CN117777104A - Novel crizotinib salt and application thereof - Google Patents
Novel crizotinib salt and application thereof Download PDFInfo
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- CN117777104A CN117777104A CN202311697557.0A CN202311697557A CN117777104A CN 117777104 A CN117777104 A CN 117777104A CN 202311697557 A CN202311697557 A CN 202311697557A CN 117777104 A CN117777104 A CN 117777104A
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- 150000004921 Crizotinib derivatives Chemical class 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- -1 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate Chemical compound 0.000 claims abstract description 53
- 239000000126 substance Substances 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- 239000002146 L01XE16 - Crizotinib Substances 0.000 claims description 5
- 229960005061 crizotinib Drugs 0.000 claims description 5
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 5
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 4
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
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- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
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- 239000000203 mixture Substances 0.000 description 3
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- 239000007787 solid Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
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- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- 238000007689 inspection Methods 0.000 description 2
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- 238000007864 suspending Methods 0.000 description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 1
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 1
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Abstract
The invention discloses a novel crizotinib salt and application thereof, comprising the following steps: 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate; 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate. According to the invention, the water-soluble and stable compound has good water solubility and high solubility, and has wide application prospect in preparing antitumor drugs.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a novel crizotinib salt and application thereof.
Background
Crizotinib is a novel anti-tumor drug for biological targeted therapy, and the chemical name is 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy]-5- [1- (piperidin-4-yl) -1H-pyrazole ]4-yl group]Pyridin-2-amines of formula C 21 H 22 Cl 2 FN 5 O. Crizotinib is a representative drug of an Anaplastic Lymphoma Kinase (ALK) inhibitor, belongs to a multi-target tyrosine kinase inhibitor, has curative effects on ALK, ROS1 and hepatocyte growth factor receptor (MET) mutation, and is mainly applied to the treatment of anaplastic lymphoma kinase positive local advanced or metastatic non-small cell lung cancer patients. However, it should be noted that crizotinib has the problems of low water solubility and poor oral bioavailability.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a novel crizotinib salt which has good water solubility and stability and high solubility and has wide application prospect in preparing anti-tumor drugs. To achieve the above objects and other advantages and in accordance with the purpose of the invention, there is provided a novel crizotinib salt comprising:
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate;
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate.
Preferably, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate is produced by the reaction of a first compound with a second compound;
the chemical structure of the first compound is as follows:
the chemical structure of the second compound is as follows:
preferably, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate is produced by the reaction of a first compound with a fourth compound;
the chemical structure of the fourth compound is as follows:
preferably, the application of the novel crizotinib salt in preparing medicines for treating cancers.
Compared with the prior art, the invention has the beneficial effects that: the compounds of the invention have a significantly higher solubility in water than the corresponding free base. The surprisingly and remarkably stable, water-soluble compounds provide advantages for effective formulations and for use in large quantities.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate of the novel crizotinib salt according to the present invention;
FIG. 2 is an X-ray powder diffraction pattern of 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate of the novel crizotinib salt according to the present invention;
FIG. 3 is a single crystal asymmetric unit structure diagram of a novel crizotinib salt of 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate according to the present invention;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipic acid of the novel crizotinib salt according to the present invention;
FIG. 5 is an X-ray powder diffraction pattern of 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipic acid of the novel crizotinib salt according to the present invention;
FIG. 6 is a single crystal asymmetric unit structure diagram of 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate of the novel crizotinib salt according to the invention;
fig. 7 is a graph comparing the dissolution of the novel crizotinib salt according to the invention with the first compound.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to fig. 1-7, a novel crizotinib salt comprising: 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate;
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate.
Further, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate is produced by the reaction of a first compound with a second compound;
the chemical structure of the first compound is as follows:
the chemical structure of the second compound is as follows:
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate was produced by the reaction of the first compound with a fourth compound;
the chemical structure of the fourth compound is as follows:
the reaction between the first compound and the second compound or the fourth compound is usually carried out under conventional salt forming conditions, including suspension stirring, suspending and stirring the first compound and the second compound or the fourth compound in an organic solvent, continuously stirring for 24-48 h at 15-60 ℃, filtering, and vacuum drying at 30-80 ℃.
The ratio of the total mass of the first compound to the second compound or the fourth compound to the volume and the dosage of the organic solvent is 1g (3-25 mL), the organic solvent is one of alcohol solvent, ethyl acetate, chloroform, acetonitrile or acetone, and the mol ratio of the first compound to the second compound or the fourth compound is 1:1.
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy]-5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl]The nuclear magnetic resonance spectrum of the pyridine-2-amine malonate is shown in fig. 1, and the data are as follows: 1 H NMR(401MHz,DMSO)δ9.08(s,1H),7.93(s,1H),7.77(d,J＝1.1Hz,1H),7.59(s,1H),7.52(dd,J＝8.7,4.9Hz,1H),7.39(t,J＝8.7Hz,1H),6.89(s,1H),6.06(d,J＝6.6Hz,1H),5.71(s,2H),4.60–4.26(m,1H),3.41(d,J＝12.5Hz,2H),3.08(t,J＝11.2Hz,2H),2.86(d,J＝2.2Hz,2H),2.25–2.05(m,4H),1.87–1.68(m,3H)。
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy]-5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl]The X-ray powder diffraction pattern of the pyridine-2-amine malonate is shown in fig. 2, and is characterized by characteristic peaks at diffraction angles (+ -0.2 deg.) of 6.38 deg., 9.68 deg., 2.72 deg., 13.42 deg., 14.40 deg., 15.02 deg., 15.94 deg., 16.66 deg., 17.20 deg., 18.64 deg., 19.14 deg., 19.88 deg., 21.08 deg., 21.60 deg., 22.1 deg., 23.08 deg., 23.62 deg., 24.04 deg., 25.48 deg., 26.88 deg., 28.14 deg., 29.04 deg., 30.48 deg.. Single crystals of the compound of formula (III) are P2 12 of an orthorhombic system 1 2 1 Is set as the unit cell parameter α＝90，β＝90, γ=90. The asymmetric unit structure of the single crystal is shown in fig. 3.
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy]-5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl]The nuclear magnetic resonance spectrum of the pyridine-2-amine adipate is shown in fig. 4, and the data are as follows: 1 H NMR(401MHz,DMSO)δ8.27(s,4H),7.91(s,1H),7.77(s,1H),7.56(s,1H),7.52(dd,J＝8.9,4.9Hz,1H),7.38(t,J＝8.7Hz,1H),6.88(s,1H),6.06(q,J＝6.6Hz,1H),5.72(d,J＝10.6Hz,2H),4.42–4.26(m,1H),3.23(d,J＝12.6Hz,2H),2.85(t,J＝11.1Hz,2H),2.12(d,J＝6.1Hz,5H),2.00(dd,J＝25.4,13.9Hz,4H),1.77(d,J＝6.6Hz,3H),1.48(s,4H)。
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy]-5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl]The X-ray powder diffraction pattern of the pyridine-2-amine adipate is shown in fig. 5, and is characterized by characteristic peaks at diffraction angles (+ -0.2 DEG) of 6.16 DEG, 7.98 DEG, 9.30 DEG, 12.32 DEG, 13.42 DEG, 15.12 DEG, 16.54 DEG, 18.12 DEG, 18.52 DEG, 19.86 DEG, 20.74 DEG, 22.94 DEG, 24.12 DEG, 25.90 DEG, 27.06 DEG, 28.82 DEG and 30.42 deg. Single crystals of the compound of formula (V) are P2 12 of an orthorhombic system 1 2 1 Is set as the unit cell parameterα=90, β=90, γ=90. The asymmetric unit structure of the single crystal is shown in fig. 6.
The compound of the invention has better stability. Stability test is carried out by referring to the method of the fourth annex of Chinese pharmacopoeia (2020 edition) of < 9001 raw material medicaments and stability test guidelines > of the preparation:
(1) high temperature test conditions: the high temperature test condition is (60+/-1) DEG C, the sample is placed for 10 days, and the samples are taken on the 5 th day and the 10 th day;
(2) strong light irradiation test conditions: placing at 25deg.C under the condition of illumination of (4500+ -500) lx for 10 days, and sampling at 5 th and 10 th days;
(3) high humidity test conditions: standing at 25deg.C under relative humidity (90+ -5)% for 10 days, and sampling at 5 days and 10 days; if the hygroscopicity was greater than 5% at a relative humidity of (90.+ -. 5)%, then the selection was made to re-test at (75.+ -. 5)% of the conditions.
Further, the purity was measured by HPLC, and three parallel tests were performed, respectively, and the results were averaged. The hygroscopicity was calculated according to the following formula:
formula 1 formula for hygroscopicity (where Wn is the weight of the sample and bottle at each time interval, ws is the weight of the sample and bottle at the beginning, and Wo is the weight of the empty bottle)
The compounds of the invention have a significantly higher solubility in water than the corresponding free base. Thus, the conventional method for determining the stability of the compounds of the present invention in aqueous solution comprises determining the extent of precipitation of the parent free base from the aqueous solution of the test compound under known temperature conditions and for a known period of time, and we have found that 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate exhibit good aqueous solution stability.
The quantitative analysis of the test compounds can be carried out in a conventional manner, usually by chromatography, for example high-pressure liquid chromatography.
As mentioned above, the compounds of the present invention have useful therapeutic activity.
Example 13 preparation of- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate
To a 10mL round bottom flask was added the first compound (2.16 g,0.0048 mol) and the second compound (0.50 g,0.0048 mol) with ethyl acetate as suspending solvent, and a proper amount of ethyl acetate solvent was added to make the mixture into a suspension state, and stirring was carried out overnight at room temperature to give a white solid after sufficient reaction, filtration and vacuum drying for 2 hours to give 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate 2.64g in 99.29% yield.
Example 23 preparation of- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate:
to a 10mL round bottom flask was added the first compound (2.160 g,0.0048 mol) and the fourth compound (0.70 g,0.0048 mol) in the form of a suspension of dichloromethane with an appropriate amount of dichloromethane solvent to give the mixture as a suspension, which was stirred overnight at room temperature to give a white solid after sufficient reaction, which was filtered and dried under vacuum for 2H to give 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate 2.83g in 98.91% yield.
Example 3
Stability studies of the first compound, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate:
the first compound, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and the fourth compound of the test sample are respectively paved on a test piece, placed in a comprehensive drug stability test box, placed for 10 days under the condition that the illuminance is 4500 lx+/-500 lx, sampled on the 5 th day and the 10 th day, and subjected to X-ray powder diffraction and HPLC detection according to stability key inspection items, and the appearance change of the test sample is particularly noted.
The first compound of the test sample, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate were respectively tiled on test pieces, and the test sample was placed in a comprehensive drug stability test box, and left at 60.+ -. 1 ℃ for 10 days, sampled on days 5 and 10, and subjected to X-ray powder diffraction and HPLC detection according to the stability key inspection item.
The first compound of the test piece, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate were respectively spread on a test piece, the test piece was placed in a comprehensive drug stability test box, and the test piece was sampled on days 5 and 10 while the weight of the test piece was accurately weighed before and after the test to examine the moisture absorption and deliquescence properties of the test piece. Hygroscopicity, X-ray powder diffraction and HPLC detection were performed as required by the stability emphasis project. If the moisture absorption weight gain is more than 5%, the test is carried out under the condition of 75% +/-5% relative humidity by the same method; if the moisture absorption gain is less than 5%, and other investigation projects meet the requirements, the test is not performed.
The crystalline forms of the first compound, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate, after 10 days of testing under light, high temperature and high humidity conditions, did not change, indicating that the novel compounds 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate had the same stability as the first compound.
The results of HPLC measurements of the first compound, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate, were shown in Table 1 after 10 days of testing under light, high temperature and high humidity conditions. From table 1, it is clear that the purity of the three compounds was maintained at 99.6% or more over 5 days and 10 days, indicating that the properties of the two new compounds were stable.
TABLE 1 determination of the purity stability of crizotinib salt
Example 4
Solubility studies of first Compounds, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate Compounds
Distilled water is used as a dissolution medium. The first compound, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate were sieved through a 80 mesh sieve, and the solid (excess 10 to 30%) and distilled water 10ml were added to a 25ml round bottom flask and the dissolution was determined at 37.+ -. 1 ℃ at 50 rpm. Supernatant fluid is respectively taken at 5 min, 10 min, 15 min, 20min, 30 min, 45 min, 60 min, 90 min and 120min, and equal amount of isothermal fresh distilled water is timely taken for replacement. The extract was filtered through a 0.22 μm PTFE filter membrane and diluted to a concentration in the range of the standard curve for HPLC detection, the specific dissolution profile is shown in FIG. 7 in mg/mL. The equilibrium solubilities of the first compound, 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate and 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate were 0.042mg/mL, 79.55mg/mL and 54.62mg/mL, respectively. Two new compounds have a very high solubility in water compared to the corresponding free base.
The number of devices and the scale of processing described herein are intended to simplify the description of the invention, and applications, modifications and variations of the invention will be apparent to those skilled in the art.
Although embodiments of the present invention have been disclosed above, it is not limited to the details and embodiments shown and described, it is well suited to various fields of use for which the invention would be readily apparent to those skilled in the art, and accordingly, the invention is not limited to the specific details and illustrations shown and described herein, without departing from the general concepts defined in the claims and their equivalents.
Claims (4)
1. A novel crizotinib salt, comprising:
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate;
3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate.
2. A novel salt of crizotinib according to claim 1, wherein 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine malonate is produced by the reaction of a first compound with a second compound;
the chemical structure of the first compound is as follows:
the chemical structure of the second compound is as follows:
3. a novel crizotinib salt according to claim 1, wherein 3- [ (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy ] -5- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] pyridin-2-amine adipate is produced by the reaction of a first compound with a fourth compound;
the chemical structure of the fourth compound is as follows:
4. use of a novel crizotinib salt according to claim 1 for the preparation of a medicament for the treatment of cancer.
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