CN104803872A - Zucapsaicin crystal, and preparation method and application thereof - Google Patents

Abstract

The invention discloses a crystal of zucasecin and its preparation method and application. In the powder X-ray diffraction spectrum using a Cu-Kα radiation source, the crystal has diffraction angles of 2θ=5.9 and 11.9 degrees. Characteristic peaks, the 2θ error range is ±0.2 degrees. The crystal purity of the zucassecin of the present invention can reach more than 99.5%, the cis-trans isomer content is less than 0.3%, the stability is good, and it is easy to filter and wash, thus helping to improve the bioavailability. The preparation method of the zucassecin crystal of the present invention is simple, and the properties of the product between different batches are stable, and the same batch of zucassecin crystals is sampled at different points, and the content is basically the same. After two crystallizations, the content of cis-trans isomers can be less than 0.3%, which is significantly lower than the 7.1% content of cis-trans isomers reported in the literature after two crystallizations.

Description

A kind of crystal of zucasicin and its preparation method and application

technical field

The present invention relates to a crystal of zucasexin and its preparation method and application.

Background technique

Zucapsaicin (Zucapsaicin) is a capsaicin isomer as described in formula I, also known as cis-capsaicin, a new type of painkiller developed by Winston pharma in Canada.

Zucassecin, its preparation method can be found in Journal of Organic Chemistry;vol.54;1989;P3477-34785. Zurcasexin inhibits pain through the same mechanism as capsaicinoids, which may act through the transient receptor potential vanilloid receptor 1 (TRPV1), reducing the CGRP (calcitonin gene-related protein, from the trigeminal neuron release) and substance P, thereby reducing the sensation of pain, and can be used to treat related diseases such as osteoarthritis pain, postherpetic neuralgia, chronic neuralgia, and cluster headache.

At present, there are no relevant literature or patent reports on the crystal form of zucassecin. Therefore, there is an urgent need in this field to develop zurcasecin crystals suitable for pharmaceutical use.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the fact that there is no zhucalcetin crystal suitable for pharmaceutical use in the prior art, so as to provide a zhucasecin crystal and its preparation method and application. The zurcasecin crystal of the present invention has excellent characteristics such as high purity, uniformity, stability, and easy filtration and washing, and is especially suitable for making diseases related to osteoarthritis pain, postherpetic neuralgia, chronic neuralgia, and cluster headache of therapeutic drugs.

The present invention provides a crystal of zucasecin, which has characteristic peaks at diffraction angles 2θ=5.9 and 11.9 degrees in the powder X-ray diffraction spectrum using Cu-Kα as the radiation source, and the 2θ error range is ±0.2 degrees.

The zucassecin has a structure as shown in formula I,

In a preferred embodiment of the present invention, in the powder X-ray diffraction spectrum, the crystals of the zucassesine also have diffraction angles of 2θ=8.2, 14.4, 15.4, 19.0, 21.2 and 23.3 degrees. There are minor characteristic peaks with a 2θ error range of ±0.2 degrees.

The melting point of the crystals described in the present invention is generally 72-74°C.

The present invention also provides the use of the zucassecin crystals in the preparation of pain-suppressing drugs, preferably in the preparation and treatment of osteoarthritis pain, postherpetic neuralgia, chronic neuralgia or cluster headache Uses in medicine.

The present invention also provides the preparation method of the crystals of zucassecin, which adopts any one of the following schemes for crystallization:

Scheme 1 includes the following steps: heating the solution containing zucasicin, cooling and crystallizing;

Scheme 2 includes the following steps: heating the solution containing zucasicin, mixing it with anti-solvent after cooling, and crystallizing;

Scheme 3 includes the following steps: the solution containing zucasicin is subjected to solvent volatilization;

Wherein, the solvent of the solution containing zucasexin is selected from isopropyl ether and/or methyl tert-butyl ether, and the anti-solvent is selected from one or more of n-hexane, n-heptane and sherwood oil Various.

In a preferred embodiment of the present invention, the preparation method further includes: repeating any one of schemes 1 to 3 for crystallization. Among them, the number of repetitions is preferably 1 or more, more preferably 1 to 4 times.

In a preferred embodiment of the present invention, the crystallization is carried out using Scheme 1, wherein the solvent of the solution containing zucassecin is isopropyl ether, and the number of repetitions is 1 time; The first crystallization, and the second crystallization using scheme one, wherein the solvent is isopropyl ether.

In a preferred embodiment of the present invention, Scheme 1 is used for the first crystallization, and then Scheme 1 is used for the second crystallization, wherein the solvent of the solution containing zucassecin during the first crystallization is formazan Base tert-butyl ether, the solvent of the solution containing zucassecin described during the second crystallization is isopropyl ether.

In a preferred embodiment of the present invention, scheme 2 is used for crystallization, and the number of repetitions is 4 times.

Wherein, the solute in the solution may be various forms of zucassecin, such as zucassecin in amorphous form. Zucassecin as a solute can be prepared by various methods in the art, such as the method in the second paragraph of the left column of Journal of Organic Chemistry; vol.54; 1989; P3478.

Wherein, in the solution, the weight-to-volume ratio of the solute beadcacetin to the solvent can be selected according to conventional methods in the art, preferably 1g/ml-1g/100ml, more preferably 1g/5ml-1g/10ml .

Wherein, the volume ratio of the solvent and the anti-solvent is preferably 1:1˜1:100, more preferably 1:1˜1:10.

Wherein, the temperature of the heating is generally suitable for dissolving the solution containing beadcasein, preferably the reflux temperature of the solvent.

Wherein, the cooling temperature is preferably -30-30°C. The cooling generally adopts natural cooling.

Wherein, in scheme one or scheme two, stirring is carried out in the process of crystallization. The stirring time is appropriate to allow the crystals to fully separate out, preferably 1-48 hours.

On the basis of conforming to common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention is:

1. The present invention provides a zucassecin crystal, which has a purity of more than 99.5%, a cis-trans isomer content of less than 0.3%, good stability, and is easy to filter and wash, thus helping to improve bioavailability.

2. The preparation method of the zucassecin crystals of the present invention is simple, and the product properties between different batches are stable, and the same batch of zucassecin crystals is sampled at different points, and the content is basically the same. After two crystallizations, the content of cis-trans isomers can be less than 0.3%, which is significantly lower than the 7.1% content of cis-trans isomers reported in the literature after two crystallizations.

Description of drawings

Fig. 1 is the powder X-ray diffraction spectrogram of the zucassecin crystal obtained in the embodiment.

Fig. 2 is the HPLC chromatogram of the zucasicin crystal obtained in the embodiment.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

The crude product of zucasicin used in the following examples was prepared according to the second paragraph of the right column of Journal of Organic Chemistry; Vol.54; 1989; P34785: compound 3b (464mg, 2.72mmol) and thionyl chloride ( 1.0 g, 8.17 mmol) was stirred at room temperature for 8 hours, heated to 100°C for 0.5 hours, and excess thionyl chloride was removed under reduced pressure. The resulting product was added together with dry ether (10ml) to a suspension of dry vanillylamine (835mg, 5.45mmol) in dry ether (30ml) under nitrogen. The resulting mixture was left at room temperature for 2 hours and then refluxed for 2 hours. After cooling, the precipitate was removed by suction filtration and the filtrate was evaporated. The evaporated product was separated and purified by column chromatography (Fuji-gel BW-200 silica gel 15g, eluent: 2:1 n-hexane-ethyl acetate) to obtain oily crude jurcassecin.

The contents of cis and trans isomers in the following examples are all in mass percent.

Example 1

Preparation of Zucassecin Crystals 1

Dissolve 2.0 g of the crude product of Zhucacesin in 16 ml of isopropyl ether, heat to reflux to dissolve, cool naturally to room temperature, and filter after stirring for 2 hours to obtain 1.5 g of the first refined product of Zhucacesin (cis-trans isopropyl ether). conformation content 0.50%).

Dissolve 1.5 g of the first refined product of zhucacesin in 12 ml of isopropyl ether, heat to reflux to dissolve, cool naturally to room temperature, and filter after stirring for 2 hours to obtain 1.2 g of the second refined product of zhucacesin ( The cis-trans isomer content is 0.29%). The crystals are white crystals, and the melting point of the crystals is 72-74°C as tested by a melting point apparatus.

Example 2

Preparation of Zucassecin Crystals 2

Dissolve 2.0 g of the crude product of zhucacetin in 20 ml of isopropyl ether, heat to reflux to dissolve, cool naturally to room temperature, add 20 ml of n-hexane, stir for 2 hours, and then filter to obtain the first refined product of zucacetin 1.9g (the cis-trans isomer content is 1.50%).

Dissolve 1.9 g of the first refined product of Zhucalcetin in 20 ml of isopropyl ether, heat to reflux to dissolve, cool naturally to room temperature, add 20 ml of n-hexane, stir for 2 hours, and then filter to obtain the second Sub-refined product 1.7g (cis-trans isomer content 0.98%).

Dissolve 1.7g of the second refined product of Zhucalcetin in 20ml of isopropyl ether, heat to reflux to dissolve, cool naturally to room temperature, add 20ml of n-hexane, stir for 2 hours, and then filter to obtain the third Sub-refined product 1.5g (cis-trans isomer content 0.45%).

Dissolve 1.5 g of the third refined product of Zhucalcetin in 20 ml of isopropyl ether, heat to reflux to dissolve, cool naturally to room temperature, add 20 ml of n-hexane, stir for 2 hours, and then filter to obtain the fourth Sub-refined product 1.3g (cis-trans isomer content 0.29%). The crystals are white crystals, and the melting point of the crystals is 72-74°C as tested by a melting point apparatus.

Example 3

Preparation of Zucassecin Crystals 3

Dissolve 2.0 g of the crude product of zucasicin in 10 ml of methyl tert-butyl ether, heat to reflux to dissolve, cool naturally to room temperature, and filter after stirring for 2 hours to obtain 1.6 g of the first refined product of zucasicin ( The cis-trans isomer content is 1.2%).

Dissolve 1.6 g of the first refined product of Zhucalcetin in 8 ml of isopropyl ether, heat to reflux to dissolve, cool naturally to room temperature, and filter after stirring for 48 hours to obtain 1.4 g of the second refined product of Zhucalcetin ( The content of cis-trans isomers is 0.45%), the crystals are white crystals, and the melting point of the crystals is 72-74 ° C after the melting point tester.

Example 4

Preparation of Zucassecin Crystals 4

Dissolve 3.0 g of the crude product of zhucacexin in 30 ml of isopropyl ether, heat to reflux to dissolve, add 300 ml of n-hexane, cool to -30°C, stir for 1 hour and then filter to obtain the first refined product of zucacetin 2.7g (the cis-trans isomer content is 4.02%).

Dissolve 2.7g of the first refined product of Zhucalcetin in 30ml of isopropyl ether, heat to reflux to dissolve, add 300ml of n-hexane, cool to -30°C, stir for 1 hour and then filter to obtain the second Sub-refined product 2.4g (cis-trans isomer content 3.2%).

After repeating the appeal operation 5 times, the cis-trans isomer content was 1.5%, the crystal was white crystal, and the melting point of the crystal was 72-74°C as tested by a melting point apparatus.

Comparative Example 1

Dissolve 0.5 g of the crude product of zhucacetin in 5 ml of ether, heat to reflux to dissolve, cool to 0°C, stir for 1 hour and no solid precipitates, add 10 ml of n-hexane dropwise, layering occurs, and an oily substance precipitates, pour it out Solvent to obtain an oily product with a cis-trans isomer content of 6.5%.

Comparative Example 2

Dissolve 1.0 g of the crude product of zhucacexin in 5 ml of diethyl ether, heat to reflux to dissolve, cool to -30°C, stir for 24 hours, but still no solid precipitates, add 10 ml of n-hexane dropwise, layering occurs, and an oily substance precipitates , The solvent was poured out to obtain an oily product with a cis-trans isomer content of 6.5%.

Effect Example 1 Powder X-ray Diffraction of Pearl Casexin Crystal

The zucassecin crystals obtained in Example 1 were subjected to powder X-ray diffraction.

Measuring method: adopt the instrument that model is RIGAKU D/max2550VB/PC, carry out powder X-ray diffraction detection with copper radiation target Cu-Kα at a scanning speed of 2° per minute, and the spectrum obtained is shown in Fig. 1, and the ordinate shows in cps X-ray intensity represented by , the abscissa shows the diffraction angle in 2θ.

Measuring results: the measuring data corresponding to FIG. 1 is shown in Table 1. The results of the powder X-ray diffraction test of the zucassecin crystals obtained in Examples 2-4 are the same as those in Example 1.

Table 1

Effect Example 2 The high-performance liquid chromatography of the crystals of Zhucacexin

The zucasicin crystals obtained in Example 1 were detected by high performance liquid chromatography.

Determination method: use octadecylsilane bonded silica gel as filler; A: water phase (water: glacial acetic acid=440:7 (v/v); B: acetonitrile; C: tetrahydrofuran, with A:B:C= 50:45:5 (v/v)) is the mobile phase, the detection wavelength is 281nm, and the spectrum is obtained, as shown in Figure 2. Instrument: HITACHI-L2000; column is Agelapromsil C18; length 250mm, diameter 4.6mm, 5μm; flow rate: 0.8ml/min; column temperature: 40 degrees Celsius.

Measurement results: the HPLC purity of the zhucacetin crystals is 99.71% (corresponding to peak No. 1, with a retention time of 14.915 min), the single impurity content is less than 0.1%, and the cis-trans isomers are less than 0.3% (retention time is 15.849 min ).

It can be seen that the zucassecin crystals of the present invention have reached the purity level required by drug regulatory agencies.

As used herein, the term "crystal" refers to a solid in which complexes of molecules or atoms are arranged in a specific arrangement.

X-ray polycrystalline diffraction is also called powder X-ray diffraction. When X-rays pass through the crystal, a series of diffractions can be produced. X-ray diffraction patterns can be obtained by using an X-ray diffractometer in the laboratory. In the patterns, different diffraction The intensity of the X-ray diffraction line and each diffraction line is determined by the atomic group of a certain structure. The diffraction patterns produced by crystals with different structures are different. Therefore, the X-ray diffraction pattern can be used to determine the structure of the crystal, that is, the crystal form.

Methods for determining X-ray diffraction patterns of crystals are known in the art. For example, use RIGAKU D/max2550VB/PC X-ray powder diffractometer to obtain spectra at a scanning speed of 2° per minute during measurement. A copper radiation target is used.

When a substance exists in an amorphous form, it does not have an exact melting point when heated. The pure crystal of the present invention has an exact melting point, that is, the crystal will change from solid to liquid within a narrow temperature range during heating.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the essential technical content of the present invention. The essential technical content of the present invention is broadly defined in the scope of the claims of the application, and any technical entity completed by others or method, if it is exactly the same as that defined in the scope of the claims of the application, or an equivalent change, it will be deemed to be included in the scope of the claims.

Claims (10)

1. the crystal that pearl jam is pungent, is characterized in that: described crystal is using in the powder x-ray diffraction spectrum that source of radiation is Cu-K α, and have characteristic peak in diffraction angle 2 θ=5.9 and 11.9 degree of places, 2 θ limit of error are ± 0.2 degree.

2. the crystal that pearl jam as claimed in claim 1 is pungent, it is characterized in that: described crystal is in described powder x-ray diffraction spectrum, in diffraction angle 2 θ=8.2,14.4,15.4,19.0,21.2 and 23.3 degree of places also have accidental quality peak, and 2 θ limit of error are ± 0.2 degree.

3. the crystal that pearl jam as claimed in claim 1 or 2 is pungent, is characterized in that: the fusing point of described crystal is 72 ~ 74 DEG C.

4. the preparation method of the crystal that the pearl jam as described in any one of claims 1 to 3 is pungent, is characterized in that: its adopt in following proposal any one carry out crystallization:

Scheme one comprises the steps: to heat containing the pungent solution of pearl jam, cooling crystallization;

Scheme two comprises the steps: to heat containing the pungent solution of pearl jam, mixes, crystallization after cooling with anti-solvent;

Scheme three comprises the steps: the solution pungent containing pearl jam to carry out solvent evaporates;

Wherein, the solvent of the described solution pungent containing pearl jam is selected from isopropyl ether and/or methyl tertiary butyl ether, described anti-solvent be selected from normal hexane, normal heptane and sherwood oil one or more.

5. preparation method as claimed in claim 4, is characterized in that: described preparation method also comprises: any one in iteration scheme one to three carries out crystallization; The number of times of described repetition is preferably more than 1 time, is more preferably 1 ~ 4 time.

6. preparation method as claimed in claim 5, it is characterized in that: employing scheme one carries out crystallization, wherein said solvent is isopropyl ether, and the number of times of described repetition is 1 time;

And/or employing scheme one carries out first time crystallization, then adopt scheme one to carry out second time crystallization, the solvent described in wherein during first time crystallization is methyl tertiary butyl ether, and the solvent described in during second time crystallization is isopropyl ether;

And/or employing scheme two carries out crystallization, the number of times of described repetition is 4 times.

7. the preparation method as described in any one of claim 4 ~ 6, is characterized in that: in described solution, and the weightmeasurement ratio of the solvent that described solute pearl jam is pungent with described is 1g/ml ~ 1g/100ml, is preferably 1g/5ml ~ 1g/10ml.

8. preparation method as claimed in claim 4, is characterized in that: the volume ratio of described solvent and described anti-solvent is 1:1 ~ 1:100, is preferably 1:1 ~ 1:10.

9. the preparation method as described in any one of claim 4 ~ 8, is characterized in that: the temperature of described heating is the reflux temperature of described solvent; And/or in scheme one or scheme two, described cooling temperature is-30 ~ 30 DEG C, and described is cooled to naturally cooling; And/or in scheme one or scheme two, stir in the process of crystallization, the time of described stirring is 1 ~ 48 hour.

10. the pungent crystal of the pearl jam as described in any one of claims 1 to 3 suppresses the purposes in medicine in preparation pain, preferably for the preparation of the purposes in treatment osteoarthritis pain, postherpetic neuralgia, chronic neuralgia or cluster headache medicine.