CN115181109A

CN115181109A - Crystal of morphinan derivative and method for producing same

Info

Publication number: CN115181109A
Application number: CN202110358891.8A
Authority: CN
Inventors: 申建伟; 石建超; 吴晶; 郑礼康; 方宇; 许悦; 李宗栋; 万国盛; 柴雨柱; 王华萍; 徐丹; 朱春霞
Original assignee: Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
Current assignee: Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
Priority date: 2021-04-02
Filing date: 2021-04-02
Publication date: 2022-10-14

Abstract

The present invention relates to crystals of morphinan derivatives and a method for producing the same. Wherein form I of the morphinan derivative has diffraction peaks at least at 7.28 + -0.2 °, 11.88 + -0.2 °, 15.57 + -0.2 °, 17.21 + -0.2 ° and 21.11 + -0.2 ° in an XRPD pattern expressed in terms of 2 θ angles; form III of the morphinan derivative has diffraction peaks at least at 9.75 ± 0.2 °, 11.54 ± 0.2 °, 14.93 ± 0.2 °, 15.14 ± 0.2 °, and 20.97 ± 0.2 ° in an XRPD pattern expressed in degrees 2 Θ. The crystal form provided by the invention has excellent stability and good solubility, and the residual amount of the solvent is low, so that the qualified range can be reached.

Description

Crystal of morphinan derivative and method for producing same

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a crystal of a morphinan derivative and a preparation method thereof.

Background

Generally, a compound having a polymorphic form sometimes has different physical properties between different crystals. In particular, in the field of medicine, there are differences in solubility, dissolution rate, stability, and absorption. Therefore, even if the same compound is used, the potency varies depending on the crystal form. Therefore, when a compound having a polymorphic form is used as a pharmaceutical, it is necessary to stably provide a compound having a uniform crystalline form to ensure uniform quality and stable efficacy thereof.

17- (cyclopropylmethyl) -3,14 beta-dihydroxy-4,5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) acrylamido ] morphinan hydrochloride (shown in formula I) has been demonstrated to be an effective active ingredient in analgesic, diuretic and antipruritic agents. The prior art CN101155814B discloses that the morphinan derivative has three crystal forms of a type, B type and C type.

In order to optimize the physical properties of the morphinan derivatives, the present invention provides crystalline forms of novel morphinan derivatives and methods for their preparation.

Disclosure of Invention

In one aspect, the invention relates to the crystal structure of the compound of formula I:

in some embodiments, there is provided crystalline form I of the compound of formula I having characteristic peaks, in an X-ray powder diffraction pattern expressed in degrees 2 Θ, at 2 Θ values of 7.28 ± 0.2 °, 11.88 ± 0.2 °, 15.57 ± 0.2 °, 17.21 ± 0.2 °, and 21.11 ± 0.2 °, using Cu-Ka radiation.

In some embodiments, the form I, in an X-ray powder diffraction pattern expressed in degrees 2 Θ, has characteristic peaks at 2 Θ values of 7.28 ± 0.2 °, 10.60 ± 0.2 °, 11.88 ± 0.2 °, 14.57 ± 0.2 °, 15.57 ± 0.2 °, 17.21 ± 0.2 °, 18.21 ± 0.2 °, 21.11 ± 0.2 °, and 22.23 ± 0.2 °.

In some embodiments, the crystalline form I, in an X-ray powder diffraction pattern expressed in degrees 2 Θ, has characteristic peaks at 2 Θ values of 7.28 ± 0.2 °, 9.71 ± 0.2 °, 10.32 ± 0.2 °, 10.60 ± 0.2 °, 11.12 ± 0.2 °, 11.67 ± 0.2 °, 11.88 ± 0.2 °, 14.57 ± 0.2 °, 14.98 ± 0.2 °, 15.57 ± 0.2 °, 17.21 ± 0.2 °, 18.21 ± 0.2 °, 21.11 ± 0.2 ° and 22.23 ± 0.2 °.

In some embodiments, the crystalline form I, in an X-ray powder diffraction pattern expressed in terms of 2 Θ angles, has characteristic peaks at 2 Θ values of 7.28 ± 0.2 °, 9.11 ± 0.2 °, 9.71 ± 0.2 °, 10.32 ± 0.2 °, 10.60 ± 0.2 °, 11.12 ± 0.2 °, 11.67 ± 0.2 °, 11.88 ± 0.2 °, 14.18 ± 0.2 °, 14.57 ± 0.2 °, 14.98 ± 0.2 °, 15.57 ± 0.2 °, 17.21 ± 0.2 °, 18.21 ± 0.2 °, 19.68 ± 0.2 °, 20.39 ± 0.2 °, 20.72 ± 0.2 °, 21.11 ± 0.2 °, 21.46 ± 0.2 °, 21.90 ± 0.2 °, 22.23 ± 0.2 °, 23.44 ± 0.2 °, 23.79 ± 0.25.59.25 ± 0.2 °, and 29.25 ± 0.2 °.

In some embodiments, the compound of formula I is crystalline form I having X-ray powder diffraction pattern analysis data as shown in table 1:

TABLE 1 analytical data for X-ray powder diffraction pattern of crystalline form I of the compound of formula I

Numbering	Angle of diffraction 2 theta	Relative strength	Number of	Angle of diffraction 2 theta	Relative strength
						1	7.28°	100.00％	27	24.15°	6.20％
2	9.11°	7.50％	28	25.05°	9.70％
						3	9.71°	15.40％	29	25.59°	12.10％
4	10.32°	16.50％	30	25.90°	8.60％
						5	10.60°	29.20％	31	26.31°	3.30％
6	11.12°	20.20％	32	26.72°	3.00％
						7	11.67°	21.40％	33	27.15°	3.00％
8	11.88°	32.10％	34	28.09°	4.70％
						9	13.32°	2.90％	35	28.52°	1.00％
10	14.18°	6.20％	36	29.02°	3.60％
						11	14.57°	29.90％	37	29.40°	8.10％
12	14.99°	19.50％	38	29.80°	2.10％
						13	15.57°	48.60％	39	30.22°	2.90％
14	17.21°	75.90％	40	30.51°	1.80％
						15	18.21°	29.00％	41	30.87°	2.80％
16	18.69°	1.30％	42	31.35°	3.90％
						17	19.50°	3.80％	43	32.19°	1.60％
18	19.68°	6.70％	44	32.62°	3.60％
						19	20.39°	10.20％	45	33.75°	1.20％
20	20.72°	6.10％	46	34.40°	1.90％
						21	21.11°	42.50％	47	34.90°	1.20％
22	21.46°	7.10％	48	35.68°	1.30％
						23	21.90°	13.40％	49	36.15°	1.90％
24	22.23°	24.90％	50	37.37°	1.60％
						25	23.45°	12.30％	51	38.47°	4.00％
26	23.79°	15.30％	52	39.62°	0.50％

。

In some embodiments, the crystalline form I has an X-ray powder diffraction pattern, expressed in degrees 2 Θ, as shown in figure 1, i.e., having the characteristics represented by the XRPD pattern shown in figure 1.

In some embodiments, the crystalline form I has 3 endothermic peaks at peak temperatures of 68.4 ± 5 ℃, 94.9 ± 5 ℃ and 215.5 ± 5 ℃ in a thermogram measured by differential scanning calorimetry; in some typical embodiments, the crystalline form I has 3 endothermic peaks at peak temperatures of 68.4 ± 3 ℃, 94.9 ± 3 ℃ and 215.5 ± 3 ℃ in a thermogram measured by differential scanning calorimetry.

In some typical embodiments, the form I has a DSC profile as shown in figure 2, i.e., has the characteristics represented by the DSC profile as shown in figure 2.

In some embodiments, the thermogravimetric analysis curve of form I has a weight loss of 4.1 ± 0.2% at 175 ± 3 ℃.

In some typical embodiments, the crystalline form I has a TGA profile as shown in figure 3, i.e., has the characteristics represented by the TGA profile shown in figure 3.

In some embodiments, there is provided crystalline form III of the compound of formula I having characteristic peaks in an X-ray powder diffraction pattern expressed in 2 Θ angles at 2 Θ values of 9.75 ± 0.2 °, 11.54 ± 0.2 °, 14.93 ± 0.2 °, 15.14 ± 0.2 ° and 20.97 ± 0.2 ° using Cu-Ka radiation.

In some embodiments, the crystalline form III, has characteristic peaks in an X-ray powder diffraction pattern expressed in degrees 2 Θ at 2 Θ of 7.54 ± 0.2 °, 9.40 ± 0.2 °, 9.75 ± 0.2 °, 11.54 ± 0.2 °, 14.93 ± 0.2 °, 15.14 ± 0.2 °, 18.39 ± 0.2 °, 20.97 ± 0.2 ° and 26.27 ± 0.2 °.

In some embodiments, the crystalline form III, in an X-ray powder diffraction pattern expressed in degrees 2 Θ, has characteristic peaks at 2 Θ values of 7.54 ± 0.2 °, 9.40 ± 0.2 °, 9.75 ± 0.2 °, 11.54 ± 0.2 °, 12.06 ± 0.2 °, 14.93 ± 0.2 °, 15.14 ± 0.2 °, 18.39 ± 0.2 °, 18.68 ± 0.2 °, 19.81 ± 0.2 °, 20.97 ± 0.2 °, 22.11 ± 0.2 °, 22.59 ± 0.2 ° and 26.27 ± 0.2 °.

In some embodiments, the crystalline form III, has a characteristic peak at a 2 Θ value of 7.54 ± 0.2 °, 9.40 ± 0.2 °, 9.75 ± 0.2 °, 11.05 ± 0.2 °, 11.54 ± 0.2 °, 12.06 ± 0.2 °, 14.93 ± 0.2 °, 15.14 ± 0.2 °, 15.70 ± 0.2 °, 18.39 ± 0.2 °, 18.68 ± 0.2 °, 19.81 ± 0.2 °, 20.97 ± 0.2 °, 21.31 ± 0.2 °, 22.11 ± 0.2 °, 22.59 ± 0.2 °, 24.29 ± 0.2 °, 24.70 ± 0.2 °, and 26.27 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 Θ angle.

In some embodiments, the compound of formula I is in crystalline form III having X-ray powder diffraction pattern analysis data as shown in table 2:

TABLE 2X-ray powder diffraction Pattern analysis data for form III of the Compound of formula I

。

In some embodiments, the crystalline form III has an X-ray powder diffraction pattern, expressed in degrees 2 Θ, as represented by the pattern shown in figure 4, i.e., having the characteristics represented by the XRPD pattern shown in figure 4.

In some embodiments, the form III has an exothermic peak at an onset temperature of 231.95 ± 5 ℃ in a thermogram measured by differential scanning calorimetry; in some exemplary embodiments, the crystalline form III has an exothermic peak at an onset temperature of 231.95 ± 3 ℃ in a thermogram measured by differential scanning calorimetry.

In some typical embodiments, the crystalline form III has a DSC profile as shown in figure 5, i.e. has the characteristics represented by the DSC profile as shown in figure 5.

In some typical embodiments, the crystalline form III has a TGA profile as shown in figure 6, i.e., has the characteristics represented by the TGA profile as shown in figure 6.

In another aspect, the invention provides the use of said form I or form III for the preparation of a medicament for the analgesia, diuresis and antipruritic.

In another aspect, the present invention also provides a preparation method of the crystalline form III, which comprises the following steps:

(1) Adding the compound of the formula I into a solvent A in an amorphous mode, wherein the solvent A is selected from one or two of methanol, ethanol, ethyl acetate, tetrahydrofuran, toluene or dichloromethane, and preferably is methanol, ethanol or a mixture of the two;

(2) Heating and pulping;

(3) Slowly cooling, stirring and crystallizing;

(4) And carrying out suction filtration and drying to obtain the crystal form III.

In some embodiments, the volume to mass ratio of the group a solvent to the compound of formula I is from 10 to 15ml/g; preferably 11 to 14ml/g.

In some embodiments, the temperature for warming and beating in the step (2) is 50-80 ℃; in some typical embodiments, the temperature for heating and beating in the step (2) is 50-70 ℃; in some more typical embodiments, the temperature for the warming and beating in the step (2) is 55-60 ℃.

In some embodiments, the time of beating in step (2) is from 1 to 5 hours; in some typical embodiments, the time of beating in step (2) is from 1 to 2 hours; in some more typical embodiments, the time of beating in step (2) is 1h.

In some embodiments, the slow cooling stirring crystallization in the step (3) is that the temperature is reduced to-5-30 ℃; in some typical embodiments, the slow cooling stirring crystallization in the step (3) is that the temperature is reduced to 0-25 ℃; in some more typical embodiments, the slow cooling stirring crystallization in the step (3) is that the temperature is reduced to 0-10 ℃.

In some embodiments, the crystallization time of the slow cooling stirring crystallization in the step (3) is 1-10 h; in some typical embodiments, the crystallization time of the slow cooling stirring crystallization in the step (3) is 1-6 h; in some more typical embodiments, the crystallization time of the slow cooling stirring crystallization in the step (3) is 1-2 h.

(a) Adding the compound of the formula I into a C-type solvent in an amorphous mode, wherein the C-type solvent is one or a combination of two of methanol, ethanol, ethyl acetate, tetrahydrofuran, toluene and dichloromethane; preferably methanol, ethanol or a mixture of the two; more preferably methanol;

(b) Heating to dissolve, and filtering to obtain a clear solution;

(c) Cooling to room temperature, adding D-type solvent under stirring, and stirring while maintaining the temperature after dropwise adding, wherein the D-type solvent is one or two selected from n-propanol, isopropanol or n-butanol; preferably isopropanol;

(d) And carrying out suction filtration and drying to obtain the crystal form III.

In some embodiments, the volume to mass ratio of the group C solvent to the compound of formula I is from 5 to 10ml/g; preferably 5 to 6ml/g.

In some embodiments, the volume ratio of group C solvent to group D solvent is 1:1-5, preferably 1:1-3; further preferably 1:3.

In some embodiments, the stirring time after the dropwise addition in the step (c) is 12-36 h; in some typical embodiments, the stirring time at the constant temperature after the dropwise addition in the step (c) is 12 to 24 hours; in some more typical embodiments, the stirring is maintained for 24 hours after the completion of the dropwise addition in step (c).

The invention has the beneficial effects that:

the invention discloses a crystal form I and a crystal form III of a compound shown in a formula I, which have excellent stability, good solubility and low solvent residue and can reach a qualified range.

Correlation definition

Unless specifically stated otherwise, the following terms used in the specification and claims have the following meanings:

herein, "XRPD" refers to X-ray powder diffraction;

in the present invention, "DSC" refers to differential scanning calorimetry;

in the present invention, "TGA" refers to thermogravimetric analysis;

in the present invention, "h" means hour, "min" means minute, "ml" means milliliter, "μ l" means microliter;

in the present invention, "room temperature" means 25 ℃;

in the present invention, "suction filtration" refers to filtration under reduced pressure.

The "X-ray powder diffraction pattern" in the present invention is measured using Cu-Ka radiation.

In the invention, "2 theta" or "2 theta angle" refers to diffraction angle, theta is Bragg angle, and the unit is degree or degree; the error range of each characteristic peak 2 θ is ± 0.20 °.

It is noted that in X-ray powder diffraction spectroscopy (XRPD), the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal aimed at. To determine if it is simultaneous with the known crystalline phase, more attention should be paid to the relative positions of the peaks rather than their relative intensities. In addition, there may be slight errors in the position of the peaks for any given crystal, which are also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, movement of the sample, calibration of the instrument, or the like, and the error in measurement of the 2 θ value is sometimes about ± 0.2 °. Therefore, this error should be taken into account when determining each crystalline structure. The peak position is usually expressed in the XRPD pattern as 2 θ angle or crystal plane distance d, with a simple conversion between the two: d = λ/2sin θ, where d represents the interplanar spacing, λ represents the wavelength of the incident X-rays, and θ is the diffraction angle. For the same crystal of the same compound, the peak positions of the XRPD spectra have similarity as a whole, and the relative intensity error may be large. It should also be noted that in the identification of mixtures, the loss of part of the diffraction lines may be due to, for example, a reduction in the content, in which case it is not necessary to rely on all the bands observed in the high-purity sample, even one band may be characteristic for a given crystal.

Differential Scanning Calorimetry (DSC) measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystal form of the same compound, the thermal transition temperature and melting point errors are typically within about 5 c, usually within about 3 c in successive analyses. When a compound is described as having a given DSC peak or melting point, that DSC peak or melting point is referred to as ± 5 ℃. DSC provides an auxiliary method to distinguish different crystal forms. Different crystal morphologies can be identified by their different transition temperature characteristics. It is noted that the DSC peak or melting point for a mixture may fluctuate over a larger range. Furthermore, the melting temperature is related to the rate of temperature rise due to decomposition that accompanies the process of melting the substance.

Thermogravimetric analysis (TGA) refers to a thermal analysis technique that measures the relationship between the mass of a sample to be measured and the change in temperature at a programmed temperature. When the substance to be measured is sublimated or vaporized in the heating process, the substance to be measured is decomposed into gas or loses crystal water, so that the mass of the substance to be measured is changed. In this case, the thermogravimetric curve is not a straight line but is decreased. By analyzing the thermogravimetric curve, the change of the measured substance at which temperature can be known, and the amount of the substance lost can be calculated according to the weight loss.

In referring to, for example, an XRPD pattern, DSC pattern, or TGA pattern, the term "as indicated by … …" includes patterns that are not necessarily identical to those delineated herein, but fall within the limits of experimental error when considered by those of skill in the art.

Drawings

FIG. 1 XRPD pattern of crystalline form I of compound of formula I

FIG. 2 DSC curve of form I of Compound I

FIG. 3 TGA Curve of crystalline form I of the Compound of formula I

FIG. 4 XRPD pattern for form III of compound of formula I

FIG. 5 DSC curve of form III of Compound I

FIG. 6 TGA Curve of form III of the Compound of formula I

FIG. 7 XRPD pattern for form A of compound of formula I

Detailed Description

The present invention is described in more detail below by way of examples. However, these specific descriptions are only used to illustrate the technical solutions of the present invention, and do not limit the present invention in any way.

The test conditions for each instrument were as follows:

in the present invention, the X-ray diffraction (also called "X-ray powder diffraction", X-ray diffraction differential, XRPD) is measured as follows:

the instrument model is as follows: d8 Advance in

And (3) testing conditions are as follows: the detailed XRPD parameters are as follows:

an X-ray generator: the concentration of Cu, k alpha,

tube voltage: 40kV, tube current: 40mA was added.

Scattering slit: 0.6mm

Detector slit: 5mm

Backscatter slit: 0.6mm

Scanning range: 3-40deg

Step length: 0.02deg

Rate: 0.3S

Sample pan rotation speed: 0rpm (not provided)

The Differential thermal analysis (also called Differential Scanning calorimetry, differential Scanning Calorimeter, DSC) test method of the present invention is as follows:

the instrument model is as follows: DSC 25

The test method comprises the following steps: a sample (1-10 mg) is placed in a DSC aluminum pot for testing, and the method comprises the following steps: room temperature to target temperature, and the heating rate is 10 ℃/min.

The thermogravimetric Analyzer (TGA) test method of the present invention is as follows:

the instrument model is as follows: TGA550

And (3) testing conditions are as follows: a sample (1-10 mg) was placed in a TGA platinum pan for testing by the method: 30-target temperature, and the heating rate is 10 ℃/min.

Reference example 1 preparation of 17- (cyclopropylmethyl) -3,14 β -dihydroxy-4,5 α -epoxy-6 β - [ N-methyl-trans-3- (3-furyl) acrylamido ] morphinan hydrochloride

i) Preparation of Compounds of formula B

Adding dichloromethane, N-diisopropylethylamine and the compound shown in the formula A into a reaction bottle in sequence, and stirring uniformly; replacing with nitrogen for three times, cooling to 0-10 ℃, and slowly dripping oxalyl chloride; after dripping, heating to 20-30 ℃ to react to the end point (the spots of the compound of the formula A basically disappear); the reaction solution was concentrated in vacuo, and methylene chloride was added to the concentrate, followed by reconcentration for further use.

ii) preparation of the Compound of formula D

Adding dichloromethane, triethylamine and the compound of the formula C (prepared by a method in reference literature) into a reaction bottle in sequence, and stirring uniformly; replacing nitrogen for three times, and dropwise adding a dichloromethane solution of the compound of the formula B at the temperature of-5 ℃; after the dripping is finished, the temperature is controlled to be minus 5 ℃ to 5 ℃ for reaction for 30 minutes, and the TLC monitors the reaction to the end point (the spot of the compound shown in the formula C basically disappears); after the reaction is completed, sodium bicarbonate aqueous solution is added into the mixture at the temperature of between 5 ℃ below zero and 5 ℃ and stirred for 10 to 20 minutes, liquid separation is carried out, the water phase (upper layer) is abandoned, the organic phase is washed by the sodium bicarbonate water for 3 times, the water phase (upper layer) is abandoned, the organic phase is dried and concentrated, and the compound of the formula D is obtained after column chromatography purification.

iii) Preparation of Compounds of formula I

Adding methanol into the reaction bottle, starting stirring, adding the compound shown in the formula D, and uniformly stirring; replacing nitrogen for three times, and dropwise adding 2M ethyl chloride solution at 20-30 ℃; after dripping, stirring for 1 hour at the temperature of 20-30 ℃; filtering, and leaching a filter cake with methanol; transferring the filter cake to a reaction bottle, adding methanol, evaporating the solvent under reduced pressure, and repeating for 2 times; adding absolute ethyl alcohol into the reaction bottle, and removing the solvent by evaporation under reduced pressure; transferring the concentrate to a vacuum drying oven for drying to obtain the amorphous compound shown in the formula I.

Reference example 2 preparation of form A of the Compound of formula I

Referring to a preparation method of nalfuraphten crystal form A disclosed in patent CN101155814B, the specific operation is as follows:

weighing 1g of the compound of the formula I prepared in reference example 1, adding the amorphous compound into a sample bottle, adding 4.5ml of methanol, heating to 40-50 ℃, stirring to dissolve, dropwise adding 13.5ml of isopropanol into the system, cooling to room temperature after dropwise adding, adding 1% of seed crystal, crystallizing for 8h at room temperature, filtering, leaching a filter cake with 2ml of isopropanol, and vacuum drying for 4h at 45-55 ℃. The crystal was characterized by XRPD for solid form (fig. 7), as form a.

Reference example 3 preparation of form a of the compound of formula I

Weighing 1g of the compound of formula I prepared in reference example 1, adding the amorphous form to a sample bottle, adding 20ml of methanol to dissolve, concentrating under reduced pressure to dryness, steaming with 20ml of ethanol, adding 24ml of ethanol, heating to reflux for 1h, cooling to room temperature, stirring overnight at room temperature, filtering, and vacuum drying at 60 ℃ for 5h. The crystal is characterized by XRPD, and the crystal is a crystal form A.

Reference example 4 preparation of form A of the Compound of formula I

Dissolving 5g of a compound shown in the formula I in an amorphous form by using 50ml of methanol, concentrating under reduced pressure until the compound is dry, adding 15ml of methanol and 35ml of ethyl acetate, heating to reflux, adding crystal form A seed crystal, refluxing for 1 hour, cooling to room temperature, keeping the temperature, crystallizing overnight, and drying in vacuum for 3 hours at 60 ℃. The crystal is characterized by XRPD, and the crystal is a crystal form A.

EXAMPLE 1 preparation of crystalline form I of the Compound of formula I

Weighing 1g of the compound of formula I prepared in reference example 1, adding the amorphous compound into a sample bottle, adding 20ml of absolute ethyl alcohol, heating to 75 ℃, stirring for 0.5h under heat preservation, slowly cooling to 25 ℃, stirring for 1-2h under heat preservation, filtering, and drying. The crystal is characterized by XRPD, DSC and TGA to obtain the patterns shown in figures 1, 2 and 3 respectively.

Example 2A preparation of form III of the Compound of formula I

Weighing 1g of the compound of formula I prepared in reference example 1, adding the amorphous compound into a sample bottle, adding 2ml of methanol and 12ml of absolute ethanol, heating to 55-60 ℃, pulping for 1h, slowly cooling to 0-10 ℃, stirring, crystallizing for 2h, performing suction filtration and leaching, and performing vacuum drying at 70-80 ℃ for 4h. The crystal was characterized by XRPD, DSC and TGA for solid form giving the patterns shown in figures 4,5 and 6, respectively.

EXAMPLE 2B preparation of form III of the Compound of formula I

Weighing 1g of the compound of formula I prepared in reference example 1, adding the amorphous compound into a sample bottle, adding 2ml of methanol and 12ml of absolute ethanol, heating to 55-60 ℃, pulping for 1h, slowly cooling to 0-10 ℃, stirring, crystallizing for 2h, performing suction filtration and leaching, and performing vacuum drying at 70-80 ℃ for 6h. The crystal is characterized by XRPD, and the crystal is in a crystal form III.

EXAMPLE 2C preparation of form III of the Compound of formula I

Weighing 100g of the compound of formula I prepared in reference example 1, adding the amorphous compound into a sample bottle, adding 1L of ethanol and 0.1L of methanol, heating to 55-60 ℃, stirring at a constant temperature for 1h, cooling to 20-30 ℃, stirring at a constant temperature for 2h, cooling to 0-10 ℃, stirring at a constant temperature for 2h, filtering, leaching a filter cake with 0.2L of ethanol, and vacuum-drying at 70-80 ℃ for 6h. The crystal is characterized by XRPD, and the crystal is in a crystal form III.

EXAMPLE 3 preparation of form III of the Compound of formula I

Adding 10g of amorphous solid of the compound shown in the formula I into 60ml of methanol, heating to dissolve, filtering to obtain a clear solution, adding 180ml of isopropanol under stirring at 25 ℃, keeping the temperature and stirring for 24 hours after the dropwise addition is finished, and performing suction filtration, leaching and drying at 70-80 ℃ to obtain the crystal form III. The crystal is characterized by XRPD, and the crystal is a crystal form III.

Example 4 residual solvent amount test

The amount of residual solvent was determined by gas chromatography for the crystalline form a of the compound of formula I prepared in reference examples 2-4 and the crystal III of the compound of formula I prepared in examples 2A-2C.

The instrument conditions were as follows:

preparing a test solution: taking about 100mg of crystal form A or crystal form III of each batch, precisely weighing, placing in a top empty bottle, precisely adding 1ml of solvent to dissolve, and sealing to obtain a test solution.

Preparing a reference substance solution: taking a proper amount of methanol, ethanol, dichloromethane, ethyl acetate, n-hexane, tetrahydrofuran, pyridine and toluene, precisely weighing, adding a solvent to dissolve and dilute to prepare a mixed solution containing 0.3mg of methanol, 0.5mg of ethanol, 0.06mg of dichloromethane, 0.5mg of ethyl acetate, 0.029mg of n-hexane, 0.072mg of tetrahydrofuran, 0.020mg of pyridine and 0.089mg of toluene in each 1ml, precisely weighing 1ml, placing in a top empty bottle, sealing, and taking the mixed solution as a reference solution.

The solvent residue in the crystal form A and the crystal form III is tested by adopting the meteorological chromatography, and the peak area is calculated according to an external standard method.

As can be seen from the above table, the solvent residue results of the crystal form III prepared by different methods are not over-limited, while the solvent residues of the crystal form a prepared by different methods are over-limited.

Claims

1. A crystalline form I of the compound of formula I, characterized in that said form I has characteristic peaks at 2 Θ values of 7.28 ± 0.2 °, 11.88 ± 0.2 °, 15.57 ± 0.2 °, 17.21 ± 0.2 ° and 21.11 ± 0.2 ° in an X-ray powder diffraction pattern expressed in 2 Θ angles using Cu-Ka radiation; preferably, the form I has characteristic peaks at 2 theta values of 7.28 +/-0.2 °, 10.60 +/-0.2 °, 11.88 +/-0.2 °, 14.57 +/-0.2 °, 15.57 +/-0.2 °, 17.21 +/-0.2 °, 18.21 +/-0.2 °, 21.11 +/-0.2 ° and 22.23 +/-0.2 ° in an X-ray powder diffraction pattern expressed by 2 theta angles; preferably, the crystal form I has characteristic peaks at 2 theta values of 7.28 +/-0.2 °, 9.71 +/-0.2 °, 10.32 +/-0.2 °, 10.60 +/-0.2 °, 11.12 +/-0.2 °, 11.67 +/-0.2 °, 11.88 +/-0.2 °, 14.57 +/-0.2 °, 14.98 +/-0.2 °, 15.57 +/-0.2 °, 17.21 +/-0.2 °, 18.21 +/-0.2 °, 21.11 +/-0.2 ° and 22.23 +/-0.2 ° in an X-ray powder diffraction pattern expressed by 2 theta angles; further preferably, the crystal form I has characteristic peaks at 2 θ values of 7.28 ± 0.2 °, 9.11 ± 0.2 °, 9.71 ± 0.2 °, 10.32 ± 0.2 °, 10.60 ± 0.2 °, 11.12 ± 0.2 °, 11.67 ± 0.2 °, 11.88 ± 0.2 °, 14.18 ± 0.2 °, 14.57 ± 0.2 °, 14.98 ± 0.2 °, 15.57 ± 0.2 °, 17.21 ± 0.2 °, 18.21 ± 0.2 °, 19.68 ± 0.2 °, 20.39 ± 0.2 °, 20.72 ± 0.2 °, 21.11 ± 0.2 °, 21.46 ± 0.2 °, 21.90 ± 0.2 °, 22.23.23 ± 0.2 °, 23.44 ± 0.2 °, 23.79 ± 0.2 °, 25.59 ± 0.2 ° and 29.40 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 θ; still further preferably, said form I has the characteristics represented by the XRPD pattern as shown in figure 1;

2. form I according to claim 1, characterized in that there are 3 endothermic peaks in the thermogram measured by differential scanning calorimetry at peak temperatures of 68.4 ± 5 ℃, 94.9 ± 5 ℃ and 215.5 ± 5 ℃; preferably, the crystalline form I has 3 endothermic peaks at peak temperatures of 68.4 ± 3 ℃, 94.9 ± 3 ℃ and 215.5 ± 3 ℃ in a thermogram measured by differential scanning calorimetry; further preferably, said form I has the characteristics represented by the DSC profile as shown in figure 2.

3. Form I according to claim 1, characterized in that it has a thermogravimetric analysis curve with a weight loss of 4.1 ± 0.2% at 175 ± 3 ℃; preferably, the crystalline form I has the characteristics represented by the TGA profile shown in figure 3.

4. A crystalline form III of a compound of formula I having characteristic peaks at 2 Θ values of 9.75 ± 0.2 °, 11.54 ± 0.2 °, 14.93 ± 0.2 °, 15.14 ± 0.2 ° and 20.97 ± 0.2 ° in an X-ray powder diffraction pattern expressed at 2 Θ angles using Cu-Ka radiation; preferably, the crystal form III has characteristic peaks at 2 theta values of 7.54 +/-0.2 °, 9.40 +/-0.2 °, 9.75 +/-0.2 °, 11.54 +/-0.2 °, 14.93 +/-0.2 °, 15.14 +/-0.2 °, 18.39 +/-0.2 °, 20.97 +/-0.2 ° and 26.27 +/-0.2 ° in an X-ray powder diffraction pattern expressed by 2 theta angles; preferably, the crystal form III has characteristic peaks at 2 theta values of 7.54 +/-0.2 °, 9.40 +/-0.2 °, 9.75 +/-0.2 °, 11.54 +/-0.2 °, 12.06 +/-0.2 °, 14.93 +/-0.2 °, 15.14 +/-0.2 °, 18.39 +/-0.2 °, 18.68 +/-0.2 °, 19.81 +/-0.2 °, 20.97 +/-0.2 °, 22.11 +/-0.2 °, 22.59 +/-0.2 ° and 26.27 +/-0.2 ° in an X-ray powder diffraction pattern expressed by 2 theta angles; further preferably, the crystal form III has characteristic peaks at 2 θ values of 7.54 ± 0.2 °, 9.40 ± 0.2 °, 9.75 ± 0.2 °, 11.05 ± 0.2 °, 11.54 ± 0.2 °, 12.06 ± 0.2 °, 14.93 ± 0.2 °, 15.14 ± 0.2 °, 15.70 ± 0.2 °, 18.39 ± 0.2 °, 18.68 ± 0.2 °, 19.81 ± 0.2 °, 20.97 ± 0.2 °, 21.31 ± 0.2 °, 22.11 ± 0.2 °, 22.59 ± 0.2 °, 24.29 ± 0.2 °, 24.70 ± 0.2 ° and 26.27 ± 0.2 ° in an X-ray powder diffraction pattern expressed by 2 θ angles; still further preferably, said form III has the characteristics represented by the XRPD pattern as shown in figure 4;

5. form III according to claim 4, characterized by an exothermic peak at an onset temperature of 231.95 ± 5 ℃ in the thermogram measured by differential scanning calorimetry; preferably, the crystal form III has an exothermic peak at the initial temperature of 231.95 +/-3 ℃ in an thermogram measured by differential scanning calorimetry; further preferably, said form III has the characteristics represented by the DSC profile as shown in figure 5.

6. The crystalline form III of claim 4, characterized by having the characteristics represented by the TGA profile shown in figure 6.

7. Use of the crystalline form of any one of claims 1-3 for the preparation of an analgesic, diuretic and antipruritic medicament.

8. Use of the crystalline form of any one of claims 4-6 for the preparation of an analgesic, diuretic and antipruritic medicament.

9. A method for preparing form III, comprising the steps of:

(2) Heating and pulping;

(3) Slowly cooling, stirring and crystallizing;

(4) Carrying out suction filtration and drying to obtain a crystal form III;

preferably, the volume-mass ratio of the A-type solvent to the compound of the formula I is 10-15 ml/g; preferably 11 to 14ml/g;

preferably, the temperature for heating and pulping in the step (2) is 50-80 ℃; preferably 50-70 ℃; more preferably from 55 to 60 ℃;

preferably, the pulping time in the step (2) is 1-5 h; preferably 1 to 2 hours; more preferably 1h;

preferably, the slow cooling stirring crystallization in the step (3) is that the temperature is reduced to-5-30 ℃; preferably 0 to 25 ℃; more preferably from 0 to 10 ℃;

preferably, the crystallization time of the slow cooling stirring crystallization in the step (3) is 1-10 h; preferably 1 to 6 hours; more preferably 1 to 2 hours.

10. A method for preparing form III, comprising the steps of:

(b) Heating to dissolve, and filtering to obtain a clear solution;

(d) Carrying out suction filtration and drying to obtain a crystal form III;

preferably, the volume-to-mass ratio of the C-type solvent to the compound of the formula I is 5-10 ml/g; preferably 5 to 6ml/g;

preferably, the volume ratio of the C-type solvent to the D-type solvent is 1:1-5, preferably 1:1-3; more preferably 1:3;

preferably, the time of heat preservation and stirring after the dropwise addition in the step (c) is 12-36 h; preferably 12 to 24 hours; further preferably 24 hours.