括将二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺与磷酸混合的步骤。
进一步地，所述的制备方法为：
将二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺与磷酸混合，反应；
进一步地，所述反应溶剂选自：乙酸乙酯、二氯甲烷、甲醇、水、三氯甲烷、乙醇、丙酮、乙腈、丁醇、二甲基甲酰胺、二甲基亚砜、甲基叔丁基醚、异丙胺和异丙醇中的一种或多种，优选地，所述反应溶剂选自：甲醇、乙醇、乙酸乙酯、丙酮和二氯甲烷中的一种或多种，更优选地，所述反应溶剂为甲醇或乙醇。
进一步地，所述反应的温度为0～30℃(如0℃、5℃、15℃、20℃、25℃、30℃)，优选地，所述反应的温度为0～15℃。
进一步地，所述反应的时间为2～6h(如2h、3h、4h、5h、6h)，优选地，为3～5h，更优选地，为4h。
进一步地，所述反应过程中加入晶种。
进一步地，所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺与磷酸的当量比为1：1～2.5(如1:1、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9、1:2、1:2.1、1:2.2、1:2.3、1:2.4、1:2.5)，优选地，所述当量比为1:1～2，更优选地，所述当量比为1:1.8～2，所述当量比为摩尔量之比。
进一步，所述二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的制备方法还包括分离产物的步骤。
进一步地，所述的分离包括过滤或离心步骤。
进一步地，所述的过滤操作是指过滤反应后所得反应体系，得到滤饼，任选地，洗涤滤饼。
进一步地，洗涤所用溶剂选自：甲醇、乙酸乙酯、乙醇和异丙醇中的一种，优选地，所述洗涤溶剂为甲醇或乙酸乙酯。
进一步，所述二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的制备方法还包括干燥步骤。
进一步地，所述的干燥步骤是指将分离所得物质进行常压干燥或减压干燥处理。
进一步地，干燥温度为0～35℃(如0℃、5℃、10℃、15℃、20℃、25℃、30℃、35℃)，优选地，干燥温度为25-35℃。
其中所述二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺可根据任意几种不同方法以克规模或千克规模制备，例如，专利文献CN201510729318.8中所述制备方法，其通过引用并入本文。
进一步地，所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的制备方法还包括二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的纯化(精制)步骤。
进一步地，所述的纯化(精制)步骤包括重结晶和/或洗涤。
进一步地，所述重结晶的溶剂选自：甲醇、乙醇和水中的一种或两种的组合，特别是甲醇-水、乙醇-水、水-甲醇、水-乙醇。
进一步地，所述洗涤的溶剂选自：甲醇、乙醇、乙酸乙酯和异丙醇中的一种，优选地，所述洗涤晶体的溶剂为甲醇或乙酸乙酯。
进一步地，所述纯化(精制)步骤包括加入晶种。
本发明第三方面提供了第一方面所述二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的非结晶型的制备方法。
进一步地，所述的制备方法选自：气液扩散法、高聚物诱导法、缓慢挥发法和缓慢降温法中的一种或多种的组合，优选地，所述的制备方法选自：气液扩散法、高聚物诱导法和缓慢挥发法中的一种或多种的组合。
进一步地，所述气液扩散法包括：将目标产物放置在敞口容器中并用正溶剂溶解，然后将敞口容器放置在装有反溶剂的密封容器中静置(室温下)，最后收集得到固体。
进一步地，所述高聚物诱导法包括：将目标产物用溶剂溶解，针膜过滤，向滤液中加入高聚物，室温下挥发得到固体。
进一步地，所述缓慢挥发法包括：将目标产物用溶剂溶解，然后干燥得到固体。
进一步地，所述缓慢降温法包括：将目标产物用溶剂溶解，在40℃-60℃下加热，搅拌平衡1-4h，溶液变澄清后过滤，将滤液从40℃-60℃缓慢降温至0℃-10℃，并在-10～30℃(如10℃、15℃、20℃、25℃、30℃)恒温放置3-8天后仍澄清，最终进行40～60℃(如40℃、45℃、50℃、55℃、60℃)挥发处理。
在本发明的一个实施方式中，所述二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的非结晶型的制备方法为缓慢挥发法，具体指在4mL玻璃瓶中称量10～20mg二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐，加入体积比为2：1的DMSO和水的混合溶液中溶解。针膜过滤(孔径0.22μm)，滤液用封口，并扎5个针孔，在设置温度条件下缓慢挥发。对最终得到的固体进行XRPD表征。实验结果表明，通过室温缓慢挥发法得到无定形的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐。
本发明第四方面提供了第一方面所述二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的晶型A。
进一步地，所述晶型A的XRPD图谱在2θ值为6.4°±0.2°、9.7°±0.2°、16.2°±0.2°、19.5°±0.2°、22.9°±0.2°、26.1°±0.2°的位置中的至少三个(或全部)位置处具有特征峰(主要特征衍射峰)。
进一步地，所述晶型A的XRPD图谱在2θ值为6.4°±0.2°、9.7°±0.2°、11.80°±0.2°、13.0°±0.2°、14.8°±0.2°、16.2°±0.2°、19.5°±0.2°、22.9°±0.2°、26.1°±0.2°的位置中的至少三个(或全部)位置处具有特征峰(主要特征衍射峰)。
进一步地，所述晶型A的XRPD图谱在2θ值为11.80°±0.2°、13.0°±0.2°、14.8°±0.2°、15.3°±0.2°、18.7°±0.2°、20.8°±0.2°、22.6°±0.2°、23.7°±0.2°的位置中的至少三个(至少四个或全部)位置处具有特征峰(次要特征衍射峰)。
进一步地，所述晶型A具有基本上如图1所示的XRPD图谱。
进一步地，所述晶型A的DSC图谱，在175-195℃(如175℃、180℃、185℃、190℃ 195℃附近)具有吸热峰。
进一步地，所述晶型A具有基本上如图2所示的DSC图谱。
进一步地，所述晶型A从22℃加热至150℃重量损失约为3％(如1.5％、2.0％、2.5％、3.0％)。
进一步地，所述晶型A具有基本上如图2所示的TGA图谱。
本发明第五方面提供了第四方面所述晶型A的制备方法。
进一步地，所述制备方法为反溶剂结晶法与反-反溶剂结晶法。
进一步地，所述反溶剂结晶法包括：将目标产物用正溶剂溶解，然后向体系中加入反溶剂，反溶剂不能溶解或仅能微溶待结晶物质，因此降低了结晶物质的溶解度，使其从混合溶液中析出。
进一步地，所述反-反溶剂结晶法包括：在用正溶剂溶解了目标产物的溶液后，将其加入一种或几种反溶剂，产品在所述溶液中处于微溶状态，从而使溶液达到过饱和状态后析出结晶的方法。
在本发明的一个实施方式中，所述二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐晶型A的反溶剂结晶法具体包括：
(1)将本发明第二方面所得反应产物与正溶剂混合；
(2)向步骤(1)所得混合溶液中滴加反溶剂；
(3)对步骤(2)所得溶液进行降温处理，分离，得到湿品；
(4)对步骤(3)所得湿品进行干燥处理，得到干品磷酸盐晶体A。
进一步地，步骤(1)所述的正溶剂选自：所述正溶剂为水、甲醇与水混合液或乙醇与水的混合液；优选的，步骤(1)所述的正溶剂为甲醇与水的混合液。
进一步地，步骤(1)所述的反溶剂选自：甲醇，乙醇、四氢呋喃、乙酸乙酯或甲苯中的一种或多种。
进一步地，步骤(3)所述的降温处理是指将温度降至0-15℃(如0℃、5℃、10℃、15℃)，优选地，步骤(3)所述的降温处理是指将温度降至5℃。
进一步地，步骤(3)所述降温处理的时间为3～16h(如3h、4h、5h、6h、7h、8h、9h、10h、11h、12h、13h、14h、15h、16h)，优选地，步骤(3)所述降温处理的时间为8-14h(如8h、9h、10h、11h、12h、13h、14h)，进一步优选地，步骤(3)所述降温处理的时间为12h。
进一步地，步骤(3)所述分离方式包括离心、过滤和/或抽滤。优选地，所述的离心是指离心反应后的混合溶液，得到固体。
进一步地，步骤(4)所述干燥处理中，干燥温度为25～35℃(如25℃、30℃、35℃)，优选地，干燥温度为30℃。
本发明第六方面提供了一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐及其晶型A在制备抗PAMP的药物中的应用。
进一步地，所述的PAMP选自：细菌脂多糖(lipopolysaccharide，LPS)、细菌基因组DNA(CpG DNA)、肽聚糖(peptidoglycan，PGN)、磷壁酸(lipoteichoic acid，LTA)、病毒RNA和酵母多糖中的一种或多种。
本发明第七方面提供了一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐及其晶型A在制备预防和/或治疗全身炎症反应综合征(SIRS)的药物中的应用。
进一步地，所述的全身炎症反应综合征为脓毒症。
本发明第八方面提供了一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐及其晶型A在制备预防和/或治疗自身免疫性疾病的药物中的应用。
进一步地，所述的自身免疫性疾病选自：器官特异性自身免疫病、系统性红斑狼疮、类风湿关节炎、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、溃疡性结肠炎中的一种或多种。
本申请所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐相对于二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺的游离碱和其他盐具有较好的稳定性和较高的动态溶解度，有利于工业化生产；其中，二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺二磷酸盐相较于二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺三磷酸盐稳定性更高，更有利于用药安全；在二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐制备过程中，采用本申请所述的磷酸当量比，盐较易从反应体系中析出，可用简单过滤操作将盐从体系中分离，极大有利于工业化大规模生产。
附图说明
图1所示为磷酸盐晶型A的XRPD图谱。
图2所示为磷酸盐晶型A的TGA/DSC图谱。
具体实施方式
本发明所用到的部分缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差式扫描量热
TGA：热重分析
在本发明中，术语“晶型”是通过X射线粉末衍射图表征证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度等。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线粉末衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线粉末衍射图不必和本文所指的实施例中的X射线粉末衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范围之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。在一些实施方案中，本发明的晶型A是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。当在本发明数值前使用术语“约”并且指代所述数值时，其意指该值的±10％的范围内，优选±5％的范围内，更优选±2％的范围内，更优选±1％的范围内的任意值。例如，“约10”应解释为意指9-11，优选为9.5-10.5，更优选为9.8-10.2，更优选为9.9-10.1。
还需要说明的是，在粉末样品X射线衍射图谱中，由晶体化合物得到的衍射谱图特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径、混合物的相对含量和其它测试条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶体并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的位置而不是它们的相对强度。
在本发明中，术语“基本上如图……所示”是指XRPD图谱或DSC图谱或TGA图 谱中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。
在本发明中，术语“室温”是指物品的温度与空间(例如所述物品位于其中的通风橱的场所)的温度接近或相同。通常，室温为约20℃至约30℃，或约22℃至27℃，或约25℃。
反溶剂结晶(也称为反溶剂添加、沉淀析晶、盐析或逼晶)法通常是通过在用正溶剂溶解了目标产物的溶液中加入一种或几种反溶剂，产品在所述溶液中处于微溶状态，从而使溶液达到过饱和状态后析出结晶的方法。反-反溶剂结晶通常是通过在用正溶剂溶解了目标产物的溶液后，将其加入一种或几种反溶剂，产品在所述溶液中处于微溶状态，从而使溶液达到过饱和状态后析出结晶的方法。
反溶剂溶解目标产物的能力比正溶剂差，比如差超过10％、20％、30％、40％、50％、60％、70％或者80％，所以，体系中的反溶剂是相对而言。正溶剂和反溶剂可以为极性溶剂或非极性溶剂，如可以选自：二甲基甲酰胺(DMF)、二甲基亚砜(二甲基亚砜)、水、醇类溶剂、醚溶剂、酮类溶剂、酯类溶剂、烷烃类溶剂、芳烃类溶剂、腈类溶剂的一种或多种。其中，醇类溶剂包括但不限于甲醇、乙醇、丙醇、异丙醇或1,3-丙二醇、1,2-丙二醇或三氯叔丁醇或其组合；醚溶剂包括但不限于诸如四氢呋喃、甲基叔丁基醚或1,4-二氧六环或其组合；酮类溶剂包括但不限于丙酮、甲乙酮或4-甲基-2-戊酮或其组合；酯类溶剂包括但不限于乙酸乙酯、乙酸异丙酯、乙酸正丁酯或乙酸叔丁酯或其组合；烷烃类溶剂包括但不限于二氯甲烷、氯仿、正己烷、环己烷或戊烷或正庚烷或其组合；芳烃类溶剂包括但不限于苯、甲苯或其组合；腈类溶剂包括但不限于乙腈、丙二腈。
反溶剂结晶、反-反溶剂结晶可以通过间歇、半间歇或连续结晶操作。反溶剂加入溶液(反溶剂结晶)中或产品溶液加入反溶剂(反-反溶剂结晶)中，可以以恒定速率滴加，也可以是起始时缓慢滴加，然后逐渐递加速率。
本文所引用的各种出版物、专利和公开的专利说明书，其公开内容通过引用整体并入本文。
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例的实验中所使用的仪器信息和方法如下：
1、X射线粉末衍射(XRPD)
X-射线粉末衍射仪(XRPD)测试条件为：使用布鲁克D2型号X-射线粉末衍射仪，在环境条件下收集样品的X-射线粉末衍射数据，X-射线发射器功率为300W。样品台无背景信号，步速为0.15s/步，总步数为1837步，步长为2θ＝0.02°，电压为30kV，电流为10mA。X-射线管采用Cu靶(Kα)，Kα2/Kα1强度比为
2、热重分析(TGA)和差示扫描量热(DSC)
使用TA Discovery系列的热重仪(TGA)收集磷酸盐的热重数据。取几毫克样品放入Tzero铝盘中，在N2保护下从室温加热到目标温度，N2流速为25mL/分钟，加热速率为10℃/分钟。使用TA Discovery系列的差式扫描量热仪(DSC)收集样品的热数据。对于晶型样品，称量几毫克样品在Tzero铝盘中，用Tzero密封盖密封，在N2保护下加热，N2流速为50mL/分钟，加热速率为10℃/分钟。对于无定形样品，设置调制模式进行测试：称量约10mg在Tzero铝盘中，用Tzero密封盖密封，在N2保护下加热，N2流速为50mL/分钟，调制温度振幅为±1℃，调制周期为40秒，加热速率为1℃/分钟，测试温度范围25℃～200℃。
3、高效液相色谱(HPLC)
使用HPLC测定样品的稳定性，具体为使用安捷伦1260型号高效液相色谱仪(配有DAD探测器)收集样品的纯度和溶解度数据，测试方法见表1。
表1

4、磷酸根离子含量
二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐，使用DIONEX ICS-6000+DP离子色谱系统收集样品的磷酸根离子含量数据，测试方法见表2。
表2
5、生物溶媒的制备
生物溶媒制备的具体操作见表3。
表3

6、引湿性的测定
引湿性的测定参考中国药典2015版药物引湿性试验指导原则，具体试验方法如下：
1.取干燥的具塞玻璃称量瓶(外径为50mm，高为15mm)，于试验前一天置于适宜的25℃±1℃恒温干燥器(下部放置氯化铵或硫酸铵饱和溶液)或人工气候箱(设定温度为25℃±1℃，相对湿度为80％±2％)内，精密称定重量(m1)。
2.取供试品适量，平铺于上述称量瓶中，供试品厚度一般约为1mm，精密称定重量(m2)。
3.将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下24小时。
4.盖好称量瓶盖子，精密称定重量(m3)。
增重百分率＝(m3-m2)/(m2-m1)×100％
5.引湿性特征描述与引湿性增重的界定
潮解：吸收足量水分形成液体。
极具引湿性：引湿增重不小于15％。
有引湿性：引湿增重小于15％但不小于2％。
略有引湿性：引湿增重小于2％但不小于0.2％。
无或几乎无引湿性：引湿增重小于0.2％。
实施例1
盐型的筛选
室温下配制二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺游离碱(以下简称为游离碱)的乙醇溶液，在HPLC小瓶中称入酸碱摩尔投料比为1:1的酸溶液，加入游离碱的乙醇溶液室温磁力搅拌；室温磁力搅拌2～4天后，少量体系得到浑浊固体，部分体系观察到黏壁、成胶现象，其余体系仍为澄清。后续处理步骤为：1)对于浑浊体系离心分离固体；2)对于黏壁/成胶体系，进行25℃～50℃循环升降温处理(升降温程序见表5)，尝试改善表观状态/得到固体；3)对于澄清或少量浑浊的体系，在5℃下磁力搅拌约5小时后-20℃静置过夜，尝试收集足量固体用于后续表征，若固体量仍然较少，进行室温缓慢挥发；若体系最终仍然澄清，进行反溶剂添加(n-heptane)或室温缓慢挥发。离心分离以上所得固体。所述试验结果如表4。
表4

α：酸碱摩尔投料比为1:1。
β：酸碱摩尔投料比为3:1。
*：固体量较少或体系澄清，低温5℃/-20℃处理后进行室温(18～22℃)缓慢挥发。
#：固体量较少或体系澄清，低温5℃/-20℃处理后进行反溶剂添加。
体系成胶，25～50℃循环升降温处理后状态无改善。
&：反应得到少量固体，但30℃真空干燥17h后成胶。
※：反应得到的固体，在室温密封放置1周成胶。
表5
稳定性测试
为评估不同盐的固态稳定性，称取约15mg样品到HPLC小瓶中，敞口置于25℃/60％RH条件下，对起始样品和储存5天和2周的样品进行化学纯度测试(HPLC)和引湿性测试。稳定性数据汇总见表6。结果显示，酸碱投料比为1制得的磷酸盐在所选条件下放置5天和2周后，性状和纯度无明显变化，而酸碱投料比为1制得的盐酸盐、硫酸盐和草酸盐以及酸碱投料比为3制得的磷酸盐在第四天就观察到粉末状固体变成了液体，且纯度均有一定程度的下降；酸碱投料比为1制得的磷酸盐引湿性为1.29％，为略有引湿性；而其他样品的引湿性均大于15％，为极具引湿性。上述实验数据说明五种盐型中，仅酸碱投料比为1制得的磷酸盐相对较稳定。酸碱投料比为1或3制得的磷酸盐固体取样测酸碱比，磷酸根离子含量测试方法见表2，测试结构表明，酸碱投料比1制得的磷酸盐的酸碱比为1.9；酸碱投料比为3制得的磷酸盐的酸碱比为3.0。
表6
使用HPLC测定样品的稳定性，具体为使用安捷伦1260型号高效液相色谱仪(配有DAD探测器)收集样品的纯度和溶解度数据，测试方法见表1。引湿性测定按照中国药典方法测定样品的引湿性，具体测定方法参加说明书部分“6、引湿性的测定”。
动态溶解度
在37℃条件下，测试磷酸盐在水和3种生物溶媒(模拟胃液SGF、模拟禁食肠液FaSSIF、模拟进食肠液FeSSIF)中的动态溶解度，溶解度测试的具体方法为：称4份30mg样品，分别加入3mL水和3种生物溶媒，恒温37℃振荡(100rpm)；1/4/24小时分别取1.0mL悬浊液(或澄清溶液)，悬浊液离心3分钟，上清液/澄清液过滤后用于溶解度测试(HPLC)和pH测定(pH计)。生物溶媒制备的具体操作见表3。
磷酸盐在水/SGF/FaSSIF/FeSSIF中溶解度>9mg/mL。使用HPLC测定样品的溶解性，具体为使用安捷伦1260型号高效液相色谱仪(配有DAD探测器)收集样品的纯度和溶解度数据，测试方法见上表1。pH值24小时内无变化。在水和模拟生物体内环境中，磷酸盐均具有较好的溶解度。
结论：与二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐不同的是，二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺的游离碱稳定性较低，室温放置7天，纯度从97.56％降低至73.73％，因此需-20℃保存。二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺盐酸盐极具吸湿性，室温条件即成呈胶状，非真空干燥无法得到具有较好固态性状的样品。酸碱投料比为1制得的硫酸盐室温条件可以形成固体，但形成的盐在室温条件下稳定性较差，为极具引湿性；L-酒石酸室温条件可以形成固体，但得到的固体在室温密封放置1周后成胶；草酸盐和酸碱投料比为3制得的磷酸盐为极具引湿性，稳定性较差，极具引湿性，导致制备过程中出现不同程度的黏壁现象，不利于工业化生产。
酸碱投料比为1制得的磷酸成盐过程混悬状态较好，盐较易从体系中析出并分离，且制得磷酸磷酸盐稳定性较好，在放置两周后，性状和纯度无明显变化，且吸湿性相对较低，极 大有利于工业化大规模生产。
盐的制备
实施例2
室温下，向100ml三口瓶中加入二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺游离碱(2g)；再加入二氯甲烷(20g)，开启搅拌，搅拌溶解并澄清，得到游离碱的二氯甲烷溶液；降温至0-5℃；
向离心管中加入磷酸(695mg，85％)，再加入乙酸乙酯10g，得到磷酸的乙酸乙酯溶液，摇匀备用；
向游离碱的二氯甲烷溶液中缓慢滴入磷酸的乙酸乙酯溶液；0-5℃搅拌反应4h，逐渐有白色固体析出，体系变浑浊，开始成球，搅拌过程中，成白色悬浊液；过滤，乙酸乙酯洗涤滤饼，得湿品；将固体放入30℃烘箱16h，烘料16h，得白色固体2.1g；固体取样测纯度、含量和酸碱比，试验结果见表8。
实施例3
室温下，向100ml三口瓶中加入二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺游离碱(1g)；再加入甲醇(10g)，开启搅拌，搅拌溶解并澄清，得到游离碱的甲醇溶液降温至0-5℃；
向离心管中加入磷酸(347.8mg,85％)，再加入甲醇5g，得到磷酸的甲醇溶液，摇匀备用；
向游离碱的甲醇溶液中缓慢滴入磷酸的甲醇溶液；0-5℃搅拌反应4h，体系刚开始澄清状态，0.5h后体系逐渐浑浊，后大量固体析出；过滤，乙酸乙酯洗涤滤饼，得湿品；将固体放入30℃烘箱，烘料16h，得白色固体1.1g；固体取样测纯度、含量和酸碱比。试验结果见表8。
实施例4
室温下，向100ml三口瓶中加入二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺游离碱(5g)；再加入甲醇(50g)，开启搅拌，搅拌溶解并澄清，得到游离碱的甲醇溶液，降温至0-5℃；
50ml烧杯中加入磷酸(1.65g,85％)，再加入甲醇25g，得到磷酸的甲醇溶液，摇匀备用；
向游离碱的甲醇溶液中缓慢滴入磷酸的甲醇溶液；0-5℃搅拌反应4h，体系刚开始澄清状态，0.5h后体系逐渐浑浊，后大量固体析出；过滤，甲醇洗涤滤饼，得白色湿品；将固体放入30℃烘箱16h，烘料16h，得白色固体5.5g；固体取样测纯度、含量和酸碱比，试验结果见表8。
实施例5
室温下，向100ml三口瓶中加入二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺游离碱(3.4g)；再加入甲醇(34g)，开启搅拌，搅拌溶解并澄清，得到游离碱的甲醇溶液，降温至0-5℃；
50ml烧杯中加入磷酸(1.12g,85％)，再加入甲醇17g，得到磷酸的甲醇溶液，摇匀备用；
向游离碱的甲醇溶液中缓慢滴入磷酸的甲醇溶液；0-5℃搅拌反应4h，体系刚开始澄清状态，0.5h后体系逐渐浑浊，后大量固体析出；过滤，甲醇洗涤滤饼，得白色湿品；将固体放入30℃烘箱，烘料16h，得白色固体5.5g；固体取样测纯度、含量和酸碱比，试验结果见表8。
实施例6
室温下，向100ml三口瓶中加入二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺游离碱(1.0g)；再加入甲醇(10g)，开启搅拌，搅拌溶解并澄清，得到游离碱的甲醇溶液，降温至0-5℃；
向离心管中加入磷酸(183mg,85％)，再加入甲醇5g，得到磷酸的甲醇溶液，摇匀备用；
向游离碱的甲醇溶液中缓慢滴入磷酸的甲醇溶液；0-5℃搅拌反应4h，过滤，甲醇洗涤滤饼，得白色湿品；将固体放入30℃烘箱，烘料16h，得白色固体0.8g；固体取样测纯度、含量和酸碱比，试验结果见表8。
研究人员发现，制备得到的酸碱比为2左右的磷酸盐，在甲醇-水或水-甲醇重结晶体系中进行重结晶后，其酸碱比几乎保持不变，在重结晶过程中比较稳定。
对比例1
室温下，向100ml三口瓶中加入二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺游离碱(1.0g)；再加入甲醇(10g)，开启搅拌，搅拌溶解并澄清，得到游离碱的甲醇溶液，降温至0-5℃；
向离心管中加入磷酸(558.3mg,85％)，再加入甲醇5g，得到磷酸的甲醇溶液，摇匀备用；
向游离碱的甲醇溶液中缓慢滴入磷酸的甲醇溶液；0-5℃搅拌反应4h，出现严重粘壁现象，将甲醇浓缩干以后，通过刮勺将粘壁固体刮下使用乙酸乙酯打浆后过滤，过滤完后吸潮严重，固体快速变成油状物，将油状物放入30℃烘箱，烘料16h，得固体，取样测纯度、含量和酸碱比，所述酸碱比为磷酸摩尔量/二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺摩尔量，也即酸碱摩尔比，磷酸根离子含量测试方法见表2；试验结 果见表7。
研究人员发现，制备得到的酸碱比为3的磷酸盐，在甲醇-水或水-甲醇重结晶体系中进行重结晶，其酸碱比会出现降低，降幅大于10％，也即磷酸当量为3.05eq制备得到的酸碱比为3的磷酸盐不稳定。
表7
从上表可以看出，游离碱和磷酸成盐过程中，得到产品纯度较高，相较于原料，纯度未下降反而提高了1％，也即游离碱和磷酸成盐过程有较大的除杂效果。
当磷酸当量为1.0eq、1.8eq或1.9eq时，反应制备得到二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐中酸碱比为1.9-2.1；且制备过程中，盐较易从反应体系中析出，可用简单过滤操作将盐从体系中分离，极大有利于工业化大规模生产；而当磷酸当量为3.05eq时，反应制备得到二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐中酸碱比为3.0；反应过程中出现严重的粘壁现象，当磷酸当量为1.9eq时，反应体系良好，生成固体均一；而当磷酸当量为3.05eq时，反应体系中的混合物明显不均一，混合体系底部偏白，中间部分有略泛黄油状物黏附在烧瓶内壁，整个反应体系无法直接采用过滤方法分离磷酸盐，需用溶剂打浆过滤，且过滤后得到固体室温条件吸潮严重，快速变成油状物，不利于产品工业化大规模生产。
晶型的制备
实施例7
参照实施例4方法，制备二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐，取制备得到的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐3.27g，加入到11.4g纯化水中，后向反应容器中缓慢加入13.3g甲醇，将反应容器内温度调至0-10℃，然后将193.0g甲醇缓慢加入反应容器中，加料结束，控制反应容器内温度0-10℃搅拌3-16 小时得到白色固体，通过离心方式分离得到湿品，25℃真空干燥之后进行XRPD表征，测得二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐为磷酸盐晶型A，二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐晶型A的XRPD图如图1所示，表8为其对应的X-射线粉末衍射图案数据，其列出了衍射角2θ和相对强度(表示为相对于最强峰的百分比)。
表8

对磷酸盐晶型A进行TGA、DSC表征，结果如图2，TGA结果显示样品从22℃加热至150℃时有2.714％的失重，该部分失重为脱吸附水失重，DSC结果显示样品在71.28℃处具有吸热峰，其为样品脱吸附水的峰，样品在185.64℃处具有吸热峰，其为样品的晶型转变对应峰，DSC加热起始的信号推测为仪器信号。
经检测，所制备得到磷酸盐晶型A，酸碱比为2.0，引湿性分类属于略有引湿性；稳定性较好，在25℃/60％RH、光照、60℃、以及80℃条件下放置2周晶型无变化。

Claims (10)

  1. 一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐，其特征在于，所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐具有如下结构：
    其中，x为1～3，优选地，所述的x为1.5～2.5，更优选地，所述的x为1.9～2.1，最优选的，所述的x为2.0。
  2. 权利要求1所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的制备方法，其特征在于，所述制备方法为：将二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺与磷酸混合，反应，得到固体；
    优选地，所述反应溶剂选自：乙酸乙酯、二氯甲烷、甲醇、水、三氯甲烷、乙醇、丙酮、乙腈、丁醇、二甲基甲酰胺、二甲基亚砜、甲基叔丁基醚、异丙胺和异丙醇中的一种或多种；进一步优选地，所述反应溶剂选自：甲醇、乙醇、乙酸乙酯、丙酮和二氯甲烷中的一种或多种；更优选地，所述反应溶剂为甲醇或/和乙醇；优选地，所述反应的温度为0～35℃。
  3. 一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的晶型A，其特征在于，所述晶型A的XRPD图谱在2θ值为6.4°±0.2°、9.7°±0.2°、16.2°±0.2°、19.5°±0.2°、22.9°±0.2°、26.1°±0.2°的位置中的至少三个位置处具有特征峰。
  4. 权利要求3所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的晶型A，其特征在于，所述晶型A的XRPD图谱还在2θ值为11.80°±0.2°、13.0°±0.2°、14.8°±0.2°、15.3°±0.2°、18.7°±0.2°、20.8°±0.2°、22.6°±0.2°、23.7°±0.2°的位置中的至少三个位置处具有特征峰。
  5. 权利要求3或4所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的晶型A，其特征在于，所述晶型A具有基本上如图1所示的XRPD图谱；优选地，所述晶型A具有基本上如图2所示的DSC图谱，优选地，所述晶型A具有基本上如图2所示的TGA图谱。
  6. 一种二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的晶型A的制备方法，其特征在于：将二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐与正溶剂混合，然后与反溶剂混合，析晶得到磷酸盐晶体A。
  7. 权利要求6所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷 酸盐的晶型A的制备方法，其特征在于，所述反应的温度为0～30℃，优选地，所述反应的温度为0～10℃，更优选地，所述反应的温度为0～5℃。
  8. 权利要求6所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的晶型A的制备方法，其特征在于，所述正溶剂为水、甲醇与水混合液或乙醇与水的混合液；所述反溶剂选自甲醇，乙醇、四氢呋喃、乙酸乙酯或甲苯中的一种或多种。
  9. 权利要求1所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐或权利要求3-5任一项所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的晶型A在制备抗PAMP的药物中的应用；
    优选地，所述的PAMP选自：细菌脂多糖、细菌基因组、肽聚糖、磷壁酸、病毒RNA和酵母多糖中的一种或多种。
  10. 权利要求1所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐或权利要求3-5任一项所述的二((N-3-氨基丙基)-(N-(3,4-二甲氧基苯丙酰基)))氨基丙基胺磷酸盐的晶型A在制备预防和/或治疗全身炎症反应综合征或自身免疫性疾病的药物中的应用；
    优选地，所述的全身炎症反应综合征为脓毒症；
    优选地，所述的自身免疫性疾病选自：器官特异性自身免疫病、系统性红斑狼疮、类风湿关节炎、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、溃疡性结肠炎中的一种或多种。
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