TWI745764B - Crystalline form of opioid receptor agonist and manufacturing method thereof - Google Patents

Abstract

The present disclosure provides a crystalline form of an opioid receptor (MOR) agonist and a manufacturing method thereof. Specifically, the present disclosure provides a crystalline form II of (1S ,4S )-4-ethoxy-N- (2-((R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl)- 1,2,3,4-tetrahydronaphthalen-1-amine fumarate (a compound of formula (I)) and a manufacturing method thereof. The Crystalline form II of the compound of formula (I) of the present disclosure has good stability and can be better used for clinical treatment.

Description

Crystal form of opioid receptor agonist and preparation method

The present disclosure provides (1 S , 4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9- (Base) ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine fumarate II crystal form and preparation method, application of II crystal form in pharmaceutical composition, and the II crystal form and combination The use of the drug in the preparation of drugs for treating and/or preventing diseases related to opioid receptor (MOR) agonists.

This application claims the priority of the Chinese patent application 201811186669.9 whose filing date is 2018/10/12. This application quotes the full text of the aforementioned Chinese patent application.

Opioid receptors are an important type of G protein coupled receptor (GPCR), which is the target of endogenous opioid peptides and opioid drugs. After the opioid receptors are activated, they can affect the immune system of the nervous system and the endocrine system. Regulating effect, opioids are currently the strongest and commonly used central analgesics. Endogenous opioid peptides are opioid active substances naturally produced in mammals. The currently known endogenous opioid peptides can be roughly divided into enkephalins, endorphins, dynorphins and neoorphins ( Pharmacol Rev 2007 ; 59: 88-123). There are corresponding opioid receptors in the central nervous system, namely μ (MOR), δ (DOR), κ (KOR) receptors and so on. MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.

。Long-term use of opioids can produce side effects such as tolerance, respiratory depression, and constipation, and these side effects have been shown to be closely related to the function of β-arrestin. To reduce the side effects of opioid drugs may be based on negative β-arrestin preference MOR ligand drug design, so that side effects mediated β -arrestin reduced, enhance the therapeutic effect, for the present disclosure oxaspiro derivative In the research as a MOR selective drug, Trevena Inc. found that the aryl benzylic position was less active when substituted ( J. Med. Chem. 2013, 56, 8019-8031), but WO2017063509 found that an aryl benzylic ring was formed. However, it exhibits high activity, significantly improved Emax, significantly improved hERG, and a single-configuration MOR compound. The structure is shown in formula (II):

.

The crystal structure of the active ingredient in medicine often affects the chemical and physical stability of the drug. The difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by other crystal forms. . Generally speaking, amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve various properties of the compound represented by formula (II).

。The present disclosure (The disclosure) to provide a formula (I), the compounds of Form II, X- ray powder diffraction pattern at the diffraction angle 2 θ represents an angle of diffraction angle 2 θ angle 6.07,10.70,13.28,16.22, There are characteristic peaks at 22.02 and 24.43,

.

In some embodiments, the crystalline form II is provided, and the X-ray powder diffraction pattern expressed by the diffraction angle 2 θ is at 6.07, 8.08, 10.7, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, 17.83, There are characteristic peaks at 18.26, 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 29.62 and 31.14.

In some embodiments, the crystalline form II is provided, and the X-ray powder diffraction pattern expressed by the diffraction angle 2 θ is at 6.07, 8.08, 10.7, 12.15, 13.28, 14.45, 15.03, 15.2, 15.5, 16.22, 17.23, There are characteristic peaks at 17.83, 18.26, 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 25.95, 26.75, 27.98, 29.62, 31.14 and 35.60.

In other embodiments, the crystalline form II is provided, and the X-ray powder diffraction pattern represented by the diffraction angle 2 θ is shown in FIG. 1.

The present disclosure also provides a method for preparing the II crystal form, the method is selected from (1) The compound represented by formula (I) is dissolved in solvent (I) and crystallized to obtain crystal form II; the solvent (I) is preferably ether or alcohol solvent, and the ether solvent is preferably ethyl ether. The alcohol solvent is preferably methanol or isopropanol, and the crystallization method is preferably room temperature crystallization, cooling crystallization or adding seed crystals to induce crystallization; The volume (ml) of the solvent (I) in this method is 1-50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times. (2) The compound represented by formula (I) is added to the solvent (II) to be slurried to obtain crystal form II; the solvent (II) is selected from alcohols or ester solvents; the ester solvent is selected from ethyl acetate, Isopropyl acetate or butyl acetate, the alcohol solvent is selected from methanol or isopropanol; The volume (ml) of the solvent (II) in this method is 1-50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times. (3) Dissolve the free state of the compound represented by formula (I) in solvent (III), add fumaric acid, precipitate solids or add seed crystals, and crystallize to obtain the target crystal form II; the solvent (III) is preferably alcohols A solvent or a mixed solvent of ethers and alcohols, the alcohol solvent is preferably methanol or isopropanol, and the mixed solvent of ethers and alcohols is preferably a mixed solvent of ether and methanol; The volume (ml) of the solvent (II) in this method is 1-50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.

On the other hand, in some embodiments, the method for preparing the crystal form in the present disclosure further includes steps such as filtration, washing or drying.

The present disclosure provides a pharmaceutical composition, which is prepared from the aforementioned compound II crystal form of formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients. For example, the II crystal form or pharmaceutical preparations of the compound represented by formula (I) of the present disclosure can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, injections) Use sterile powder and concentrated solution for injection), suppositories, inhalants or sprays. In addition, the pharmaceutical composition described in the present disclosure can also be administered to patients or subjects in need of such treatment in any suitable way of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral mixtures, etc. Suspensions, syrups, etc. When made into oral preparations, the pharmaceutical preparations may also contain suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical preparations can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When made into an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When preparing injections, the pharmaceutical preparations may not be added with additives, or suitable additives may be added according to the nature of the drug. When used for rectal administration, the pharmaceutical preparations can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparations can be made into inhalants or sprays. In certain preferred embodiments, the crystalline form II of the compound represented by formula (I) of the present disclosure is present in the pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the crystalline form II of the compound represented by formula (I) of the present disclosure is present in the pharmaceutical composition or medicine in the form of a unit dose.

The present disclosure also provides a method for preparing a pharmaceutical composition, which includes the step of mixing the foregoing crystal form II or the crystal form II prepared by the foregoing method with a pharmaceutically acceptable carrier, diluent or excipient.

The present disclosure also provides the use of the pharmaceutical composition of crystal form II and crystal form II in the preparation of drugs for treating related diseases mediated by opioid receptor (MOR) agonists.

Related diseases mediated by the MOR receptor agonists of the present disclosure are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.

The present disclosure also provides the use of the pharmaceutical composition of crystal form II and crystal form II of the compound represented by formula (I) in the preparation of drugs for preventing or treating pain and pain-related diseases.

The pain described in the present disclosure is selected from postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, or pain caused by inflammation.

The cancer described in the present disclosure is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.

The present disclosure also provides the use of the pharmaceutical composition of the II crystal form and the II crystal form of the compound represented by formula (I) in the preparation of drugs for agonizing or antagonizing MOR receptors.

In addition, the present application also provides a method for inhibiting diseases associated with opioid receptor (MOR) agonists, which comprises administering to a subject in need thereof a therapeutically and/or preventively effective amount of the formula (I ) The II crystal form of the compound, or the pharmaceutical composition of the present disclosure.

In certain preferred embodiments, the disease is a disease associated with an opioid receptor (MOR) agonist, selected from pain. X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC) were used to determine the structure and the crystal form of the obtained crystalline form of the compound represented by formula (I). The method of recrystallization of the II crystal form is not particularly limited, and it can be carried out by a usual recrystallization operation method. For example, the compound represented by formula (I) can be used as a raw material to dissolve in an organic solvent and then add an anti-solvent to crystallize. After the crystallization is completed, filter and dry to obtain the desired crystal.

The crystallization methods of the present disclosure include volatilization crystallization, room temperature crystallization, cooling crystallization, adding seed crystals to induce crystallization, and the like.

The starting material used in the method for preparing the crystal form of the present disclosure can be any form of the compound represented by formula (I), and the specific form includes, but is not limited to: amorphous, any crystal form, and the like.

Disclosure details

In the specification of this application and the scope of the patent application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, in order to better understand the present disclosure, definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

_{The "C 1-6} alkyl group" mentioned in the present disclosure means a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms. Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, second butyl, tertiary butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl Group, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.

The "hydroxyl group" in the present disclosure refers to groups such as -OH.

The "cyano group" in the present disclosure refers to a group such as -CN.

The "ether solvent" mentioned in the present disclosure refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include, but are not limited to: tetrahydrofuran, diethyl ether, and propylene glycol methyl ether , Methyl tertiary butyl ether or 1,4-dioxane.

The "alcohol solvent" mentioned in the present disclosure refers to a group derived from one or more "hydroxyl groups" substituting one or more hydrogen atoms on the _{"C 1-6 alkyl group". The "hydroxyl group" and "C 1-6 alkyl group" 1-6} alkyl" is as defined above, and specific examples include but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.

The "ester solvent" mentioned in the present disclosure refers to a combination of a lower organic acid containing 1 to 4 carbon atoms and a lower alcohol containing 1 to 6 carbon atoms. Specific examples include but are not limited to: acetic acid Ethyl, isopropyl acetate or butyl acetate.

The "mixed solvent" mentioned in the present disclosure refers to a solvent formed by mixing one or more different types of organic solvents in a certain ratio, or a solvent formed by mixing an organic solvent and water in a certain ratio; the mixed solvent is preferably an alcohol A mixed solvent with ethers; the mixed solvent of alcohols and ethers is preferably a mixed solvent of methanol and ether, and the ratio is preferably 1:10.

The "X-ray powder diffraction pattern" described in this disclosure is measured using Cu-Kα radiation, where λ=1.5418 Å.

The “X-ray powder diffraction pattern or XRPD” mentioned in the present disclosure refers to the Bragg formula 2 d sin θ = nλ (where λ is the wavelength of X-rays, λ=1.5418Å, and the diffraction order n is any positive Integer, generally take the first-order diffraction peak, n=1), when X-rays are incident on the crystal or part of the crystal sample with d lattice plane spacing at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle) On the atomic surface, the Bragg equation can be satisfied, and this set of X-ray powder diffraction patterns can be measured. The "differential scanning calorimetry or DSC" mentioned in the present disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference material during the temperature rise or constant temperature process of the sample to characterize all the physical changes and chemistry related to the thermal effect. Change, get the phase change information of the sample.

The "2 θ or 2 θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, in degrees or degrees, and the error range of 2 θ is ±0.3, which can be -0.30, -0.29, -0.28,- 0.27, -0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11 -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, more preferably ±0.2.

The "interplanar spacing or interplanar spacing (d value)" mentioned in the present disclosure means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect two adjacent lattice points. The matrix is divided into juxtaposed parallelepiped units, called interplanar spacing. The spatial lattice is divided according to the determined parallelepiped unit lines to obtain a set of linear grids, called spatial lattices or lattices. Lattice and lattice use geometric points and lines to reflect the periodicity of the crystal structure. For different crystal planes, the interplanar spacing (that is, the distance between two adjacent parallel crystal planes) is different; the unit is Å Or angstrom.

The drying temperature in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and it can be dried under normal pressure or under reduced pressure. Preferably, drying is dried under reduced pressure.

The beneficial effects of the present disclosure

Compared with the prior art, the technical solution of the present disclosure has the following advantages: Studies have shown that the crystal form II of the compound represented by formula (I) prepared by the present disclosure has good solubility and high purity, and the crystal form has not changed by XRPD detection under the conditions of high temperature, high humidity, and light, and the crystal form is stable. Good performance; the II crystal form of the compound represented by the formula (I) obtained by the technical scheme of the present disclosure can meet the medicinal requirements of production, transportation and storage, the production process is stable, repeatable and controllable, and can be adapted to industrial production.

The present disclosure will be explained in more detail below in conjunction with embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.

Test conditions of the instrument used in the experiment: 1. Differential Scanning Calorimeter (DSC) Instrument model: Mettler Toledo DSC3 ⁺ Stare ^e System Purge gas: Nitrogen (50mL/min) Heating rate: 10.0℃/min Temperature Range: 20-250℃ 2. X-ray Powder Diffraction (XRPD) Instrument model: Rigaku UltimaIV X-ray powder diffractometer Ray: monochromatic Cu-Kα rays (λ=1.5418 Å) Scanning method : Θ /2 θ , scanning range: 3-45 ^o Voltage: 40kV, current: 40mA 3. Thermogravimetric Analysis (TGA) Instrument model: Mettler Toledo TGA2 STAR ^e System Purge gas: Nitrogen heating rate: 10.0 ℃/min Temperature range: 20-250℃ 4. Dynamic Vapour Sorption (DVS) Instrument Model: TAQ5000VSA Temperature: 25℃ Solvent: Water Humidity Change: 0-95-0-95-0%RH, step by step 10%, the judgment criterion is that the quality change within 10000 min is less than 0.01%

Comparative example 1, (1 S , 4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9- (Yl)ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine (amorphous compound 19)

The first step, ( S )-1,2,3,4-tetrahydronaphthalene-1-t-butyl carbamate (11a)

( S )-1,2,3,4-tetrahydro-1-naphthylamine (10a) (3 g, 20.41 mmol, using " Angewandte Chemie-International Edition, 45(28), 4641-4644, 2006" is published Was prepared by the method described above) was dissolved in 100 mL of dichloromethane, triethylamine (5.7 mL, 40.82 mmol) was added, di-tertiary butyl dicarbonate (4.9 g, 22.45 mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was washed sequentially with water (100 mL) and saturated sodium bicarbonate solution (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 11a (5.6 g, pale yellow oil) , The product is directly subjected to the next step without purification.

MS m/z (ESI): 248.3 [M+1].

The second step, ( S )-4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tertiary butyl ester (11b)

The crude ( S )-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester (11a) (5.6 g, 20.41 mmol) was dissolved in 90 mL of acetone and water (V/V = 2: 1) In the mixed solvent, magnesium sulfate (5.5 g, 45.66 mmol) was added, potassium permanganate (7.22 g, 45.66 mmol) 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 obtain the title product 11b (3.1 g, off-white solid), yield: 52%.

MS m/z (ESI): 262.3 [M+1].

The third step, (1 S ,4 S )-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester (14a)

唑硼烷(0.1 ml，0.076 mmol)，攪拌5分鐘，加入硼烷甲基硫醚(0.88 ml，0.76 mmol)，攪拌反應2小時。加入50 ml飽和氯化鈉溶液淬滅反應，用乙酸乙酯萃取(30 mL×3)，合併有機相，有機相用飽和氯化鈉溶液洗滌(30 mL×3)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜法以二氯甲烷和甲醇為洗脫劑純化所得殘餘物，得到標題產物14a (60 mg，白色固體)，產率60%。Dissolve ( S )-4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester (11b) (100 mg, 0.883 mmol) in 5 mL of toluene, and cool to 0°C , Add ( R )-2-methyl-CBS-

Azaboridine (0.1 ml, 0.076 mmol) was stirred for 5 minutes, borane methyl sulfide (0.88 ml, 0.76 mmol) was added, and the reaction was stirred for 2 hours. Add 50 ml saturated sodium chloride solution to quench the reaction, extract with ethyl acetate (30 mL×3), combine the organic phases, wash the organic phase with saturated sodium chloride solution (30 mL×3), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the residue obtained was purified by thin-layer chromatography using dichloromethane and methanol as eluents to obtain the title product 14a (60 mg, white solid) with a yield of 60%.

MS m/z (ESI): 208.3 [M-55].

The fourth step, (1 S ,4 S )-4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester (19a)

The crude product (1 S )-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester (14a) (850 mg, 3.23 mmol), silver oxide (76 mg, 0.33 mmol) ) And iodoethane (1.3 mL, 16.15 mmol) were dissolved in dichloromethane (30 mL), and the reaction was stirred for 48 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title product 19a (800 mg, yellow oil), which was directly subjected to the next reaction without purification.

MS m/z (ESI): 236.1 [M-55].

The fifth step, (1 S ,4 S )-4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-amine (19b)

The crude compound 19a (698 mg, 2.4 mmol) was dissolved in 4 mL of dichloromethane, and 8 mL of 4 M hydrogen chloride in 1,4-dioxane was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, slurried with ethyl acetate (30 mL), filtered, and the filter cake was dissolved in a mixed solvent of dichloromethane and methanol (20 mL, V:V = 5:1) and adjusted with saturated sodium bicarbonate solution The pH of the reaction solution is 7~8, the reaction solution is concentrated under reduced pressure, washed with a mixed solvent of dichloromethane and methanol (V:V=5:1) (30 mL×2), filtered, and the filtrate is concentrated under reduced pressure to obtain the crude title The product 19b (310 mg, yellow liquid), the product was directly subjected to the next step without purification.

MS m/z (ESI): 191.1 [M+1].

The sixth step, (1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9 -Yl)ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine (19)

( R )-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (5a) (500 mg, 1.85 mmol, using patent application "WO2012129495 "Prepared by the published method), the crude compound 19b (310 mg, 1.85 mmol) was dissolved in dichloroethane (30 mL), and the reaction was stirred for 40 minutes. Sodium triacetoxyborohydride (980 mg, 4.63 mmol), the reaction was stirred for 2 hours. Wash the organic phase with saturated sodium bicarbonate solution (30 mL×3) and saturated sodium chloride solution (30 mL×3) successively. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained was purified with methyl chloride and methanol as eluents to obtain the title product 19 (280 mg, yellow viscous solid), yield: 35%.

Comparative Example 2, (1 S , 4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9- (Base) ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine fumarate (I crystal form) preparation

(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Base)-1,2,3,4-tetrahydronaphthalene-1-amine fumarate (50 mg, 0.09 mmol) and tetrahydrofuran (0.5 mL) were added to the reaction flask, heated to a slight boiling, stirred and dissolved. It was naturally cooled to room temperature, and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filter cake was rinsed with ethyl acetate (1 mL×3). The filter cake was collected and dried under vacuum to obtain a solid (25 mg, yield 50%). The XRPD pattern of the crystalline sample is shown in Figure 4, No. 2 The positions of the characteristic peaks of θ are shown in the following table: Table 1. Characteristic peaks of crystal form I

。Example 1, (1 S , 4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9- (Pyryl) ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine fumarate (II crystal form) preparation

.

(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Base)-1,2,3,4-tetrahydronaphthalene-1-amine (88 mg, 0.2 mmol) was dissolved in ether (2.5 mL), fumaric acid (23.2 mg, 0.2 mmol) was dissolved in methanol (0.25 mL) was added dropwise to the above solution. A white solid precipitated during the dropping process, which became clear after stirring. Continue stirring to precipitate a large amount of white solids, and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filter cake was rinsed with ether (2 mL×3). The filter cake was collected and dried in vacuum to obtain a white solid product (70 mg, yield 60%). The XRPD spectrum of the crystalline sample is shown in Figure 1, and its DSC spectrum The graph is shown in Figure 2. The initial melting temperature is 161.45°C, the peak value is about 163.17°C, and the TGA spectrum is shown in Figure 3, indicating that the II crystal form is anhydrous; its characteristic peak positions are shown in the table below.

MS m/z (ESI): 435.5 [M+1].

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 8.43-8.66 (m, 1H), 7.69-7.80 (m, 1H), 7.42-7.52 (m, 1H), 7.28-7.36 (m, 1H), 7.23 (s, 4H), 6.51 (s, 2H), 4.26-4.35 (m, 1H), 3.85-3.97 (m, 1H), 3.60 (m, 3H), 3.39-3.51 (m, 1H), 2.52- 2.61 (m, 1H), 2.30-2.45 (m, 2H), 2.07-2.20 (m, 1H), 1.85-2.07 (m, 3H), 1.20-1.84 (m, 12H), 1.11 (t, 3H), 0.93-1.03 (m, 1H), 0.57-0.72 (m, 1H). Table 2. Characteristic peaks of crystal form II

Example 2

(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Yl)-1,2,3,4-tetrahydronaphthalene-1-amine (176mg, 0.4 mmol) was dissolved in ether (5 mL), fumaric acid (46.4 mg, 0.4 mmol) was dissolved in methanol (0.5 mL) ), it was added dropwise to the above solution, a white solid was precipitated during the dropwise addition, and it became clear after stirring, a large amount of white solid was precipitated after stirring, and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filter cake was rinsed with ether (5 mL×3). The filter cake was collected and dried under vacuum to obtain a white solid product (160 mg, yield 70%). The crystalline sample was confirmed to be crystal form II by XRPD characterization.

Example 3

(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Base)-1,2,3,4-tetrahydronaphthalene-1-amine fumarate (50 mg, 0.09 mmol) and isopropanol (0.5 mL) were added to the reaction flask, and the temperature was raised to 60°C and stirred to clear. It was naturally cooled to room temperature, and the reaction was stirred for 16 hours. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate (1 mL×3), the filter cake was collected and dried in vacuum to obtain a white solid compound (crystal form II) (30 mg, yield 60%), which was confirmed by XRPD characterization II crystal form; DVS characterization, under the condition of 25℃, the water absorption of the sample increases with the increase of humidity between 0%RH~80%RH, and the weight change is 0.033%, which is less than 0.2%. This sample has no or Almost no hygroscopicity; comparing the XRPD spectra before and after the DVS detection, the crystal form of the sample has not changed before and after the DVS measurement; the DVS spectrogram is shown in Figure 5. The X-powder diffraction comparison chart before and after DVS shows that the crystal form before and after DVS has not changed. (See Figure 6).

Example 4

The product of Example 1 (50 mg) was placed in a reaction flask, isopropyl acetate (0.5 mL) was added, and the slurry was beaten at room temperature for 48 hours, filtered and dried. The yield was 62%. The sample was characterized by X-ray powder diffraction, and the product was confirmed to be in crystal form II.

Example 5

The product of Example 1 (50 mg) was placed in a reaction flask, isopropanol (0.5 mL) was added, the slurry was beaten at room temperature for 48 hours, filtered and dried, and the yield was 65%. The sample was characterized by X-ray powder diffraction, and the product was confirmed to be in crystal form II.

Example 6

The product of Example 1 (50 mg) was placed in a reaction flask, isopropanol (0.5 mL) was added, and the slurry was beaten at 40° C. for 48 h, filtered and dried, and the yield was 70%. The sample was characterized by X-ray powder diffraction, and the product was confirmed to be in crystal form II.

Example 7

(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Yl)-1,2,3,4-tetrahydronaphthalene-1-amine (88 mg, 0.2 mmol) was dissolved in isopropanol (2.5 mL), and fumaric acid (23.2 mg, 0.2 mmol) was added to isopropanol (2.5 mL). Alcohol (0.25 mL) was added dropwise to the above solution, heated to 80°C and reacted for 2h, cooled to 40°C without precipitation, continued cooling to 25°C, added seed crystals to precipitate a white solid, filtered, and the filter cake was rinsed with ether ( 5 mL×3), the filter cake was collected and dried in vacuum to obtain a white solid product (68 mg, yield 78.1%). The crystalline sample was confirmed to be crystal form II by XRPD characterization.

Example 8

(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Yl)-1,2,3,4-tetrahydronaphthalene-1-amine (88 mg, 0.2 mmol) was dissolved in isopropanol (2.5 mL), and fumaric acid (23.2 mg, 0.2 mmol) was added to isopropanol (2.5 mL). Add alcohol (0.25 mL) dropwise to the above solution, heat to 80°C for 2h, cool to room temperature to precipitate solids, filter, rinse the filter cake with ether (5 mL×3), collect the filter cake, and dry in vacuo White solid product (67 mg, yield 76.9%), the crystalline sample was confirmed to be crystal form II by XRPD characterization.

Example 9

(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Yl)-1,2,3,4-tetrahydronaphthalene-1-amine (88 mg, 0.2 mmol) was dissolved in isopropanol (2.5 mL), and fumaric acid (23.2 mg, 0.2 mmol) was added to isopropanol (2.5 mL). Alcohol (0.25 mL), add dropwise to the above solution, react at room temperature for 4h, precipitate a solid, filter, rinse the filter cake with ether (5 mL×3), collect the filter cake, and dry in vacuo to obtain a white solid product (65 mg , The yield is 74.6%), the crystalline sample was confirmed to be crystal form II by XRPD characterization.

Example 10

The crystalline form I (50 mg) of the product obtained in Comparative Example 2 was placed in a reaction flask, isopropanol (0.5 mL) was added, and the slurry was beaten at room temperature for 48 h, filtered and dried. The yield was 63%. The sample was characterized by X-ray powder diffraction, and the product was determined to be crystalline form II, which indicated that crystalline form II was more stable than crystalline form I.

The solubility comparison of embodiment 11, II crystal form and the compound represented by formula (II)

Test product: Compound (free state) and II crystal form of formula (II) obtained in Comparative Example 1; Solvent: pure water; experimental method: Solubility test of crystal form II samples: accurately weigh 53.55 mg of the sample into a vial, add 1.5 mL of aqueous solution, add a stir bar, and magnetically stir for 24 hr. After the sample is not completely dissolved, centrifuge at 12000 rpm for 40 min. The supernatant was diluted 1000 times and transferred to HPLC for analysis.

Determination of the solubility of the compound represented by formula (II) (free state): accurately weigh 1.29 mg of the sample into a vial, add 1.0 mL of aqueous solution, add a stir bar, and magnetically stir for 24 hr. The sample is not completely dissolved. Centrifuge at 12000 rpm for 40 min. The clear liquid was transferred to HPLC for analysis.

HPLC chromatographic conditions: fluidity: acetonitrile-0.1%TFA aqueous solution (50:50), detection wavelength 264nm, injection volume 10μL, flow rate 1.0 mL/min.

Test results: Table 3. Comparison of solubility between crystal form II and free state

Test Conclusions: The solubility of crystalline form II in water is better than that of the free state.

Example 12, Investigation of the stability of the influencing factors of crystal form II

The crystalline form II sample obtained in Example 1 was placed in an open flat, and the chemical stability of the sample under the conditions of light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH90%) was investigated. The sampling time is 5 days and 10 days. The chemical purity and chiral purity of the samples are investigated. The purity detected by HPLC is shown in the table below.

Test results: Table 4. Stability of influencing factors of crystal form II samples (HPLC purity)

Test Conclusions: Crystal Form II is left open for 10 days under light and high temperature (40°C, 60°C), the chemical purity and chiral purity are significantly reduced, and it is left open for 10 days under high humidity (RH75%, RH90%) conditions. There is little change in purity and chiral purity; XRPD detects the crystal form II under the conditions of light (4500Lux), high temperature (40℃, 60℃), high humidity (RH75%, RH90%) for 10 days, the crystal form has not changed , Which shows that the stability of the II crystal form is better.

Example 13, Long-term and accelerated stability investigation of the II crystal form

The II crystal form sample obtained in Example 1 was placed flat in the dark and sealed, and the stability of the sample under long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) was investigated, and the sampling time was 0.5 Month, 1 month, 2 months, 3 months, XRPD detects whether the crystal form changes.

Test results: Table 5, Stability of crystal form II samples (HPLC purity)

Test Conclusions: The crystal form II obtained in Example 1 has good stability after long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) storage for 3 months under light-shielded and sealed conditions. At the same time, the XRPD peak of crystal form II The type has not changed, and the crystal type is stable.

without

Fig. 1 is the XRPD pattern of the crystal form of compound II represented by formula (I). Figure 2 is a DSC chart of the crystalline form of compound II represented by formula (I). Fig. 3 is a TGA chart of the crystal form of compound II represented by formula (I). Figure 4 is the XRPD pattern of the crystal form of compound I represented by formula (I). Figure 5 is a DVS spectrum of the crystal form of compound II represented by formula (I). Fig. 6 shows the XRPD patterns of the compound II crystalline form represented by formula (I) before and after DVS (the upper picture is the XRPD picture after the moisture absorption experiment, and the lower picture is the XRPD picture before the moisture absorption experiment).

Claims (12)

A crystalline form II of the compound represented by formula (I), wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.07, 10.70, 13.28, 16.22, 22.02 and 24.43,

Wherein, the 2θ angle error range is ±0.30. The crystal form II according to claim 1, wherein the X-ray powder diffraction pattern expressed by the diffraction angle 2θ angles is 6.07, 8.08, 10.70, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, 17.83, There are characteristic peaks at 18.26, 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 29.62, and 31.14; wherein the error range of the 2θ angle is ±0.30. The II crystal form according to claim 2, wherein the X-ray powder diffraction pattern expressed by the diffraction angle 2θ angle is 6.07, 8.08, 10.70, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, 17.23, There are characteristic peaks at 17.83, 18.26, 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 25.95, 26.75, 27.98, 29.62, 31.14, and 35.60; wherein the 2θ angle error range is ±0.30. The crystal form II according to any one of claims 1 to 3, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Fig. 1; wherein the error range of the 2θ angle is ±0.30. A method for preparing the II crystal form according to any one of claims 1-4, wherein the method is selected from (1) The compound represented by formula (I) is dissolved in solvent (I) and crystallized to obtain crystal form II. The solvent (I) is selected from ethers and alcohol solvents; (2) the formula (I) is It is shown that the compound is added to the solvent (II) to be slurried to obtain crystal form II; the solvent (II) is selected from alcohol or ester solvents; the ester solvent is selected from ethyl acetate, isopropyl acetate or butyl acetate, The alcohol solvent is selected from methanol or isopropanol; or (3) dissolving the free state of the compound represented by formula (I) in solvent (III), adding fumaric acid to precipitate a solid or adding seed crystals, and crystallize to obtain In crystal form II, the solvent (III) is an alcohol solvent or a mixed solvent of ethers and alcohols. The method for preparing crystalline form II according to claim 5, wherein the ether solvent of the solvent (I) is diethyl ether, the alcohol solvent is methanol or isopropanol, and the ether of the solvent (III) The mixed solvent with alcohols is a mixed solvent of ether and methanol. The method for preparing crystalline form II according to claim 5, wherein the crystallization method is room temperature crystallization, cooling crystallization, or adding seed crystals to induce crystallization. A pharmaceutical composition prepared from the crystalline form II described in any one of claims 1-4, and one or more pharmaceutically acceptable carriers, diluents or excipients. A preparation method of a pharmaceutical composition, comprising combining the crystal form II described in any one of claims 1-4 or the crystal form II prepared by the method described in any one of claims 5-7 with a pharmaceutically acceptable The step of mixing carriers, diluents or excipients. A crystalline form II according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 8 in the preparation of a medicine for treating related diseases mediated by opioid receptor (MOR) agonists the use of. The use according to claim 10, wherein the related diseases mediated by the MOR receptor agonist are selected from the group consisting of pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory tract disease. The use according to claim 11, wherein the related disease mediated by the MOR receptor agonist is pain.

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