WO2020073984A1 - Crystal form of opioid receptor (mor) agonist and preparation method thereof - Google Patents

Abstract

A crystal form of an opioid receptor (MOR) agonist and a preparation method thereof. In particular, provided are crystal 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 represented by formula (I)) and a preparation method thereof. The crystal form II of the compound of formula (I) has good crystal stability and can be better used in clinical treatment.

Description

Crystal form and preparation method of opioid receptor (MOR) agonist

This application requires the priority of Chinese patent application 201811186669.9 with an application date of 2018/10/12. This application refers to the entire text of the aforementioned Chinese patent application.

Technical field

The present disclosure provides (1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) Ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine fumarate II crystal form and preparation method, application of the II crystal form in the pharmaceutical composition and the II crystal form, composition in Use in the preparation of a medicament for the treatment and / or prevention of diseases associated with opioid receptor (MOR) agonists.

Background technique

Opioid receptors are an important class of G protein-coupled receptors (GPCRs). They are targets for the binding of endogenous opioid peptides and opioids. After activation, opioid receptors are immune to the nervous system and endocrine system. With regulatory effects, opioids are currently the strongest and most commonly used central analgesics. Endogenous opioid peptides are naturally-occurring opioid-like active substances in mammals, and currently known endogenous opioid peptides are roughly divided into enkephalins, endorphins, dynorphins, and neomorphin (Pharmacol Rev 2007 ; 59: 88-123). There are corresponding opioid receptors in the central nervous system, namely μ (MOR), δ (DOR), and κ (KOR) receptors. MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.

Long-term use of opioids will produce side effects such as tolerance, respiratory depression, and constipation. These side effects have been shown to be closely related to the function of β-arrestin. In order to reduce the side effects of opioids, the drugs can be designed based on the negative β-arrestin preference ligand of MOR to reduce the side effects mediated by β-arrestin and enhance the therapeutic effect. For the oxaspiro derivatives of the present disclosure In the study as a MOR selective drug, Trevena Inc research found that the activity of aryl benzyl substitution is poor (J. Med. Chem. 2013, 56, 8019-8031), but WO2017063509 discovered an aryl benzyl After the ring, it shows high activity, Emax is significantly improved, hERG is significantly improved, and the single-configuration MOR compound has the structure shown in formula (II):

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

Summary of the invention

The disclosure provides an II crystal form of the compound represented by formula (I), an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, whose diffraction angle is 2θ at 6.07, 10.70, 13.28, 16.22, 22.02 And characteristic peaks at 24.43,

Some embodiments provide the II crystal form, the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, at 6.07, 8.08, 10.7, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, 17.83, 18.26 , 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 29.62 and 31.14 have characteristic peaks.

Some embodiments provide the II crystal form, the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, at 6.07, 8.08, 10.7, 12.15, 13.28, 14.45, 15.03, 15.2, 15.5, 16.22, 17.23, 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 have characteristic peaks.

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

The present disclosure also provides a method of preparing the II crystal form, the method selected from

(1) The compound represented by formula (I) is dissolved in a solvent (I) and crystallized to obtain crystal form II; the solvent (I) is preferably an ether type or alcohol type solvent, and the ether type solvent is preferably diethyl 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) used in this method is 1 to 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 obtain the crystal form II by beating; 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 isopropyl alcohol;

The volume (ml) of the solvent (II) used in this method is 1 to 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 the solvent (III), add fumaric acid, precipitate solids or add seed crystals, and crystallize to obtain the target II crystal form; the solvent (III) is preferably an alcohol A solvent or a mixed solvent of ethers and alcohols, the alcoholic solvent is preferably methanol or isopropanol, and the mixed solvent of the ethers and alcohols is preferably a mixed solvent of ether and methanol;

The volume (ml) of the solvent (II) used in this method is 1 to 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 crystalline form of the present disclosure further includes steps such as filtration, washing, or drying.

The present disclosure provides a pharmaceutical composition prepared from the compound II crystal form represented by the aforementioned formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients. For example, the crystalline form II or pharmaceutical preparation 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 powders and concentrated solutions for injection), suppositories, inhalants or sprays. In addition, the pharmaceutical composition of the present disclosure can also be administered to patients or subjects in need of such treatment by any suitable method of administration, such as oral, parenteral, rectal, pulmonary or local 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 Suspension, syrup, etc. When prepared as an oral preparation, the pharmaceutical preparation may further contain suitable fillers, binders, disintegrating agents, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. When prepared as an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When preparing an injection, no additional agent may be added to the pharmaceutical preparation, or an appropriate additional agent may be added according to the nature of the drug. When used for rectal administration, the pharmaceutical preparation 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 drug 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 drug in unit dosage form.

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

The present disclosure also provides the use of the crystalline form II and the crystalline form II pharmaceutical composition in the preparation of a medicament for treating diseases related to opioid receptor (MOR) agonists.

The related diseases mediated by the MOR receptor agonist described in the present disclosure are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.

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

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

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 crystalline form II and the crystalline form II of the compound represented by the formula (I) in the preparation of a medicament for agonizing or antagonizing the MOR receptor.

In addition, the present application also provides a method of inhibiting a disease associated with an opioid receptor (MOR) agonist, which includes administering to a subject in need thereof a therapeutically and / or prophylactically effective amount of the disclosed formula ( I) Form II 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. The X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC) of the obtained compound represented by formula (I) were used for structure determination and crystal form study. The method of recrystallization of the crystal form II is not particularly limited, and can be carried out by a general recrystallization operation method. For example, the compound represented by the raw material formula (I) can be dissolved in an organic solvent and then added to an anti-solvent for crystallization. After the crystallization is completed, the desired crystal can be obtained by filtration and drying.

The crystallization methods of the present disclosure include volatile crystallization, room temperature crystallization, cooling crystallization, and addition of seed crystals to induce crystallization.

The starting material used in the crystalline form preparation method of the present disclosure may be any form of the compound represented by formula (I), and specific forms include but are not limited to: amorphous, any crystalline form, and the like.

Disclosure details

In the description and claims of this application, unless otherwise stated, the scientific and technical terms used herein have the meanings generally 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 interpretations of the terms provided in this application are inconsistent with the meanings generally understood by those skilled in the art, the definitions and interpretations of the terms provided in this application shall prevail.

The "C _1-6 alkyl group" in the present disclosure means a linear or branched alkyl group containing 1-6 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, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.

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

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

The "ether solvent" described 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 tert-butyl ether or 1,4-dioxane.

The "alcoholic solvent" described in the present disclosure refers to a group derived from one or more "hydroxyl groups" in place of one or more hydrogen atoms on the "C _1-6 alkyl group". The "hydroxyl group" and "C _"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" described in the present disclosure 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. Specific examples include but are not limited to: acetic acid Ethyl acetate, isopropyl acetate or butyl acetate.

The "mixed solvent" in the present disclosure refers to a solvent in which one or more different kinds of organic solvents are mixed in a certain ratio, or a solvent in which an organic solvent and water are mixed in a certain ratio; the mixed solvent is preferably A mixed solvent of alcohols and 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. among them,

The “X-ray powder diffraction pattern or XRPD” described in this disclosure refers to the Bragg formula 2d sinθ = nλ (where, λ is the wavelength of X-ray,

The order of diffraction n is any positive integer, generally the first order diffraction peak is taken, n = 1), when X-rays enter the crystal or part of the crystal sample at a grazing angle θ (coincidence of incident angle, also known as Bragg angle) When an atomic plane with a d-lattice plane spacing meets the Bragg equation, the X-ray powder diffraction pattern is measured. The "differential scanning calorimetry or DSC" mentioned in this disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference substance during the sample heating or constant temperature to characterize all physical changes and chemistry related to the thermal effect Change, get the phase change information of the sample.

The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ 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 "crystal plane spacing or crystal plane spacing (d value)" described in this disclosure means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect two adjacent lattice points, and they will point The array is divided into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection to obtain a set of straight-line grids, called space grids or lattices. The lattice and lattice reflect the periodicity of the crystal structure with geometric dots and lines, respectively. Different crystal planes have different surface spacings (ie, the distance between two adjacent parallel crystal planes); the unit is

Or Egypt.

The drying temperature in the present disclosure is generally 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C, and can be dried under normal pressure or under reduced pressure. Preferably, the drying is done 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 compound of formula (I) prepared by the present disclosure has good solubility and high purity of the crystal form II, and the crystal form has not been changed by XRPD detection and the crystal form is stable under the conditions of high temperature, high humidity and light. The crystalline form II of the compound represented by the formula (I) obtained by the technical scheme of the present disclosure can meet the pharmaceutical requirements for production, transportation and storage. The production process is stable, repeatable and controllable, and can be adapted to industrial production.

BRIEF DESCRIPTION

Fig. 1 is an XRPD pattern of the compound II crystal form represented by formula (I).

Fig. 2 is a DSC chart of the crystal form of Compound II represented by formula (I).

FIG. 3 is a TGA pattern of the crystal form of compound II represented by formula (I).

FIG. 4 is an XRPD pattern of the crystal form of Compound I represented by formula (I).

FIG. 5 is a DVS pattern of the crystal form of Compound II represented by formula (I).

FIG. 6 is a XRPD pattern before and after DVS of the compound II crystal form of formula (I) (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).

detailed description

The present disclosure will be explained in more detail in conjunction with embodiments below. 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 spectrum (X-ray Powder Diffraction, XRPD)

Instrument model: Rigaku Ultima IV X-ray powder diffractometer

Ray: Monochrome Cu-Kα Ray

Scanning method: θ / 2θ, scanning range: 3-45 °

Voltage: 40kV, current: 40mA

3. Thermogravimetric Analysis (TGA)

Instrument model: Mettler Toledo TGA2STAR ^e System

Purge gas: nitrogen

Heating rate: 10.0 ℃ / min

Temperature range: 20-250 ℃

4. Dynamic Vapor Sorption (DVS)

Instrument model: TAQ5000VSA

Temperature: 25 ℃

Solvent: water

Humidity change: 0-95-0-95-0% RH, the step is 10%, the judgment standard is that the quality change within 10000min is less than 0.01%

Comparative Example 1 (1S, 4S) -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)

first step

(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), 4641-4644, 2006" (Acquired) was dissolved in 100 mL of dichloromethane, triethylamine (5.7 mL, 40.82 mmol) was added, di-tert-butyl dicarbonate (4.9 g, 22.45 mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was washed successively with water (100 mL), 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, light yellow oil), product The next step was carried out without purification.

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

Second step

(S) -4-Carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11b

Dissolve crude (S) -1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11a (5.6 g, 20.41 mmol) in 90 mL of acetone and water (V / V = 2: 1) mixed solvent In it, 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 obtain the title product 11b (3.1 g, off-white solid), yield: 52%.

MS “m / z (ESI): 262.3 [M + 1]

third step

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

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, cool to 0 ° C, and add (R) -2-Methyl-CBS-oxazolylborane (0.1 ml, 0.076 mmol), stirred for 5 minutes, added borane methyl sulfide (0.88 ml, 0.76 mmol), and stirred to react for 2 hours. The reaction was quenched by adding 50 ml of saturated sodium chloride solution, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined. The organic phase was washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using dichloromethane and methanol as eluents to obtain the title product 14a (60 mg, 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

The crude (1S) -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) was 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). The product was directly subjected to the next step without purification.

MS “m / z (ESI): 236.1 [M-55]

the fifth step

(1S, 4S) -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, 8 mL of 4M 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 the reaction solution was adjusted with saturated sodium bicarbonate solution The pH 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 product 19b ( 310 mg, yellow liquid), the product was directly subjected to the next reaction 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] 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 (500mg, 1.85mmol, using the patent application "WO2012129495" published (Prepared by the method), the crude compound 19b (310mg, 1.85mmol) was dissolved in dichloroethane (30mL), the reaction was stirred for 40 minutes, sodium triacetoxyborohydride (980mg, 4.63mmol) was added, and the reaction was stirred for 2 hours . It was sequentially washed with saturated sodium bicarbonate solution (30 mL × 3), washed with saturated sodium chloride solution (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using thin layer chromatography with dichloromethane The resulting residue was purified using methane and methanol as eluents to obtain the title product 19 (280 mg, yellow sticky solid), yield: 35%.

Comparative example 2.

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl)- Preparation of 1,2,3,4-tetrahydronaphthalene-1-amine fumarate (Form I)

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl) -1,2,3,4-Tetrahydronaphthalene-1-amine fumarate (50 mg, 0.09 mmol) and tetrahydrofuran (0.5 mL) were added to the reaction flask, and the temperature was raised to slightly boiling and stirred to dissolve. 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 in vacuo to obtain a solid (25 mg, yield 50%). The XRPD pattern of the crystalline sample is shown in FIG. 4 and its 2θ characteristic peak The location is shown in the table below:

Table 1. I-shaped characteristic peaks

Example 1

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

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine (88mg, 0.2mmol) was dissolved in ether (2.5mL), fumaric acid (23.2mg, 0.2mmol) was dissolved in methanol (0.25mL) , Dropwise added to the above solution, white solid precipitated during the dropwise addition, cleared after stirring, continued stirring to precipitate a large amount of white solid, and stirred to react for 16 hours. The reaction solution was filtered, and the filter cake was rinsed with ether (2mL × 3). The filter cake was collected and dried in vacuo to give a white solid product (70mg, yield 60%). The XRPD pattern of the crystal sample is shown in Figure 1, and the DSC spectrum is shown in Figure 2, the initial melting temperature is 161.45 ℃, the peak value is about 163.17 ℃, the TGA spectrum is shown in Figure 3, indicating that the crystal form II is anhydrous; its characteristic peak position is shown in the following table:

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

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine (176mg, 0.4mmol) was dissolved in ether (5mL), fumaric acid (46.4mg, 0.4mmol) was dissolved in methanol (0.5mL), It was added dropwise to the above solution, and a white solid precipitated during the dropwise addition. It was clarified after stirring, and a large amount of white solid was precipitated by continuing 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 in vacuo to obtain a white solid product (160 mg, yield 70%). The crystal sample was confirmed to be Form II by XRPD characterization.

Example 3

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl) -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 dissolve. 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 in vacuo to obtain a white solid compound (crystal form II) (30 mg, yield 60%), which was confirmed to be crystal II by XRPD characterization. type;

DVS characterization, under 25 ℃ condition, the water absorption also increases with the increase of humidity between 0% RH and 80% RH, the weight change is 0.033%, less than 0.2%, the sample has no or almost no moisture ; Compare the XRPD spectrum before and after DVS detection, the sample did not change the crystal form before and after DVS determination;

The DVS spectrum is shown in Figure 5, and the X-powder diffraction comparison chart before and after DVS shows that the crystal form has not changed before and after DVS (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, pulped at room temperature for 48 h, filtered and dried, and the yield was 62%. The sample was characterized by X-ray powder diffraction, and the product was determined to be the II crystal form.

Example 5

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

Example 6

The product of Example 1 (50 mg) was placed in a reaction bottle, 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 determined to be the II crystal form.

Example 7

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine (88mg, 0.2mmol) was dissolved in isopropanol (2.5mL), fumaric acid (23.2mg, 0.2mmol) was added to isopropanol (0.25 mL), added dropwise to the above solution, heated to 80 ℃ for 2h, cooled to 40 ℃ without precipitation, continue to cool to 25 ℃, add a seed crystal to precipitate a white solid, filter, rinse the filter cake with ether (5mL × 3 ), The filter cake was collected and dried in vacuo to give a white solid product (68 mg, yield 78.1%). The crystal sample was confirmed to be Form II by XRPD characterization.

Example 8

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine (88mg, 0.2mmol) was dissolved in isopropanol (2.5mL), fumaric acid (23.2mg, 0.2mmol) was added to isopropanol (0.25 mL), added dropwise to the above solution, heated to 80 ℃ for 2h, cooled to room temperature to precipitate solid, filtered, the filter cake was rinsed with ether (5mL × 3), the filter cake was collected, and dried in vacuo to give a white solid product (67mg , Yield 76.9%), the crystalline sample confirmed by XRPD characterization of the II crystal form.

Example 9

(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine (88mg, 0.2mmol) was dissolved in isopropanol (2.5mL), fumaric acid (23.2mg, 0.2mmol) was added to isopropanol (0.25 mL), added dropwise to the above solution, reacted at room temperature for 4h, precipitated a solid, filtered, the filter cake was rinsed with ether (5mL × 3), the filter cake was collected and dried in vacuo to give a white solid product (65mg, yield 74.6%) The X-ray crystallographic sample was confirmed to be Form II by XRPD characterization.

Example 10

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

Example 11. Comparison of the solubility of the crystal form II and the compound represented by formula (II)

Test product: Compound (free state), crystal form II of formula (II) obtained in Comparative Example 1;

Solvent: pure water;

experimental method:

Solubility test of crystal form II sample: Weigh 53.55mg of the sample in a vial, add 1.5mL of aqueous solution, add a stirrer, and after magnetic stirring for 24hr, the sample is not completely dissolved and centrifuge at 12000rpm for 40min. The supernatant was diluted 1000-fold and transferred to HPLC analysis.

Solubility detection of the compound (free state) shown in formula (II): Weigh 1.29 mg of the sample in a vial, add 1.0 mL of aqueous solution, add a stirrer, and stir the sample magnetically for 24 hr. The sample is not completely dissolved. Centrifuge at 12000 rpm for 40 min. The liquid was transferred to HPLC analysis.

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

test results:

Table 3. Comparison of solubility of crystal form II and free state

Test Conclusions:

The solubility of crystal form II in water is better than that in the free state.

Example 12, the stability of factors affecting the II crystal form

Place the sample of Form II obtained in Example 1 flat and open to investigate the chemical stability of the sample under the conditions of light (4500 Lux), high temperature (40 ° C, 60 ° C), and high humidity (RH75%, RH90%). Sampling time is 5 days, 10 days, check the chemical purity and chiral purity of the sample, HPLC detection purity is shown in the table below.

test results:

Table 4. Factors affecting the crystal form II stability (HPLC purity)

Test Conclusions:

The crystal form II is exposed to light and high temperature (40 ° C, 60 ° C) for 10 days, and the chemical purity and chiral purity decrease significantly. When exposed to high humidity (RH75%, RH90%) for 10 days, the chemical The purity and chiral purity changes little; XRPD detection II crystal form is placed for 10 days under the conditions of light (4500 Lux), high temperature (40 ° C, 60 ° C), high humidity (RH75%, RH90%), and the crystal form has not changed , Indicating that the II crystal form has better stability.

Example 13, the long-term, accelerated stability of the II crystal form

The sample of Form II obtained in Example 1 was protected from light and placed in a sealed flat position, and the stability of the sample under long-term (25 ° C, 60% RH) and acceleration (40 ° C, 75% RH) was investigated. The sampling time was 0.5 Months, 1 months, 2 months, 3 months, XRPD detects whether the crystal form has changed.

test results:

Table 5. Stability of crystalline sample II (HPLC purity)

Test Conclusions:

The II crystal form obtained in Example 1 has good stability under long-term (25 ° C, 60% RH) and accelerated (40 ° C, 75% RH) storage for 3 months under the condition of light shielding and sealing, and the XRPD peak of the II crystal form The type has not changed, and the crystal form is stable.

Claims (10)

1. A crystal form II of a compound represented by formula (I), characterized by an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, having characteristic peaks at 6.07, 10.70, 13.28, 16.22, 22.02, and 24.43,

   
2. The crystal form II according to claim 1, wherein the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ is 6.07, 8.08, 10.70, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, There are characteristic peaks at 17.83, 18.26, 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 29.62 and 31.14.
3. The II crystal form according to claim 2, characterized in that the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ is 6.07, 8.08, 10.70, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, There are characteristic peaks at 17.23, 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.
4. The crystal form II according to at least one of claims 1 to 3, characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Fig. 1.
5. The II crystal form according to at least one of claims 1 to 4, characterized in that the 2θ angle error range is ± 0.30.
6. A method for preparing the crystal form II according to at least one of claims 1-5, characterized in that the method is selected from

   (1) The compound represented by formula (I) is dissolved in a solvent (I) and crystallized to obtain crystal form II; the solvent (I) is preferably an ether type or alcohol type solvent, and the ether type solvent is preferably diethyl 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;

   (2) The compound represented by formula (I) is added to the solvent (II) to obtain the crystal form II by beating; 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 isopropyl alcohol;

   (3) Dissolve the free state of the compound represented by formula (I) in the solvent (III), add fumaric acid, precipitate solids or add seed crystals, and crystallize to obtain the target II crystal form; the solvent (III) is preferably an alcohol A solvent or a mixed solvent of ethers and alcohols, the alcoholic solvent is preferably methanol or isopropanol, and the mixed solvent of the ethers and alcohols is preferably a mixed solvent of ether and methanol.
7. A pharmaceutical composition is prepared from the crystal form II according to at least one of claims 1 to 5, and one or more pharmaceutically acceptable carriers, diluents or excipients.
8. A method for preparing a pharmaceutical composition, comprising combining the crystalline form II of at least one of claims 1-5 or the crystalline form II prepared by the method of claim 6 with a pharmaceutically acceptable carrier, diluent or excipient The step of mixing agent.
9. A pharmaceutical composition according to at least one of claims 1 to 5 or the pharmaceutical composition according to claim 7 in preparation for treatment and opioid receptor (MOR) agonist-mediated Use in medicine for related diseases.
10. The use according to claim 9, wherein the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory tract Disease, preferably pain.

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