CN115403528A - Process for preparing amorphous 3, 4-dihydroquinazoline derivatives - Google Patents
Process for preparing amorphous 3, 4-dihydroquinazoline derivatives Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- LGACUMPRRMLUFZ-UHFFFAOYSA-N 1,4-dihydroquinazoline Chemical class C1=CC=C2CN=CNC2=C1 LGACUMPRRMLUFZ-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 18
- 230000008569 process Effects 0.000 claims abstract description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 22
- 239000012296 anti-solvent Substances 0.000 claims description 19
- 230000001476 alcoholic effect Effects 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000002386 leaching Methods 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 15
- 238000009826 distribution Methods 0.000 abstract description 9
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- 238000012512 characterization method Methods 0.000 abstract description 6
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- 239000000203 mixture Substances 0.000 description 10
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- 238000006243 chemical reaction Methods 0.000 description 4
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
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- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000013526 supercooled liquid Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- 238000002425 crystallisation Methods 0.000 description 2
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
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- 230000007704 transition Effects 0.000 description 2
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- PZIBVWUXWNYTNL-UHFFFAOYSA-N 1-(3-methoxyphenyl)piperazine Chemical compound COC1=CC=CC(N2CCNCC2)=C1 PZIBVWUXWNYTNL-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
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- 108090000790 Enzymes Proteins 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- FWYSMLBETOMXAG-QHCPKHFHSA-N letermovir Chemical compound COC1=CC=CC(N2CCN(CC2)C=2N([C@@H](CC(O)=O)C3=CC=CC(F)=C3N=2)C=2C(=CC=C(C=2)C(F)(F)F)OC)=C1 FWYSMLBETOMXAG-QHCPKHFHSA-N 0.000 description 1
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- YAGXZDADEJXXMM-UHFFFAOYSA-M potassium chloride hydrate Chemical compound [OH-].Cl.[K+] YAGXZDADEJXXMM-UHFFFAOYSA-M 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen 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
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the preparation of an amorphous 3, 4-dihydroquinazoline derivative which produces an amorphous compound of formula I in which no esterified by-products are detectable and which gives a solid product having a particle size distribution d 90 The particle size is not more than 10 mu m, XRPD characterization shows that no detectable crystal content/signal exists within the detection limit, the preparation requirements are met, and meanwhile, the preparation process is simple and convenient to operate, safe and environment-friendly and easy to realize industrial mass production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an amorphous 3, 4-dihydroquinazoline derivative and a preparation method thereof.
Background
The compounds of formula I are novel non-nucleoside Cytomegalovirus (CMV) inhibitors that inhibit viral replication by specifically targeting the viral terminator enzyme complex. Currently, the development for the prevention of CMV infection, for the prevention of CMV infection and related diseases in adult patients who are CMV seropositive after receiving allogeneic Hematopoietic Stem Cell Transplantation (HSCT), is under the chemical name (4S) - { 8-fluoro-2- [4- (3-methoxyphenyl) piperazin-1-yl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydroquinazolin-4-yl } acetic acid, having the following chemical structure:
current research has not found that the compound can be reproducibly crystallized in zwitterionic form and maintained in its stable polymorphic form, i.e. the compound of formula I needs to be isolated in its amorphous state with sufficient yield and purity, while maintaining its physicochemical properties, which enable sufficient dissolution characteristics to be achieved in a tablet or capsule formulation for oral administration.
Patent CN105555771A provides a process for the preparation of amorphous compounds of formula I suitable for use in solid oral dosage forms by precipitation from water miscible solvents acetone or acetonitrile into excess water as anti-solvent.
Disclosure of Invention
The present invention provides a process for preparing amorphous form I compound, which process produces amorphous form I compound with no detectable esterification by-products.
In one aspect, the invention provides a process for the preparation of an amorphous compound of form I,
adding an alcohol solvent into the compound of the formula I to form a solution, adding the solution into an anti-solvent for precipitation, and separating the precipitate to obtain the amorphous compound of the formula I, wherein the alcohol solvent is a C3-C6 alcohol solvent, and the anti-solvent is water.
In some embodiments, the alcoholic solvent is selected from one or more of isopropanol, n-propanol, and butanol.
In some embodiments, the alcoholic solvent is isopropanol.
In some embodiments, the mass to volume ratio of the compound of formula I to the alcoholic solvent is from 35mg/mL to 250mg/mL, preferably from 80mg/mL to 200mg/mL, more preferably from 112mg/mL to 200mg/mL, and even more preferably 200mg/mL.
In some embodiments, the volume ratio of the alcoholic solvent to the antisolvent is 1.
In some embodiments, the compound of formula I is dissolved with stirring after addition of the alcoholic solvent.
In some typical embodiments, the compound of formula I is dissolved by stirring with heating at 40-60 deg.C, preferably 50-55 deg.C, after adding the alcoholic solvent.
In some embodiments, the method of preparing the compound of formula I further comprises a washing and drying step after the separation, wherein the separation step is suction filtration.
In some preferred embodiments, the present invention provides a process for the preparation of an amorphous form I compound, comprising the steps of:
(1) Adding isopropanol into the compound of the formula I, heating and stirring;
(2) Cooling, filtering, adding the filtrate into an anti-solvent, and precipitating;
(3) The suspension is stirred and filtered to obtain a solid.
(4) And (5) leaching and drying to obtain the compound shown in the formula I.
In some embodiments, the stirring time of step (1) is 0.5 to 2 hours, preferably 0.5 hour.
In some embodiments, the cooling of step (2) is natural cooling.
In some embodiments, the filtrate of step (2) is added to the anti-solvent in a manner that is stirred.
In another aspect, the invention provides an amorphous form I compound having an XRPD pattern as shown in figure 1.
In the present invention, the following terms have the following meanings, unless otherwise specified:
as used herein, "XRPD" refers to X-ray powder diffraction;
in the present invention, "GC" means gas chromatography;
in the present invention, "h" means hour, "ml" means milliliter, and "μ l" means microliter;
in the present invention, "room temperature" means 25 ℃;
in the present invention, "suction filtration" means filtration under reduced pressure;
in the present invention, "d 90 "refers to the corresponding particle size when the cumulative percentage of particle size distribution of the sample reaches 90%;
in the present invention, "RSC" means a residual amount of a solvent;
in the present invention, "RRT" is a relative retention time, which refers to the ratio of the corrected retention time of a certain component to the corrected retention time of the corresponding sample;
in the present invention, "glass transition temperature" means a temperature corresponding to a transition from a high elastic state to a glassy state or a transition from a glassy state to a high elastic state;
in the present invention, "amorphous" is also called vitreous. The arrangement of atoms or molecules in the super-cooled liquid is aperiodic, and the super-cooled liquid can be regarded as supercooled liquid like glass, rosin, gelatin and the like. The amorphous solid has the following general properties; the macroscopic property has uniformity, and the uniformity is derived from the statistical regularity of disordered distribution of atoms; the physical properties are generally invariant to the direction of measurement, called isotropy; cannot spontaneously form a polyhedral shape; no fixed melting point; due to the aperiodic structure, no diffraction effect can be produced on the X-rays.
In the present invention, the XRPD is determined as follows:
the instrument model is as follows: d8 Advance
And (3) testing conditions:
an X-ray generator: the concentration of Cu, k alpha,
tube voltage: 40kV, tube current: 40mA.
Scattering slit: 0.6mm
Detector slit: 5mm
Scanning range: 3-40deg
Step length: 0.02deg
Rate: 0.3S
It is noted that in X-ray powder diffraction spectroscopy (XRPD), the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensities of the bands (especially at low angles) may vary due to preferential orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal in question, and it is judged whether, at the same time as the known crystalline phase, it is more important to note the relative positions of the peaks rather than their relative intensities. In addition, there may be slight errors in the position of the peaks for any given crystal, which are also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, a movement of the sample, or a calibration of the instrument, etc., and the measurement error of the 2 θ value is sometimes about ± 0.5 °, preferably about ± 0.3 °, and more preferably about ± 0.2 °. Therefore, this error should be taken into account when determining each crystalline structure, and 2 θ values within the error are also within the scope of the present invention. Peak position is usually expressed in XRPD patterns by 2 θ angle or crystal plane distance d, with a simple conversion between the two: d = λ/2sin θ, where d represents the interplanar spacing (also called "interplanar spacing"), λ represents the wavelength of the incident X-rays, and θ is the diffraction angle. For the same crystal of the same compound, the peak positions of the XRPD spectra have similarity as a whole, and the relative intensity error may be large. It should also be noted that in the identification of mixtures, the loss of part of the diffraction lines may be due to, for example, a reduction in the content, in which case it is not necessary to rely on all the bands observed in the high-purity sample, even one band may be characteristic for a given crystal.
The preparation method provided by the invention has no detected by-product of isopropanol esterification, and the obtained solid product has the particle size distribution d 90 No more than 10 μm, XRPD characterization showed no detectable crystalline content/signal within the detection limitsMeets the requirements of the preparation, and meanwhile, the preparation process is simple and convenient to operate, safe and environment-friendly and easy to realize industrial mass production.
Drawings
FIG. 1 is an XRPD spectrum of the compound of formula I obtained in example 4.
FIG. 2 is an XRPD spectrum of the compound of formula I obtained in example 5.
FIG. 3 is an XRPD spectrum of the compound of formula I obtained in example 7.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention.
The reagents and raw materials used in the present invention are commercially available products.
The analytical methods for the substance analysis tests in the examples described in the present invention are as follows:
a chromatographic column: YMC-Pack Pro C18 (4.6 mm. Times.150mm, 3 μm)
Flow rate: 1.0mL/min
Column temperature: 35 deg.C
Detection wavelength: 215nm
Sample injection amount: 2 mu L of the solution;
mobile phase A:0.1% phosphoric acid solution;
and (3) mobile phase B: acetonitrile
The gradient elution was as follows:
the method for determining the residual solvent in the isopropanol of the embodiment of the invention is as follows (GC):
a chromatographic column: CP-Volamine (30 m.times.0.32 mm);
sample inlet temperature: 200 ℃;
column flow rate: 0.8mL/min;
column temperature: the initial temperature is 35 ℃, the temperature is increased to 90 ℃ at the rate of 5 ℃ per minute and maintained for 6 minutes, and then the temperature is increased to 240 ℃ at the rate of 20 ℃ per minute and maintained for 6 minutes;
headspace bottle equilibrium temperature: 110 ℃, equilibration time: 40 minutes
The particle size distribution test method of the embodiment of the invention comprises the following steps:
taking a proper amount of a sample to be measured, and referring to a particle size and particle size distribution determination method (0982 third method of the four general rules of China pharmacopoeia 2020 edition): (Sympatec RODOS L-HR1 or a laser particle size analyzer with equivalent performance), a sample introduction rate of 20% and a dispersion pressure of 3.0bar.
EXAMPLE 1 preparation of crude Compound of formula I
The preparation of the crude compounds of formula I for use in the present invention is described in more detail with reference to patent CN104144916A, by way of example below. This synthesis is merely an example and should in no way be construed as limiting. The preparation method comprises the following steps:
step 1: a commercially available solution of the compound of formula I-1 in chlorobenzene (800L) was heated to reflux and azeotropically dried. Phosphorus oxychloride (144 kg) was added and the reaction mixture was stirred at reflux for 3h. Then, DBU (95 kg) and chlorobenzene (45L) were added and stirred under reflux for an additional 9h. The reaction mixture was cooled to room temperature, hydrolyzed by addition of water, diluted with chlorobenzene (80 l), and neutralized with aqueous ammonia (25%). The phases were separated, the organic phase was washed with water and the solvent was distilled off. The remaining residue was dissolved in dioxane (170L). 3-Methoxyphenylpiperazine (66 kg), DBU (52 kg) and a further 90L of dioxane were added and the reaction mixture was heated at reflux for 4h. The reaction mixture was cooled to room temperature, added to ethyl acetate (1300L), washed once with water, three times with 0.2N HCl, once with aqueous NaCl, and the solvent was distilled off. The resulting residue was dissolved in ethyl acetate (800L) and added to a solution of (2s, 3s) -2, 3-bis [ (4-methylbenzoyl) oxy ] succinic acid (121 kg) in ethyl acetate (600L). The resulting mixture was stirred at room temperature for about 60 minutes, then inoculated with a compound of formula I-2 and stirred at room temperature for 3 days. It was then cooled to 0-5 ℃ and stirred for an additional 3h. The suspension is filtered and the remaining solid is washed again with ethyl acetate in portions to give the compound of formula I-2.
And 2, step: the compound of formula I-2 (1 salt) (141 kg, calculated as dry weight) was suspended in ethyl acetate (1400L) and dissolved by heating to reflux (77 ℃). The solution was filtered and slowly cooled to room temperature, which resulted in spontaneous crystallization. The suspension was stirred at room temperature for 16h, then cooled to 0-5 ℃ and stirring was continued for 3h. The suspension was filtered and the remaining solid was washed again with cold ethyl acetate. The crystals were dried in vacuo at about 40 ℃ for 16h to give a solid of the compound of formula I-2.
And step 3: a mixture of the compound of formula I-2 (30.8 kg), sodium bicarbonate (16.4 kg) and water (315L) was mixed with MTBE (160L). The phases were separated and the organic phase was treated with 35L of an approximately 7% aqueous solution of sodium bicarbonate. The phases were separated and the organic phase was added to 125L of an approximately 4% aqueous solution of sodium hydroxide. The reaction mixture was heated to reflux, the solution was evaporated to dryness and the reactor contents were then stirred for a further 5h at 55-60 ℃. The reaction mixture was then added to MTBE (160L) and water (65L) at about 22 ℃ and stirred. The phases were separated and the organic phase was extracted with an approximately 6% aqueous solution of sodium chloride (30L). The combined aqueous phases were mixed with water (25L) and MTBE (160L) and the pH was adjusted to about 6.5 with about 1N hydrochloric acid. The organic phase was separated, the solvent was evaporated to dryness and the residue was dissolved in acetone (ca 75L). The solvent was changed to acetone (6 distillations, about 130L each). The final product is then precipitated by the addition of water, isolated by centrifugation and dried to give the crude compound of formula I.
Example 2
Adding 8.0mL of isopropanol into 303.8mg of the crude product of the compound shown in the formula I, promoting dissolution by ultrasonic waves, adding 12mL of anti-solvent purified water into the solution under the stirring condition, enabling the system to be turbid, continuously stirring for half an hour, enabling colloidal precipitate to appear, continuously stirring for gelling, and stopping the test.
Example 3
To 300.9mg of the crude compound of formula I was added 1.0mL of 2-butanone, the dissolution was facilitated by sonication, and the mixture was added to 12mL of purified water as an anti-solvent with stirring to precipitate a gum. The gelling phenomenon was not improved by continuing stirring for one hour and the test was terminated.
In addition, the inventors have tried to replace isopropanol with 1, 4-dioxane to obtain an amorphous sample with a satisfactory particle size, and the analysis results of the related substances showed that the purity of the main peak of the compound was 99.81%, but the residual 1, 4-dioxane was difficult to remove, and the residual amount exceeded the limit of 380ppm and approached 30-fold, and was about 11000 ppm.
In an attempt to replace purified water with n-heptane as an anti-solvent, an amorphous sample was obtained that met the particle size requirements and the analysis of the material showed a major compound peak purity of 99.87%, but the sample yield was too low, only 31.3%, to facilitate scale-up.
Example 4
To 49.8mg of the crude compound of formula I, 0.6mL of isopropanol was added, dissolution was facilitated by sonication, the mixture was added to 2mL of purified water as the anti-solvent with stirring, the product precipitated, and the suspension was stirred for an additional hour. And (4) carrying out suction filtration to separate out a solid, leaching with purified water, carrying out vacuum drying at 45 ℃ for 2 hours, and then collecting the solid. As shown in fig. 1, XRPD characterization showed the resulting solid sample to be in an amorphous state.
Example 5
To 300.6mg of the crude compound of formula I was added 3.2mL of isopropanol, the dissolution was facilitated by sonication, the mixture was added to 12mL of purified water as the anti-solvent with stirring, the product precipitated, and the suspension was stirred for an additional hour. And (3) carrying out suction filtration to separate out a solid, leaching the solid with purified water, carrying out vacuum drying at 45 ℃ for 5 hours, and then collecting the solid, wherein the recovery rate is 79.6%. As shown in fig. 2, XRPD characterization showed the resulting solid sample to be in an amorphous state; the analysis result of related substance content shows that the purity of the main peak of the compound is 99.86 percent; the particle size distribution test result shows d of the sample 90 ＝4.88μm。
Example 6
8.0mL of isopropanol was added to 903.3mg of the crude compound of formula I, the dissolution was facilitated by sonication, the filtrate was filtered and added to 36mL of purified water as anti-solvent with stirring, the product precipitated and the suspension was stirred for an additional hour. And (3) carrying out suction filtration to separate out a solid, leaching with purified water, carrying out vacuum drying at 45 ℃ for 9 hours, and then collecting the solid, wherein the yield is as follows: 84.11 percent. The results of the GC analysis showed that the residual amount of the isopropyl alcohol solvent in the sample was 0.02%.
Example 7
Adding 25mL of isopropanol into 5g of the crude product of the compound of the formula I, magnetically stirring at 50-55 ℃ for about 0.5 hour to promote dissolution, and then naturally cooling at room temperature. The filtrate was filtered and added to 200mL of purified water as an anti-solvent with stirring, after which the product precipitated. The suspension was stirred for an additional hour, the solid was isolated by suction filtration, rinsed twice with purified water, and the solid was collected after 10 hours of vacuum drying at 45 ℃ with a yield of 84.0%. The obtained solid sample was subjected to characteristic analysis concerning the substance, the residual solvent amount, the particle size distribution and XRPD.
HPLC analysis results show that the purity of the main peak of the compound is 99.91 percent, and GC analysis results show that the content of residual solvent isopropanol in the sample is 0.05 percent; the particle size distribution test result shows that d of the sample 90 =7.93 μm. As shown in fig. 3, XRPD characterization showed the resulting solid sample to be in an amorphous state.
Example 8
1. Preparation of amorphous samples of different residual amounts of isopropanol solvent
When a lower alcohol (such as methanol or ethanol) is used in the above precipitation step, re-esterification with the carboxyl group in the structure of the compound of formula I can occur under stress conditions (elevated temperature), and there is theoretically some risk of esterification when isopropanol is used in the precipitation step in the currently developed amorphous preparation method. By developing a stability prediction test, the reliability of the preparation method can be inspected and evaluated, so that a sample with large isopropanol residual quantity is prepared for carrying out a subsequent stability prediction test.
The specific preparation experimental scheme is as follows: 6.5mL of isopropanol was added to 1.1g of the crude compound of formula I, and after promoting dissolution by magnetic stirring (about 500 rpm/min) at 50-55 ℃ for about 0.5 hour, the mixture was allowed to cool naturally at room temperature. Filtration and addition of the filtrate under stirring (about 320 rpm/min) to 52mL of purified water as anti-solvent, after which the product precipitates. The suspension was stirred for an additional hour, the solid was separated by filtration, rinsed twice with purified water, air dried naturally and collected. GC analysis showed 0.54% residual solvent isopropanol in the sample.
2. Isopropyl ester impurity preparation
0.71g of a compound of the formula I, 0.4g of K 2 CO 3 And 7mL of DMF is added into a 25mL three-necked bottle, the mixture is cooled to 0 ℃ under the protection of nitrogen, 0.31g of iodoisopropane is added dropwise, the mixture is transferred to room temperature or 25 ℃ for continuous reaction, the mixture is stirred overnight, and sampling monitoring is carried out to complete the reaction. Adding 14mL of water and 7mL of ethyl acetate into the reaction solution, stirring for 5min, standing, separating, washing the upper organic layer with water (14 mL multiplied by 3), concentrating, and drying in vacuum at 40 ℃ to obtain a compound of formula II, MS: m/z =614.99[ (M + H) + ]。
3. 34 solid powder samples of the amorphous form I compound with 0.54% isopropanol were taken at 20mg each and placed in respective 8-mL open sample vials. Then, another 8mL open sample bottle was taken, and saturated saline (lithium chloride, anhydrous potassium fluoride, potassium carbonate, sodium chloride, potassium chloride) controlled to correspond to different humidities were put into the sample bottles, and the constructed humidity and the corresponding saturated saline were as shown in table 1:
TABLE 1 preparation of saturated brine
| Reagent | Humidity (% RH) | Preparation method |
| Lithium chloride | 11 | To 5g of the salt was added 3mL of water |
| Anhydrous potassium fluoride | 21 | To 7g of salt was added 3mL of water |
| Potassium carbonate | 41，42 | To 4g of salt was added 3mL of water |
| Sodium chloride | 74，75 | To 4g of salt was added 3mL of |
| Potassium chloride | ||
| 79，80 | To 4g of salt was added 3mL of water |
The sample bottle, the saturated saline bottle and the wireless temperature and humidity sensor (RH Temp 1000, madgeTech) are put into a 125-mL wide-mouth Merson bottle (Mason Ball Jar, USA), and the bottle cap is screwed to ensure the inside of the bottle to be in a sealed state. And then, placing the sealed Messen bottle into a high-temperature constant-temperature incubator, and recording the actual lofting time. After the sample is placed according to the corresponding time in table 1 and table 2 under different temperature and humidity combination conditions, the sample bottle is taken out, placed in a sealed container with silica gel desiccant, cooled to room temperature, sealed, subjected to HPLC characterization (transferred to 4 ℃ for storage before analysis), and detected whether the sample generates isopropyl ester impurities after being placed under the corresponding conditions.
Table 2 stability test results
Wherein RRT =1.30 is the relative retention time of isopropyl ester; RRT =1.00 is the relative retention time of the compound of formula I; "/" indicates no detection.
The results show that isopropyl ester impurity was not detected under each condition, and therefore, the risk of esterification during standing of the sample of amorphous form I compound prepared using the isopropanol solvent system was low.
Claims (10)
1. A process for the preparation of an amorphous compound of formula I,
adding an alcohol solvent into the compound of the formula I to form a solution, adding the solution into an anti-solvent for precipitation, and separating the precipitate to obtain the amorphous compound of the formula I, wherein the alcohol solvent is a C3-C6 alcohol solvent, and the anti-solvent is water.
2. The method of claim 1, wherein the alcoholic solvent is selected from one or more of isopropanol, n-propanol and butanol;
preferably, the alcoholic solvent is isopropanol.
3. The method of claim 1, wherein the mass-to-volume ratio of the compound of formula I to the alcoholic solvent is 35mg/mL to 250mg/mL, preferably 80mg/mL to 200mg/mL, more preferably 112mg/mL to 200mg/mL, and even more preferably 200mg/mL.
4. The method according to claim 1, wherein the volume ratio of the alcoholic solvent to the antisolvent is 1.
5. The process of claim 1, wherein the compound of formula I is dissolved by stirring after addition of the alcoholic solvent.
6. The method of claim 5, wherein the compound of formula I is dissolved in the alcoholic solvent under stirring with heating at 40-60 deg.C, preferably 50-55 deg.C.
7. The process of claim 1, wherein the process for the preparation of the compound of formula I further comprises a washing and drying step after the separation, wherein the separation step is suction filtration.
8. A process for preparing an amorphous compound of form I comprising the steps of:
(1) Adding isopropanol into the compound of the formula I, heating and stirring;
(2) Cooling, filtering, adding the filtrate into an anti-solvent, and precipitating;
(3) Stirring the suspension, and performing suction filtration to obtain a solid;
(4) Leaching and drying to obtain a compound shown in the formula I;
preferably, the stirring time of step (1) is 0.5 to 2 hours, preferably 0.5 hour;
preferably, the cooling of step (2) is natural cooling.
9. The method of claim 8, wherein the filtrate of step (2) is added to the anti-solvent in a manner of stirring.
10. An amorphous form I compound having an XRPD pattern as shown in figure 1.
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