CN115181109B - Crystal of morphinan derivative and process for producing the same - Google Patents

Abstract

The present invention relates to crystals of morphinan derivatives and a process for preparing the same. Wherein the crystal 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 the XRPD pattern expressed in terms of 2θ angle; diffraction peaks are present in the XRPD pattern expressed in terms of 2θ for form III of the morphinan derivative at least at 9.75±0.2°, 11.54±0.2°, 14.93±0.2°, 15.14±0.2° and 20.97±0.2°. The crystal form provided by the invention has excellent stability and good solubility, and the solvent residue is low, so that the qualified range can be reached.

Description

Crystal of morphinan derivative and process for producing the same

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to crystals of morphinan derivatives and a preparation method thereof.

Background

In general, a compound having a polymorphic form sometimes has different physical properties between different crystals. In particular, in the medical field, there are differences in solubility, dissolution rate, stability, or absorbance. Thus, even if the same compound is used, its potency varies depending on its crystal form. Therefore, when a compound having a polymorphic form is used as a medicine, it is necessary to stably provide the 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-furanyl) acrylamido ] morphinan hydrochloride (shown as formula I) has been shown to be useful as an active ingredient of analgesic, diuretic and antipruritic agents. Prior art CN101155814B discloses that the morphinan derivative has three crystal forms of a type, B type, and C type.

The present invention provides a novel crystalline form of a morphinan derivative and a process for producing the same, in order to optimize the physical properties of the morphinan derivative.

Disclosure of Invention

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

In some embodiments, crystalline form I of the compound of formula I is provided, having characteristic peaks in the X-ray powder diffraction pattern expressed in degrees 2Θ at 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 crystalline form I has characteristic peaks in an X-ray powder diffraction pattern expressed in degrees 2Θ at 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 has characteristic peaks in an X-ray powder diffraction pattern expressed in degrees 2Θ at 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 has characteristic peaks in an X-ray powder diffraction pattern expressed in degrees 2Θ at 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±0.2°、25.59±0.2° and 29.40 ± 0.2 °.

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

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

Numbering device	Diffraction angle 2 theta	Relative intensity	Numbering device	Diffraction angle 2 theta	Relative intensity
						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 X-ray powder diffraction of form I expressed in terms of 2θ has a profile as shown in fig. 1, i.e., has characteristics represented by the XRPD pattern shown in fig. 1.

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

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

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

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

In some embodiments, crystalline form III of the compound of formula I is provided having characteristic peaks in an X-ray powder diffraction pattern expressed in terms of 2Θ at 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 terms of 2Θ at 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 some embodiments, the crystalline form III has characteristic peaks in an X-ray powder diffraction pattern expressed in degrees 2Θ at 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 characteristic peaks in an X-ray powder diffraction pattern expressed in degrees 2Θ at a2Θ 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 some embodiments, the compound of formula I is in form III, whose X-ray powder diffraction pattern resolution data is 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 X-ray powder diffraction of form III expressed in terms of 2θ has a profile as shown in fig. 4, i.e., has characteristics represented by the XRPD pattern shown in fig. 4.

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

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

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

In another aspect, the invention provides the use of form I or form III for the preparation of an analgesic, diuretic and antipruritic drug.

In still another aspect, the present invention also provides a preparation method of the crystal form III, which includes the steps of:

(1) Amorphous adding a compound of formula I to a solvent of type a, wherein the solvent of type a is selected from one or a combination of two of methanol, ethanol, ethyl acetate, tetrahydrofuran, toluene or dichloromethane, preferably methanol, ethanol or a mixture of both;

(2) Heating and pulping;

(3) Slowly cooling, stirring and crystallizing;

(4) And (5) carrying out suction filtration and drying to obtain a crystal form III.

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

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

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

In some embodiments, the slow cooling, stirring and crystallization in step (3) is performed by cooling to-5 to 30 ℃; in some typical embodiments, the slow cooling, stirring and crystallization in step (3) is a temperature drop to 0-25 ℃; in some more typical embodiments, the slow cooling, stirring crystallization in step (3) is a temperature drop 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 stirred crystallization in step (3) is 1 to 2 hours.

In still another aspect, the present invention also provides a preparation method of the crystal form III, which includes the steps of:

(a) Amorphous adding a compound of formula I to a C-type solvent, wherein the C-type solvent is selected from one or a combination of methanol, ethanol, ethyl acetate, tetrahydrofuran, toluene or dichloromethane; preferably methanol, ethanol or a mixture of both; more preferably methanol;

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

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

(d) And (5) carrying out suction filtration and drying to obtain a crystal form III.

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

In some embodiments, the time of heat preservation and stirring after the completion of the dripping in the step (c) is 12-36 hours; in some typical embodiments, the time of incubation and stirring after the completion of the dropwise addition in step (c) is 12 to 24 hours; in some more typical embodiments, the incubation and agitation time after the completion of the dropwise addition in step (c) is 24 hours.

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 and good solubility, and the solvent residue is low, so that the qualified range can be reached.

Correlation definition

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

In the present invention, "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, "μl" means microliter;

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

In the present invention, "suction filtration" means reduced pressure filtration.

The X-ray powder diffraction pattern is obtained by using Cu-K alpha radiation measurement.

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

In X-ray powder diffraction spectra (XRPD), diffraction patterns derived from crystalline compounds are often characteristic for specific crystals, 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 for the crystals aimed at. It is determined whether or not the relative positions of peaks, rather than their relative intensities, are concurrent with the known crystalline phases. Furthermore, there may be slight errors in the position of the peaks for any given crystal, as is also well known in the crystallographic arts. For example, the position of the peak may be shifted due to a change in temperature at the time of analyzing the sample, a sample shift, calibration of the instrument, or the like, and a measurement error of the 2θ value may be about ±0.2°. Therefore, this error should be taken into account when determining each crystalline structure. The peak position is typically represented in the XRPD pattern by a 2θ angle or a crystal plane distance d, with a simple scaling relationship between the two: d=λ/2sin θ, where d represents the crystal face distance, λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. For isomorphous crystals of the same compound, the peak positions of the XRPD spectra have similarities overall, and the relative intensity errors may be large. It should also be noted that in the identification of mixtures, the loss of part of the diffraction lines may be caused by content reduction, etc., and that, in this case, it is not necessary to rely on all bands observed in the high purity sample, even one band may be characteristic for a given crystallization.

Differential Scanning Calorimetry (DSC) determines the transition temperature when a crystal absorbs or releases heat due to its crystal structure changing or the crystal melting. For the isoforms of the same compound, the thermal transition temperature and melting point errors are typically within about 5 ℃, usually within about 3 ℃ in successive assays. When a compound is described as having a given DSC peak or melting point, it is referred to that DSC peak or melting point ± 5 ℃. DSC provides an auxiliary method to distinguish between different crystal forms. Different crystal morphologies can be identified based on their different transition temperature characteristics. It should be noted that the DSC peak or melting point of the mixture may fluctuate over a larger range. Furthermore, since decomposition is accompanied during melting of the substance, the melting temperature is related to the rate of temperature rise.

Thermogravimetric analysis (TGA) refers to a thermal analysis technique that measures the relationship between the mass and temperature change of a sample under test at a programmed temperature. When the measured substance sublimates or evaporates in the heating process, the measured substance is decomposed into gas or loses crystal water, and the measured substance is caused to change in quantity. At this time, the thermogravimetric curve is not a straight line but is reduced. By analyzing the thermal weight curve, the temperature at which the measured substance changes can be known, and the amount of the lost substance can be calculated according to the lost weight.

The term "as shown at … …" when referring to, for example, an XRPD pattern, DSC pattern, or TGA pattern includes patterns that are not necessarily the same as those depicted herein, but fall within the limits of experimental error when considered by one of skill in the art.

Drawings

FIG. 1 XRPD pattern for Compound of formula I Crystal form I

FIG. 2 DSC curve of form I of a compound of formula I

FIG. 3 TGA curve of form I of the compound of formula I

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

FIG. 5 DSC curve of form III of a compound of formula I

FIG. 6 TGA curve of form III of a compound of formula I

FIG. 7 XRPD pattern for Compound of formula I Crystal form A

Detailed Description

The invention is described in more detail below by means of examples. However, these specific descriptions are only for illustrating the technical scheme of the present invention, and do not limit the present invention in any way.

The test conditions of each instrument are as follows:

In the present invention, the method for measuring X-ray diffraction (also called "X-ray powder diffraction", X-raypowder diffractometer, XRPD) is as follows:

instrument model: d8 Advance

Test conditions: the detailed XRPD parameters are as follows:

x-ray generator: cu, kα,

Tube voltage: 40kV, tube current: 40mA.

Scattering slit: 0.6mm

Detector slit: 5mm of

Backscatter slit: 0.6mm

Scanning range: 3-40deg

Step size: 0.02deg

Rate of: 0.3S

Sample disk rotational speed: 0rpm (not shown)

The differential thermal analysis (also called as "differential scanning calorimetry", DIFFERENTIAL SCANNING Calorimeter, DSC) test method in the present invention is as follows:

instrument model: DSC 25

The testing method comprises the following steps: samples (1-10 mg) were taken and placed in DSC aluminum pans for testing by the following method: the temperature rising rate is 10 ℃/min from room temperature to target temperature.

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

Instrument model: TGA550

Test conditions: samples (1-10 mg) were taken and placed in a TGA platinum pan for testing by: 30-target temperature, and the temperature rising rate is 10 ℃/min.

Reference example 1 preparation of 17- (cyclopropylmethyl) -3, 14. Beta. -dihydroxy-4, 5. Alpha. -epoxy-6. Beta. -N-methyl-trans-3- (3-furyl) acrylamido ] morphinan hydrochloride salt

I) Preparation of Compounds of formula B

Sequentially adding dichloromethane, N-diisopropylethylamine and a compound of formula A into a reaction bottle, and uniformly stirring; nitrogen is replaced for three times, the temperature is reduced to 0 ℃ to 10 ℃ and oxalyl chloride is slowly added dropwise; after the dripping, heating to 20-30 ℃ to react to an end point (spots of the compound of the formula A basically disappear); the reaction solution was concentrated in vacuo, dichloromethane was added to the concentrate, and concentrated again for use.

Ii) preparation of the Compounds of formula D

Sequentially adding dichloromethane, triethylamine and a compound shown in a formula C (prepared by a literature method) into a reaction bottle, and uniformly stirring; nitrogen is replaced for three times, and a dichloromethane solution of the compound of the formula B is dropwise added at the temperature of-5 ℃ to 5 ℃; after the dripping is finished, controlling the temperature to be between minus 5 ℃ and 5 ℃ for 30 minutes, and monitoring the reaction to an end point by TLC (the spot of the compound shown as the formula C basically disappears); after the reaction is completed, adding sodium bicarbonate aqueous solution at the temperature of-5 ℃ to 5 ℃ for stirring for 10 minutes to 20 minutes, separating liquid, discarding an aqueous phase (upper layer), washing an organic phase with sodium bicarbonate for 3 times, discarding the aqueous phase (upper layer), drying and concentrating the organic phase, and purifying by column chromatography to obtain the compound of the formula D.

Iii) Preparation of Compounds of formula I

Adding methanol into a reaction bottle, starting stirring, adding a compound of formula D, and uniformly stirring; nitrogen is replaced for three times, and 2M ethyl hydrogen chloride solution is dropwise added at the temperature of 20-30 ℃; after the dripping is finished, stirring for 1 hour at the temperature of 20-30 ℃; filtering, and leaching a filter cake by using methanol; transferring the filter cake into 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 evaporating the solvent under reduced pressure; transferring the concentrate into a vacuum drying oven for drying to obtain amorphous compound of formula I.

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

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

1g of the compound of formula I prepared in reference example 1 is weighed, added into a sample bottle in an amorphous manner, 4.5ml of methanol is added, the temperature is raised to 40-50 ℃ and the mixture is stirred for dissolving, 13.5ml of isopropanol is added dropwise into the system, after the dropwise addition, 1% seed crystal is added at room temperature after the dropwise addition is finished, the mixture is crystallized at room temperature for 8 hours, filtration is carried out, 2ml of isopropanol is used for leaching a filter cake, and vacuum drying is carried out for 4 hours at 45-55 ℃. The crystals were characterized by XRPD as solid form (fig. 7), form a.

Reference example 3 preparation of form A of the Compound of formula I

1G of the compound of formula I prepared in reference example 1 was weighed out, added into a sample bottle in an amorphous form, dissolved by adding 20ml of methanol, concentrated to dryness under reduced pressure, steamed with 20ml of ethanol, added with 24ml of ethanol, heated to reflux for 1h, cooled to room temperature, stirred overnight at room temperature, filtered, and dried under vacuum at 60℃for 5h. The crystals were form a as characterized by XRPD.

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

5G of the compound of formula I is dissolved in 50ml of methanol, concentrated to dryness under reduced pressure, 15ml of methanol and 35ml of ethyl acetate are added, the temperature is raised to reflux, crystal form A seed crystals are added, the reflux is carried out for 1h, the temperature is reduced to room temperature, the crystallization is carried out overnight, and the vacuum drying is carried out at 60 ℃ for 3h. The crystals were form a as characterized by XRPD.

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

1G of the compound of the formula I prepared in reference example 1 is weighed, added into a sample bottle in an amorphous manner, 20ml of absolute ethyl alcohol is added, the temperature is raised to 75 ℃, the mixture is kept at the temperature for 0.5h, the temperature is slowly lowered to 25 ℃, the mixture is kept at the temperature for 1-2h, and the mixture is subjected to suction filtration and drying. The crystals were characterized by XRPD, DSC and TGA for solid forms, giving the patterns shown in figures 1, 2, 3, respectively.

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

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

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

Weighing 1g of the compound of the formula I prepared in reference example 1, adding the amorphous compound into a sample bottle, adding 2ml of methanol and 12ml of absolute ethyl alcohol, heating to 55-60 ℃ for pulping for 1h, slowly cooling to 0-10 ℃, stirring for crystallization for 2h, filtering, leaching, and vacuum drying for 6h at 70-80 ℃. The crystals were form III as characterized by XRPD.

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

Weighing 100g of the compound of the 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 ℃, carrying out heat preservation and stirring for 1h, reducing the temperature to 20-30 ℃, carrying out heat preservation and stirring for 2h, reducing the temperature to 0-10 ℃, carrying out heat preservation and stirring for 2h, filtering, leaching a filter cake by 0.2L of ethanol, and carrying out vacuum drying at 70-80 ℃ for 6h. The crystals were form III as characterized by XRPD.

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

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

EXAMPLE 4 residual solvent test

Solvent residue detection was performed by gas chromatography on crystal form a of the compound of formula I prepared in reference examples 2 to 4 and crystal III of the compound of formula I prepared in examples 2A to 2C.

Instrument conditions:

Preparing a test solution: taking about 100mg of each batch of crystal form A or crystal form III, precisely weighing, placing into a headspace bottle, precisely adding 1ml of solvent to dissolve, and sealing to obtain a sample solution.

Preparing a reference substance solution: taking proper amounts of methanol, ethanol, methylene dichloride, ethyl acetate, normal hexane, tetrahydrofuran, pyridine and toluene, precisely weighing, dissolving in a solvent, diluting to prepare a mixed solution which contains 0.3mg of methanol, 0.5mg of ethanol, 0.06mg of methylene dichloride, 0.5mg of ethyl acetate, 0.029mg of normal hexane, 0.072mg of tetrahydrofuran, 0.020mg of pyridine and 0.089mg of toluene in each 1ml, precisely weighing 1ml, placing in a headspace bottle, and sealing to obtain a reference substance solution.

The residual solvent amounts in the crystal form A and the crystal form III are 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 for form III prepared by the different methods do not exceed the limit, while the solvent residue for form A prepared by the different methods exceeds the limit.

Claims (28)

1. A crystalline form III of a compound of formula I, characterized in that it has characteristic peaks in an X-ray powder diffraction pattern expressed in terms of 2-theta angles at a 2-theta 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 DEG using Cu-Ka radiation,

2. Form III according to claim 1, characterized in that it has the characteristics represented by the XRPD pattern shown in fig. 4.

3. Form III according to claim 1, characterized in that in the thermogram of differential scanning calorimetry, there is an exothermic peak at an initial temperature of 231.95 ±5 ℃.

4. Form III according to claim 1, characterized in that it has an exothermic peak at an onset temperature of 231.95 ±3 ℃ in a thermogram of differential scanning calorimetry.

5. Form III according to claim 1, characterized in that it has the characteristics represented by the DSC profile as shown in figure 5.

6. Form III according to claim 1, characterized in that it has the characteristics represented by the TGA profile shown in figure 6.

7. Use of the crystalline form of any one of claims 1-6 for the preparation of an analgesic, diuretic, and antipruritic drug.

8. A process for the preparation of the crystalline form III according to any one of claims 1 to 6, comprising the steps of:

(1) Amorphous adding a compound of the formula I into a solvent A, wherein the solvent A is selected from one or two of methanol, ethanol, ethyl acetate, tetrahydrofuran, toluene and dichloromethane, and the volume mass ratio of the solvent A to the compound of the formula I is 10-15 ml/g;

(2) Heating and pulping, specifically, heating and pulping at 50-80 ℃ for 1-5 h;

(3) Slowly cooling, stirring and crystallizing, specifically, slowly cooling, stirring and crystallizing until the temperature is reduced to-5-30 ℃ and the crystallizing time is 1-10 h;

(4) And (3) carrying out suction filtration and drying to obtain a crystal form III, wherein the drying temperature is 70-80 ℃.

9. The method according to claim 8, wherein the solvent of type a in step (1) is methanol, ethanol or a mixture thereof.

10. The process according to claim 8, wherein the volume to mass ratio of the solvent of type a to the compound of formula I in step (1) is 11 to 14ml/g.

11. The method according to claim 8, wherein the temperature of the elevated temperature beating in the step (2) is 50-70 ℃.

12. The method according to claim 11, wherein the temperature of the elevated temperature beating in the step (2) is 55-60 ℃.

13. The method according to claim 8, wherein the beating time in the step (2) is 1 to 2 hours.

14. The method of claim 13, wherein the beating time in step (2) is 1h.

15. The method according to claim 8, wherein the slow cooling, stirring and crystallization in the step (3) is performed at a temperature of 0-25 ℃.

16. The method according to claim 15, wherein the slow cooling, stirring and crystallization in the step (3) is performed at a temperature of 0-10 ℃.

17. The method according to claim 8, wherein the crystallization time of the slow cooling stirring crystallization in the step (3) is1 to 6 hours.

18. The method according to claim 17, wherein the crystallization time of the slow cooling and stirring crystallization in the step (3) is 1 to 2 hours.

19. The method according to claim 8, wherein the drying time in the step (4) is 6 hours.

20. A process for the preparation of the crystalline form III according to any one of claims 1 to 6, comprising the steps of:

(a) Amorphous adding a compound of the formula I into a C-type solvent, wherein the C-type solvent is selected from one or two of methanol, ethanol, ethyl acetate, tetrahydrofuran, toluene and methylene dichloride, and the volume-mass ratio of the C-type solvent to the compound of the formula I is 5-10 ml/g;

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

(c) Cooling to room temperature, stirring while adding a D-type solvent, and after dripping, preserving heat and stirring for 12-36 h, wherein the D-type solvent is one or two of n-propanol, isopropanol or n-butanol, and the volume ratio of the C-type solvent to the D-type solvent is 1:1-5;

(d) And (3) carrying out suction filtration and drying to obtain a crystal form III, wherein the drying temperature is 70-80 ℃.

21. The method of claim 20, wherein the C-solvent in step (a) is methanol, ethanol or a mixture thereof.

22. The method of claim 21, wherein the C-solvent in step (a) is methanol.

23. The method of claim 20, wherein the D-type solvent in step (c) is isopropyl alcohol.

24. The process according to claim 20, wherein the ratio of the volume mass of the solvent of group C to the compound of formula I in step (a) is from 5 to 6ml/g.

25. The method according to claim 20, wherein the volume ratio of the C-type solvent to the D-type solvent in the step (C) is 1:1-3.

26. The method of claim 25, wherein the volume ratio of the C-solvent to the D-solvent in step (C) is 1:3.

27. The method according to claim 20, wherein the time of stirring is 12 to 24 hours after the completion of the dropping in step (c).

28. The method according to claim 27, wherein the time of stirring is kept at 24 hours after the completion of the dropping in the step (c).