CN108727347B - Crystal form of opioid receptor (MOR) agonist and preparation method thereof - Google Patents
Crystal form of opioid receptor (MOR) agonist and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a crystalline form of an opioid receptor (MOR) agonist and a process for its preparation. In particular, the invention relates to (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decyl-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalene-1-amine crystal form A and a preparation method thereof. The crystal form A of the compound shown in the formula (I) has good crystal form stability, and the used crystallization solvent has low toxicity and low residue, and can be better used for clinical treatment.
Description
Technical Field
The invention relates to a crystal form A of (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridine-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalene-1-amine, a preparation method thereof, application thereof in a pharmaceutical composition and application of the crystal form A and the composition in preparation of medicines for treating and/or preventing diseases related to opioid receptor (MOR) agonists.
Background
Opioid receptors are important G Protein Coupled Receptors (GPCRs), are target points for combination of endogenous opioid peptides and opioid drugs, have a regulating effect on nervous system immunity and endocrine system after being activated, and are the strongest and commonly used central analgesics at present. Endogenous opioid peptides are opioid active substances naturally produced in mammals, and currently known endogenous opioid peptides are roughly classified into enkephalins, endorphins, dynorphins and neokephalins (Pharmacol Rev 2007; 59: 88-123). The central nervous system has its corresponding opioid receptors, i.e., μ (MOR), δ (DOR), κ (KOR), etc. MOR is the target of action of opioid analgesics such as endogenous enkephalin and morphine.
In order to reduce the side effects of the opioid, the drug can be designed based on negative β -arrestin preferential ligand of MOR, so that the β -arrestin mediated side effects are reduced, and the treatment effect is enhanced, in the research of the oxaspiro derivative as MOR selective drug, the TrevenaInc company researches and finds that the activity is poor when aryl benzyl position is substituted (J.Med.Chem.2013,56,8019-8031), but WO 2016363509 (patent application No. PCT/CN2016/101064, application date 2016-09-30) discloses a MOR compound which shows high activity after aryl benzyl position is cyclized, obviously improves Emax, obviously improves hERG and has a single configuration, and the structure is shown as the formula (I):
at present, no crystal form report of the compound shown in the formula (I) exists, and it is known that the crystal form structure of the compound used as a medicinal active ingredient influences the chemical stability of the medicament, and the crystal structure of the compound may be changed due to the difference of crystallization conditions and storage conditions, and sometimes other crystal forms are generated. In general, amorphous drug products do not have a regular crystalline structure and often have other drawbacks, such as poor product stability, difficult filtration, easy caking, poor flowability, etc. Therefore, there is a need to improve various properties of the above products.
Disclosure of Invention
The invention aims to provide a crystal form A of (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridine-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalene-1-amine (shown in a formula (I)), and the crystal form has good stability.
The technical scheme of the invention is as follows:
the invention provides a crystal form A of a compound shown as a formula (I), which is characterized in that Cu-K α is used for radiation to obtain an X-ray powder diffraction pattern expressed by a diffraction angle 2 theta angle, the diffraction angle 2 theta angle of the X-ray powder diffraction pattern has characteristic peaks at 6.01, 6.09, 11.23, 11.33, 12.14, 12.23, 13.19, 16.86, 17.07, 19.21, 21.00, 22.85, 23.14 and 24.56, wherein the error range of 2 theta of each characteristic peak is +/-0.2,
in one embodiment of the invention, the diffraction angle 2 θ has characteristic peaks at 6.01, 6.09, 11.23, 11.33, 12.14, 12.23, 12.46, 13.19, 16.05, 16.54, 16.86, 17.07, 18.32, 18.83, 19.21, 21.00, 21.63, 21.70, 22.28, 22.85, 23.14, 23.74, 24.56, 26.53 and 31.71, wherein the error range of 2 θ for each characteristic peak is ± 0.2.
In one embodiment of the present invention, the diffraction angle 2 θ angle has characteristic peaks at 6.01, 6.09, 8.43, 11.23, 11.33, 12.14, 12.23, 12.46, 12.94, 13.19, 16.05, 16.54, 16.86, 17.07, 18.32, 18.83, 19.21, 21.00, 21.63, 21.70, 22.28, 22.85, 23.14, 23.74, 24.56, 25.12, 26.53, 27.50, 27.87, 31.71, 32.23, 37.33 and 40.02, wherein the error range of 2 θ of each characteristic peak is ± 0.2.
In one embodiment of the present invention, the present invention provides a crystalline form a of a compound of formula (I) characterized by: the melting point is from 85 ℃ to 98 ℃, preferably from 88.6 ℃ to 92 ℃, and more preferably 90.23 ℃.
The invention also relates to a method for preparing form a, characterized in that the method comprises:
(1) dissolving a compound shown in a formula (I) in a solvent, crystallizing, filtering and drying to obtain a target crystal form A;
(2) adding a compound shown as a formula (I) into a solvent, pulping, filtering and drying to obtain a target crystal form A;
the crystallization method is selected from volatilization crystallization, room temperature crystallization, cooling crystallization or crystal seed adding induction crystallization.
The solvent in the method (1) in the above scheme is selected from esters, aliphatic hydrocarbons, alcohols, ketones, nitriles or ethers;
the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol; the ketone solvent is selected from acetone, acetophenone, methyl isobutyl ketone or methyl pyrrolidone; the aliphatic hydrocarbon solvent is selected from pentane, n-hexane or n-heptane; the alicyclic hydrocarbon solvent is selected from cyclopentane or cyclohexane; the nitrile solvent is selected from acetonitrile or propionitrile; the ether solvent is selected from tetrahydrofuran, diethyl ether, propylene glycol methyl ether or methyl tert-butyl ether.
The solvent in the method (2) in the above scheme is selected from aliphatic hydrocarbons, esters, ethers, alicyclic hydrocarbons, halogenated hydrocarbons, nitriles, water or mixed solvents, preferably halogenated hydrocarbons, esters, nitriles or mixed solvents of halogenated hydrocarbons and esters;
the aromatic hydrocarbon is selected from benzene, toluene or xylene; the halogenated hydrocarbon is selected from dichloromethane, chloroform, chlorobenzene or dichlorobenzene; the mixed solvent of the halogenated hydrocarbons and the esters is preferably a mixed solvent consisting of dichloromethane and ethyl acetate; the aliphatic hydrocarbon solvent is selected from pentane, n-hexane or n-heptane; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the alicyclic hydrocarbon solvent is selected from cyclopentane or cyclohexane; the nitrile solvent is selected from acetonitrile or propionitrile; the ether solvent is selected from tetrahydrofuran, diethyl ether, propylene glycol methyl ether or methyl tert-butyl ether.
The present invention further provides a pharmaceutical composition of form a, characterized by comprising one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention also provides an application of the crystal form A and the pharmaceutical composition of the crystal form A in preparing medicines for treating related diseases mediated by opioid receptor (MOR) agonists.
The MOR receptor agonist mediated related disorders of the present invention are selected from the group consisting of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric disorders, urinary and reproductive disorders, cardiovascular disorders and respiratory disorders, preferably pain.
The invention also provides application of the crystal form A and the pharmaceutical composition of the crystal form A in preparation of medicines for preventing or treating pain and pain-related diseases.
The pain according to the invention is selected from postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain or inflammation-induced pain.
The cancer of the invention is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, ovarian tumors, hemophilia and leukemia.
The invention also provides application of the crystal form A and the pharmaceutical composition of the crystal form A in preparing medicines for exciting or antagonizing MOR receptors.
The crystal form A of the compound shown in the formula (I) is subjected to structure determination and crystal form research through an X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The method for recrystallization of form a is not particularly limited, and can be carried out by a usual recrystallization operation method. For example, the compound represented by the formula (I) as a raw material is dissolved in an organic solvent, and then an anti-solvent is added to the solution to crystallize the compound, and after completion of crystallization, the crystals are filtered and dried to obtain desired crystals.
The crystallization method comprises the steps of volatilization crystallization, room temperature crystallization, cooling crystallization, seed crystal addition induction crystallization and the like.
The starting materials used in the preparation method of the crystal form of the invention can be compounds represented by formula (I) in any form, and specific forms include but are not limited to: amorphous, random crystalline, and the like.
Detailed Description
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
Said "C" of the present invention1-6Alkyl "denotes a straight or branched chain alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
The "hydroxyl group" in the present invention means a group such as-OH.
The "cyano group" in the present invention means a group such as-CN.
The "ketone solvent" according to the present invention refers to a compound in which a carbonyl group (-C (O)) is bonded to two hydrocarbon groups, and the ketone can be classified into aliphatic ketone, alicyclic ketone, aromatic ketone, saturated ketone and unsaturated ketone according to the difference of the hydrocarbon groups in the molecule, and specific examples include, but are not limited to: acetone, acetophenone, methyl isobutyl ketone or methyl pyrrolidone.
The "ester solvent" according to the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to: ethyl acetate, isopropyl acetate or butyl acetate.
The "ether solvent" according to the present invention refers to a chain compound or a cyclic compound containing an ether bond-O-and having 1 to 10 carbon atoms, and specific examples include, but are not limited to: tetrahydrofuran, diethyl ether, propylene glycol methyl ether, methyl tert-butyl ether or 1, 4-dioxane.
The term "alcoholic solvent" as used herein means a compound in which one or more "hydroxyl groups" are substituted for "C1-6Radicals derived from one or more hydrogen atoms of alkyl radicals, said "hydroxy" and "C1-6Alkyl "is as defined above, specific examples include, but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.
The "nitrile solvent" in the invention means that one or more "cyano groups" are substituted for "C1-6Groups derived from one or more hydrogen atoms of alkyl groups, said "cyano" and "C1-6Alkyl "is as defined above, specific examples include, but are not limited to: acetonitrile or propionitrile.
The "aliphatic hydrocarbon solvent" of the present invention refers to a hydrocarbon compound having basic properties of aliphatic compounds, in which carbon atoms in a molecule are connected to form a chain carbon skeleton, both ends of the chain carbon skeleton are open and not in a ring, and the number of carbon atoms is 1-10, such as saturated aliphatic hydrocarbons, including alkane solvents, and specific examples include but are not limited to: n-butane, n-pentane, n-hexane or n-heptane.
The "alicyclic hydrocarbon solvent" according to the present invention refers to a hydrocarbon compound having a cyclic carbon skeleton, similar to aliphatic hydrocarbons in properties, and having 1 to 8 ring atoms, and specific examples include, but are not limited to: cyclopentane or cyclohexane.
The term "aromatic hydrocarbon solvent" as used herein refers to a generic term for carbocyclic compounds and derivatives thereof having a conjugated system with a closed ring in the molecule and п electron numbers conforming to the Huckel rule, and specific examples include, but are not limited to, benzene, toluene, cumene or xylene.
The "halogenated hydrocarbon solvent" in the present invention refers to a group derived by substituting one or more "halogen atoms" for one or more hydrogen atoms on an alkyl or aryl group, and specific examples include, but are not limited to: methyl chloride, methylene chloride, chloroform, carbon tetrachloride, chloroform, chlorobenzene or dichlorobenzene.
The mixed solvent is a solvent formed by mixing one or more different organic solvents according to a certain proportion, or a solvent formed by mixing an organic solvent and water according to a certain proportion; the mixed solvent is preferably a mixed solvent of a halogenated hydrocarbon solvent and esters; the mixed solvent of the halogenated hydrocarbon solvent and the ester is preferably a mixed solvent of dichloromethane and ethyl acetate.
The "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern obtained by dividing the X-ray beam according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-ray,
the order n of diffraction is any positive integer, a first-order diffraction peak is generally taken, n is 1, when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The differential scanning calorimetry or DSC in the invention refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance in the process of heating or keeping constant temperature of the sample so as to represent all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.
The term "2 theta or 2 theta angle" as used herein means a diffraction angle, theta is a Bragg angle in degrees or less, and the error range of 2 theta is + -0.1 to + -0.5, preferably + -0.1 to + -0.3, more preferably + -0.2.
The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is parallel six according to the determinedAnd dividing the unit connecting lines of the surface body to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
The invention also relates to a pharmaceutical composition comprising the crystal form A of the compound shown in the formula (I) and optionally one or more medicinal carriers and/or diluents. The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, the form a or the pharmaceutical preparation of the present invention may be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.
In addition, the pharmaceutical compositions of the present invention may be administered to a patient or subject in need of such treatment by any suitable mode of administration, for example, oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, oral solid preparations such as tablets, capsules, pills, granules and the like; or oral liquid preparations such as oral solution, oral suspension, syrup, etc. When formulated into oral preparations, the pharmaceutical preparations may further contain suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When prepared into injections, the pharmaceutical composition may be manufactured by a conventional method in the existing pharmaceutical field. When preparing injection, the pharmaceutical preparation can be added with no additive, or added with proper additive according to the nature of the medicine. When used for rectal administration, the pharmaceutical preparation may be formulated into suppositories and the like. For pulmonary administration, the pharmaceutical formulation may be formulated as an inhalant or a spray. In certain preferred embodiments, the crystalline form a of the present invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the form a of the present invention is present in a pharmaceutical composition or medicament in the form of a unit dose.
The crystal form A of the compound shown in the formula (I) can be used for preparing medicaments for treating diseases related to opioid receptor (MOR) agonists. The present application therefore also relates to the use of the crystalline form a of the compound of formula (I) according to the invention for the preparation of a medicament for use in a medicament for the treatment of a disease associated with an opioid receptor (MOR) agonist. Furthermore, the present application relates to a method of inhibiting a disease associated with an opioid receptor (MOR) agonist comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the crystalline form a of the compound of formula (I) of the present invention, or the pharmaceutical composition of the present invention.
In certain preferred embodiments, the disease is a disease associated with an opioid receptor (MOR) agonist, selected from pain.
Advantageous effects of the invention
Compared with the prior art, the technical scheme of the invention has the following advantages:
researches show that the crystal form A of the compound shown in the formula (I) prepared by the invention has excellent solubility and higher purity, and the crystal form is not changed and has good stability under the conditions of illumination, high temperature and high humidity through XRPD detection; the HPLC purity change is small, and the chemical stability is high; the crystal form A of the compound shown in the formula (I) obtained by the technical scheme of the invention can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be suitable for industrial production.
Drawings
Figure 1 is an XRPD pattern of form a of compound represented by formula (I).
FIG. 2 is a DSC of crystal form A of compound shown in formula (I).
FIG. 3 is a TGA profile of the crystalline form of Compound A shown in formula (I).
FIG. 4 is an XRPD pattern of an amorphous form of the compound of formula (I).
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the experiment:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: mettler Toledo DSC 3+STAReSystem
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 20-350 deg.C
2. X-ray Powder Diffraction Spectroscopy (XRPD)
The instrument model is as follows: rigaku ultimaIV X-ray powder diffractometer
Monochromatic Cu-K α ray
The scanning mode is as follows: θ/2 θ, scan range: 3-45 °
Voltage: 40kV, current: 40mA
3. Thermogravimetric Analyzer (TGA)
The instrument model is as follows: mettler Toledo TGA2 STAReSystem
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 20-250 deg.C
Comparative example 1 preparation of (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine (amorphous form of Compound 19)
First step of
(S) -1,2,3, 4-Tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11a
(S) -1,2,3, 4-tetrahydro-1-naphthylamine 10a (3g, 20.41mmol, prepared by the method disclosed in "Angewandte Chemie-International Edition,45(28)," 4641-one 4644,2006 ") was dissolved in 100mL of dichloromethane, triethylamine (5.7mL, 40.82mmol) was added, di-tert-butyl dicarbonate (4.9g, 22.45mmol) was added, and the reaction was stirred for 12 hours. The reaction was washed successively with water (100mL), saturated sodium bicarbonate solution (100mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 11a (5.6g, a pale yellow oil) which was reacted without purification.
MS m/z(ESI):248.3[M+1]
Second step of
(S) -4-carbonyl-1, 2,3, 4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11b
Crude tert-butyl (S) -1,2,3, 4-tetrahydronaphthalene-1-carbamate 11a (5.6g, 20.41mmol) was dissolved in 90mL of a mixed solvent of acetone and water (V/V ═ 2:1), magnesium sulfate (5.5g, 45.66mmol) was added, potassium permanganate (7.22g, 45.66mmol) was slowly added with stirring, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using n-hexane and ethyl acetate as eluents to give the title product 11b (3.1g, off-white solid) in yield: 52 percent.
MS m/z(ESI):262.3[M+1]
The third step
(1S,4S) -4-hydroxy-1, 2,3, 4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 14a
(S) -tert-butyl 4-carbonyl-1, 2,3, 4-tetrahydronaphthalene-1-carbamate 11b (100mg, 0.883mmol) was dissolved in 5mL of toluene, cooled to 0 ℃ and (R) -2-methyl-CBS-oxazaborolidine (0.1mL, 0.076mmol) was added and stirred for 5 minutes, borane methyl sulfide (0.88mL, 0.76mmol) was added and stirred for reaction for 2 hours. The reaction was quenched by the addition of 50mL of saturated sodium chloride solution, extracted with ethyl acetate (30mL × 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using dichloromethane and methanol as eluents to give the title product 14a (60mg, white solid) in 60% yield.
MS m/z(ESI):208.3[M-55]
The fourth step
(1S,4S) -4-ethoxy-1, 2,3, 4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 19a
Crude tert-butyl (1S) -4-hydroxy-1, 2,3, 4-tetrahydronaphthalene-1-carbamate 14a (850mg, 3.23mmol), silver oxide (76mg, 0.33mmol) and iodoethane (1.3mL, 16.15mmol) were dissolved in dichloromethane (30mL) and the reaction was stirred for 48 hours. Filtration and concentration of the filtrate under reduced pressure gave the crude title product 19a (800mg, yellow oil) which was reacted without purification.
MS m/z(ESI):236.1[M-55]
The fifth step
(1S,4S) -4-ethoxy-1, 2,3, 4-tetrahydronaphthalen-1-amine 19b
Crude compound 19a (698mg, 2.4mmol) was dissolved in 4mL of dichloromethane, 8mL of 4M 1, 4-dioxane solution of hydrogen chloride was added, and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, slurried with ethyl acetate (30mL), filtered, the cake was dissolved in a mixed solvent of dichloromethane and methanol (20mL, V: V ═ 5:1), the pH of the reaction mixture was adjusted to 7 to 8 with a saturated sodium bicarbonate solution, the reaction mixture was concentrated under reduced pressure, washed with a mixed solvent of dichloromethane and methanol (V: V ═ 5:1) (30mL × 2), filtered, and the filtrate was concentrated under reduced pressure to give a crude title product 19b (310mg, yellow liquid), which was reacted without purification.
MS m/z(ESI):191.1[M+1]
The sixth step
(1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydro
Naphthalene-1-amines 19
(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetaldehyde 5a (500mg, 1.85mmol, prepared by the method disclosed in patent application "WO 2012129495"), crude compound 19b (310mg, 1.85mmol) was dissolved in dichloroethane (30mL), reacted with stirring for 40 minutes, sodium triacetoxyborohydride (980mg, 4.63mmol) was added, and reacted with stirring for 2 hours. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography using dichloromethane and methanol as eluents to give the title product 19(280mg, yellow viscous solid), yield: 35 percent.
The yellow viscous solid was amorphous by XRPD, and the XRPD pattern of the amorphous form is shown in fig. 4.
Example 1
(1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine (100mg) was placed in a reaction flask, ethyl acetate (0.1mL) was added to the flask, and dissolved by rapid heating from 25 ℃ to 50 ℃ and, after a certain period of time, slowly cooled to 5 ℃, filtered, dried, giving a yield of 80%, and the XRPD pattern of the crystalline sample is shown in FIG. 1, the DSC pattern is shown in FIG. 2, the initial melting temperature is 88.67 ℃, the peak is about 90.23 ℃, and the characteristic peak positions are shown in the following table:
TABLE 1 characteristic peaks of form A
Example 2
Putting (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridine-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalene-1-amine (100mg) into a reaction bottle, adding ethanol (0.1mL), rapidly heating from 25 ℃ to 50 ℃ to dissolve the ethanol, keeping for a while, slowly cooling to 25 ℃, if no crystal is precipitated, adding a small amount of seed crystal to induce crystallization, slowly cooling to 5 ℃, filtering and drying, wherein the yield is 70%. The sample is characterized by having characteristic peaks at 6.08, 11.02, 12.01, 12.21, 17.11, 18.38, 18.81, 19.19, 20.94, 22.26, 22.79, 24.61, 27.52 and 37.34 by X-ray powder diffraction, and the product is determined to be A crystal form.
Example 3
(1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine (10mg) was placed in a reaction flask and acetophenone (0.5mL) was added. The reaction flask was placed in a fume hood for evaporation and the solids in the sample flask were collected. The sample is characterized by X-ray powder diffraction to have characteristic peaks at 5.97, 6.07, 11.25, 12.13, 13.16, 16.08, 16.59, 16.84, 17.16, 18.30, 18.80, 19.22, 20.98, 21.65, 21.92, 22.25, 22.84, 23.18, 23.72, 24.53, 25.11, 26.56, 27.49, 27.84, 31.68, 32.21 and 37.28, and the product is determined to be A crystal form.
Example 4
Putting (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridine-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalene-1-amine (100mg) into a reaction bottle, adding acetonitrile (0.1mL), rapidly heating from 25 ℃ to 50 ℃ to dissolve the acetonitrile, keeping for a period of time, slowly cooling to 25 ℃, adding a small amount of seed crystals to induce crystallization if no crystals are precipitated, slowly cooling to 5 ℃, filtering and drying, wherein the yield is 70%. The sample is characterized by X-ray powder diffraction and has characteristic peaks at 6.05, 11.24, 11.89, 12.14, 12.24, 12.98, 13.18, 16.05, 16.79, 17.22, 18.35, 18.85, 19.25, 20.94, 21.58, 21.87, 22.27, 22.76, 22.89, 24.59, 27.51, 27.85, 31.69, 32.31 and 37.32, and the product is determined to be the A crystal form.
Example 5
(1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine (10mg) was placed in a reaction flask, N-hexane (0.1mL) was added, slurried at room temperature for 48 hours, filtered, and dried. And (5) performing X-ray powder diffraction characterization on the sample to determine that the product is in the A crystal form.
Example 6
(1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine (10mg) was placed in a reaction flask, propylene glycol methyl ether (0.5mL) was added, evaporated to dryness at room temperature, and the solid was collected. And (5) performing X-ray powder diffraction characterization on the sample to determine that the product is in the A crystal form.
Example 7 stability study of influence factors of form A
The sample of form A obtained in example 1 was placed open and spread, and the stability of the sample was examined under the conditions of illumination (4500Lux), high temperature (40 ℃, 60 ℃), high humidity (RH 75%, RH 90%), the sampling time was 5 days and 10 days, and the purity results of HPLC were shown in the following table.
And (3) test results:
TABLE 2 high temperature test results
Dash "-" indicates no detection.
TABLE 3 results of high humidity test
Dash "-" indicates no detection.
TABLE 4 results of the light test
Dash "-" indicates no detection.
Conclusion of the experiment
The stability test results in tables 2,3 and 4 show that:
under the open placement conditions of illumination, high humidity and high temperature, the color of the crystal form A is changed when the temperature is higher and the time is longer, and impurities and enantiomer impurities are increased; the longer the illumination time, the more impurities and enantiomeric impurities increase; the crystal form is relatively stable under the high humidity condition; the XRPD detection shows that the crystal form is not changed under the open placement conditions of illumination, high humidity and high temperature, which shows that the A crystal form of the invention has good stability.
Example 8, long term, accelerated stability study of form A
The crystal form A sample obtained in example 1 is placed in a dark place, sealed and flatly placed, the stability of the sample under long-term (25 ℃, 60% RH) and accelerated (40 ℃, 75% RH) is examined, the sampling time is examined to be 0.5 month, 1 month, 2 months and 3 months, and XRPD detects whether the crystal form is transformed.
The experimental results are as follows:
TABLE 5 stability of form A samples (HPLC purity)
And (4) test conclusion:
the crystal form A obtained in the example 1 has good stability after being placed for 3 months under the conditions of light shielding and sealing and long-term (25 ℃, 60% RH) and accelerated (40 ℃, 75% RH), and the XRPD peak pattern of the crystal form A is not changed and the crystal form is stable.
Claims (11)
1. A crystal form of the compound shown in the formula (I) is characterized in that Cu-K α is used for radiation to obtain an X-ray powder diffraction pattern expressed by diffraction angle 2 theta angles, and the diffraction angle 2 theta angles of the X-ray powder diffraction pattern have characteristic peaks at 6.01, 6.09, 11.23, 11.33, 12.14, 12.23, 13.19, 16.86, 17.07, 19.21, 21.00, 22.85, 23.14 and 24.56, wherein the error range of each characteristic peak 2 theta is +/-0.2,
2. the crystalline form a according to claim 1, characterized in that the diffraction angle 2 Θ angle has characteristic peaks at 6.01, 6.09, 11.23, 11.33, 12.14, 12.23, 12.46, 13.19, 16.05, 16.54, 16.86, 17.07, 18.32, 18.83, 19.21, 21.00, 21.63, 21.70, 22.28, 22.85, 23.14, 23.74, 24.56, 26.53, and 31.71, wherein the error range of each characteristic peak 2 Θ is ± 0.2.
3. The crystalline form a according to claim 2, characterized in that the diffraction angle 2 Θ angle has characteristic peaks at 6.01, 6.09, 8.43, 11.23, 11.33, 12.14, 12.23, 12.46, 12.94, 13.19, 16.05, 16.54, 16.86, 17.07, 18.32, 18.83, 19.21, 21.00, 21.63, 21.70, 22.28, 22.85, 23.14, 23.74, 24.56, 25.12, 26.53, 27.50, 27.87, 31.71, 32.23, 37.33 and 40.02, wherein the error range of each characteristic peak 2 Θ is ± 0.2.
4. A process for preparing the crystalline form a of any one of claims 1-3, comprising:
(1) dissolving a compound shown in a formula (I) in a solvent, crystallizing, filtering and drying to obtain a target crystal form A, wherein the solvent is selected from esters, aliphatic hydrocarbons, alcohols, ketones, nitriles or ethers;
(2) adding a compound shown as a formula (I) into a solvent, pulping, filtering and drying to obtain a target crystal form A, wherein the solvent is selected from esters, aliphatic hydrocarbons, nitriles or ethers.
5. The method according to claim 4, wherein the crystallization method is selected from room temperature crystallization, cooling crystallization, volatile crystallization or seeding-induced crystallization.
6. The process according to claim 4, wherein the ester solvent in the process (1) is selected from ethyl acetate, isopropyl acetate or butyl acetate; the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol; the ketone solvent is selected from acetone, acetophenone, methyl isobutyl ketone or methyl pyrrolidone; the aliphatic hydrocarbon solvent is selected from pentane, n-hexane or n-heptane; the nitrile solvent is selected from acetonitrile or propionitrile; the ether solvent is selected from tetrahydrofuran, diethyl ether, propylene glycol methyl ether or methyl tert-butyl ether.
7. The method according to claim 4, wherein the aliphatic hydrocarbon solvent in the method (2) is selected from pentane, n-hexane or n-heptane; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate; the nitrile solvent is selected from acetonitrile or propionitrile; the ether solvent is selected from tetrahydrofuran, diethyl ether, propylene glycol methyl ether or methyl tert-butyl ether.
8. Pharmaceutical composition containing the crystalline form a according to any one of claims 1 to 3, characterized by comprising one or more pharmaceutically acceptable excipients.
9. Use of the crystalline form a according to any one of claims 1 to 3, or the crystalline form a according to claim 8, in the manufacture of a medicament for the treatment of a disease associated with opioid receptor (MOR) agonist mediation.
10. The use according to claim 9, wherein said MOR receptor agonist-mediated related disorder is selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric disorders, urinary and reproductive disorders, cardiovascular disorders and respiratory disorders.
11. The use according to claim 9, wherein said MOR receptor agonist-mediated related disorder is pain.
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| Xiao-Tao Chen et al..Structure-Activity Relationships and Discovery of a G Protein Biased μOpioid Receptor Ligand,[(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine(TRV130),for the Treatment of Acute Severe Pain.《J.Med.Chem.》.2013,第56卷第8019-8031页. * |
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