CN108727381B - ALK tyrosine kinase inhibitor salt and preparation method thereof - Google Patents
ALK tyrosine kinase inhibitor salt and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to salts of compounds of formula (I) and processes for their preparation.
Description
Technical Field
The invention relates to a salt of N-isopropyl-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -6, 7-dihydro-5H-pyrrolo [2, 3-d ] pyrimidin-4-yl) amino) benzenesulfonamide (a compound of formula (I)), in particular to a salt of a compound of formula (I) with a pharmaceutically acceptable acid and a preparation method thereof.
Background
The compound of the formula (I) is a high-selectivity small-molecule ALK tyrosine kinase inhibitor, has the inhibitory action of nanomolar action intensity on ALK tyrosine kinase at the cellular level, has complete inhibitory action on the tumor growth of non-small cell lung cancer and lymphoma caused by abnormal high expression of ALK (anaplastic lymphoma kinase) fusion protein in an animal body, and has particularly remarkable inhibitory action on ALK kinase mutant subtypes closely related to the drug resistance of the similar ALK inhibitor crizotinib at present clinically leading.
The synthesis of this compound is disclosed in WO2012092880, but no reference is made to the case of salts of the compound, and no other document reports on salts of the compound of formula (I). Salts of a drug have different physical and pharmaceutical properties from the free base, such as shape, density, hardness, deformability, stability, purity, hygroscopicity, flowability, compactness, dissolution properties, etc., which can affect the manufacturability, processability, pharmacokinetic properties (e.g., bioavailability) of the drug. Further, it has been found that the free base of the product has a problem in stability, is easily oxidized, and easily generates an oxidizing impurity when stored for a long period of time, and it is necessary to study a salt thereof. Researches show that the salified product can obviously improve the absorption in vivo, obviously increase the stability and avoid the generation of related impurities.
Disclosure of Invention
In one aspect, the present invention provides a hydrochloride salt of the compound of formula (I), which salt has an X-ray powder diffraction pattern as shown in fig. 1, a measurement error of 2 θ of ± 0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in table 1.
In another aspect, the invention relates to a Differential Scanning Calorimetry (DSC) analysis of the hydrochloride salt of the compound of formula (I) having a DSC profile as shown in figure 2.
In another aspect, the present invention provides a process for the preparation of the hydrochloride, p-toluenesulfonate, citrate, succinate, maleate, fumarate, sulfate, phosphate, malate, tartrate, methanesulfonate, malonate, and acetate salts of the compound of formula (I). The compound of formula (I) is synthesized according to a patent WO2012092880, and the preparation method of the salt of the compound of formula (I) is to perform salt formation operation on the compound of formula (I) purified by a chromatographic column and different acids in different solvents.
In some embodiments, a method of preparing a hydrochloride salt of a compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, introducing hydrogen chloride gas, separating out solids, and carrying out suction filtration after complete salification to obtain the hydrochloride of the compound of the formula (I).
In some embodiments, a method of preparing an L- (-) -malate salt of a compound of formula (I) comprises: dissolving the compound shown in the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of L- (-) -malic acid, removing the solvent after complete salification, and recrystallizing the residue with methanol to obtain the L- (-) -malate of the compound shown in the formula (I).
In some embodiments, the process for preparing the L- (+) -tartrate salt of the compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of L- (+) -tartaric acid, after complete salt formation, precipitating a solid, and performing suction filtration to obtain the L- (+) -tartrate of the compound of the formula (I).
In some embodiments, a method of preparing a maleate salt of a compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of maleic acid, after complete salification, precipitating a solid, and performing suction filtration to obtain the maleate of the compound of the formula (I).
In some embodiments, a method of preparing a fumarate salt of a compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of fumaric acid, completely salifying, precipitating a solid, and performing suction filtration to obtain the fumarate of the compound of the formula (I).
In some embodiments, a method of preparing a succinate salt of a compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of succinic acid, removing the solvent after complete salt formation, and recrystallizing the residue with methanol to obtain the succinate salt of the compound of the formula (I).
In some embodiments, a method of preparing a sulfate salt of a compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding concentrated sulfuric acid, removing the solvent after complete salification, and recrystallizing the residue with ethyl acetate to obtain the sulfate of the compound of the formula (I).
In some embodiments, a method of preparing a phosphate salt of a compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding phosphoric acid, completely salifying, precipitating a solid, and performing suction filtration to obtain the phosphate of the compound of the formula (I).
In some embodiments, a method of preparing a citrate salt of a compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of citric acid, removing the solvent after complete salification, and recrystallizing the residue with methanol to obtain the citrate of the compound of the formula (I).
In some embodiments, a process for preparing a p-toluenesulfonic acid salt of a compound of formula (I) comprises: dissolving the compound shown in the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of p-toluenesulfonic acid, removing the solvent after salt formation is completed, and recrystallizing the residue with ethyl acetate to obtain the p-toluenesulfonic acid salt of the compound shown in the formula (I).
In some embodiments, a method of preparing a mesylate salt of a compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of methanesulfonic acid, removing the solvent after salt formation is completed, and recrystallizing the residue with ethyl acetate to obtain the mesylate of the compound of the formula (I).
In some embodiments, the method of preparing the malonate salt of the compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of malonic acid, removing the solvent after complete salt formation, and recrystallizing the residue with ethyl acetate to obtain the malonate of the compound of the formula (I).
In some embodiments, the process for preparing the acetate salt of the compound of formula (I) comprises: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, dropwise adding a methanol solution of acetic acid, removing the solvent after complete salification, and recrystallizing the residue with ethyl acetate to obtain the acetate of the compound of the formula (I).
In some embodiments, a method of making a hydrochloride, p-toluenesulfonate, citrate, succinate, maleate, fumarate, sulfate, phosphate, L- (-) -malate, L- (+) -tartaric acid, malonate, methanesulfonate, or acetate salt of a compound of formula (I) comprises: salifying, crystallizing, filtering in a solvent or a mixed solvent of two solvents, and vacuum drying to remove solvent and water.
In some embodiments, a method of making a hydrochloride, a tosylate, a citrate, a succinate, a maleate, a fumarate, a sulfate, a phosphate, a malate, a tartrate, a mesylate, or an acetate salt of a compound of formula (I) comprises: dissolving the compound of formula (I) in a solvent or a mixed solvent of two solvents, introducing hydrogen chloride gas or a methanol solution of p-toluenesulfonic acid, citric acid, succinic acid, maleic acid, fumaric acid, concentrated sulfuric acid, phosphoric acid, malic acid, tartaric acid, methanesulfonic acid, malonic acid or acetic acid, crystallizing, filtering, and drying to obtain hydrochloride, p-toluenesulfonic acid salt, citrate, succinate, maleate, fumarate, sulfate, phosphate, malate, tartrate, methanesulfonate, malonate, or acetate of the compound of formula (I). Subjecting the hydrochloride salt of the compound of formula (I) to X-ray powder diffraction analysis, having the X-ray powder diffraction pattern shown in figure 1; the measurement error of 2 theta is +/-0.10 degrees, and a plurality of characteristic peaks are contained between 0 and 50 degrees and are shown in the table 1. As can be seen from the X-ray powder diffraction pattern, there are characteristic peaks at the following positions expressed in 2 θ: 3.943,7.850,9.522,9.798, 10.375, 10.751, 11.754, 13.171, 13.588, 14.152, 15.732, 16.061, 17.490, 18.006, 18.438, 19.004, 19.650, 20.836, 21.156, 22.245, 23.084, 24.064, 25.269, 26.710, 27.115, 28.521, 30.553, 31.016.
Table 1 d-values and 2 theta angles for the hydrochloride salt of the compound of formula (I).
| d- | 2 theta angle | Relative strength |
| 22.41 | 3.94 | 58.93 |
| 11.26 | 7.85 | 49.63 |
| 9.29 | 9.52 | 49.74 |
| 9.03 | 9.80 | 38.17 |
| 8.53 | 10.37 | 41.39 |
| 8.23 | 10.75 | 52.65 |
| 7.53 | 11.75 | 100.00 |
| 6.72 | 13.17 | 87.02 |
| 6.52 | 13.59 | 47.29 |
| 6.26 | 14.15 | 62.02 |
| 5.63 | 15.73 | 59.85 |
| 5.52 | 16.06 | 66.53 |
| 5.07 | 17.49 | 76.49 |
| 4.26 | 20.84 | 43.93 |
| 4.00 | 22.25 | 42.38 |
| 3.70 | 24.06 | 77.05 |
| 3.34 | 26.71 | 40.45 |
The Differential Scanning Calorimetry (DSC) spectrum of the hydrochloride salt of the compound of formula (I) (onset temperature 25 deg.C, end temperature 250 deg.C, heating rate 10 deg.C/min) is shown in FIG. 2.
The melting points of the hydrochloride, methanesulfonate, sulfate, p-toluenesulfonate, maleate, malonate, L- (+) -tartrate, or acetate salts of the compounds of formula (I) (melting point investigation with reference to the melting point determination method (appendix VI C of the second part of the chinese pharmacopoeia, version 2010)) are shown in table 2.
The results of measuring the solubility of the free base of the compound of the formula (I) with the hydrochloride, L- (-) -malate, sulfate, p-toluenesulfonate, maleate, fumarate or succinate salt of the compound of the formula (I) in water at pH 1.0, 4.5, 6.8 or 7.0 are shown in tables 3 to 10.
Hydrochloride, sulfate, p-toluenesulfonate, maleate, fumarate, phosphate, L- (-) -malate, citrate, succinate, or L- (+) -tartrate of the compound of the formula (I) was subjected to hygroscopicity examination at 25. + -. 1 ℃ and a relative humidity of 80. + -. 2%, and the results are shown in Table 11.
Pharmacokinetic studies of the hydrochloride salt of the compound of formula (I) show that: as can be seen from comparison of PK data for the free base of the compound of formula (I), the pharmacokinetic properties of the hydrochloride salt of the compound of formula (I) are significantly better than those of the free base of the compound of formula (I), and the results are shown in tables 12 and 13.
Stability of the hydrochloride salt of the compound of formula (I) compared to the free base of the compound of formula (I): the stability of the hydrochloride salt of the compound of formula (I) and the free base of the compound of formula (I) was examined for 30 days at 40 ± 2 ℃ and 75 ± 5% relative humidity, and the results are shown in table 14, which indicates that the stability of the hydrochloride salt of the compound of formula (I) is significantly better than that of the free base.
Drawings
FIG. 1 is an XRD pattern of the hydrochloride salt of the compound of formula (I).
FIG. 2 is a DSC of the hydrochloride salt of the compound of formula (I).
Detailed Description
The present invention will be described in further detail with reference to examples of specific embodiments.
Unless otherwise indicated, the following experimental runs were conducted at room temperature and one atmosphere of pressure.
Example 1, preparation of hydrochloride salt of compound of formula (I).
Adding a compound (5.0g) of a compound shown as a formula (I), dichloromethane (30mL) and methanol (10mL) into a 250mL three-neck flask, introducing hydrogen chloride gas under magnetic stirring, stirring for 5 hours, carrying out suction filtration, rinsing a filter cake with methanol (20mL), and drying the obtained solid at 40 ℃ for 24 hours in vacuum to obtain 2.1g of off-white solid.
1H-NMR(400MHz，DMSO-d6)δ：12.18～13.2(brs，2H)，9.47(s，1H)，8.87(s，1H)，8.71(s，1H)，7.97(d，J＝6.8Hz，1H)，7.87(d，J＝7.6Hz，1H)，7.60～7.87(m，3H)，7.39(t，J＝8.0Hz，1H)，7.14～7.34(m，1H)，6.88～7.16(m，1H)，3.50～3.86(m，18H)，3.15～3.40(m，3H)，2.85(s，3H)，2.10～2.42(m，4H)，0.94(d，J＝6.4Hz，6H)。
Example 2 preparation of the L- (-) -malate salt of the compound of formula (I).
Compound of formula (I) (5.0g), dichloromethane (30mL) and methanol (10mL) were added to a 250mL three-necked flask, a methanol solution of L- (-) -malic acid (2.21g malic acid in 10mL methanol) was added dropwise with magnetic stirring, and after the addition was completed, the mixture was stirred at room temperature overnight. The solvent was removed, the residue was recrystallized from methanol and the resulting solid was dried under vacuum at 40 ℃ for 24h to give 6.0g of an off-white solid.
1H-NMR(400MHz，DMSO-d6)δ：8.52～11.53(brs，4H)，8.40(d，J＝8.4Hz，1H)，8.25(s，1H)，7.85(J＝8.0Hz，1H)，7.78(d，J＝8.8Hz，1H)，7.75(d，J＝8.0Hz，1H)，7.46(t，J＝7.6Hz，1H)，7.24(s，1H)，7.05(t，J＝7.6Hz，1H)，6.74(s，1H)，6.61(d，J＝1.6Hz，1H)，6.42(dd，J＝8.8Hz，2.0Hz，1H)，4.10(t，J＝6.4Hz，2H)，3.80(s，3H)，3.68(d，J＝12.0Hz，2H)，3.53(t，J＝8.4Hz，2H)，3.23～3.31(m，1H)，2.54～2.96(m，15H)，2.51(s，3H)，2.38(dd，J＝15.6Hz，6.0Hz，2H)，1.89(d，J＝11.8Hz，2H)，1.51～1.59(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 3, preparation of citrate salt of compound of formula (I).
A compound of the formula (I) (5.0g), methylene chloride (30mL) and methanol (10mL) were added to a 250mL three-necked flask, a methanol solution of citric acid (3.47g of citric acid dissolved in 25mL of methanol) was added dropwise under magnetic stirring, after the addition was completed, the mixture was stirred at room temperature overnight, the solvent was removed, the residue was recrystallized from methanol, and the resulting solid was dried under vacuum at 40 ℃ for 24 hours to give 5.9g of an off-white solid.
1H-NMR(400MHz，DMSO-d6)δ：10.20～11.61(brs，6H)，8.39(d，J＝8.4Hz，1H)，8.25(s，1H)，7.85(J＝8.0Hz，1H)，7.79(d，J＝8.8Hz，1H)，7.75(d，J＝7.6Hz，1H)，7.46(t，J＝8.0Hz，1H)，7.25(s，1H)，7.05(t，J＝8.0Hz，1H)，6.75(s，1H)，6.62(s，1H)，6.43(d，J＝8.0Hz，1H)，3.81(s，3H)，3.69(d，J＝11.6Hz，2H)，3.53(t，J＝8.4Hz，2H)，3.23～3.32(m，1H)，2.71～3.11(m，10H)，2.56～2.66(m，13H)，1.90(d，J＝10.8Hz，2H)，1.55～1.61(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 4, preparation of maleate salt of compound of formula (I).
Adding a compound (5.0g) of a compound shown as a formula (I), dichloromethane (30mL) and methanol (10mL) into a 250mL three-neck flask, dropwise adding a methanol solution of maleic acid (1.92g of maleic acid is dissolved in 15mL of methanol) under magnetic stirring, stirring overnight at room temperature after dropwise adding, precipitating a large amount of solid, performing suction filtration, leaching a filter cake with methanol (50mL), and drying the obtained solid for 24 hours at 40 ℃ in vacuum to obtain 3.0g of off-white solid.
1H-NMR(400MHz，DMSO-d6)δ：12.0～15.5(brs，4H)，8.41(s，1H)，7.79～8.20(m，4H)，7.49～7.76(m，3H)，7.21(s，1H)，6.66(s，1H)，6.48(d，J＝8.0Hz，1H)，6.15(s，4H)，3.75～3.81(m，5H)，3.58(t，J＝8.0Hz，2H)，3.25～3.30(m，1H)，3.59～3.32(m，16H)，1.93(d，J＝11.2Hz，2H)，1.51～1.59(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 5, preparation of fumarate salt of compound of formula (I).
Adding a compound (5.0g) of a compound shown as a formula (I), dichloromethane (30mL) and methanol (10mL) into a 250mL three-neck flask, dropwise adding a methanol solution of fumaric acid (1.92g of maleic acid dissolved in 30mL of methanol) under magnetic stirring, stirring overnight at room temperature after dropwise adding, precipitating a large amount of solid, carrying out suction filtration, leaching a filter cake with methanol (50mL), and drying the obtained solid for 24 hours at 40 ℃ in vacuum to obtain 5.6g of off-white solid.
1H-NMR(400MHz，DMSO-d6)δ：9.05～13.50(brs，4H)，8.40(d，J＝8.4Hz，1H)，8.26(s，1H)，7.85(d，J＝8.0Hz，1H)，7.78(d，J＝8.8Hz，1H)，7.74(d，J＝8.4Hz，1H)，7.46(t，J＝7.6Hz，1H)，7.25(s，1H)，7.05(t，J＝7.6Hz，1H)，6.75(s，1H)，6.61(d，J＝1.6Hz，1H)，6.58(s，4H)，6.42(dd，J＝8.8Hz，2.0Hz，1H)，3.80(s，3H)，3.67(d，J＝12.0Hz，2H)，3.53(t，J＝8.4Hz，2H)，3.23～3.32(m，1H)，2.59～2.82(m，12H)，2.42～2.50(m，4H)，1.87(d，J＝11.6Hz，2H)，1.51～1.59(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 6, preparation of succinate salt of compound of formula (I).
The compound of formula (I) (5.0g), dichloromethane (30mL) and methanol (10mL) were added to a 250mL three-necked flask, a methanol solution of succinic acid (1.95g in 20mL methanol) was added dropwise under magnetic stirring, after the addition was completed, the mixture was stirred overnight at room temperature, the solvent was removed, the residue was recrystallized from methanol, and the resulting solid was dried under vacuum at 40 ℃ for 24 hours to give 4.7g of an off-white solid.
1H-NMR(400MHz，DMSO-d6)δ：9.61～13.60(brs，2H)，8.41(d，J＝8.4Hz，1H)，8.26(s，1H)，7.84(d，J＝8.0Hz，1H)，7.77(d，J＝8.8Hz，1H＝，7.75(d，J＝8.4Hz，1H)，7.46(t，J＝8.0Hz，1H)，7.23(s，1H)，7.05(t，J＝7.6Hz，1H)，6.74(s，1H)，6.60(d，J＝2.0Hz，1H)，6.41(dd，J＝8.8Hz，1.6Hz，1H)，3.80(s，3H)，3.66(d，J＝12.0Hz，2H)，3.53(t，JJ＝8.4Hz，2H)，3.23～3.32(m，1H)，2.80(t，J＝8.4Hz，2H)，2.30～2.64(m，15H)，2.24(s，3H)，1.85(d，J＝11.2Hz，2H)，1.48～1.56(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 7 preparation of the L- (+) -tartaric acid salt of the compound of formula (I).
Adding a compound (5.0g) of a compound shown as a formula (I), dichloromethane (30mL) and methanol (10mL) into a 250mL three-neck flask, dropwise adding a methanol solution of L- (+) -tartaric acid (2.48g of tartaric acid is dissolved in 25mL of methanol) under magnetic stirring, stirring at room temperature overnight after dropwise adding, precipitating a large amount of solid, performing suction filtration, leaching a filter cake by using methanol (50mL), and drying the obtained solid for 24 hours at 40 ℃ in vacuum to obtain 4.8g of white-like solid.
1H-NMR(400MHz，DMSO-d6)δ：8.61～11.10(brs，8H)，8.40(d，J＝8.0Hz，1H)，8.26(s，1H)，7.85(d，J＝8.0Hz，1H)，7.78(d，J＝8.8Hz，1H)，7.75(d，J＝8.8Hz，1H)，7.46(t，J＝7.2Hz，1H)，7.25(s，1H)，7.05(t，J＝7.6Hz，1H)，6.75(s，1H)，6.10(d，J＝2.0Hz，1H)，6.42(dd，J＝8.8Hz，2.0Hz，1H)，4.14(s，4H)，3.80(s，3H)，3.67(d，J＝12.0Hz，2H)，3.53(t，J＝8.4Hz，2H)，3.23～3.31(m，1H)，2.59～2.95(m，13H)，2.49(s，3H)，1.88(d，J＝11.2Hz，2H)，1.52～1.60(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 8 preparation of p-toluenesulfonate salt of the compound of formula (I).
The compound of formula (I) (5.0g), dichloromethane (30mL) and methanol (10mL) were added to a 250mL three-necked flask, a methanol solution of p-toluenesulfonic acid (3.1g p-toluenesulfonic acid in 25mL methanol) was added dropwise with magnetic stirring, after the addition was completed, the mixture was stirred at room temperature overnight, the solvent was removed, the residue was purified by slurrying with ethyl acetate, and the resulting solid was dried at 40 ℃ for 24 hours in vacuo to give 6.2g of a yellow solid.
1H-NMR(400MHz，DMSO-d6)δ：10.30～11.83(brs，2H)，8.90～9.80(brs，1H)，8.49(s，1H)，7.82～7.84(m，2H)，7.51～7.66(m，2H)，7.50(d，J＝7.6Hz，4H)，7.21～7.35(m，2H)，7.12(d，J＝8.0Hz，4H)，6.69(s，1H)，6.52(s，1H)，3.81(s，3H)，3.54～3.64(m，2H)，3.36～3.42(m，2H)，3.24～3.34(m，1H)，2.61～3.14(m，16H)，2.29(s，6H)，1.82～2.13(m，2H)，1.41～1.75(m，2H)，0.95(d，J＝6.4Hz，6H)。
Example 9 preparation of the sulfate salt of the compound of formula (I).
Adding a compound (5.0g) of a compound shown as a formula (I), dichloromethane (30mL) and methanol (10mL) into a 250mL three-neck flask, dropwise adding a concentrated sulfuric acid methanol solution (1.62g of concentrated sulfuric acid dissolved in 5mL of methanol) under magnetic stirring, stirring at room temperature overnight after dropwise adding is finished, precipitating a large amount of solid, carrying out suction filtration, leaching a filter cake by using methanol (20mL), and drying the obtained solid for 24 hours at 40 ℃ in vacuum to obtain 5.3g of a white-like solid.
1H-NMR(400MHz，DMSO-d6)δ：9.0～12.0(brs，2H)，8.45(s，1H)，7.71～8.22(m，4H)，7.32～7.65(m，3H)，7.26(t，J＝6.8Hz，1H)，6.69(s，1H)，6.50(d，J＝8.0Hz，1H)，3.71～3.90(m，5H)，3.58(t，J＝7.6Hz，2H)，1.98(d，J＝11.2Hz，2H)，1.52～1.63(m，2H)，0.93(d，J＝6.4Hz，6H)。
Example 10, preparation of phosphate salt of compound of formula (I).
Adding a compound (5.0g) of a compound shown as a formula (I), dichloromethane (30mL) and methanol (10mL) into a 250mL three-neck flask, dropwise adding a methanol solution of phosphoric acid (1.9g of phosphoric acid is dissolved in 5mL of methanol) under magnetic stirring, separating out a large amount of solid after dropwise adding, continuing to react for 5 hours, carrying out suction filtration, leaching a filter cake by using methanol (20mL), and drying the obtained solid for 24 hours at 40 ℃ in vacuum to obtain 6.0g of white-like solid.
1H-NMR(400MHz，DMSO-d6)δ：8.50～10.10(brs，2H)，8.39(d，J＝7.6Hz，1H)，8.26(s，1H)，7.70～7.91(m，1H)，7.77(d，J＝8.8Hz，1H)，7.74(d，J＝8.0Hz，1H)，7.46(t，J＝8.4Hz，1H)，7.24(s，1H＝，7.05(t，J＝7.6Hz，1H)，6.75(s，1H)，6.64～6.86(brs，1H)，6.61(d，J＝2.0Hz，1H)，6.42(dd，J＝8.8Hz，2.0Hz，1H)，3.80(s，3H)，3.68(d，J＝12.4Hz，2H)，3.53(t，J＝8.8Hz，2H)，3.21～3.35(m，1H)，2.59～2.88(m，13H)，2.46(s，3H)，1.89(d，J＝11.2Hz，2H)，1.50～1.57(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 11, preparation of the mesylate salt of the compound of formula (I).
The compound of formula (I) (5.0g), dichloromethane (30mL) and methanol (10mL) were added to a 250mL three-necked flask, a methanol solution of methanesulfonic acid (1.59g methanesulfonic acid in 15mL methanol) was added dropwise with magnetic stirring, after the addition was completed, the mixture was stirred overnight at room temperature, the solvent was removed, the residue was recrystallized from methanol, and the resulting solid was dried under vacuum at 40 ℃ for 24 hours to give 5.2g of an off-white solid.
1H-NMR(400MHz，DMSO-d6)δ：8.61～12.60(brs，2H)，8.40(d，J＝8.8Hz，1H)，8.25(s，1H)，7.86(d，J＝8.4Hz，1H)，7.78(d，J＝8.8Hz，1H)，7.76(d，J＝8.0Hz，1H)，7.49(t，J＝8.0Hz，1H)，7.24(s，1H)，7.06(t，J＝8.0Hz，1H)，6.74(s，1H)，6.61(d，J＝1.6Hz，1H)，6.41(dd，J＝8.0Hz，1.6Hz，1H)，3.80(s，3H)，3.68(d，J＝12.4Hz，2H)，3.53(t，J＝8.8Hz，2H)，3.21～3.35(m，1H)，2.67(s，3H)，2.59～2.88(m，13H)，2.46(s，3H)，1.89(d，J＝11.2Hz，2H)，1.50～1.57(m，2H)，0.94(d，J＝6.4Hz，6H)
Example 12 preparation of the malonate salt of the compound of formula (I).
Adding a compound (5.0g) of a compound shown as a formula (I), dichloromethane (30mL) and methanol (10mL) into a 250mL three-neck flask, dropwise adding a methanol solution of malonic acid (1.72g of methanesulfonic acid is dissolved in 25mL of methanol) under magnetic stirring, stirring overnight at room temperature after dropwise adding is finished, precipitating a large amount of solid, performing suction filtration, leaching a filter cake by using methanol (30mL), and drying the obtained solid for 24 hours at 40 ℃ in vacuum to obtain 3.7g of a white-like solid.
1H-NMR(400MHz，DMSO-d6)δ：11.59～12.78(brs，4H)，8.39(d，J＝7.6Hz，1H)，8.25(s，1H)，7.85(d，J＝8.0Hz，1H)，7.77(d，J＝8.4Hz，1H)，7.74(d，J＝8.0Hz，1H)，7.42(t，J＝7.6Hz，1H)，7.24(s，1H)，7.05(t，J＝7.6Hz，1H)，6.75(s，1H)，6.61(d，J＝2.0Hz，1H)，6.39(dd，J＝8.8Hz，1.6Hz，1H)，3.81(s，3H)，3.66(d，J＝12.0Hz，2H)，3.54(t，JJ＝8.4Hz，2H)，3.45(s，4H)，3.21～3.31(m，1H)，2.80(t，J＝8.4Hz，2H)，2.31～2.65(m，11H)，2.25(s，3H)，1.86(d，J＝11.2Hz，2H)，1.50～1.56(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 13, preparation of the acetate salt of the compound of formula (I).
Adding a compound (5.0g) of a compound shown as a formula (I), dichloromethane (30mL) and methanol (10mL) into a 250mL three-neck flask, dropwise adding a methanol solution of acetic acid (0.99g of methanesulfonic acid is dissolved in 10mL of methanol) under magnetic stirring, stirring at room temperature overnight after dropwise adding is finished, precipitating a large amount of solid, carrying out suction filtration, leaching a filter cake by using methanol (20mL), and drying the obtained solid for 24 hours at 40 ℃ in vacuum to obtain 4.2g of white-like solid.
1H-NMR(400MHz，DMSO-d6)δ：8.96～13.57(brs，2H)，8.40(d，J＝8.4Hz，1H)，8.25(s，1H)，7.85(d，J＝8.8Hz，1H)，7.76(d，J＝8.0Hz，1H)，7.73(d，J＝7.6Hz，1H)，7.41(t，J＝8.0Hz，1H)，7.23(s，1H)，7.05(t，J＝8.0Hz，1H)，6.75(s，1H)，6.61(d，J＝2.0Hz，1H)，6.40(dd，J＝8.8Hz，1.6Hz，1H)，3.80(s，3H)，3.73(d，J＝11.6Hz，2H)，3.51(t，J＝8.4Hz，2H)，3.45(s，6H)，3.23～3.32(m，1H)，2.71～3.11(m，4H)，2.56～2.66(m，13H)，1.90(d，J＝10.8Hz，2H)，1.55～1.61(m，2H)，0.94(d，J＝6.4Hz，6H)。
Example 14, the melting point of the hydrochloride, mesylate, sulfate, p-toluenesulfonate, maleate, L- (+) -tartrate, acetate, or malonate salt of the compound of formula (I) was determined, the rate of temperature increase: 1.5 ℃/min, heating medium: the results of the melting point test on the silicone oil (see melting point measurement method (appendix VI C of the second part of the Chinese pharmacopoeia 2010) are shown in Table 2.
Table 2 melting points of hydrochloride, malonate, methanesulfonate, sulfate, p-toluenesulfonate, maleate, L- (+) -tartrate, and acetate salts of the compounds of formula (I).
| Sample name | Initial temperature/. degree.C | Initial melting temperature/. degree.C | Final fusion temperature/. degree.C | Melting Point/. degree.C |
| Hydrochloride salt | 100 | 207.1 | 208.0 | 207.1-208.0 |
| |
100 | 168.5 | 170.1 | 168.5-170.1 |
| Sulfates of |
100 | 143.8 | 146.5 | 143.8-146.5 |
| P- |
100 | 144.5 | 147.8 | 144.5-147.8 |
| |
100 | 139.4 | 141.0 | 139.4-141.0 |
| L- (+) - |
100 | 143.4 | 144.4 | 143.4-144.4 |
| |
100 | 219.5 | 221.2 | 219.5-221.2 |
| |
100 | 141.0 | 141.4 | 141.0-141.4 |
Example 15 determination of the solubility of the free base of the compound of formula (I) with the hydrochloride, sulfate, L- (-) -malate, p-toluenesulfonate, maleate, fumarate or succinate salt of the compound of formula (I) in water at pH 1.0, 4.5, 6.8 or 7.0, the results are shown in tables 3-10.
Table 3 solubility of the hydrochloride salt of the compound of formula (I) in water at different pH.
Table 4 solubility of the sulfate salt of the compound of formula (I) in water at different pH.
Table 5 solubility of the maleate salt of the compound of formula (I) in water at different pH.
Table 6 solubility of the L- (-) -malate salt of the compound of formula (I) in water at different pH.
Table 7 solubility of p-toluenesulfonate salt of compound of formula (I) in water at different pH.
Table 8 solubility of fumarate salt of compound of formula (I) in water at different pH.
Table 9 solubility of the succinate salt of the compound of formula (I) in water at different pH.
Table 10 solubility of the free base of the compound of formula (I) in water at different pH.
From the solubility data, the solubility of the hydrochloride and sulfate salts of the invention in water is significantly better than that of the free base, and the solubility of the L- (-) -malate, succinate, p-toluenesulfonate, maleate and fumarate salts is also greatly improved.
Example 16, hydrochloride, citrate, sulfate, p-toluenesulfonate, maleate, fumarate, L- (+) -tartrate, phosphate, succinate and L- (-) -malate salts of the compound of formula (I) were placed at 25. + -. 1 ℃ and 80. + -. 2% relative humidity for hygroscopicity examination, and as a result, the hygroscopicity of the product was within an acceptable range as shown in Table 11.
Table 11, hygroscopicity data for hydrochloride, citrate, sulfate, p-toluenesulfonate, maleate, fumarate, L- (+) -tartrate, phosphate, succinate, and L- (-) malate salts of compounds of formula (I).
| Sample name | Time (h) | Weight gain (%) |
| Hydrochloride salt | 24 | 1.70 |
| Citric acid salt | 24 | 1.39 |
| Sulfates of sulfuric acid | 24 | 1.10 |
| P-toluenesulfonate salt | 24 | 1.58 |
| Maleic acid salt | 24 | 1.97 |
| L- (+) -tartrate salt | 24 | 1.79 |
| Fumarate salt | 24 | 1.75 |
| Phosphate salts | 24 | 1.43 |
| L- (-) -malate salt | 24 | 1.25 |
| Succinate salts | 24 | 1.03 |
Example 17 pharmacokinetic studies were performed on the hydrochloride salt of the compound of formula (I) and its free base, the results of which are shown in tables 12 and 13. The pharmacokinetic properties of the hydrochloride salt are significantly better compared to the free base of the compound of formula (I).
Table 12, data for PK for hydrochloride salt of compound of formula (I).
| Parameter(s) | Unit of | PO 5mg/kg |
| t1/2 | hr | 7.43 |
| Tmax | hr | 4.58 |
| Cmax | ng/mL | 1452 |
| AUC0-INF | hr*ng/mL | 19850 |
Table 13, PK data for the free base of compound of formula (I).
| Parameter(s) | Unit of | PO 5mg/kg |
| t1/2 | hr | 8.95 |
| Tmax | hr | 4.67 |
| Cmax | ng/mL | 1204 |
| AUC0-INF | hr*ng/mL | 9737 |
Example 17 stability of the hydrochloride salt of the compound of formula (I) compared to its free base. The hydrochloride salt of the compound of formula (I) and its free base were placed at 40. + -. 2 ℃ and 75. + -. 5% relative humidity for 30 days for stability examination, and the HPLC normalized purity was measured for 0 day, 10 days, and 30 days, respectively, and the results are shown in Table 14.
Table 14 stability data of the hydrochloride salt of the compound of formula (I) compared to its free base over 30 days.
From the stability data, the impurities of the free base of the compound of formula (I) at hplc retention times of 2.87, 17.56, and 19.95 minutes increased significantly over 10 days and 30 days, while the hydrochloride salt of the compound of formula (I) did not tend to increase, indicating that the stability of the hydrochloride salt of the compound of formula (I) is significantly better than the stability of the free base.
Claims (2)
1. A salt of a compound of formula (I), wherein the salt of the compound of formula (I) is formed from a compound of formula (I) and a pharmaceutically acceptable acid,
the salt of the compound of formula (I) is hydrochloride, and its X-ray powder diffraction pattern is shown in figure 1.
2. A process for preparing a salt of a compound of formula (I) according to claim 1, the process comprising: dissolving the compound of the formula (I) in a mixed solvent of dichloromethane and methanol, introducing hydrogen chloride gas, separating out solids, and carrying out suction filtration after complete salification to obtain the hydrochloride of the compound of the formula (I).
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