CN116715662A - Amorphous B-RAF kinase dimer inhibitors - Google Patents

Amorphous B-RAF kinase dimer inhibitors Download PDF

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CN116715662A
CN116715662A CN202310498552.9A CN202310498552A CN116715662A CN 116715662 A CN116715662 A CN 116715662A CN 202310498552 A CN202310498552 A CN 202310498552A CN 116715662 A CN116715662 A CN 116715662A
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compound
amorphous form
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张国良
周昌友
孙熀彬
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Baiji Shenzhou Beijing Biotechnology Co ltd
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Baiji Shenzhou Beijing Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

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Abstract

The present invention relates to a stable amorphous form of the B-RAF kinase dimer inhibitor 1- ((1 s,1as,6 bs) -5- ((7-oxo-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy) -1a, 6B-dihydro-1H-cyclopropa [ B ] benzofuran-1-yl) -3- (2, 4, 5-trifluorophenyl) urea (sometimes referred to hereinafter as compound 1), a process for the preparation of said amorphous compound and the therapeutic use of said amorphous compound.

Description

Amorphous B-RAF kinase dimer inhibitors
The present application is a divisional application based on a patent application with the application date of 2019, 1 month and 25 days, the application number of 201910077266.9 and the name of amorphous B-RAF kinase dimer inhibitor.
Technical Field
The present invention relates to a stable amorphous form of the B-RAF kinase dimer inhibitor 1- ((1 s, las,6 bs) -5- ((7-oxo-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy) -1a, 6B-dihydro-1H-cyclopropa [ B ] benzofuran-1-yl) -3- (2, 4, 5-trifluorophenyl) urea (sometimes referred to hereinafter as compound 1), a process for the preparation of said amorphous compound and the therapeutic use of said amorphous compound.
Background
Second generation B-RAF inhibitors are disclosed in PCT patent application WO 2014/206343 A1, which include 1- ((1 s,1as,6 bs) -5- ((7-oxo-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy) -1a, 6B-dihydro-1H-cyclopropa [ B ] benzofuran-1-yl) -3- (2, 4, 5-trifluorophenyl) urea. The structure of compound 1 is shown below:
as a second-generation B-RAF inhibitor, the compound 1 has a strong inhibition effect on RAF family of serine/threonine kinase, in particular BRAF/CRAF dimer. The compound has targeted therapeutic effect on cancers with mutations (including B-RAF mutation and K-RAS/N-RAS mutation) on MAK channels, and is a molecular targeted therapeutic agent. Compound 1 is improved over the first generation B-RAF inhibitors, such as vemurafenib (vemurafenib) and dabrafenib (dabrafenib).
Compound 1 in crystalline form as an organically synthesized free base has low solubility in water and thus low oral bioavailability.
The amorphous form is one of the substance polymorphism and is an amorphous state. Various physicochemical properties and clinical pharmacodynamic characteristics of amorphous drugs are often different from those of general crystalline drugs. Therefore, in the study of polymorphic forms of solid drugs, intensive investigation of amorphous substances is also of great importance. In general, amorphous forms have a high dispersibility and a high energy state compared to crystalline forms, and thus have higher solubility and bioavailability compared to crystalline forms. However, the amorphous form has a very limited application in the pharmaceutical industry due to its poor stability.
The inventors of the present invention have found a pure amorphous form of compound 1 which has a relatively long stability unlike the general amorphous form and a relatively high bioavailability compared to the crystalline form.
Disclosure of Invention
The present invention provides a pure amorphous form of compound 1 that does not undergo a crystalline form transformation during the 14 day test period, i.e. does not exhibit any diffraction peaks during the 14 day test period; and the amorphous form has a relatively high bioavailability compared to the crystalline form. This demonstrates the potential utility of the amorphous forms of the invention for drug preparation.
In a first aspect, the present invention provides a pure amorphous form of compound 1, characterized in that said pure amorphous form has an X-ray powder diffraction pattern without diffraction peaks, as shown in fig. 7.
Preferably, the pure amorphous form of the present invention has the form as shown in FIG. 11 1 H-NMR spectrum.
Preferably, the glass transition temperature of the pure amorphous form of the present invention is between about 135 to 143 ℃, more preferably about 138.3 ℃.
Preferably, the pure amorphous form of the present invention has a particle size D of between about 60 and about 80 μm 90 D between about 2 and about 6 μm 50 D between about 1 and about 2 μm 10 The method comprises the steps of carrying out a first treatment on the surface of the More preferably D 90 About 69.9 μm, D 50 About 3.5 μm, and D 10 About 1.4 μm.
In a second aspect, the present invention provides a process for preparing a pure amorphous form of compound 1, said process comprising: spray drying a solution of the crystalline form of compound 1 in a polar solvent gives a powdery substance.
Preferably, the polar solvent comprises ethers, carboxylic acid esters, nitriles, ketones, amides, sulfones, sulfoxides or halogenated hydrocarbons. More preferably, the polar solvent includes, but is not limited to, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, tertiary butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. Preferably, the polar solvent is a mixture of halogenated hydrocarbons/alcohols, such as a mixture of DCM/MeOH.
Preferably, the spray drying is performed by a spray dryer. Preferably, the inlet temperature of the spray dryer is set at about 50 to 70 ℃, and the outlet temperature of the spray dryer is set at about 25 to 45 ℃; more preferably, the inlet temperature of the spray dryer is set at about 60 ℃, and the outlet temperature of the spray dryer is set at about 35 ℃.
Preferably, the crystalline form of compound 1 is crystalline form a. In one embodiment, the crystalline form a is characterized by an X-ray powder diffraction pattern comprising at least three, four, five, or six diffraction peaks having a value of 2Θ independently selected from: 4.7.+ -. 0.2, 9.4.+ -. 0.2, 13.6.+ -. 0.2, 14.0.+ -. 0.2, 14.9.+ -. 0.2 and 15.6.+ -. 0.2 °. Preferably, the crystalline form a is characterized by an X-ray powder diffraction pattern comprising at least three, four, five or six diffraction peaks having a value of 2Θ independently selected from the group consisting of: 4.7.+ -. 0.2, 9.4.+ -. 0.2, 13.6.+ -. 0.2, 14.0.+ -. 0.2, 14.9.+ -. 0.2, 15.6.+ -. 0.2, 21.2.+ -. 0.2, 24.3.+ -. 0.2, 24.7.+ -. 0.2, 25.1.+ -. 0.2 and 29.1.+ -. 0.2 °. More preferably, the crystalline form a is characterized by an x-ray powder diffraction pattern comprising diffraction peaks having a value of 2θ° independently selected from the group consisting of: 4.7.+ -. 0.2, 9.4.+ -. 0.2, 10.2.+ -. 0.2, 13.6.+ -. 0.2, 14.0.+ -. 0.2, 14.9.+ -. 0.2, 15.6.+ -. 0.2, 17.2.+ -. 0.2, 17.4.+ -. 0.2, 18.7.+ -. 0.2, 20.0.+ -. 0.2, 20.4.+ -. 0.2, 21.2.+ -. 0.2, 22.3.+ -. 0.2, 24.3.+ -. 0.2, 24.7.+ -. 0.2, 25.1.+ -. 0.2, 25.5.+ -. 0.2, 26.8.+ -. 0.2, 27.4.+ -. 0.2, 27.8.+ -. 0.2, 29.1.+ -. 0.2, 30.2.+ -. 0.2, 31.8.+ -. 0.2, 32.0.+ -. 0.2, 33.1.+ -. 0.2, 34.1.+ -. 0.2 and 34.6..2. In a preferred embodiment, the crystalline form a is characterized by an X-ray powder diffraction pattern substantially as shown in figure 1.
Preferably, the crystalline form of compound 1 is single crystal a.
In one embodiment, the single crystalline form a has unit cell parameters of
In one embodiment, the single crystalline form a is a monoclinic (crystalline) P2 1 。
In a preferred embodiment, the crystalline form a is prepared by a commercial scale process.
In a third aspect, the application discloses a method of treating or preventing a disease or disorder responsive to inhibition of Raf kinase in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein compound 1 is in the pure amorphous form disclosed herein.
In one embodiment, the disease or disorder is a cancer selected from the group consisting of: brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma or thyroid tumor and complications thereof.
In another embodiment, the disease is BRAF (V600E or non-V600E) or NRAS or KRAS mutant cancer selected from the group consisting of: brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, lymphoma or thyroid tumor and complications thereof.
In another embodiment, compound 1 is administered at a dose of 1-200 mg/day and at a frequency of one to three times per day.
In another embodiment, compound 1 is administered at a dose of 2.5-100 mg/day and at a frequency of one to three times per day.
In another embodiment, compound 1 is administered at a dose of 5-50 mg/day and at a frequency of once daily.
In one embodiment, the subject is a rat, dog or human.
In a fourth aspect, the application discloses pharmaceutical compositions comprising a therapeutically effective amount of compound 1, said compound 1 being in the pure amorphous form disclosed herein. Wherein the active compound, compound 1, may comprise 1 to 99% by weight, preferably 1 to 50% by weight, more preferably 1 to 30% by weight, or most preferably 1 to 20% by weight of the pharmaceutical composition.
The pharmaceutical composition may be administered in the following form: orally, for example in the form of capsules, tablets, pills, powders, in the form of sustained release injections (such as sterile solutions, suspensions or emulsions); by topical treatment forms such as pastes, creams or ointments; or by suppositories, such as in the form of suppositories. The pharmaceutical composition may be in unit dosage form suitable for precision dosage applications.
Suitable pharmaceutical carriers include water, various organic solvents, and various inert diluents or fillers. The pharmaceutical composition may contain various additives such as perfume, binder and excipient, if necessary. For oral administration, tablets and capsules may contain various excipients, such as citric acid; various disintegrants, such as starch, alginic acid and some silicates; and various binders such as sucrose, gelatin, and acacia. In addition, lubricants comprising magnesium stearate and talc fillers are commonly used in the production of tablets. The same types of solid components can also be used to formulate soft and hard gelatin capsules. When aqueous suspensions are desired for oral administration, the active compounds may be combined with various sweetening or flavouring agents, pigments or dyes. If desired, various emulsifiers may be used or suspensions may be produced; diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof may be used.
The above pharmaceutical composition is preferably administered orally.
The above pharmaceutical composition is preferably in the form of a capsule or tablet.
The invention comprises the following steps:
a pure amorphous form of- ((1 s,1as,6 bs) -5- ((7-oxo-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy) -1a,6 b-dihydro-1H-cyclopropa [ b ] benzofuran-1-yl) -3- (2, 4, 5-trifluorophenyl) urea characterized by an x-ray powder diffraction pattern of said amorphous form having no diffraction peaks, as shown in figure 7.
2. The pure amorphous form of item 1, characterized in that the pure amorphous form has a 1H-NMR spectrum as shown in fig. 11.
3. The pure amorphous form of item 1, wherein the glass transition temperature of the pure amorphous form is between about 135 and 143 ℃, more preferably about 138.3 ℃.
4. The pure amorphous form of item 1, characterized by a particle size of D90 between about 60 to about 80 μm, D50 between about 2 to about 6 μm, D10 between about 1 to about 2 μm; more preferably, D90 is about 69.9 μm, D50 is about 3.5 μm, and D10 is about 1.4 μm.
5. A process for preparing the pure amorphous form of any one of claims 1-4, the process comprising: a solution of a crystalline form of 1- ((1 s,1as,6 bs) -5- ((7-oxo-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy) -1a,6 b-dihydro-1H-cyclopropa [ b ] benzofuran-1-yl) -3- (2, 4, 5-trifluorophenyl) urea in a polar solvent is spray dried to give a powdered material.
6. The method of item 5, characterized in that the polar solvent comprises ethers, carboxylic acid esters, nitriles, ketones, amides, sulfones, sulfoxides or halogenated hydrocarbons.
7. The method of item 6, characterized in that the polar solvent is selected from the group consisting of acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof.
8. The method of item 5, wherein the inlet temperature of the spray dryer is set at about 50 to 70 ℃ and the outlet temperature of the spray dryer is set at about 25 to 45 ℃; more preferably, the inlet temperature of the spray dryer is set at about 60 ℃, and the outlet temperature of the spray dryer is set at about 35 ℃.
9. The method of item 5, wherein the crystalline form of the compound is crystalline form a.
10. The method of item 9, characterized in that the crystalline form a comprises at least three, four, five or six x-ray powder diffraction patterns having diffraction peaks independently selected from the group consisting of 2Θ° values: 4.7.+ -. 0.2, 9.4.+ -. 0.2, 13.6.+ -. 0.2, 14.0.+ -. 0.2, 14.9.+ -. 0.2 and 15.6.+ -. 0.2 °; preferably, the crystalline form a comprises an X-ray powder diffraction pattern of at least three, four, five or six diffraction peaks having a value of 2Θ independently selected from: 4.7±0.2, 9.4±0.2, 13.6±0.2, 14.0±0.2, 14.9±0.2, 15.6±0.2, 21.2±0.2, 24.3±0.2, 24.7±0.2, 25.1±0.2, and 29.1±0.2°; more preferably, the crystalline form a comprises an X-ray powder diffraction pattern having diffraction peaks independently selected from the following group of 2θ° values: 4.7.+ -. 0.2, 9.4.+ -. 0.2, 10.2.+ -. 0.2, 13.6.+ -. 0.2, 14.0.+ -. 0.2, 14.9.+ -. 0.2, 15.6.+ -. 0.2, 17.2.+ -. 0.2, 17.4.+ -. 0.2, 18.7.+ -. 0.2, 20.0.+ -. 0.2, 20.4.+ -. 0.2, 21.2.+ -. 0.2, 22.3.+ -. 0.2, 24.3.+ -. 0.2, 24.7.+ -. 0.2, 25.1.+ -. 0.2, 25.5.+ -. 0.2, 26.8.+ -. 0.2, 27.4.+ -. 0.2, 27.8.+ -. 0.2, 29.1.+ -. 0.2, 30.2.+ -. 0.2, 31.8.+ -. 0.2, 32.0.+ -. 0.2, 33.1.+ -. 0.2, 34.1.+ -. 0.2 and 34.6..2.
11. The method of item 10, wherein the crystalline form a is substantially as shown in the x-ray powder diffraction pattern of figure 1.
Drawings
Figure 1 shows the x-ray diffraction pattern (crystallization from isopropanol/water) of one crystalline form of compound 1 (form a).
Figure 2 shows an X-ray diffraction pattern of another crystalline form (form a) of compound 1.
Fig. 3 shows the absolute structure of single crystals of compound 1 (form a) (single crystals obtained by crystallization from ethyl acetate/heptane).
Fig. 4 shows the crystal packing of single crystals (form a) of compound 1.
Fig. 5 illustrates hydrogen bonding of single crystals (form a) of compound 1.
Fig. 6 shows the theoretical XRPD pattern of single crystals (form a) of compound 1 calculated using MERCURY software.
Figure 7 shows the X-ray diffraction pattern of the pure amorphous form of compound 1 (form B).
FIG. 8 shows the crystalline form of Compound 1 (form A) 1 H-NMR spectrum.
FIG. 9 shows the crystalline form of Compound 1 (form A) 13 C-NMR spectrum.
Figure 10 shows DVS hygroscopicity (i.e., moisture absorption) of crystalline form a of the compounds.
FIG. 11 shows compound I in pure amorphous form (form B) 1 H-NMR spectrum.
Figure 12 shows the overlap of the pure amorphous form of compound 1 (form B).
Detailed Description
Definitions and general terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.
"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of the compounds. Crystalline forms of a substance may be obtained by a variety of methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, such as in a nanopore or capillary, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallizing anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, solvent drop milling, and the like.
"amorphous" or "amorphous form" refers to a substance that forms when particles (molecules, atoms, ions) of the substance are non-periodically arranged in three dimensions, characterized by a diffuse, non-spiking X-ray powder diffraction pattern. Amorphous is a special physical form of solid material whose locally ordered structural features suggest a myriad of interactions with crystalline material. Amorphous forms of the material may be obtained by a variety of methods known in the art. These methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others. The term "pure amorphous form" as used herein refers to an amorphous form consisting only of compound 1, without any other excipients.
The "polar solvent" refers to a solvent containing a polar group such as a hydroxyl group or a carbonyl group, and has strong polarity and a large dielectric constant. Polar solvents suitable for the purposes of the present invention include, but are not limited to, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, tertiary butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures of two, three or more thereof, and the like.
Crystalline forms or amorphous forms may be determined by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
The X-ray powder diffraction (XRPD) can detect the information of crystal form change, crystallinity, crystal structure state and the like, and is a common means for identifying the crystal form. The peak positions of the XRPD patterns are largely dependent on the structure of the crystalline form, relatively insensitive to experimental details, and their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak locations, substantially as shown in the XRPD patterns provided in the figures of the invention. Meanwhile, the measure of 2θ of the XRPD pattern may have experimental errors, and the measure of 2θ of the XRPD pattern may slightly differ from instrument to instrument and sample to sample, so the value of 2θ cannot be considered absolute. Depending on the instrument conditions used in the test according to the invention, diffraction peaks have a margin of error of + -0.2 deg..
Differential Scanning Calorimeter (DSC) is controlled by a program to continuously heat or cool to measure the temperature of a sample and an inert reference (commonly used alpha-Al 2 O 3 ) Techniques in which the energy difference between them varies with temperature. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms or amorphous forms of the invention are characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profile provided in the accompanying figures of the invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so that the peak position or the value of the DSC endothermic peak cannot be regarded as absolute. Depending on the instrument conditions used in the test according to the invention, melting peaks have an error margin of + -3 ℃.
Glass transition refers to the transition of an amorphous substance between a highly elastic state and a glassy state, an inherent property of the substance; the transition temperature corresponding to the glass transition temperature (Tg) is an important physical property of amorphous substances. Glass transition is a phenomenon associated with molecular motion. Thus, the glass transition temperature (Tg) is largely dependent on the structure of the material and is relatively insensitive to experimental details and the like. In some embodiments, the amorphous glass transition temperature (Tg) of the invention is characterized by a glass transition temperature of 138.3 ℃ as determined by Differential Scanning Calorimetry (DSC). According to the instrument conditions used in the test according to the invention, there is an error margin of + -3℃for the glass transition temperature.
Differential Scanning Calorimetry (DSC) can also be used to detect the presence or absence of seeding or miscibility of an analytical crystalline form.
Solids of the same chemical composition often form, under different thermodynamic conditions, isoforms of different crystal structures, or variants, a phenomenon known as polymorphism or homopoly-phase. When temperature and pressure conditions change, a mutual transition occurs between variants, a phenomenon known as crystalline transformation. The mechanical, electrical, magnetic and other properties of the crystal can be changed greatly due to the crystal form transformation. When the temperature of the crystal form transition is within a measurable range, the transition process can be observed on a Differential Scanning Calorimeter (DSC) chart, which is characterized in that the DSC chart has an exothermic peak reflecting the transition process and simultaneously has two or more endothermic peaks, which are characteristic endothermic peaks of different crystal forms before and after the transition.
Thermogravimetric analysis (TGA) is a technique for measuring the mass of a substance with temperature by program control, and is suitable for checking the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can be used for estimating the content of crystal water or a crystallization solvent in the crystal. The quality change exhibited by the TGA profile depends on many factors such as sample preparation and instrumentation; the quality of TGA detection varies slightly from instrument to instrument and from sample to sample. Depending on the instrument conditions used for the test according to the invention, there is a margin of error of + -0.1% for the mass change.
In the context of the present application, the 2 theta values in the x-ray powder diffraction pattern are all in degrees (°).
The term "substantially as shown in the figures" means that 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 of the x-ray powder diffraction pattern or DSC pattern are shown in the figure.
When referring to a spectrogram or/and data appearing in the graph, a "peak" refers to a feature that one skilled in the art can recognize that is not attributable to background noise.
"relative intensity" refers to the ratio of the intensity of the first intensity peak to the intensity of the first intensity peak in all diffraction peaks of an x-ray powder diffraction pattern (XRPD) at 100%.
The term "about" as used herein means that the amount (e.g., temperature, pH, volume, etc.) can vary within + -10%, preferably within + -5%, unless otherwise indicated.
In one embodiment, the crystalline form of the present application is synthesized according to scheme 1 below. Notably, the disclosed methods are particularly useful for the manufacture of compound 1 or crystalline form a thereof on a commercial scale in high quality, high yield, reproducible.
Scheme 1
The following synthetic methods, specific examples and efficacy tests further describe the application, but they should not be construed as limiting or restricting the scope of the application in any way.
Examples
The following examples are intended to be illustrative. Although efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), some experimental errors and deviations should be accounted for. Unless otherwise indicated, temperatures are in degrees celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, alfa Aesar or TCI and used without further purification unless otherwise indicated.
Unless otherwise indicated, the following reactions were carried out under positive pressure of nitrogen or argon or in anhydrous solvents using dry tubes; the reaction flask was fitted with a rubber septum for introducing substrate and reagents via syringe; the glassware is oven dried and/or heat dried.
Column chromatography purification was performed on a Biotage system with silica gel column (manufacturer: dyax Corporation) or on a silica SepPak column (Waters) or on a Teledyne Isco Combiflash purification system using a pre-packed silica gel column, unless otherwise indicated.
Recording on a 400MHz operating Varian instrument 1 H NMR spectra 13 C NMR spectrum.
A Bruker APEX-II CCD diffractometer (Cu ka radiation,) X-ray intensity data from colorless plate crystals were measured at 173 (2) K. Polarized light photomicrographs were taken at room temperature.
In the following examples, the following abbreviations may be used:
example 1
Preparation of crystalline form A of Compound 1
Step 1: synthesis of INTQ-1
1, 4-dioxane (1.5 volumes) was added to a 2L 4-neck round bottom flask, which was evacuated and flushed three times with nitrogen. Pd (OAc) is then added 2 (2 wt%,0.50 kg) and XantPhos (9 wt%,2.25 kg) were added to the flask, and the flask was evacuated and flushed with nitrogen three times. The mixture was stirred at room temperature for 0.5 to 1 hour under nitrogen atmosphere. NaOH (12.25 kg,1.6 eq.) and H 2 O (1 volume, 25L) and 1, 4-dioxane (8 volume, 200L) were added to a 20L reactor. The mixture was stirred until clear, then SM3 (26.75 kg,1.2 eq) was added to the mixture. The catalyst solution was transferred to the reactor described above under a nitrogen atmosphere. SM1 (25.00 kg,1.0 eq) was then added drop wise to the reactor. The system was heated to 65.+ -. 5 ℃ and maintained at 65.+ -. 5 ℃ for at least 5 hours. HPLC was used to monitor the reaction until the SM1 content did not exceed 1.0%. The reaction mixture was cooled to 30±5 ℃, then filtered, and the filter cake was washed with 1, 4-dioxane (1.0 volume). Will H 2 O (4 volumes) was added to the filtrate and concentrated to 5 volumes. Then H is taken up 2 O (2 volumes) was added to the residue and concentrated to 5 volumes. The residue was cooled to room temperature and filtered. The filter cake is treated with H 2 O (2 volumes) wash. The filter cake was then slurried with IPA (2 volumes) for 3 hours at 25.+ -. 5 ℃. The mixture was filtered and the filter cake was washed with IPA (0.5 vol). The solid was dried in an oven under reduced pressure.
Step 2 and 3: synthesis of INTQ-3
THF (25 volumes) and INTQ-1 (16.00 kg,1.0 eq) were added to the reactor. The mixture was stirred and cooled to-80 to-70 ℃. n-BuLi (n-hexane solution, 2.5M,51.20kg,2.5 eq.) was then added dropwise to the mixture at-80-70 ℃. After 1-2 hours of reaction at-80 to-70 ℃, the reaction was monitored by TLC. A solution of DMF (9.92 kg,1.8 eq.) in THF (1.4 vol.) was then added dropwise to the reaction at-80-70 ℃. After 1-2 hours of reaction at-80 to-70 ℃, the reaction was monitored by TLC. A solution of AcOH in THF (1.4 volumes) was added dropwise to the mixture at-80-70℃to adjust the pH to 6-7. TEA (8.00 kg,1.05 eq.) was then added to the reaction at-80-70 ℃. To the reaction mixture was added dropwise a solution of methyltriphenyl phosphoranylidene acetate (26.4 kg,1.05 eq.) in DCM (19 volumes). The mixture was stirred at-80 to-70 ℃ for 10 hours, then the reaction was monitored by TLC. Will H 2 O (10.5 volumes) and citric acid (32.00 kg,2.1 eq) were added to another reactor. The mixture was stirred to dissolve and cooled to 0-5 ℃. The temperature was cooled to-20 ℃ and the solution was transferred to the 3L 4-neck round bottom flask described above. Then, the mixture was stirred at 20℃or lower for 1 hour, and the pH was confirmed to be 4 to 7. The organic layer was separated and washed with 25% nacl (17 vol). The organic phase was then concentrated to 5 volumes and EtOAc (17 volumes) was added to the mixture and concentrated to 5 volumes. EtOAc (17 volumes) was added to the mixture and concentrated to 5 volumes. This solution was used directly in the next step.
Step 4: synthesis of INTQ-4
A solution of INTQ-3 in EtOAc was added to the reactor. The solution was stirred and cooled to-5 ℃. HCl was added to the mixture at-5 to 5℃for 2 hours. The mixture is then heated to 20-30 ℃. After 5 hours of reaction, the reaction was monitored every 2 hours using HPLC until the content of INTQ-3 was less than 0.5%. The reaction mixture was concentrated to 10 volumes and cooled to 0-5 ℃. The residue was stirred at 0-5℃for 1 hour. The mixture was filtered and the filter cake was added to H 2 O (15 volumes). The mixture was stirred at 20-30℃for 2 hours. The mixture was filtered and the filter cake was purified using H 2 O (3 volumes) wash. The filtrate was then transferred to another reactor and Na 2 CO 3 Added to the mixture to adjust the pH to 8-9. The mixture was then filtered and the cake was purified using H 2 O (4 volumes) wash. After drying in a vacuum oven, 20.73kg (yield: 69.0%, purity: 95.0%) of INTQ-4 was obtained.
Step 5: synthesis of INTQ-5
INTQ-4 (10.40 kg,1.0 eq), pd/C (15% wt,1.25 kg) and THF (11 vol) were added to the reactor. The mixture was stirred and heated to 30-35 ℃. Hydrogen was added to a pressure of 10 atm. After 15 hours of reaction, the reaction was monitored every 2 hours using HPLC until the content of INTQ-4 was less than 0.5%. The reaction mixture was cooled to 20-30 ℃ and filtered through celite (0.2 wt). The filter cake was washed with THF (2 volumes). The filtrate was concentrated to 3 volumes and EtOH (6 volumes) was added to the mixture. The solution was concentrated to 3 volumes and EtOH (6 volumes) was added to the mixture. The mixture was concentrated to 3 volumes and used directly in the next step.
Step 6: synthesis of BGB-INTQ-6
A solution of INTQ-5 (from the previous step) in EtOH (3 volumes), etOH (7 volumes) and Et 3 N (22% wt,2.29 kg) was added to the reactor. The solution was heated to 70-80 ℃. After 15 hours of reaction, the reaction was monitored by HPLC every 2 hours until the INTQ-5 content was less than 1.0%. The reaction mixture was cooled to 30-40 ℃ and concentrated to 5 volumes. The mixture was cooled to-5 to 0 ℃ and stirred for 2 hours. The mixture was filtered and the filter cake was washed with EtOH (1 vol). After drying in an oven at 45.+ -. 5 ℃ 7.58kg (yield: 87.1%, purity: 99.5%) of INTQ-6 are obtained.
Step 7: synthesis of INTQ-7
Potassium hydroxide (49.9 Kg,1.7 eq) was added to a solution of 4-methoxyphenol (65 Kg,1.0 eq) in DMSO (65L, 1 vol). The system was heated to 120 ℃. Bromoacetaldehyde diethyl acetal (123.8 kg,1.2 eq.) was added dropwise while maintaining the temperature at 120-140 ℃. After completion of the reaction, the reaction mixture was cooled to 20 to 40 ℃ as monitored by HPLC. N-heptane (2 volumes) and water (2 volumes) were added to the reaction mixture. The mixture was filtered through celite (0.2 wt) and the filter cake was washed with n-heptane (0.5 vol). The filtrate was allowed to stand for at least 30 minutes. The organic layer was separated and the aqueous layer was extracted with n-heptane (2 volumes). The combined organic layers were washed with 2N aqueous NaOH (2 vol). The organic layer was washed twice with 15% aqueous nacl (2 volumes). The organic layer was concentrated to 3 volumes. Toluene (3 volumes) was added and concentration continued to 3 volumes. The toluene solution of INTQ-7 was used directly in the next step.
Step 8: synthesis of INTQ-8
Amberlyst-15 (3.8 Kg,0.1 wt) was added to toluene (760L, 20 pieces)Product) of the Chinese medicine composition. At N 2 The system was heated to 110 ℃ with protection. A solution of INTQ-7 (38 Kg/batch, 3 batches, 1.0 eq.) in toluene was added dropwise while maintaining the temperature at 105-110 ℃. After 1 hour of reaction, the reaction system was concentrated to 17 volumes at a constant pressure of 105 to 110 ℃. Toluene (3 volumes) was added to the system. After completion of the reaction, the reaction mixture was cooled to 20 to 40 ℃ as monitored by HPLC. The mixture was filtered through celite (0.1 wt) and the filter cake was washed with toluene (0.5 vol). The filtrate was washed with 2n naoh aqueous solution (2 volumes). The organic layer was washed twice with 20% aqueous nacl (2 volumes). The organic layer was concentrated to 2 volumes. The crude product was distilled below 110 ℃ to give INTQ-8 as an off-white solid (43 Kg, yield = 61.2%, purity ≡ 98.0%).
Step 9: synthesis of INTQ-9
1-dodecanethiol (147.0 Kg,3.5 eq) was added to a solution of INTQ-8 (43 Kg,1.0 eq) in NMP (260L, 6 vol). The system was heated to 75±5 ℃. Sodium ethoxide (69.0 kg,3.5 eq.) was added in portions while maintaining the temperature below 120 ℃. The reaction mixture was heated to 130±5 ℃. The mixture was sampled hourly for HPLC until the pH-BEI-BGB-3289-INTQ-8 content was 3.0% or less after 16 hours of reaction at 130.+ -. 5 ℃. The reaction mixture was cooled to 60±5 ℃, and then 8 volumes of water were added to the mixture. The reaction mixture was cooled to 25±5 ℃, and then 3 volumes of petroleum ether were added to the mixture. The mixture was stirred for at least 30 minutes and allowed to stand for at least 30 minutes to separate. The organic phase is temporarily stored. The aqueous phase was adjusted to ph=1-2 with 6N HCl. The aqueous phase was extracted with 5 volumes and 3 volumes of ethyl acetate, respectively. The aqueous residue was combined with the temporary organic phase, followed by the addition of 4 volumes of ethanol and 4 volumes of petroleum ether. The mixture was stirred for at least 30 minutes and left to stand for at least 30 minutes, then separated. The aqueous phase was adjusted to ph=1-2 with 6n HC1. The aqueous phase was extracted with 5 volumes of ethyl acetate. The organic phases of ethyl acetate are combined and concentrated to 3 volumes at a pressure below 50 ℃. To the residue add 5 volumes of n-heptane were added and the mixture was adjusted to ph=9 to 10 with 5% naoh. The mixture was stirred for at least 30 minutes and allowed to stand for at least 30 minutes to separate. The aqueous phase was adjusted to ph=1-2 with 6N HCl. The aqueous phase was extracted with 5 volumes and 3 volumes of ethyl acetate, respectively. The organic phases of ethyl acetate are then combined, using 6 volumes of 10% H 2 O 2 And concentrated HCl (0.15 wt) wash. Then use 6 volumes 5%H 2 O 2 And concentrated HCl (0.15 wt) was used to wash the organic phase. With 4 volumes of 5% Na 2 SO 3 The organic layer was washed. The organic layer was washed three times with 3 volumes of brine. The organic layer was concentrated to 3 volumes. Dichloromethane (5 volumes) was added and concentration continued until no significant fraction (fraction) was present. The crude product of INTQ-9 was used directly in the next step.
Step 10: synthesis of INTQ-10
Et is added to 3 N (48.2 Kg,2.0 eq) was added to a solution of INTQ-9 (32 Kg,1.0 eq) in dichloromethane (10 vol) below 40 ℃. The mixture was cooled to-5±5 ℃. Tmcl (1.3 eq.) was added dropwise to dichloromethane (1 vol) while maintaining the temperature at-5±5 ℃. The mixture was sampled per hour for gas chromatography until the INTQ-9 content was 2.0% or less after 1 hour of reaction at-5.+ -. 5 ℃. The mixture was concentrated to 3 volumes at a pressure below 40 ℃.15 volumes of n-hexane were added to the residue, and the mixture was stirred for at least 30 minutes. The mixture was filtered and the filtrate was concentrated to no significant fraction at a pressure below 40 ℃. The crude product was distilled below 120 ℃ to give INTQ-10 as a pale yellow oil (40 Kg, yield = 81.4%, purity ≡ 97.5%).
Step 11: synthesis of INTQ-11
INTQ-10 (20 Kg/batch, 2 batches, 1.0 eq.) in methylene chloride (5 vol.) was slurried with CuI (0.1 wt.) at 25.+ -. 5 ℃ C. For 2-3Hours. At N 2 Copper (I) triflate (2:1 complex with toluene, 0.11% wt) and (S, S) -2, 2-bis (4-phenyl-2-oxazolin-2-yl) propane (0.15% wt) were stirred in methylene chloride (4 volumes) for 2-3 hours under an atmosphere at 20-30 ℃. A solution of INTQ-10 in methylene chloride was added through a small pore filter and a solution of ethyl diazoacetate (2.0 eq.) in methylene chloride (10 vol.) was slowly added dropwise over 15-25 hours at 20-30 ℃. The mixture was stirred at 20-30 ℃ for 30-60 minutes and washed three times with 4 volumes of 0.05N disodium edetate dihydrate at 20-30 ℃. The organic portion was washed twice with 3 volumes of 25% aqueous nacl solution. The organic fraction was concentrated under vacuum below 35 ℃ until the system did not exceed 3 volumes. The crude product of INTQ-11 was used directly in the next step.
Steps 12 and 13: synthesis of INTQ-13
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Step 12: the crude product of INTQ-11 was dissolved in methanol (3 volumes), 38% HCl/EtOH (0.1 volumes) was added to the mixture and stirred at 20-30℃for 2-3 hours. Et was added dropwise to the mixture 3 N to adjust ph=7. The mixture was concentrated to 2 volumes under pressure. Ethyl acetate (2 volumes) was added and concentration to 2 volumes continued under pressure. N-heptane (2 volumes) was added and concentration continued to 2 volumes under pressure. Dichloromethane (2 volumes) was added to dissolve the material completely. The residue was purified by silica gel chromatography (eluting with EtOAc: pe=1:5, total about 100 volumes) to give INTQ-12 as a yellow solid.
Step 13: INTQ-12 was added to EtOAc (1.5 vol) and n-heptane (20 vol) and the mixture was heated to 75-85℃until clear. The clear solution was stirred at 75-85 ℃ for 1 hour and then gradually cooled to 15-20 ℃. The mixture was filtered and washed with n-heptane (2 volumes) to give the product. The wet product was dried at 55.+ -. 5 ℃ for at least 16 hours to give INTQ-13 as a pale yellow to off-white solid.
Steps 14 and 15: synthesis of INTQ-15
Step 14: INTQ-13 (16 Kg,1.0 eq.) and INTQ-6 (12.7 Kg,1.05 eq.) were added to DMF (5 vol.). The system was heated to 55.+ -. 5 ℃. Cesium carbonate (29.6 kg,1.25 eq.) was added. The reaction mixture was heated to 110±5 ℃. The mixture was sampled hourly for HPLC until the INTQ-13 content was 0.5% or less after 2 hours of reaction at 110.+ -. 5 ℃. The reaction mixture was cooled to 30±5 ℃ and then adjusted to ph=6 with acetic acid (5 wt) at 30±5 ℃. Water (30 volumes) was added to the mixture at 25.+ -. 5 ℃. The mixture was stirred for 1-2 hours and filtered to give a wet product. The wet product was reslurried with water (5 volumes). The filter cake was used directly in the next step.
Step 15: the wet product of INTQ-14 was added to a mixture of 1N NaOH (10 vol) and THF (20 vol). The system was stirred at 25.+ -. 5 ℃. Samples were taken every hour for HPLC until the INTQ-14 content was 0.5% or less after 4 hours of reaction at 25.+ -. 5 ℃. The system was adjusted to ph=4-5 with 4N HCl at 25±5 ℃ and stirred for 1 hour. The system was concentrated to 8 volumes at a pressure below 50 ℃ and then filtered to give a wet product. The wet product was reslurried with THF (10 volumes). The mixture was stirred for 1-2 hours and filtered to give a wet product. The wet product was dried at 55.+ -. 5 ℃ for at least 30 hours to give INTQ-15 as a light brown to off-white solid.
Steps 16 and 17 and 18: synthesis of INTQ-18
Vacuumizing the reactor to less than or equal to-0.08 MPa, and then filling inert nitrogen. 1, 4-dioxane (10.0 volumes) and INTQ-15 (3.6 Kg,1.0 eq) were added to the reactor. The mixture was concentrated to 6.0 to 6.5 volumes at less than 50 ℃ and the mixture was sampled to obtain the water content. Et is added to 3 N (1.1 eq.) was added to the reactor. The mixture was heated to 30.+ -. 5 ℃ and DPPA (1.1 eq.) was added drop wise to the reactionIn the reactor. After 2 hours of reaction at 30.+ -. 5 ℃ the mixture was sampled for HPLC analysis until the INTQ-15 content was 1.0% or less. A solution of INTQ-16 was obtained.
Vacuumizing the reactor to less than or equal to-0.08 MPa, and then filling inert nitrogen. t-BuOH (20.0 vol), (Boc) 2 O (0.5 eq.) and DMAP (0.02 eq.) were added to the reactor. The mixture was heated to 85.+ -. 5 ℃ and stirred for 2-3 hours and the water content of the mixture was sampled. The standard is KF less than or equal to 0.01 percent. The solution of INTQ-16 was added dropwise to the reactor of the t-BuOH system described above (for at least 3 hours) at 85.+ -. 5 ℃. After 2 hours of reaction at 85.+ -. 5 ℃ the mixture was sampled for HPLC analysis until the INTQ-16 content was less than or equal to 1.0%. The mixture is then cooled to below 50 ℃ and concentrated below 50 ℃ to 3.0 to 4.0 volumes.
DCM (10.0 vol×2) was added to the residue and the mixture was concentrated to 3.0-4.0 vol below 50 ℃. DCM (10.0 vol) was added to the residue. A1 wt% aqueous NaOH solution (20.0 volumes) was then added to the reactor and stirred at 25.+ -. 5 ℃ for at least 1 hour. The mixture was filtered through celite and then separated. The organic phase was washed with water (5.0 volumes) and separated. The organic phase was further washed with 25wt% brine (5.0 vol) and separated by filtration over a pad of silica gel to remove some of the impurities. The organic phase is concentrated to 6.0-7.0 volumes below 40 ℃. DCM was added to 7.0 volumes. The mixture was then cooled to no more than 15 ℃ and hydrochloric acid (1.2 volumes) was added dropwise to the reactor at a temperature no higher than 15 ℃. After 3 hours of reaction at 15.+ -. 5 ℃ the mixture was sampled for HPLC analysis until the INTQ-17 content was 4.0% or less. The mixture was heated to 25±5 ℃, and water (3.0 volumes) was added to the reactor.
INTQ-16： 1 H NMR(400MHz，DMSO-d6)δ10.48(s，1H)，7.95(d，J＝5.6Hz，1H)，7.34(d，J＝2.4Hz，1H)，7.05(d，J＝8.4Hz，1H)，7.00(dd，J＝8.8，2.4Hz，1H)，6.25(d，J＝5.6Hz，1H)，5.42(d，J＝5.2Hz，1H)，3.56(dd，J＝5.2，2.8Hz，1H)，2.92(t，J＝7.6Hz，2H)，2.54(d，J＝8.0Hz，2H)，1.51(d，J＝3.2Hz，1H).MS：M/e 364(M+1) Ten times .
INTQ-17： 1 H NMR(400MHz，DMSO-d6)δ10.49(s，1H)，7.94(d，J＝6.0Hz，1H)，7.34(s，1H)，7.18(s，1H)，6.96-6.83(m，2H)，6.22(d，J＝5.6Hz，1H)，4.86(d，J＝5.6Hz，1H)，2.92(t，J＝7.6Hz，2H)，2.86(d，J＝4.8Hz，1H)，2.54(t，J＝7.6Hz，2H)，2.12(s，1H)，1.39(s，9H).MS：M/e 410(M+1) + .
And (3) pH adjustment: a4 wt% aqueous NaOH solution was added dropwise to the reactor to adjust the pH to 2.7-3.1. If pH > 3.1, hydrochloric acid (0.2 vol) is added, then 4wt% aqueous NaOH solution is added dropwise to the reactor to adjust the pH to 2.7-3.1 (precision pH paper, range 2.7-4.7); the mixture was separated and the emulsion phase was collected as the aqueous phase. The mixture was filtered through celite and the resulting aqueous phase was washed once with DCM (2.0 vol). DCM (6.0 vol) and EtOH (5.0 vol) were added to the remaining aqueous phase in the reactor. 10.0wt% Na 2 CO 3 The solution was added drop-wise to the reaction to adjust the pH to 8-9 at 25±5 ℃. The mixture was stirred for 10 to 15 minutes and left to stand for 10 to 15 minutes. The mixture was separated and the aqueous phase extracted 2 times with DCM (4.0 volumes). The organic phases were combined, washed with water (2.0 volumes), separated and the organic phase washed once with 25wt% brine (5.0 volumes). The organic phase was concentrated to 3.0 to 4.0 volumes below 45 ℃ and then n-heptane (4.0 volumes) was added to the residue. The mixture was concentrated below 45 ℃ to 3.0-4.0 volumes, then n-heptane (4.0 volumes) was added to the residue. The mixture was concentrated to 3.0 to 4.0 volumes below 45 ℃. The residue was cooled to 25±5 ℃, then centrifuged and the solid was washed with n-heptane (2.0 volumes). The filter cake was transferred to a vacuum oven and after drying at 45.+ -. 5 ℃ for 4 hours, the mixture was sampled for Loss On Drying (LOD) until LOD was 1.0% or less. The purity of INTQ-18 (2.25 kg) is reported. The product is packaged in a double LDPE plastic bag and stored at 2-30 ℃.
INTQ-18： 1 H NMR(400MHz，DMSO-d6)δ10.81(s，1H)，8.87(s，3H)，8.05(d，J＝6.0Hz，1H)，7.33(t，J＝1.2Hz，1H)，7.07-6.95(m，2H)，6.34(d，J＝6.0Hz，1H)，5.24(d，J＝6.0Hz，1H)，3.32(dd，J＝6.0，2.0Hz，1H)，2.97(t，J＝7.6Hz，2H)，2.59(t，J＝7.6Hz，2H)，2.46(s，1H).MS：M/e 310(M+1) + .
Step 19: synthesis of INTQ-19
Vacuumizing the reactor to less than or equal to-0.08 MPa, and then filling inert nitrogen. THF (6.0 vol.), H 2 O (3.0 vol), 2,4, 5-trifluoroaniline (1.0 eq), naHCO 3 (1.2 eq.) was added to the reactor. The mixture was cooled to 0 ℃, and phenyl chloroformate was slowly added at 0±5 ℃. The mixture was stirred for at least 2 hours. The mixture was sampled for LCMS until 2,4, 5-trifluoroaniline was 0.2% or less. EA (15.0 volumes) was then added. By H 2 The organic phase was washed with O (5.0 volumes) and then 2 times with 5wt% aqueous HCl (5.0 volumes) and 2 times with saturated NaCl (5.0 volumes). The organic phase was concentrated to 10.0 volumes at less than 45 ℃. N-heptane (10.0 volumes) was added to the residue. The mixture was concentrated to 10.0 volumes, and then n-heptane (10.0 volumes) was added to the residue. The mixture was concentrated to 10.0 volumes and centrifuged, and the solid was washed with n-heptane (2.0 volumes). The filter cake was sampled for LCMS analysis, with the standard for INTQ-19 > 99%. The filter cake was then transferred to a vacuum oven and after drying at 35.+ -. 5 ℃ for 10 hours, LOD was sampled until LOD was 2.0%. The purity of INTQ-19 is reported. The product was packaged in double LDPE plastic bags and stored at 2-30 ℃.
INTQ-19： 1 H NMR(400MHz，DMSO-d6)δ10.20(s，1H)，7.82(dt，J＝12.0，8.0Hz，1H)，7.66(td，J＝10.8，7.6Hz，1H)，7.44(t，J＝7.6Hz，2H)，7.33-7.20(m，3H).
Step 20: synthesis of crystalline form of Compound 1 (form A)
Vacuumizing the reactor to less than or equal to-0.08 MPa, and then filling inert nitrogen. DMSO (9.0 volumes), INTQ-18 (1.63 Kg,1.0 eq) and N-methylmorpholine (NMM, 1.0 eq) were added to the reactor. The mixture was stirred at 20.+ -. 5 ℃ for at least 0.5 hours. INTQ-19 (1.27 Kg,0.9 eq.) was added to the reactor at 20.+ -. 5 ℃. After 3 hours of reaction at 20.+ -. 5 ℃ the mixture was sampled for HPLC analysis until the INTQ-19 content was less than or equal to 0.3%. After the reaction was completed, the mixture of compound 1 was added dropwise through a microfilter to a 0.5% hydrochloric acid solution, which was also slowly filtered through a microfilter (30.0 volumes) at 20±5 ℃. The mixture was stirred for at least 4 hours and centrifuged. The filter cake was washed with purified water (5.0 vol. Times.2).
Pulping operation: DMSO (9.0 volumes) and 0.5% hydrochloric acid were added to the reactor through a micron filter (30.0 volumes) and the filter cake was added to the reactor and the mixture was stirred at 20±5 ℃ for at least 4 hours and then centrifuged. The filter cake was washed with purified water (5.0 vol. Times.2). The filter cake was sampled for HPLC analysis, with compound 1 standard being greater than or equal to 98.0%. If compound 1<98.0%, the "slurrying operation" is repeated. Purified water (40.0 volumes) and filter cake were added to the reactor and the mixture was stirred at 20±5 ℃ for at least 4 hours and then centrifuged. The filter cake was washed with purified water (5.0 vol. Times.2). The filter cake was then dried in vacuo at 45.+ -. 5 ℃ for at least 8 hours until LOD was 3.0% or less. If the solvent residue is not standard, the residual solvent is removed by slurrying: purified water (40.0 volumes) and the product were added to the reactor and the mixture was stirred at 20±5 ℃ for at least 4 hours and then centrifuged. The filter cake was washed with purified water (5.0 vol. Times.2). The filter cake was dried in vacuo at 45.+ -. 5 ℃ for at least 8 hours until LOD was 3.0% or less. The filter cake was sampled to obtain a solvent residue. If the solvent residue is not standard, the "remove residual solvent by slurrying" procedure is repeated until the solvent residue is standard. The sample material was analyzed by HPLC, and the standard of Compound 1 was 98.0% (2.02 kg). The product was packaged in a double LDPE bag with desiccant and stored at room temperature.
Compound 1: 1 H NMR(400MHz，DMSO-d6)δ10.47(s，1H)，8.54(s，1H)，8.23-8.07(m，1H)，7.96(d，J＝5.6Hz，1H)，7.65-7.51(m，1H)，7.23(s，1H)，7.01(d，J＝2.0Hz，1H)，6.96-6.87(m，2H)，6.25(d，J＝5.6Hz，1H)，4.98(d，J＝6.0Hz，1H)，2.97(dd，J＝5.6，1.6Hz，1H)，2.93(t，J＝7.6Hz，2H)，2.54(t，J＝7.6Hz，2H)，2.26(s，1H).
the amorphous or crystalline nature of the resulting powder prepared in example 1 was evaluated by x-ray powder diffraction pattern techniques. The resulting powder prepared in example 1 was identified as crystalline (sometimes referred to as "form a" throughout the application) as evidenced by the crystallization peaks in the XRPD curve in fig. 1. The powder obtained is also obtained by 1 H-NMR spectra 13 The C-NMR spectrum was characterized as shown in FIG. 8 and FIG. 9, respectively.
The X-ray powder diffraction pattern of the crystalline form of compound 1 (form a) has the following characteristic peak diffraction angles (where "spacing" is shown in fig. 1 as "d value"):
table 1: x-ray powder diffraction pattern of crystalline form of compound 1 (form a)
Long term stability of form a
Long-term stability studies of form a showed that no significant chemical purity change occurred at 25 ℃/60% rh for up to 12 months (total impurity: t0=1.0%, t12=1.0%) and at 40 ℃/75% rh for up to 6 months (total impurity: t0=1.0%, t12=1.0%). Furthermore, no change in optical purity was observed when stored for up to 12 months at 25 ℃/60% rh and up to 6 months at 40 ℃/75% rh. XRPD data of the test samples showed that form a was stable at 40 ℃/75% rh at 6 months and form a was also stable at 25 ℃/60% rh at 6 months, but became crystalline at 12 months (sometimes referred to as "form a").
XRPD of form a is shown in figure 2. The X-ray powder diffraction pattern of another crystalline form of compound 1 (form a) has the following characteristic peak diffraction angles (where "spacing" is shown in fig. 2 as "d value"):
table 2: x-ray powder diffraction pattern of another crystalline form of compound 1 (form a)
Peak numbering Diffraction angle (2-theta) Spacing of Relative intensity
1 9.21 9.59050 76.3％
2 10.76 8.21514 2.4％
3 12.26 7.21638 1.3％
4 13.95 6.34232 100.0％
5 15.37 5.75948 41.0％
6 16.46 5.38091 3.2％
7 18.14 4.88565 6.1％
8 18.72 4.73555 17.7％
9 19.29 4.59811 8.6％
10 19.79 4.48301 9.9％
11 20.53 4.32170 41.1％
12 21.64 4.10256 5.7％
13 22.31 3.98220 5.8％
14 23.17 3.83593 1.8％
15 23.97 3.70913 30.0％
16 24.93 3.56837 30.0％
17 26.69 3.33777 3.9％
18 27.80 3.20666 2.7％
19 28.72 3.10596 14.7％
20 29.37 3.03820 14.9％
21 30.92 2.88941 2.2％
22 33.23 2.69417 1.9％
23 37.87 2.37384 1.1％
24 38.15 2.35726 1.1％
Stability studies indicate that form a is chemically stable and can be stored for more than 12 months without significant decomposition.
As shown in fig. 10, the hygroscopicity of form a was also assessed by Dynamic Vapor Sorption (DVS). Figure 10 shows that form a is moderately hygroscopic with a 4.96% weight gain at 80% rh.
As discussed in the preclinical studies below, oral absorption of form a in rats was relatively poor with a bioavailability of 21%, in part due to the low solubility of form a (found to be less than 0.1 μg/mL in water).
Form a has limited use in direct pharmaceutical formulations due to the low bioavailability observed in preclinical studies. However, form a is a good candidate for purification of API and is used as a starting material for preparing amorphous solid dispersions. Although a change in crystalline form (i.e. form a to form a) was observed at 12 months under the above conditions, long term storage (i.e. 12 months) had no effect on the subsequent amorphous MBP preparation, since compound 1 was anyway dissolved in DMA before co-precipitation occurred.
The physicochemical properties of form a prepared in example 1 are summarized in table 3.
Table 3: principal physicochemical Properties of form A
Example 2
Single crystals of Compound 1 (form A)
Plate-like single crystals of EtOAc solvate of compound 1 for single crystal X-ray diffraction characterization were crystallized from EtOAc solvent by slow evaporation. The experimental details are detailed below. First, 1.8mg of Compound 1 was weighed into a 3mL glass vial, and 0.5mL of EtOAc solvent was added. After vortexing and ultrasonic shaking to accelerate dissolution, the suspension was filtered through a PTFE filtration membrane (0.45 μm) and the filtrate was transferred to a clean 4mL shell vial (44.6 mm x 14.65 mm). Subsequently, the shell bottles were sealed with PE-Plug with a pinhole therein and placed in a fume hood to evaporate slowly at ambient temperature and humidity. After six days, a plate-like crystal sample was obtained.
The structure of the plate-like crystals was determined using a set of diffraction data collected from single crystals grown slowly cooled in EtOAc and referred to as single crystals of compound 1 or form a. The crystal data and structural finishes for form a are listed in fig. 3-6.
Table 4: single crystal data and structural finishing of form A
As shown in fig. 3, the single structure asymmetric unit consisted of two independent molecules of compound 1 and two EtOAc solvent molecules, indicating that the crystal was an EtOAc solvate of compound 1. Single crystal structure measurement confirmed that when compound 1 molecule was taken as an example, the absolute configuration of compound 1 was { C15 (S), C16 (S), C17 (S) }. The unit cell of the single crystal consisted of four molecules of compound 1 and four molecules of EtOAc solvent, as shown in fig. 4. The potential classical H-bonds in the single crystal structure are shown in figure 5. The results of the theoretical XRPD pattern of single crystalline form (i.e. form a) of compound 1 calculated using the MERCURY software are shown in figure 6.
Example 3
Preparation of pure amorphous form of Compound 1 (form B)
A solution of crystalline form A of compound 1 in DCM/MeOH (2:1) was spray dried to give a white powder. The spray drying conditions were as follows: a solution of crystalline form A of Compound 1 (2.0 g) in 100mL of mixed solvent (DCM/MeOH=2:1 volume ratio) was spray dried through a spray dryer (BUCHI-290 & BUCHI-295). The product powder was dried by infrared lamp at 50℃for 16 hours. 1.06g of powder was obtained. The operating parameters of the spray dryer (BUCHI-290 & BUCHI-295) are as follows: inlet temperature: 60 ℃; outlet temperature: 35 ℃, air extractor: 100%; pump%: 15%; nozzle cleaner: 2.
the structure of the resulting powder was characterized using a powder X-ray diffraction pattern method, and was confirmed to be in an amorphous form, for example, the powder X-ray diffraction pattern of fig. 7 had no diffraction peaks. In the present description, the amorphous form of compound 1 is referred to as the pure amorphous form or form B of compound 1. Form B 1 The H-NMR spectrum is shown in FIG. 11. The glass transition temperature of form B was determined to be 138.3 ℃. The sample of form B was a white powder with particle sizes d90=69.9 μm, d50=3.5 μm, d10=1.4 μm. XRPD data of the test samples indicated that form B was stable for 14 days at 40 ℃/75% rh. For example, the XRPD data of fig. 12 confirm that the test sample still does not show any diffraction peaks at 14 days.
Example 14
Form A, B pharmacokinetic comparison in rats.
1. Drugs and reagents:
form a powder having a particle size d90=62.4 μm after micronization. The content (purity) of the substance is not less than 98.0%.
Powder of form B having a particle size d90=69.9 μm, d10=3.5 μm, d50=1.4 μm after micronization. The content (purity) of the substance is not less than 98.0%.
2. Experimental animals:
male and female rats were used in this study.
3. Preparation of the medicine:
the appropriate amount of each material was weighed and dispersed in 0.5% sodium carboxymethyl cellulose. For each substance, a suspension was prepared with the desired concentration of compound 1. All doses and concentrations of compound 1 were calculated in this study using the free base.
4. Dosing and sample collection:
the dosing solution was freshly prepared prior to dosing. The actual body weight and the actual volume injected are recorded accordingly. Rats were fasted overnight and allowed to ingest food 4 hours after dosing. Each suspension was orally administered to rats at a dose of 0.5 to 5 mg/kg. Blood samples (-1.0 mL) were collected through the head venous plexus at various times, pre-dose and post-dose up to 36 hours. Whole blood was processed by centrifugation and plasma samples were collected and stored in a refrigerator prior to analysis. Plasma samples were treated by protein precipitation. The concentration of compound 1 in the plasma samples was determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Plasma concentration-time data were analyzed using a non-compartmental model using Pharsight WinNonlin. C of each substance max And the area under the concentration-time curve are shown in table 5.
Table 5: oral and intravenous PK profile of forms a and B of compound 1 in rats
The pure amorphous form of compound 1 (form B) also exhibits higher C than the crystalline form (form a) max (ng/mL)、AUC 0-inf (ng.h/mL) and F (%). The oral bioavailability of the pure amorphous form of compound 1 (form B) reaches approximately 50% of intravenous injection, whereas the oral bioavailability of crystalline form a is only about 20% of intravenous injection. This shows that the pure amorphous form of the application greatly improves the oral bioavailability relative to the crystalline form.
The foregoing description of the examples and embodiments is illustrative, and not limiting, of the application, which is defined by the claims. Numerous variations and combinations of the features described above may be used without departing from the application as set forth in the claims. All such variations are included within the scope of the present application. All references cited are incorporated herein by reference in their entirety.

Claims (14)

1. Use of an amorphous form of a compound of formula I in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition responsive to inhibition of Raf kinase in a subject, wherein the amorphous form has an X-ray powder diffraction pattern with no diffraction peaks as shown in figure 7,
2. Use of an amorphous form of a compound of structural formula I according to claim 1 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition responsive to inhibition of Raf kinase in a subject, wherein the pure amorphous form has a 1H-NMR spectrum as shown in figure 11.
3. Use of an amorphous form of a compound of formula I according to claim 1 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition responsive to inhibition of Raf kinase in a subject, wherein the glass transition temperature of the pure amorphous form is between 135 and 143 ℃.
4. The use of an amorphous form of a compound of formula I according to claim 1 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition responsive to inhibition of Raf kinase in a subject, wherein the pure amorphous form has a particle size D of between about 60 and about 80 μm 90 D between about 2 and about 6 μm 50 D between about 1 and about 2 μm 10 。
5. Use of an amorphous form of a compound of structural formula I according to claim 1 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition responsive to inhibition of Raf kinase in a subject, wherein the disease or condition is BRAF (V600E or non-V600E) or NRAS or KRAS mutated cancer.
6. Use of the amorphous form of a compound of structural formula I according to claim 5 for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition responsive to inhibition of Raf kinase in a subject, wherein the cancer is brain, lung, kidney, bone, liver, bladder, breast, head and neck, ovarian, melanoma, skin, adrenal, cervical, lymphoma or thyroid tumour and complications thereof.
7. Use of an amorphous form of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition responsive to inhibition of Raf kinase in a subject, wherein compound 1 is administered at a dose of 1-200 mg/day at a frequency of one to three times per day.
8. Use of an amorphous form of a compound of structural formula I according to claim 1 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition responsive to inhibition of Raf kinase in a subject, wherein the subject is a rat, canine or human.
9. A pharmaceutical composition comprising a compound of formula I, wherein the compound is in an amorphous form having an X-ray powder diffraction pattern without diffraction peaks as shown in figure 7,
10. The pharmaceutical composition of claim 1, wherein the pure amorphous form has the form shown in figure 11 1 H-NMR spectrum.
11. The pharmaceutical composition of claim 1, wherein the glass transition temperature of the pure amorphous form is between 135 and 143 ℃.
12. The pharmaceutical composition of claim 1, wherein the pure amorphous form has a particle size D of between about 60 and about 80 μm 90 D between about 2 and about 6 μm 50 D between about 1 and about 2 μm 10 。
13. Pharmaceutical composition according to claim 1, wherein the compound comprises 1-99% by weight, preferably 1-50% by weight, more preferably 1-30% by weight, or most preferably 1-20% by weight of the pharmaceutical composition.
14. The pharmaceutical composition of claim 1 or 12, further comprising a pharmaceutical excipient optionally from at least one of a pharmaceutically acceptable carrier, diluent or excipient.
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