WO2017177781A1 - Ahu377 crystal forms, and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to AHU377 crystal forms, and a preparation method therefor and the use thereof. Provided are AHU377 crystal forms III and IV, and the crystal forms III and IV have a good stability, a low hygroscopicity, a high impurity removal capacity, and a good purifying effect, and have a very high economic value.

Description

Crystal form of AHU377 and preparation method and use thereof Technical field

The invention belongs to the field of chemical medicine, and particularly relates to a crystal form of AHU377, a preparation method and use thereof.

Background technique

AHU377, chemical name is (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, the structural formula is as shown in formula (I):

Patent US5354892A discloses for the first time the preparation of the AHU377 structure and its sodium salt; however, the AHU377 crystal form is not involved in this patent.

Patent CN102702119A discloses a dual-acting complex LCZ696 having the structural formula shown in formula (II). The complex has AHU377 and valsartan as active ingredients, and the two active ingredients are connected by hydrogen bonding. The patent also discloses a method for preparing LCZ696 using AHU377 or a salt thereof. LCZ696 has been clinically proven to be useful in the treatment of a variety of cardiovascular and/or renal diseases. Clinical data suggest that LCZ696 is expected to be the drug of choice for anti-heart failure treatment.

The inventors summarized the prior art and found that AHU377 exists in the form of a thick substance at room temperature. In the process of industrial production of LCZ696, the transfer and quantification of the thick AHU377 raw material has insurmountable operational difficulties. The prior art can only achieve the purpose of material transfer and accurate quantification by preparing AHU377 as a solid salt first, but the subsequent preparation of LCZ696 still needs to break the salt into AHU377 free acid. The existing process is not only cumbersome to operate, but also introduces a large amount of impurity ions, which is not conducive to process quality control.

Based on the problems of the prior art, finding the solid form of AHU377 is convenient for accurate quantification and transfer in the LCZ696 preparation process, avoiding the introduction of impurity ions, and simplifying the process.

Summary of the invention

The technical problem to be solved by the present invention is to provide a new crystal form of AHU377 suitable for pharmaceutical research and industrial production.

In order to solve the above technical problems, the present invention adopts the following technical solutions:

It is an object of the present invention to provide a crystal form III of AHU377,

The X-ray powder diffraction pattern of the crystal form III measured by CuKα ray has a characteristic peak at a 2theta value of 6.1 ° ± 0.2 °, 13.2 ° ± 0.2 °, and 19.0 ° ± 0.2 °.

According to a particular aspect of the invention, the X-ray powder diffraction pattern of Form III measured by CuKα ray is also one of 2theta values of 12.3°±0.2°, 21.1°±0.2°, 19.2°±0.2°. There are characteristic peaks at or at multiple locations. Preferably, the X-ray powder diffraction pattern of the crystalline form III measured by CuKα ray has a characteristic peak at 2theta values of 12.3°±0.2°, 21.1°±0.2°, and 19.2°±0.2°.

According to another specific aspect of the invention, the X-ray powder diffraction pattern of the crystalline form III measured by CuKα ray is also in the 2theta value of 9.6°±0.2°, 25.4°±0.2°, 19.8°±0.2°. One or more points have characteristic peaks. Preferably, the X-ray powder diffraction pattern of the crystalline form III measured by CuKα ray has a characteristic peak at 2theta values of 9.6°±0.2°, 25.4°±0.2°, and 19.8°±0.2°.

According to a most preferred aspect, the crystalline form III is an X-ray powder diffraction pattern measured by CuKα ray. It also has characteristic peaks at 2theta values of 12.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 19.2 ° ± 0.2 °, 9.6 ° ± 0.2 °, 25.4 ° ± 0.2 °, and 19.8 ° ± 0.2 °. In a specific embodiment according to this embodiment, the X-ray powder diffraction pattern of Form III is substantially identical to that of FIG.

In the present invention, the crystalline form III is a hemi-toluene solvate. Here, the hemi-toluene solvate means that the number of moles of toluene participating in the crystal lattice is 0.5 times the number of moles of the compound of the formula (I).

Still preferably, said Form III has a weight loss gradient of about 9.6% when heated to around 150 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.

Still preferably, said Form III begins to exhibit an endothermic peak near heating to about 48 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.

A second object of the present invention is to provide a process for preparing the AHU377 crystal form III, which comprises starting from a product solution for synthesizing AHU377, which comprises AHU377 and a reaction for synthesizing AHU377. a solvent, the method comprising the steps of:

(a) adding toluene to the product solution, followed by distillation under reduced pressure to remove the reaction solvent in the system as much as possible, and then selectively adding toluene to the system, lowering to room temperature or lower, and then adding an anti-solvent. Crystallization and separation to obtain a solid wet product; or directly, the product solution of the AHU377 is distilled off under reduced pressure to obtain an oily substance, and then toluene is added to the oil and heated to dissolve the oil, and finally cooled to room temperature or lower. Adding the anti-solvent, performing crystallization and separating to obtain a solid wet product;

(b) The solid wet product was dried at a temperature of 40 ° C or lower to obtain the AHU377 crystal form III.

Further, the anti-solvent may be, for example, a combination of one or more selected from the group consisting of n-heptane, mixed heptane, and cyclohexane.

Preferably, the reaction solvent has a boiling point lower than the boiling point of toluene. Commonly used reaction solvents such as dichloromethane, acetone, ethyl acetate and the like.

According to a specific aspect of the present invention, in the step (a), after adding the anti-solvent, the mixture is aged for more than 8 hours, filtered, and rinsed with an anti-solvent to obtain a solid wet product, the method further comprising performing the step (a) once. And after (b), one or more crystallizations are repeated, the crystallization is obtained by heating and dissolving the dried product obtained in the previous step in toluene, cooling to room temperature or less, adding an anti-solvent to crystallization, and finally filtering the precipitated crystal. Rinse with anti-solvent and dry.

Preferably, the vacuum distillation is carried out at 45 to 55 °C.

Preferably, crystallization is carried out at 10 to 25 °C.

A third object of the present invention is to provide an AHU377 Form IV,

The X-ray powder diffraction pattern of the Form IV measured by CuKα ray has a characteristic peak at a 2theta value of 11.6°±0.2°, 5.7°±0.2°, and 17.8°±0.2°.

According to a particular aspect of the invention, the X-ray powder diffraction pattern of Form IV measured by CuKα ray is also one of 2theta values of 23.1°±0.2°, 24.9°±0.2°, and 21.2°±0.2°. There are characteristic peaks at or at multiple locations. Preferably, the X-ray powder diffraction pattern of the Form IV measured by CuKα ray has a characteristic peak at 2theta values of 23.1°±0.2°, 24.9°±0.2°, and 21.2°±0.2°.

According to another specific aspect of the present invention, the X-ray powder diffraction pattern of the Form IV measured by CuKα ray is also in the 2theta value of 19.9°±0.2°, 9.6°±0.2°, 14.5°±0.2°. One or more points have characteristic peaks. Preferably, the X-ray powder diffraction pattern of the Form IV measured by CuKα ray has a characteristic peak at 2theta values of 19.9°±0.2°, 9.6°±0.2°, and 14.5°±0.2°.

According to a most preferred aspect, the X-ray powder diffraction pattern of Form IV measured by CuKα ray is also 2theta value of 23.1°±0.2°, 24.9°±0.2°, 21.2°±0.2°, 19.9°± There are characteristic peaks at 0.2°, 9.6°±0.2°, and 14.5°±0.2°. In a specific embodiment according to the embodiment, the X-ray powder diffraction pattern of Form IV is substantially identical to that of FIG.

In the present invention, the crystalline form IV is a mono-toluene solvate. Here, the mono-toluene solvate means that the number of moles of toluene participating in the crystal lattice is equal to the number of moles of the compound of the formula (I).

Still preferably, said Form IV has a weight loss gradient of about 17.8% when heated to around 180 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.

Still preferably, said Form IV begins to exhibit an endothermic peak near heating to about 48 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.

A fourth object of the present invention is to provide a method for preparing the AHU377 Form IV, which comprises the method (1) or the method (2) or the method (3):

Method (1), the crystalline form III of the present invention is stirred in a mixed solution of n-heptane and toluene to obtain Crystal form IV;

The method (2), the method comprises starting a product solution of AHU377, wherein the synthetic AHU377 product solution comprises AHU377 and a reaction solvent used in synthesizing AHU377, and the method comprises the following steps:

Toluene is added to the product solution, followed by distillation under reduced pressure to remove the reaction solvent in the system as much as possible, and then toluene is selectively added to the system, and the temperature is lowered to below room temperature, and the anti-solvent is added to perform crystallization and separation. Obtaining a solid wet product; or directly, the product solution of the AHU377 is distilled under reduced pressure to remove the reaction solvent to obtain an oil, and then adding toluene to the oil and heating to dissolve the oil, and then dropping to room temperature or lower, and finally adding the The anti-solvent is subjected to crystallization and separation to obtain a solid wet product which is directly used as a final product without drying, or is further subjected to one or more crystallizations to obtain a final product which is obtained by drying the solid wet product. Heating and dissolving in toluene, then falling below room temperature, adding anti-solvent for crystallization;

Method (3), preparing a toluene solution of AHU377, stirring at room temperature or lower, adding a seed crystal of Form IV, depositing a solid, and then selectively adding an anti-solvent to obtain the crystal form IV.

According to an aspect of the invention, the method for preparing Form IV comprises the method (1) and further comprises preparing the Form III using the above-described preparation method of Form III of the present invention.

Further, in the method (2), the anti-solvent may be a combination of one or more selected from the group consisting of n-heptane, mixed heptane, and cyclohexane. Preferably, the reaction solvent has a boiling point lower than the boiling point of toluene. Commonly used reaction solvents such as dichloromethane, acetone, ethyl acetate and the like. Preferably, the vacuum distillation is carried out at 45 to 55 °C. Preferably, crystallization is carried out at 10 to 25 °C.

Preferably, after the seed crystal of Form IV is added, the anti-solvent is added dropwise, after the addition is completed, the ripening is carried out, and finally, the product is centrifuged to obtain a final product.

The invention also provides a further preparation method of AHU377 crystal form III, which comprises the step of drying AHU377 crystal form IV at 40 ° C or lower.

In view of the conversion relationship between the AHU377 crystal form III and the AHU377 crystal form IV of the present invention, it can be reasonably predicted that the actually obtained product under certain conditions contains both AHU377 crystal form III and AHU377 crystal form IV.

A fifth object of the present invention is to provide a use of the above-described Form III or Form IV as described above or any ratio thereof in the preparation of AHU377 and valsartan complex.

A sixth object of the present invention is to provide a process for producing a composite of AHU377 and valsartan which is formed by mixing crystal form III as described above or form IV or valsartan as described above or any ratio thereof. Anti-heart failure drugs.

Due to the application of the above technical solutions, the present invention has the following advantages compared with the prior art:

The crystal form III and the crystal form IV of the AHU377 prepared by the invention have good stability, low wettability, strong impurity removal ability, good purification effect and strong economic value.

Form III and Form IV of AHU377 prepared by the present invention can be used for the preparation of anti-heart failure drug LCZ696. The difficulty in transferring and accurately quantifying the use of AHU377 thick material as a starting material in the prior art is overcome, and the process flow is simplified, which is of great significance for industrial production and quality control of LCZ696.

DRAWINGS

1 is an XRPD pattern of Form III prepared in Example 1;

2 is a TGA diagram of Form III prepared in Example 1;

3 is a DSC chart of Form III prepared in Example 1;

4 is a ¹ H NMR chart of Form III prepared in Example 1;

Figure 5 is an XRPD pattern of Form IV prepared in Example 4;

Figure 6 is a TGA diagram of Form IV prepared in Example 4;

Figure 7 is a DSC chart of Form IV prepared in Example 4;

Figure 8 is a ¹ H NMR chart of Form IV prepared in Example 4;

Figure 9 is a PLM diagram of Form IV prepared in Example 4.

detailed description

The present invention will be further described in detail below in conjunction with specific embodiments. The embodiments are intended to illustrate the basic principles, main features and advantages of the invention, and the invention is not limited by the following examples. The implementation conditions employed in the examples can be further adjusted according to specific requirements, and the unspecified implementation conditions are usually the conditions in the conventional experiment.

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric analysis

¹ H NMR: liquid nuclear magnetic

PLM: polarized light microscope

X-ray powder diffraction pattern of the present invention in Panalytical Empyrean X-ray powder Collected on the ejector, the test temperature is at a normal temperature, such as 25 ° C. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

X-ray reflection parameters: Cu, Kα

Kα1

1.540598; Kα2

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV)

Current: 40 milliamps (mA)

Scan range: from 3.0 to 40.0 degrees

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:

Scanning rate: 10 ° C / min;

Protective gas: nitrogen.

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

Scanning rate: 10 ° C / min;

Protective gas: nitrogen.

Example 1: Preparation of AHU377 Form III:

3.39 kg of the product solution of the synthesized AHU377 (the product solution solution containing about 726 g of AHU377, the solvent was dichloromethane) was weighed into a 20 L jacketed reaction vessel. Add 7.5 L of toluene, raise to 50 ° C, distill it under reduced pressure to the remaining 5 L volume, reduce to room temperature, add 2.5 L of toluene, add 1.2 L of n-heptane, and add 4.8 L of n-heptane after the solids are precipitated. Into the kettle. It was stirred and aged overnight, filtered and rinsed with 1 L of n-heptane and dried under vacuum at 40 °C. The dried solid was placed in a 20 L jacketed reaction vessel, 8.5 L of toluene was added, and the mixture was warmed to 50 ° C and then cooled to 20 ° C. Adding 1.36 L of n-heptane appeared turbid, adding 200 mL of toluene and re-raising to 50 ° C to dissolve, and cooling to 20 ° C spontaneous crystallization. 5 L of n-heptane was added dropwise to the kettle at a rate of 8 mL/min, and the mixture was aged overnight. Filtration and leaching with 1.5 L of n-heptane gave a wet product which was dried at 40 ° C under vacuum to give a solid product.

The nuclear magnetic data of Form III are as follows: ¹ H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.25 (dd, J = 7.8, 3.7 Hz, 3H), 7.15 (dd, J = 15.5, 7.4 Hz, 1H), 4.04 - 3.85 (m, 3H), 2.76 - 2.61 (m, 2H), 2.38 (t, J = 6.9 Hz, 2H), 2.35 - 2.20 (m, 4H), 1.76 (ddd, J = 13.7, 9.8, 3.9 Hz, 1H), 1.43 - 1.33 (m, 1H), 1.11 (t, J = 7.1 Hz, 3H), 1.05 (d, J = 7.1 Hz, 3H).

Upon examination, the solid product obtained in this example was Form III, and the X-ray powder diffraction data thereof is shown in Table 1. Its XRPD diagram is shown in Figure 1, its TGA diagram is shown in Figure 2, its DSC diagram is shown in Figure 3, and its nuclear magnetic diagram is shown in Figure 4.

Table 1

Theta	d interval	strength%
4.71	18.77	1.99
6.11	14.45	100.00
7.70	11.48	1.30
9.57	9.25	6.65
10.55	8.39	0.87
11.48	7.71	3.20
12.33	7.18	12.03
13.2	6.69	17.51
14.39	6.16	2.05
15.79	5.61	4.29
17.99	4.93	2.68
19.03	4.66	14.54
19.84	4.47	2.80
20.41	4.35	1.53
21.06	4.22	11.59
22.03	4.03	0.65
22.80	3.90	0.80
23.62	3.77	2.79
25.43	3.50	4.57
26.85	3.32	3.46
28.19	3.17	0.51
29.15	3.06	0.51
30.14	2.96	0.25

30.62	2.92	0.25
31.10	2.88	0.11
32.02	2.80	0.28
32.99	2.72	1.42
34.13	2.63	0.27
34.89	2.57	0.24
36.48	2.46	0.28
37.32	2.41	0.39
37.83	2.38	0.31
39.01	2.31	0.43

Example 2: Preparation of Form IV Seeds

100 mg of the solid of Form III obtained in Example 1 was added to 1 mL of a mixed solution of n-heptane and toluene in a volume ratio of 1:1, stirred at room temperature overnight, and centrifuged to obtain a solid product.

Upon examination, the solid product obtained in this example was Form IV, and its X-ray powder diffraction data is shown in Table 2.

Table 2

Theta	d interval	strength%
5.75	15.38	87.56
9.60	9.21	92.32
11.60	7.63	87.80
14.49	6.11	40.80
15.11	5.86	39.24
17.36	5.11	59.16
17.81	4.98	96.99
18.31	4.85	67.58
20.03	4.43	96.99
21.21	4.19	100.00
23.23	3.83	83.08
24.96	3.57	41.91
27.77	3.21	20.06
29.09	3.07	10.55

Example 3: Preparation of AHU377 Form IV

A product solution of 3.39 kg of synthetic AHU377 was weighed (the product solution contained about 726 g of AHU377 and the solvent was dichloromethane). 7.5 L of toluene was added, and the mixture was distilled under reduced pressure to 50 ° C to a remaining volume of 5 L, and the temperature was lowered to room temperature, and 2.5 L of toluene was added. 1.2 L of n-heptane was added, and after solids were precipitated, 4.8 L of n-heptane was added dropwise to the kettle. It was stirred and aged overnight, filtered and rinsed with 1 L of n-heptane and dried under vacuum at 40 °C. The dried solid was placed in a 20 L jacketed reaction vessel, 8.5 L of toluene was added, and the mixture was warmed to 50 ° C and then cooled to 20 ° C. Adding 1.36 L of n-heptane appeared turbid, adding 200 mL of toluene and re-raising to 50 ° C to dissolve, and cooling to 20 ° C spontaneous crystallization. 5 L of n-heptane was added dropwise to the kettle at a rate of 8 mL/min, and the mixture was aged overnight. Filtration and rinsing with 1.5 L of n-heptane gave the wet solid product. Upon examination, the wet product obtained in this example was in the same crystal form as the crystal form obtained in Example 2, that is, Form IV.

Example 4: Preparation of AHU377 Form IV

255.0 g of AHU377 methanol solution (concentration: 31.9%, obtained from a batch of AHU377 Form III dissolved in methanol) was weighed and placed under reduced pressure at 50 ° C, and concentrated to dryness. 1 L of toluene was added, the solution was dissolved, and concentrated under reduced pressure to a volume of about 800 mL, cooled to room temperature and stirred overnight. AHU377 Form IV seed crystals (obtained according to the method of Example 3) were added to rapidly precipitate the solid. 500 mL of n-heptane was added using a metering pump at a drop rate of 3 mL/min. After the addition was completed, the ripening was continued and centrifugation gave a solid product.

The nuclear magnetic data are as follows: ¹ H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.58 (d, J = 8.2 Hz) , 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.28 - 7.22 (m, 5H), 7.16 (dd, J = 15.2, 7.2 Hz, 4H) , 4.07–3.82 (m, 3H), 2.77–2.60 (m, 2H), 2.38 (t, J=6.8 Hz, 2H), 2.32–2.24 (m, 6H), 1.76 (ddd, J=13.8, 9.8, 4.1 Hz, 1H), 1.43 - 1.34 (m, 1H), 1.25 (s, 1H), 1.11 (t, J = 7.1 Hz, 3H), 1.05 (d, J = 7.1 Hz, 3H), 0.86 (t, J=6.9Hz, 0H).

Upon examination, the solid product obtained in this example was Form IV, and its X-ray powder diffraction data is shown in Table 3. Its XRPD diagram is shown in Fig. 5. Its TGA diagram is shown in Fig. 6, its DSC diagram is shown in Fig. 7, and nuclear magnetic diagram is shown in Fig. 8.

table 3

Theta	d interval	strength%
5.70	15.49	84.94
9.61	9.20	15.32
10.41	8.50	2.39

11.60	7.63	100.00
13.20	6.71	3.65
14.53	6.10	12.61
15.17	5.84	7.21
15.82	5.60	3.63
16.85	5.26	5.89
17.83	4.97	59.58
18.85	4.71	8.03
19.55	4.54	15.97
19.94	4.45	12.17
21.24	4.18	26.57
21.92	4.05	11.80
23.09	3.85	39.69
24.33	3.66	6.74
24.99	3.56	38.08
26.51	3.36	5.37
27.81	3.21	5.30
28.64	3.12	7.82
29.95	2.98	6.27
30.66	2.92	9.06
31.16	2.87	2.30
32.70	2.74	1.54
34.38	2.61	5.87
36.51	2.46	1.68
39.24	2.30	1.58

Example 5 Example of Preparing LCZ696 Using AHU377 Form III as Raw Material

24.3 mg of AHU377 Form III and 23.2 mg of valsartan were placed in a glass vial, 6.3 mg of NaOH was added, then 2.0 mL of acetone was added, and the mixture was stirred at room temperature overnight, and the solid was separated to obtain LCZ696.

Example 6 Example of Preparing LCZ696 Using AHU377 Form IV as Raw Material

6.2 mg of AHU377 Form IV and 23.0 mg of valsartan were placed in a glass vial and then added 6.2 mg NaOH, then 2.0 mL of acetone was added and allowed to stand at room temperature overnight, and the solid was isolated to give LCZ 696.

Example 7 APL377 Form IV PLM

The AHU377 crystal form IV obtained in Example 1 of the present invention was subjected to a polarizing microscope photograph, as shown in FIG. From the results of the polarizing microscope, the AHU377 crystal form IV of the present invention is in the form of a sheet, has a good crystal form, and has a distinct crystal form advantage over the prior art oil.

Example 8 Purification of Form AIV of Form AHU377

The preparation of AHU377 Form IV can serve as a purification agent for the drug substance. As shown in Preparation Example 4 of Form IV, the purity was improved from 96.05% to 99.13% by HPLC purity test, and the purification effect was remarkable, as shown in Table 6:

Table 4 Comparison of purity before and after purification of crystal form IV

	Starting materials	Form IV
Relative retention time	area(%)	area(%)
0.64 (impurities)	0.05	0.05
0.85 (impurities)	0.05	0.03
1.00 (AHU377)	96.05	99.13
1.24 (impurities)	3.79	0.79
2.84 (impurities)	0.05	\

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (22)

1. AHU377 crystal form III, AHU377 structural formula is shown in formula (I):

   

   It is characterized in that the X-ray powder diffraction pattern of the crystal form III measured by CuKα ray has a characteristic peak at a 2theta value of 6.1°±0.2°, 13.2°±0.2°, and 19.0°±0.2°.
2. The crystal form III of AHU377 according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form III measured by CuKα ray is further at a 2theta value of 12.3°±0.2°, 21.1°±0.2°, One or more of 19.2 ° ± 0.2 ° has a characteristic peak.
3. The crystal form III of AHU377 according to claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystal form III measured by CuKα ray is still 2theta value of 9.6°±0.2°, 25.4°±0.2. °, one or more of 19.8 ° ± 0.2 ° has a characteristic peak.
4. The crystal form III of AHU377 according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form III measured by CuKα ray is further at a 2theta value of 12.3°±0.2°, 21.1°±0.2°, 19.2°±0.2°, 9.6°±0.2°, 25.4°±0.2°, and 19.8°±0.2° have characteristic peaks.
5. The crystal form III of AHU377 according to any one of claims 1 to 4, wherein the crystal form III is a hemi-toluene solvate.
6. A method for preparing AHU377 crystal form III according to any one of claims 1 to 5, wherein the method comprises starting a product solution of AHU377, wherein the synthetic AHU377 product solution comprises AHU377 and A reaction solvent used in the synthesis of AHU377, the method comprising the steps of:

   (a) adding toluene to the product solution, followed by distillation under reduced pressure to remove the reaction solvent in the system as much as possible, and then selectively adding toluene to the system, lowering to room temperature or lower, and then adding an anti-solvent. Crystallization and separation to obtain a solid wet product; or directly, the product solution of the AHU377 is distilled off under reduced pressure to obtain an oily substance, and then toluene is added to the oil and heated to dissolve the oil, and finally cooled to room temperature or lower. Adding the anti-solvent, performing crystallization and separating to obtain a solid wet product;

   (b) The solid wet product was dried at a temperature of 40 ° C or lower to obtain the AHU377 crystal form III.
7. The method for preparing Form AIII of AHU377 according to claim 6, wherein the anti-solvent is a combination of one or more selected from the group consisting of n-heptane, mixed heptane and cyclohexane.
8. The method for preparing AHU377 crystal form III according to claim 6, wherein the reaction solvent has a boiling point lower than a boiling point of toluene.
9. The method for preparing AHU377 crystal form III according to any one of claims 6 to 8, wherein in step (a), after adding an anti-solvent, the mixture is aged for more than 8 hours, filtered, and rinsed with an anti-solvent. Obtaining a solid wet product, the method further comprising, after performing one step (a) and (b), repeating one or more crystallizations, wherein the dried product obtained in the previous step is heated and dissolved in toluene, and then After cooling to room temperature or lower, an anti-solvent is added for crystallization, and finally, the precipitated crystals are filtered, rinsed with an anti-solvent, and dried.
10. The structural formula of AHU377 crystal form IV and AHU377 is as shown in formula (I):

    

    It is characterized in that the X-ray powder diffraction pattern of the crystalline form IV measured by CuKα ray has a characteristic peak at a 2theta value of 11.6°±0.2°, 5.7°±0.2°, and 17.8°±0.2°.
11. The crystal form IV of AHU377 according to claim 10, wherein the X-ray powder diffraction pattern of the crystal form IV measured by CuKα ray is still 2theta value of 23.1°±0.2°, 24.9°±0.2°, One or more of 21.2 ° ± 0.2 ° has a characteristic peak.
12. The crystal form IV of AHU377 according to claim 10 or 11, wherein the X-ray powder diffraction pattern of the crystal form IV measured by CuKα ray is still 2theta value of 19.9°±0.2°, 9.6°±0.2. °, one or more of 14.5 ° ± 0.2 ° has a characteristic peak.
13. The crystal form IV of AHU377 according to claim 10, wherein the X-ray powder diffraction pattern of the crystal form IV measured by CuKα ray is still 2theta value of 23.1°±0.2°, 24.9°±0.2°, There are characteristic peaks at 21.2 ° ± 0.2 °, 19.9 ° ± 0.2 °, 9.6 ° ± 0.2 °, and 14.5 ° ± 0.2 °.
14. The crystalline form IV of AHU377 according to any one of claims 10 to 13, wherein the crystalline form IV is a mono-toluene solvate.
15. A method for preparing a crystalline form IV of AHU377 according to any one of claims 12 to 18, wherein the method for preparing the crystalline form IV comprises the method (1) or the method (2) or the method (3) ):

    The method (1), the crystal form III according to any one of claims 1 to 5 is stirred in a mixed solution of n-heptane and toluene to obtain the crystal form IV;

    The method (2), the method comprises starting a product solution of AHU377, wherein the synthetic AHU377 product solution comprises AHU377 and a reaction solvent used in synthesizing AHU377, and the method comprises the following steps:

    Toluene is added to the product solution, followed by distillation under reduced pressure to remove the reaction solvent in the system as much as possible, and then toluene is selectively added to the system, and the temperature is lowered to below room temperature, and the anti-solvent is added to perform crystallization and separation. Obtaining a solid wet product; or directly, the product solution of the AHU377 is distilled under reduced pressure to remove the reaction solvent to obtain an oil, and then adding toluene to the oil and heating to dissolve the oil, and then dropping to room temperature or lower, and finally adding the The anti-solvent is subjected to crystallization and separation to obtain a solid wet product which is directly used as a final product without drying, or is further subjected to one or more crystallizations to obtain a final product which is obtained by drying the solid wet product. Heating and dissolving in toluene, then falling below room temperature, adding anti-solvent for crystallization;

    Method (3), preparing a toluene solution of AHU377, stirring at room temperature or lower, adding a seed crystal of Form IV, depositing a solid, and then selectively adding an anti-solvent to obtain the crystal form IV.
16. The method for preparing a crystalline form IV of AHU 377 according to claim 15, wherein the method for preparing the crystalline form IV comprises the method (1) and further comprising the use of the crystalline form according to any one of claims 8 to 11. Form III is prepared to prepare Form III.
17. The method for preparing Form AIV of AHU377 according to claim 15, wherein in the method (2), the anti-solvent is one or more selected from the group consisting of n-heptane, mixed heptane and cyclohexane. Combination of species.
18. The method for preparing AHU377 Form IV according to claim 15, wherein in the method (2), the boiling point of the reaction solvent is lower than the boiling point of toluene.
19. The method for preparing Form AIV of AHU377 according to any one of claims 15 to 18, wherein after adding the seed crystal of Form IV, the anti-solvent is added dropwise, and after the addition is completed, the aging is performed. Finally centrifuge and centrifuge the product as the final product.
20. A process for the preparation of Form AIII of AHU377 according to any one of claims 1 to 5, which comprises placing AHU377 Form IV according to any one of claims 10 to 40 in 40 The drying step is carried out below °C.
21. Form A according to any one of claims 1 to 5 or Form IV according to any one of claims 10 to 14 or any ratio thereof in the preparation of AHU377 and valsartan complex the use of.
22. A method for producing a composite of AHU377 and valsartan, characterized in that it is obtained by the crystal form III according to any one of claims 1 to 5 or the method according to any one of claims 10 to Form IV or a mixture thereof in any ratio is combined with valsartan to form an anti-heart failure drug.

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