阅读说明：本技术 一种苯并哌啶类衍生物的盐、其晶型及盐、其晶型的制备方法 (A kind of preparation method of the salt of benzo piperidine derivatives, its crystal form and salt, its crystal form ) 是由 尤凌峰 邵成 冯君 于 2018-06-19 设计创作，主要内容包括：公开了一种苯并哌啶类衍生物的盐、其晶型及盐、其晶型的制备方法。具体地,公开了(E)-3-(4-((1R,3R)-2-(4-环丙基苯基)-6-(1-乙基-1H-吡唑-4-基)-3-甲基-1,2,3,4-四氢异喹啉-1-基)苯基)丙烯酸的L-赖氨酸盐、其I晶型及其制备方法。式(I)化合物、其I晶型具备良好的稳定性、工艺简单易于操作,可更好地用于临床治疗。<Image he="340" wi="557" file="DDA0002240959120000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Disclose a kind of salt of benzo piperidine derivatives, the preparation method of its crystal form and salt, its crystal form.Specifically, disclose (E) -3- (4- ((1R, 3R) -2- (4- cyclopropyl phenyl) -6- (1- ethyl -1H- pyrazoles -4- base) -3- methyl-1,2,3,4- tetrahydroisoquinoline -1- bases) phenyl) the L-lysine salt of acrylic acid, its I crystal and preparation method thereof.It is easily operated that formula (I) compound, its I crystal have good stability, a simple process, can be preferably applied to clinical treatment.)

A pharmaceutically acceptable salt of a compound (E) -3- (4- ((1R,3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-yl) phenyl) acrylic acid represented by the formula (II),

the pharmaceutically acceptable salt is selected from inorganic or organic salts, preferably lysine salt, 2-aminoethanol salt, diethanolamine salt, sodium salt, hydrochloride salt or N-methyl-D-glucamine salt.

The pharmaceutically acceptable salt according to claim 1 wherein the lysine is selected from the group consisting of L-lysine.

The pharmaceutically acceptable salt according to claim 2, wherein the chemical ratio of (E) -3- (4- ((1R,3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-yl) phenyl) acrylic acid to L-lysine is 1:1, and the pharmaceutically acceptable salt has the structure shown in formula (I),

a process for producing a pharmaceutically acceptable salt according to claim 3, which comprises the step of subjecting (E) -3- (4- ((1R,3R) -2- (4-cyclopropylphenyl) -6- (1-ethyl-1H-pyrazol-4-yl) -3-methyl-1, 2,3, 4-tetrahydroisoquinolin-1-yl) phenyl) acrylic acid to salt-forming reaction with L-lysine.

The process according to claim 4, wherein the salt-forming reaction is carried out in a solvent selected from the group consisting of water, alcohol solvents, ether solvents, nitrile solvents, ketone solvents, ester solvents, halogenated hydrocarbon solvents, amide solvents, aliphatic hydrocarbon solvents, alicyclic hydrocarbon solvents, aromatic hydrocarbon solvents, nitroalkane solvents, mixed solvents of alcohol solvents and ether solvents, mixed solvents of halogenated hydrocarbon solvents and nitrile solvents, mixed solvents of alcohol solvents and water, mixed solvents of ketone solvents and water, mixed solvents of amide solvents and water, and mixed solvents of nitrile solvents and water; the alcohol solvent is preferably methanol, ethanol or isopropanol, the ether solvent is preferably diethyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane, the nitrile solvent is preferably acetonitrile, the ketone solvent is preferably acetone, the ester solvent is preferably ethyl acetate, isopropyl acetate or butyl acetate, the halogenated hydrocarbon solvent is preferably dichloromethane, the amide solvent is preferably N, N-dimethylformamide or N, N-dimethylacetamide, the aliphatic hydrocarbon solvent is preferably N-heptane, the alicyclic hydrocarbon solvent is preferably cyclohexane, the aromatic hydrocarbon solvent is preferably xylene or isopropyl benzene, the nitroalkane solvent is preferably nitromethane,

the mixed solvent of the alcohol solvent and the ether solvent is preferably a mixed solvent of diethyl ether and methanol,

the mixed solvent of the halogenated hydrocarbon solvent and the nitrile solvent is preferably a mixed solvent of dichloromethane and acetonitrile,

the mixed solvent of the alcohol solvent and water is preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water,

the mixed solvent of the ketone solvent and water is preferably a mixed solvent of acetone and water,

the mixed solvent of the amide solvent and water is preferably a mixed solvent of N, N-dimethylformamide and water.

A crystalline form I of a compound of formula (I) characterized by: which has characteristic peaks at diffraction angle 2 theta angles of 8.5, 9.8 and 18.9 in an X-ray powder diffraction pattern expressed by the diffraction angle 2 theta angle using Cu-Ka radiation, wherein the error range of 2 theta angle of each characteristic peak is +/-0.2,

the crystalline form I of claim 6, characterized in that the diffraction angle 2 Θ angles have characteristic peaks at 8.5, 9.8, 10.5, 11.8, 13.1, 15.2, 17.8, 18.9, 20.1, 20.5, 22.1, and 23.0, wherein each characteristic peak has a 2 Θ angle error range of ± 0.2.

The crystalline form I of claim 7, wherein the diffraction angle 2 Θ angles have characteristic peaks at 8.5, 9.8, 10.5, 11.8, 13.1, 15.2, 16.5, 17.3, 17.8, 18.9, 20.1, 20.5, 21.2, 22.1, 23.0, 23.6, 24.4, 25.3, 25.5, and 25.9, wherein the error range for each characteristic peak 2 Θ angle is ± 0.2.

A process for preparing the crystalline form I according to any one of claims 6 to 8, which is selected from process (1) or process (2):

reacting free compound shown in formula (I) with L-lysine in a solvent, stirring, crystallizing, filtering and drying to obtain the crystal form I;

dissolving the compound shown in the formula (I) in a solvent, crystallizing, filtering and drying to obtain the crystal form I; the crystallization method is selected from room temperature crystallization, cooling crystallization, volatile solvent crystallization or seed crystal addition induced crystallization, the cooling crystallization temperature is selected from-10 ℃ to 25 ℃, and the seed crystal induced crystallization is preferably added in the crystallization method;

the solvent is selected from nitrile solvents or mixed solvents of nitrile solvents and water, and is preferably selected from acetonitrile or mixed solvents of acetonitrile and water.

A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 1 to 3 or the crystalline form I according to any one of claims 6 to 8, and one or more pharmaceutically acceptable carriers, diluents or excipients.

Use of a pharmaceutically acceptable salt according to any one of claims 1 to 3, a crystalline form I according to any one of claims 6 to 8 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated or dependent on an estrogen receptor.

The use according to claim 11, wherein the estrogen receptor mediated or dependent disease or condition is selected from the group consisting of cancer, central nervous system deficiency, cardiovascular system deficiency, blood system deficiency, immune and inflammatory diseases, susceptible infections, metabolic deficiency, neurological deficiency, mental deficiency, or reproductive deficiency; the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia or leukemia, preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer, more preferably breast cancer.