阅读说明：本技术 利托那韦中间体的晶体及其制备方法 (Crystal of ritonavir intermediate and preparation method thereof ) 是由 叶辉青 詹宁辛 廖伟龙 孙垚 范玉林 陈勇 黄芳芳 于 2021-08-24 设计创作，主要内容包括：本发明涉及一种利托那韦中间体的晶体及其制备方法。所述晶体的结构中胺、酸和水的摩尔比为4:2:5,所述晶体属于单斜晶系,P21空间群,所述晶体的晶胞参数为α＝γ＝90°,β＝89.9633(16)°,晶胞体积为所述单晶的晶胞内不对称单元数z为2。本发明中利托那韦中间体的晶体为形状规则、无色透明的棒块状晶体,其质量较好,适合进行单晶测试和确定其立体构型信息,可以为利托那韦中间体和利托那韦的制备及它们的质量控制提供帮助和依据。(The invention relates to a ritonavir intermediate crystal and a preparation method thereof. The molar ratio of amine, acid and water in the structure of the crystal is 4:2:5, the crystal belongs to a monoclinic system, P21 space group, and the unit cell parameter of the crystal is α ═ γ ═ 90 °, β ═ 89.9633(16) ° and unit cell volume The number z of asymmetric units in the unit cell of the single crystal is 2. The ritonavir intermediate crystal is a rod-shaped crystal which is regular in shape, colorless and transparent, has good quality, is suitable for single crystal test and determination of three-dimensional configuration information, and can provide help and basis for preparation of the ritonavir intermediate and ritonavir and quality control of the ritonavir intermediate and the ritonavir.)

1. A crystal of a ritonavir intermediate having the structure shown in formula I:

the crystal has a structure in which the molar ratio of amine, acid and water is 4:2: 5.

2. The crystal of ritonavir intermediate as claimed in claim 1, characterized in that the crystal has an X-ray powder diffraction pattern having diffraction peaks at one or more of the positions having 2 Θ angles of 5.03 ± 0.2 °, 8.18 ± 0.2 °, 14.10 ± 0.2 °, 15.02 ± 0.2 °, 16.42 ± 0.2 °, 20.08 ± 0.2 °, 25.18 ± 0.2 °;

optionally, the crystal has an X-ray powder diffraction pattern having diffraction peaks at one or more of the positions 5.03 ± 0.2 °, 8.18 ± 0.2 °, 10.04 ± 0.2 °, 14.10 ± 0.2 °, 15.02 ± 0.2 °, 16.42 ± 0.2 °, 18.10 ± 0.2 °, 18.77 ± 0.2 °, 20.08 ± 0.2 °, 21.98 ± 0.2 °, 25.18 ± 0.2 ° at 2 Θ angles;

optionally, the X-ray powder diffraction pattern of the crystal has a peak at ± 0.2 °, 6.68 ± 0.2 °, 8.18 ± 0.2 °, 10.04 ± 0.2 °, 11.96 ± 0.2 °, 13.11 ± 0.2 °, 14.10 ± 0.2 °, 15.02 ± 0.2 °, 16.42 ± 0.2 °, 16.70 ± 0.2 °, 17.60 ± 0.2 °, 18.09 ± 0.2 °, 18.77 ± 0.2 °, 19.66 ± 0.2 °, 20.08 ± 0.2 °, 20.29 ± 0.2 °, 21.13 ± 0.2 °, 21.98 ± 0.2 °, 22.77 ± 0.2 °, 23.26 ± 0.2 °, 23.58 ± 0.2 °, 25.18 ± 0.2 °, 25.50 ± 0.2 °, 27.19 ± 0.2 °, 28.75 ± 0.2 °, 23.26 ± 0.2 °, 23.84 ± 0.2 °, 35 ± 0.83 °, 2 ± 0.83 °, or 2 ± 0.83 °;

optionally, the crystal has an X-ray powder diffraction pattern substantially as shown in figure 4.

3. The crystal of ritonavir intermediate as claimed in claim 1 or 2, wherein the crystal belongs to the monoclinic system, P2₁Space group, the crystal has unit cell parameters of α ═ γ ═ 90 °, β ═ 89.9633(16) ° and unit cell volumeThe number z of asymmetric units in the unit cell of the crystal is 2.

4. A process for the preparation of crystals of ritonavir intermediate as claimed in any of claims 1 to 3 comprising the steps of:

and mixing and heating the ritonavir intermediate and a crystallization solvent, stopping heating after the solution is clarified, cooling, and crystallizing to obtain the crystal.

5. The method according to claim 4, wherein the crystallization solvent is selected from the group consisting of alcohol compounds and ester compounds;

optionally, the alcohol compound comprises at least one of methanol and ethanol;

optionally, the ester compound comprises at least one of methyl acetate, ethyl acetate, isopropyl acetate, and n-butyl acetate;

optionally, the alcohol compound and/or the ester compound are provided in the form of a solution, and the volume ratio of the alcohol compound to the ester compound is 1 (0.5-5).

6. The method according to claim 4, wherein the heating temperature is 40-70 ℃;

optionally, the final temperature of the heating is 55-65 ℃.

7. The process of claim 4, wherein the ritonavir intermediate is a trihydrate of the compound of formula I, the molar ratio of amine, acid and water being 2:1: 6;

the mass ratio of the ritonavir intermediate to the crystallization solvent is 1 (6-30).

8. The method according to claim 4, wherein the final temperature of the temperature reduction is 0 ℃ to 30 ℃;

optionally, the temperature is reduced by 4-6 ℃ and then kept at the constant temperature for 3.5-4.5 hours.

9. The method according to any one of claims 4 to 8, wherein the crystallization is standing crystallization, and the standing time is 1 to 3 days.

10. The method according to any one of claims 4 to 8, wherein the stirring is carried out during the cooling and crystallization, and the cooling and crystallization time is 0.5h-12 h.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a ritonavir intermediate crystal and a preparation method thereof.

Background

Ritonavir is a potent inhibitor of the aspartic protease of human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-2) that blocks the enzyme from forming the polyprotein required for morphologically mature HIV particles, keeping the HIV particles in an immature state, thereby slowing the spread of HIV in the cell to prevent the onset of a new round of infection and delaying disease progression.

The prior ritonavir (API) mainly has two crystal forms, wherein the crystal form I is in a tablet shape and is suitable for single crystal diffraction test, but the crystal form I is a metastable crystal form and is unstable and difficult to obtain by means of crystallization; form II is a stable form, but it is a pin-fin form, which is not suitable for structural testing (cf. Organic Process Research & Development 2000,4, 413-); wherein the ritonavir in the crystal form I and the ritonavir in the crystal form II are shown in a figure 1.

Therefore, it is very difficult to obtain a single crystal capable of structural testing for a compound, particularly a compound having a common structural segment with ritonavir as an intermediate of ritonavir.

The ritonavir intermediate shown in the formula I is one of important intermediates required in the process of preparing ritonavir or a preparation product thereof, can be used for preparing the ritonavir, and can also be used for quality detection and control processes of the ritonavir or a plurality of intermediates thereof. The ritonavir intermediate shown in the formula I has 3 chiral centers, and the information such as the stereo configuration and the like is difficult to determine, so that the compound is difficult to detect and locate in the quality detection or control of the ritonavir intermediate. If the crystal, especially the single crystal, of the ritonavir intermediate shown in the formula I can be obtained, the quality detection and control are very useful and favorable for the preparation of the ritonavir intermediate shown in the formula I, the preparation of the ritonavir and the three-dimensional structure of the ritonavir intermediate; however, in the prior art, the crystal information of the ritonavir intermediate shown in the formula I is not disclosed, and the related information and preparation method of the single crystal are not disclosed.

Disclosure of Invention

The present invention aims to solve at least to some extent at least one of the technical problems of the prior art. Therefore, the invention provides a crystal of a ritonavir intermediate and a preparation method thereof. The ritonavir intermediate crystal provided by the invention can be used for preparing ritonavir and can also be used in the quality detection control process of the ritonavir intermediate and the ritonavir.

In one aspect of the invention, the invention provides a crystal of a ritonavir intermediate. According to an embodiment of the invention, the structure of the ritonavir intermediate is shown as formula I:

the crystal structure of the ritonavir intermediate has a molar ratio of amine, acid and water of 4:2: 5.

According to an embodiment of the present invention, the crystal of ritonavir intermediate described above may further include at least one of the following technical features:

according to an embodiment of the present invention, the crystal of ritonavir intermediate has an X-ray powder diffraction pattern having diffraction peaks at one or more of positions 5.03 ± 0.2 °, 8.18 ± 0.2 °, 14.10 ± 0.2 °, 15.02 ± 0.2 °, 16.42 ± 0.2 °, 20.08 ± 0.2 °, and 25.18 ± 0.2 ° in 2 θ angle.

According to an embodiment of the present invention, the crystal of ritonavir intermediate has an X-ray powder diffraction pattern having diffraction peaks at one or more of positions 5.03 ± 0.2 °, 8.18 ± 0.2 °, 10.04 ± 0.2 °, 14.10 ± 0.2 °, 15.02 ± 0.2 °, 16.42 ± 0.2 °, 18.10 ± 0.2 °, 18.77 ± 0.2 °, 20.08 ± 0.2 °, 21.98 ± 0.2 °, and 25.18 ± 0.2 ° at 2 θ angles.

According to embodiments of the present invention, an X-ray powder diffraction pattern of the crystal of ritonavir intermediate has a diffraction peak at ± 0.2 °, 6.68 ± 0.2 °, 8.18 ± 0.2 °, 10.04 ± 0.2 °, 11.96 ± 0.2 °, 13.11 ± 0.2 °, 14.10 ± 0.2 °, 15.02 ± 0.2 °, 16.42 ± 0.2 °, 16.70 ± 0.2 °, 17.60 ± 0.2 °, 18.09 ± 0.2 °, 18.77 ± 0.2 °, 19.66 ± 0.2 °, 20.08 ± 0.2 °, 20.29 ± 0.2 °, 21.13 ± 0.2 °, 21.98 ± 0.2 °, 22.77 ± 0.2 °, 23.26 ± 0.2 °, 23.58 ± 0.2 °, 25.18 ± 0.2 °, 25.50 ± 0.2 °, 27.19 ± 0.19.28.2 °, 22.77 ± 0.2 °, 23.84 ± 0.31 ± 0.81 ± 0.83 °, 2 ± 0.83 °, 2 °, or ± 0.83 °.

According to an embodiment of the present invention, the crystals of ritonavir intermediate have an X-ray powder diffraction pattern substantially as shown in figure 4.

In some embodiments, according to embodiments of the present invention, the ritonavir intermediate is a crystalline ritonavir intermediate.

According to an embodiment of the present invention, the crystal or single crystal of ritonavir intermediate described above may further include at least one of the following technical features:

according to an embodiment of the invention, the single crystal belongs to the monoclinic system, P2₁Space group, the single crystal has unit cell parameters ofα ═ γ ═ 90 °, β ═ 89.9633(16) ° and unit cell volumeThe crystal cell of the single crystal is internally asymmetricThe number of elements z is 2. The single crystal has good quality and is suitable for single crystal test analysis.

According to an embodiment of the invention, the single crystal has an X-ray powder diffraction pattern substantially as shown in fig. 4.

It should be noted that, depending on the measurement conditions, the 2 θ angle and the relative intensity of each peak in the X-ray powder diffraction pattern vary, and generally, the variation of the 2 θ angle is within ± 0.2 °, and the relative intensity is within ± 0.2% is considered as a reasonable error.

According to the embodiment of the invention, the single crystal is a rod-shaped crystal which is regular in shape, colorless and transparent, has good quality, is suitable for single crystal test, can obtain the information of the three-dimensional structure configuration through single crystal diffraction test, and can provide help and basis for the preparation and quality control of ritonavir intermediates and ritonavir.

In yet another aspect of the invention, the invention provides a process for preparing the crystals of ritonavir intermediate described above.

At present, the method for preparing the single crystal is various, such as a solvent slow volatilization method, a solvothermal method, a diffusion method and the like, and the conditions influencing the growth of the single crystal are complex and various and have no fixed rule. The inventor cultures the ritonavir single crystal through a large number of experiments in the earlier stage, and the result shows that the ritonavir crystal form I has extremely poor reproducibility, the crystal suitable for single crystal testing is difficult to obtain, only the flocculent crystal form II can be obtained, and the requirement of single crystal testing cannot be met.

The inventors have also found through multiple trials that single crystals of the ritonavir intermediate of formula I are also difficult to obtain. Based on this, the inventors have conducted a number of experiments, attempting to perform single crystal culture of the ritonavir intermediate, and successfully obtained single crystals suitable for structural test analysis after a number of experiments. Thus, the present invention provides a process for the preparation of the crystals of ritonavir intermediate described above.

According to an embodiment of the present invention, the method for preparing the crystal of ritonavir intermediate described above comprises the steps of: and mixing and heating the ritonavir intermediate and a crystallization solvent, stopping heating after the solution is clarified, cooling, and crystallizing to obtain the crystal.

The method provided by the invention is simple to operate, and can efficiently and quickly obtain the crystal of the ritonavir intermediate, particularly can obtain a single crystal, and the crystal can be used for preparing ritonavir. The inventor obtains the spatial configuration information of the single crystal by performing single crystal diffraction test on the obtained crystal, particularly the single crystal, and can provide a basis for quality control of ritonavir or an intermediate thereof.

According to an embodiment of the present invention, the crystallization solvent is selected from alcohol compounds and ester compounds. The inventor finds that the crystal, particularly the single crystal, of the ritonavir intermediate has better growth effect in the mixed solution of the alcohol compound and the ester compound through a large number of experiments.

According to an embodiment of the present invention, the alcohol compound includes at least one of methanol and ethanol. Therefore, the effect of using the alcohol compound to culture the crystal, particularly the single crystal, of the ritonavir intermediate is more ideal.

According to an embodiment of the present invention, the ester compound includes at least one of methyl acetate, ethyl acetate, isopropyl acetate, and n-butyl acetate. Therefore, the effect of using the ester compound to culture the crystal, particularly the single crystal, of the ritonavir intermediate is more ideal.

According to the embodiment of the invention, the alcohol compound and/or the ester compound are provided in the form of solution, and the volume ratio of the alcohol compound to the ester compound is 1 (0.5-5); preferably, the volume ratio of the alcohol compound to the ester compound is 1 (0.5-2).

The inventor finds that the alcohol compound and the ester compound can influence the formation of crystals, particularly single crystals, of the ritonavir intermediate through a large number of experiments, and the crystals, particularly the single crystals, of the ritonavir intermediate have better growth effect when the alcohol compound and the ester compound are adopted according to the proportion; when the ratio of the alcohol compound to the ester compound is too large or too small, the crystal growth effect, particularly the single crystal growth effect, of the ritonavir intermediate can be influenced, so that the crystal of the ritonavir intermediate cannot be subjected to single crystal test.

According to the embodiment of the invention, the heating temperature is 40-70 ℃, and the temperature range is favorable for obtaining the crystal, especially the single crystal, of the ritonavir intermediate in a follow-up manner.

According to the embodiment of the invention, the final temperature of the heating is 55-65 ℃. The inventor finds out through experiments that the heating temperature range is beneficial to dissolving the ritonavir intermediate and avoiding the ritonavir intermediate from degradation or configuration transformation due to high temperature, so that crystals with high purity and good effect, particularly single crystals, are obtained. The inventor also finds that when the heating temperature is too high, the alcohol compound is volatilized due to high temperature during slow temperature reduction, so that a large amount of solid impurities are separated out, and crystals of the ritonavir intermediate suitable for single crystal testing cannot be obtained.

According to an embodiment of the present invention, in the method for preparing the crystals of ritonavir intermediate as described above, the ritonavir intermediate used is a trihydrate of the compound represented by formula I, the molar ratio of amine, acid and water is 2:1: 6; the mass ratio of the ritonavir intermediate to the crystallization solvent is 1 (6-30). The inventor finds through a large number of experiments that when the addition amounts of the ritonavir intermediate and the crystallization solvent are in the above proportion, the ritonavir intermediate is favorably dissolved and the growth of crystals, particularly single crystals, of the ritonavir intermediate is promoted, and the advantages of shortening the preparation time, improving the effect of the crystals, particularly the single crystals, and the like are achieved. When the addition ratio of the ritonavir intermediate to the crystallization solvent is too high or too low, the growth of crystals, particularly single crystals, is affected, and crystals suitable for single crystal testing cannot be obtained.

In the case of the structure of the ritonavir intermediate, the amine refers to tert-butyl ((2S,4S,5S) -5-amino-4-hydroxy-1, 6-diphenylhex-2-yl) carbamate, and the acid refers to succinic acid.

According to an embodiment of the invention, the final temperature of the temperature reduction is 0 ℃ to 30 ℃. By adopting the cooling temperature, the obtained crystal, especially the single crystal, has better effect. In some embodiments, the final temperature of the temperature reduction can be 20 ℃ to 30 ℃, which is easy to operate and control and is beneficial to obtain single crystals.

According to the embodiment of the invention, the temperature is reduced by keeping constant temperature for 3.5-4.5 hours after reducing the temperature by 4-6 ℃. The inventor finds that the cooling mode is beneficial to the growth of crystals, particularly single crystals, and the phenomenon that the obtained crystals cannot be used for single crystal testing due to explosive crystallization is avoided through a large number of tests; in addition, the cooling mode is convenient for actual test operation and control. The inventors have also found that when the cooling rate is too fast, the saturation is higher when the temperature is reduced to room temperature, resulting in precipitation of a large amount of solid impurities, and crystals of the ritonavir intermediate suitable for single crystal testing cannot be obtained.

According to the embodiment of the invention, the crystallization is standing crystallization, and the standing time is 1-3 days. The ritonavir intermediate crystal prepared by adopting the conditions has better effect especially on the single crystal.

According to the embodiment of the invention, in the method, stirring is carried out during cooling and crystallization, and the stirring time is 0.5h-12h (h), so as to obtain the crystal.

In some embodiments, the present invention provides a process for preparing the crystals of ritonavir intermediate described above comprising the steps of: and mixing and heating the ritonavir intermediate and a crystallization solvent, stopping heating after the solution is clarified, cooling, stirring and crystallizing to obtain the crystal, wherein the crystal can be used for single crystal diffraction test.

According to the method disclosed by the invention, the obtained crystal (single crystal) is colorless and transparent and has a regular shape, the spatial configuration information of the crystal can be obtained through single crystal diffraction test, and the method provides help and basis for obtaining a high-quality ritonavir intermediate, controlling the quality of the ritonavir intermediate, and preparing and controlling the quality of the ritonavir.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:

figure 1 is a crystal morphology diagram of ritonavir form I and form II;

FIG. 2 is an X-ray powder diffraction pattern of the single crystal obtained in the example of the present invention and the raw material (ritonavir intermediate) used;

FIG. 3 is a structural analysis diagram of a single crystal obtained in the example of the present invention;

FIG. 4 is an X-ray powder diffraction pattern of a single crystal obtained in an example of the present invention;

FIG. 5 is a DSC spectrum of a single crystal obtained in the example of the present invention;

FIG. 6 is a drawing (magnified 25 times) of a polarization microscope (PLM) of a single crystal obtained in example of the present invention;

FIG. 7 is a photograph (magnified 100 times) of a polarizing microscope (PLM) showing the solid obtained in control 1.

Detailed Description

The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention.

It should be noted that the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Further, in the description of the present invention, "a plurality" means two or more unless otherwise specified.

The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

It should be noted that the structure of the ritonavir intermediate in the embodiment of the present invention is shown in formula I:it is a trihydrate, an amineThe molar ratio of acid to water is 2:1: 6.

In reference to the structure of the ritonavir intermediate, the amine refers to tert-butyl ((2S,4S,5S) -5-amino-4-hydroxy-1, 6-diphenylhex-2-yl) carbamate and the acid refers to succinic acid.

The specific detection method in the embodiment of the invention is as follows:

x-ray single crystal diffraction: the single crystal is analyzed by an X-ray single crystal diffractometer, reduced and absorbed and corrected by a CryAlispPro program, the unit cell parameters of the single crystal are refined, data are obtained for structure analysis, an initial structure is directly obtained by a SHELXTL program, all non-hydrogen atom positions are found out by a difference Fourier method, and anisotropic refinement and mapping are carried out.

X-ray powder diffraction (XRPD): x-ray powder diffraction patterns were collected on a PANalytical Empyrean X-ray diffractometer in the netherlands equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. Wherein the radiation source is (Cu, K alpha, K alpha 1)1.540598；Kα21.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50), the voltage is set at 45KV, the current is set at 40mA, the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 6.6 mm; and obtaining an effective 2 theta range of 3-60 degrees by adopting a theta-theta continuous scanning mode. A proper amount of sample is taken under the environmental condition (about 18-32 ℃) at the position of a circular groove of a zero-background sample rack, a clean glass slide is used for light pressing to obtain a flat plane, the zero-background sample rack is fixed, and then the sample generates a traditional XRPD pattern within the range of 3-60 degrees 2 theta +/-0.2 degrees by scanning steps of 0.0167 degrees. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus.

Differential Scanning Calorimetry (DSC): DSC measurements were performed in a TA Instruments model Q2000 using a sealed pan apparatus, samples (approximately 1-3 mg) were weighed in an aluminum pan, closed with Tzero caps, precision recorded to hundredths of a milligram, and transferred to an instrument for measurement, the instrument was purged with nitrogen at 50mL/min and data was collected at a heating rate of 10 ℃/min between 30 ℃ and 300 ℃, then plotted endothermic peak down, data analyzed and presented with TA Universal Analysis.

Polarizing microscopy (PLM): the pictures were taken using a germany Leica DM1000 erecting microscope, a 2.5 times objective lens, a Leica MC170 HD microscope.

Examples of preparation of crystals of ritonavir intermediate

Example 1:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 1ml of isopropyl acetate, heating to 60 ℃ under stirring, slowly adding 1ml of methanol, stirring until the mixture is clear, stopping stirring after obtaining a clear solution, cooling to room temperature (25 ℃) in a manner of keeping the temperature constant for 4 hours every time the temperature is reduced by 5 ℃, standing, and crystallizing for 2 days to obtain long rod-shaped single crystals. Sampling the single crystal and ritonavir intermediate raw materials, carrying out X-ray powder diffraction detection, carrying out X-ray single crystal diffraction detection and differential scanning calorimetry detection on the single crystal, shooting a PLM (planar polarization mode) diagram, and carrying out single crystal structure analysis, wherein the reference is respectively shown in figures 2-6. Wherein the single crystal is characterized by unit cell parameters approximately equal to:

the single crystal belongs to a monoclinic system,α＝γ＝90°，β＝89.9633(16)°，P2₁space group, cell volume ofThe number z of asymmetric units in the unit cell is 2.

Example 2:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 1ml of isopropyl acetate, heating to 60 ℃ under stirring, slowly adding 1ml of methanol, stirring until the mixture is clear, stopping stirring after obtaining a clear solution, cooling to 0 ℃ in a manner of keeping the temperature constant for 4 hours every time the temperature is reduced by 5 ℃, standing, and crystallizing for 2 days to obtain a long rod-shaped single crystal. The single crystal and ritonavir intermediate raw materials are sampled to carry out X-ray powder diffraction detection, the single crystal is subjected to X-ray single crystal diffraction detection, differential scanning calorimetry detection and PLM image shooting, single crystal structure analysis is carried out, and the detection result is the same as that of the single crystal in the embodiment 1, and particularly, the detection results are shown in figures 2 to 6.

Example 3:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 2ml of isopropyl acetate, heating to 60 ℃ under stirring, slowly adding 1ml of methanol, stirring until the mixture is clear, stopping stirring after obtaining a clear solution, cooling to room temperature (25 ℃) in a manner of keeping the temperature constant for 4 hours every time the temperature is reduced by 5 ℃, standing, and crystallizing for 1 day to obtain long rod-shaped single crystals. The single crystal and ritonavir intermediate raw materials are sampled to carry out X-ray powder diffraction detection, the single crystal is subjected to X-ray single crystal diffraction detection, differential scanning calorimetry detection and PLM image shooting, single crystal structure analysis is carried out, and the detection result is the same as that of the single crystal in the embodiment 1, and particularly, the detection results are shown in figures 2 to 6.

Example 4:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 1ml of isopropyl acetate, heating to 60 ℃ under stirring, slowly adding 0.5ml of methanol, stirring until the mixture is clear, stopping stirring after obtaining a clear solution, cooling to 20 ℃ in a manner of keeping the temperature constant for 4 hours every time when the temperature is reduced to 5 ℃, standing, and crystallizing for 1 day to obtain long rod-shaped single crystals. The single crystal and ritonavir intermediate raw materials are sampled to carry out X-ray powder diffraction detection, the single crystal is subjected to X-ray single crystal diffraction detection, differential scanning calorimetry detection and PLM image shooting, single crystal structure analysis is carried out, and the detection result is the same as that of the single crystal in the embodiment 1, and particularly, the detection results are shown in figures 2 to 6.

Example 5:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 1ml of ethyl acetate, stirring, heating to 60 ℃, slowly adding 1ml of methanol, stirring until the mixture is clear, stopping stirring after obtaining a clear solution, cooling to room temperature (25 ℃) in a manner of keeping the temperature constant for 4 hours every time the temperature is reduced by 5 ℃, standing, and crystallizing for 3 days to obtain long rod-shaped single crystals. The single crystal and ritonavir intermediate raw materials are sampled to carry out X-ray powder diffraction detection, the single crystal is subjected to X-ray single crystal diffraction detection, differential scanning calorimetry detection and PLM image shooting, single crystal structure analysis is carried out, and the detection result is the same as that of the single crystal in the embodiment 1, and particularly, the detection results are shown in figures 2 to 6.

Example 6:

weighing 400mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 2ml of methanol, heating to 65 ℃ under stirring, stirring until the ritonavir intermediate is dissolved, slowly adding 1ml of ethyl acetate, keeping a clear solution, stopping stirring, cooling to 15 ℃ in a manner of keeping the temperature constant for 4 hours every time the temperature is reduced to 5 ℃, standing and crystallizing for 1 day to obtain a long rod-shaped single crystal. The single crystal and ritonavir intermediate raw materials are sampled to carry out X-ray powder diffraction detection, the single crystal is subjected to X-ray single crystal diffraction detection, differential scanning calorimetry detection and PLM image shooting, single crystal structure analysis is carried out, and the detection result is the same as that of the single crystal in the embodiment 1, and particularly, the detection results are shown in figures 2 to 6.

Example 7:

weighing 5g of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 25ml of methanol, heating to 60 ℃ under stirring, stirring until the ritonavir intermediate is clear, slowly adding 50ml of ethyl acetate, stopping heating, cooling to room temperature (25 ℃) under the condition of stirring in a room temperature environment, filtering, and drying at the room temperature to obtain 4.75g of white-like solid with the mass yield of about 95%; a sample was taken for X-ray powder diffraction and the single crystal obtained in examples 1 to 6 had the same XRPD but could not be subjected to single crystal testing.

Control group for preparing crystals of ritonavir intermediate

Control group 1:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 1ml of methanol, heating to 60 ℃ under stirring, stirring until the ritonavir intermediate is dissolved clearly to obtain a clear solution, stopping stirring, cooling to room temperature (25 ℃) in a manner of keeping the temperature constant for 4 hours every time the ritonavir intermediate is cooled to 5 ℃, standing and crystallizing for 2 days to obtain white flocculent solid with poor appearance, and referring to fig. 7, obtaining no crystal suitable for single crystal test.

Control group 2:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 2ml of ethanol, heating to 60 ℃ under stirring, stirring until the ritonavir intermediate is dissolved clearly to obtain a clear solution, stopping stirring, cooling to room temperature (25 ℃) in a constant temperature manner of 4 hours after cooling to 5 ℃, standing for crystallization for 2 days to obtain a white solid with poor morphology, wherein crystals suitable for single crystal test are not obtained.

Control group 3:

weighing 100mg ritonavir intermediate, adding into a glass container, adding 1ml ethyl acetate, heating to 60 ℃ under stirring, and stirring for 1h to ensure that the ritonavir intermediate cannot be dissolved clearly and crystals suitable for single crystal test are not obtained.

Control group 4:

weighing 100mg ritonavir intermediate, adding into a glass container, adding 1ml isopropyl acetate, heating to 60 ℃ under stirring, and stirring for 1h to obtain crystals suitable for single crystal test.

Control group 5:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 2ml of isopropanol, heating to 60 ℃ under stirring, stirring until the ritonavir intermediate is dissolved clearly to obtain a clear solution, stopping stirring, cooling to room temperature (25 ℃) in a constant temperature manner for 4 hours after cooling to 5 ℃, standing for crystallization for 2 days to obtain white floccule, which has poor appearance and does not obtain crystals suitable for single crystal testing.

Control group 6:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 1ml of methanol, heating to 60 ℃ under stirring, stirring until the ritonavir intermediate is dissolved clearly to obtain a clear solution, adding 2ml of ethyl formate, stopping stirring, standing, cooling to room temperature (25 ℃) in a manner of keeping the temperature for 4 hours after cooling to 5 ℃, standing, crystallizing for 2 days, drying to obtain a jelly, and obtaining a crystal which is poor in appearance and suitable for single crystal test.

Control group 7:

weighing 100mg ritonavir intermediate, adding into a glass container, adding 1ml methanol, heating to 60 ℃ under stirring, stirring until the ritonavir intermediate is dissolved clearly to obtain a clear solution, adding 6ml ethyl acetate, and separating out a large amount of white floccules with poor morphology without obtaining crystals suitable for single crystal testing.

Control group 8:

weighing 25mg ritonavir intermediate, adding into a glass container, adding 75ul methanol and 75ul ethyl acetate, heating to 60 ℃ under stirring, and not dissolving to obtain crystals suitable for single crystal test.

Control group 9:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 1ml of ethyl acetate, heating to 80 ℃ under stirring, slowly adding 1ml of methanol, stirring until the mixture is clear, stopping stirring after obtaining a clear solution, cooling in a constant temperature manner for 4 hours after cooling to 5 ℃, standing for crystallization, and finding that a large amount of white solid is separated out when the temperature is reduced to 60 ℃, the appearance is poor, and crystals suitable for single crystal test are not obtained. The inventor finds that when the heating temperature is too high, methanol is volatilized due to high temperature when the temperature is slowly reduced, a large amount of solid impurities are separated, and crystals suitable for single crystal testing are not obtained.

Control group 10:

weighing 100mg of ritonavir intermediate, adding the ritonavir intermediate into a glass container, adding 1ml of ethyl acetate, stirring, heating to 60 ℃, slowly adding 1ml of methanol, stirring until the mixture is clear to obtain a clear solution, then stopping stirring, cooling to room temperature (25 ℃) in a cooling rate manner of 10 ℃/h, standing for crystallization, and precipitating a large amount of white solid impurities at room temperature, wherein the morphology is poor, and crystals suitable for single crystal test are not obtained. The inventor finds that when the temperature reduction rate is too fast, the saturation is higher when the temperature is reduced to room temperature, a large amount of solid impurities are separated out, and crystals suitable for single crystal testing are not obtained.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.