WO2019127994A1 - Sacubitril sodium salt, eutectic of sacubitril free acid and acetic acid, crystal form thereof, method for preparing crystal form, and use thereof - Google Patents

Abstract

The present invention relates to a sacubitril sodium salt as represented by formula IV, a eutectic of sacubitril free acid and acetic acid, a crystal form of the eutectic and a preparation method for the crystal form, and a method for using the eutectic having the described crystal form to prepare LCZ696. The eutectic provided by the present invention may form a stable crystal form and does not easily absorb moisture; the eutectic has good thermal stability, facilitates the purification of sacubitril, is good for storage, and is helpful in synthesizing LCZ696. Moreover, the eutectic provided by the present invention may be directly used for preparing LCZ696 without additional ion exchange, thus being helpful in controlling the type and content of counter cations.

Description

Method for preparing eutectic of sacuronium sodium salt, sacurbitic free acid and acetic acid, crystal form and crystal form thereof Technical field

The invention relates to the field of pharmaceutical polymorphs, in particular to a sulphate sodium salt, a eutectic of sabbitix free acid and acetic acid, a crystal form thereof, a preparation method and use of the crystal form.

Background technique

LCZ696 is a new antihypertensive drug developed by Novartis, which contains Novartis's Daiwen (common name: valsartan) and experimental drug Sacubitril (AHU-377). Two components, in which Shakubiqu can block the action of two peptides that threaten to lower blood pressure, the drug was approved by the US FDA on July 7, 2015 for heart failure with reduced ejection fraction (heart failure) Patients, reduce the risk of cardiovascular death and hospitalization for heart failure. LCZ696 is usually obtained by co-crystallizing Diovan and Sacubitril in an equimolar ratio in a mixed solvent of an excess of aqueous sodium hydroxide solution and an organic solvent. The chemical composition of LCZ696 is shown in Formula II, and its chemical composition is Diovan: Sacubitril: Na. :H ₂ O=1:1:3:2.5.

Shakubiqu has received extensive attention as an important component of LCZ696. The chemical name of Shakubiqu is:

4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid, Chinese name: 4-{[( 2S,4R)-1-(4-biphenyl)-5-ethoxy-4-methyl-5-oxo-2-pentyl]amino}-4-oxobutanoic acid, the chemical structure of which is Formula III shows:

Due to the influence of long-chain alkyl groups in its molecular structure, the Shakubiqu is a colorless viscous liquid in the large production process, which makes it difficult to purify the sand and the quality is difficult to control. Not conducive to purification, storage and subsequent development of LCZ696 formulations. Moreover, the inventors have intensively studied and found that the sodium salt formed by Shakubiqu and sodium hydroxide has high hygroscopicity and cannot form a stable crystal form, which is not conducive to quality control and storage. In addition, although the patents US Pat. No. 5,217,996, WO2006086456, WO2007056546, and WO2007056546 disclose that Shakupit can also be prepared into various salt type compounds, such as alkali metal salts, alkaline earth metal salts, alkylamine salts, hydroxyalkylamine salts, etc., however, The LCZ696 prepared from the obtained salt type compound needs to be further freed, thereby causing residue of other cations or amines, and it is not suitable to control the content of other counter cations and residual organic amines of LCZ696.

Therefore, it is necessary to develop a more stable aggregation state of Shakubite sodium salt, in order to overcome the difficulty in purifying and being hygroscopic, difficult to form stable crystal form, difficult to control, and unfavorable for storage. And defects that do not meet the development needs of LCZ696.

Summary of the invention

In order to achieve the above object, the present invention provides a eutectic as shown in Formula IV,

The present invention also provides a crystal form of a eutectic according to Formula IV, the powder X-ray diffraction spectrum of the eutectic having the crystal form having the following characteristic peak represented by 2θ angle: 5.3 ° ± 0.2 °, 10.6 °±0.2°, 19.9±0.2°, 20.8±0.2°.

In some embodiments, the powder X-ray diffraction spectrum of the eutectic having the crystalline form has the following characteristic peaks represented by 2 theta angles: 5.3° ± 0.2°, 10.6° ± 0.2°, 10.9° ± 0.2°, 17.5 ±0.2°, 19.9±0.2°, 20.3±0.2°, 20.8±0.2°, 22.2±0.2°.

In a preferred embodiment, the powder X-ray diffraction spectrum of the eutectic having the crystalline form has the following characteristic peaks represented by the 2 theta angle: 5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 10.9 ° ± 0.2 ° , 12.3 ° ± 0.2 °, 14.8 ° ± 0.2 °, 15.9 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.5 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.4 ° ± 0.2 °, 19.9 °±0.2°, 20.3°±0.2°, 20.8°±0.2°, 21.6°±0.2°, 21.9°±0.2°, 22.2°±0.2°, 26.9°±0.2°, 27.3±0.2°, 27.7°±0.2 °.

In some embodiments, each characteristic peak in the powder X-ray diffraction spectrum of the eutectic having the crystalline form has a diffraction intensity as shown in the following table:

2θ angle (°)	Relative diffraction intensity (%)
5.3±0.2°	40.8
10.6±0.2°	83.2
10.9±0.2°	24.6
12.3±0.2°	18.8
14.8 ± 0.2 °	18.8
15.9±0.2°	15.3
16.9±0.2°	14.1
17.1±0.2°	15.5

17.5±0.2°	25.4
18.8±0.2°	8.2
19.4±0.2°	14.1
19.9±0.2°	62.3
20.3±0.2°	21.7
20.8±0.2°	100.0
21.6±0.2°	13.9
21.9±0.2°	11.9
22.2 ± 0.2 °	25.4
26.9 ± 0.2 °	16.5
27.3±0.2°	12.6
27.6 ± 0.2 °	13.8

In some embodiments, the eutectic having the crystalline form has a melting range of 118 to 120 ° C and a DSC peak temperature of 119.01 ° C.

It is well known to those skilled in the art that the diffraction intensities within ±20% of the relative diffraction intensities shown by the crystalline form XRD of the present application are within the tolerances of the relative XRD relative diffraction intensity of the present invention.

The invention also provides a preparation method of a eutectic having the above crystal form, comprising the steps of: dissolving the shakubic acid in methylene chloride, adding sodium acetate, and incubating the reaction at 30-35 ° C, and then The filtrate was filtered and collected, and the resulting filtrate was added to n-heptane and crystallised.

In some embodiments, the reaction time is from 0.5 to 2 hours, preferably 1 hour.

In some embodiments, the resulting filtrate is added to n-heptane at 0-5 °C.

In some embodiments, the crystallization is carried out in the range of 0 to 5 °C.

In some embodiments, the step of filtering and/or drying the resulting crystals is also included after crystallization.

In some embodiments, the molar ratio of shakubiqu to sodium acetate is 1: (1.0 to 1.2), preferably 1: 1.1.

In some embodiments, the ratio of the moles of sirolimus to the volume of methylene chloride is 1 mol: (1 to 2) L, 1 mol: 1.5 L.

In some embodiments, the volume ratio of dichloromethane to n-heptane is 1: (5-15), preferably 1:10.

The invention also provides the use of a eutectic as shown in Formula IV in the preparation of LCZ696.

The invention also provides the use of a eutectic as shown in Formula IV having the above crystalline form for the preparation of LCZ696.

In some embodiments, the preparation of LCZ696 in the above use is carried out by dissolving the eutectic having the above crystal form in a mixed solvent of isopropyl acetate and acetone, adding the valsartan after the temperature is dissolved, and then adding dropwise An aqueous solution of sodium hydroxide is distilled off, and a part of the solvent is distilled off, and then isopropyl acetate is added, and the step of distilling off the solvent and adding isopropyl acetate is repeated for 2 to 3 times, followed by cooling and crystallization, and drying by filtration. For example, vacuum drying gives LCZ696.

Preferably, the molar ratio of the eutectic to valsartan is from 1:0.95 to 1.10, preferably 1:1.05.

Preferably, the molar ratio of eutectic to sodium hydroxide is from 1:2.25 to 3.00, preferably 2.5.

Preferably, the crystallization is carried out at a temperature of 20 to 30 ° C, preferably at a temperature of 25 ° C.

Preferably, the aqueous sodium hydroxide solution has a mass concentration of 10%.

Preferably, the solvent is distilled off using vacuum distillation.

Preferably, the step of distilling off the solvent is carried out at a temperature of 35 ± 5 ° C; when the isopropyl acetate is added, the temperature of the reaction system is 40 ± 3 ° C.

Preferably, after the step of distilling off the solvent and adding isopropyl acetate, a step of keeping warming is further included, preferably a holding time of 0.5 hours.

The beneficial effects of the invention are:

(1) The eutectic having the crystal form of the present invention can be stably present and is not easy to absorb moisture, and the eutectic has good thermal stability, is convenient for purifying the sulco, and is convenient for storage, and is useful for synthesizing LCZ696.

(2) The eutectic having the crystalline form of the present invention can be directly used for the preparation of LCZ696 without additional ion exchange, which helps to control the type and content of the counter cation.

DRAWINGS

1 is a ¹ H NMR chart of a eutectic prepared in Example 1 of the present invention;

2 is an XPRD pattern of the eutectic prepared in Example 1 of the present invention;

Figure 3 is a DSC chart of the eutectic prepared in Example 1 of the present invention;

4 is an XPRD chart of the LCZ696 prepared in Example 2 of the present invention;

Figure 5 is a DSC chart of LCZ696 prepared in Example 2 of the present invention.

Detailed ways

In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described below in conjunction with the specific embodiments and the accompanying drawings.

The sulphate used in the examples was synthesized according to the preparation method disclosed in U.S. Patent 5,217,996.

Instrument information used in the examples:

¹ H NMR was measured using a Brukeravance 400 nuclear magnetic resonance instrument;

Powder XRD diffraction was measured by PANalytical "X'pert Powder" powder X-ray diffractometer, copper palladium, incident wavelength: 1.54 angstroms;

Atomic emission spectroscopy was measured using a Thermo Fisher inductively coupled plasma (ICP) atomic emission spectrometer;

The DSC test was carried out using a METTLER TOLEDO differential scanning calorimeter with a sample loading of 5.00 mg and a heating rate of 10.00 K/min.

The KF method for moisture content testing was carried out using a METTLER TOLEDO Karl Fischer moisture tester by coulometric method and volumetric method.

The high performance liquid chromatograph model is Waters 2695.

The acetic acid content of the eutectic was measured by gas chromatography headspace method, and the gas chromatograph model was Agilent-7890.

The following is an operation example of the present invention.

Comparative Example: Preparation of Shakubite Sodium Salt

Add 50 mL of ethanol, 50 mL of tetrahydrofuran, 40.0 g of Sacurbitium free acid oil to the reaction flask, stir and dissolve, add 6 mL of 2 mol/L sodium hydroxide aqueous solution, and react at room temperature for 20 hours at 20-25 ° C for 1 hour. After 50 mL of solvent was removed by pressure, a flocculent solid was formed, and the obtained flocculent solid was filtered under a nitrogen stream, and dried under vacuum to obtain 3.91 g of sacurbitium sodium salt, the yield was 90%, and the chromatographic purity was 99.1%.

Example 1: Preparation of eutectic IV of shakupitide sodium salt, shakupitide free acid and acetic acid

Into the reaction flask, 150 mL of dichloromethane, 41.1 g of a free acid oil of sakubitin was added, and the mixture was stirred and dissolved, and then 9.0 g of anhydrous sodium acetate was added thereto, and the mixture was heated to 30 to 35 ° C for 1 hour, and the heat retention was completed, followed by filtration. Add 1500 mL of n-heptane to another reaction flask and cool to 0-5 ° C. At this temperature, the dichloromethane solution obtained by the previous step filtration is slowly added dropwise to n-heptane, and the temperature is controlled to 0 to 5. Incubate at °C for 1 hour. Filtration and vacuum drying gave eutectic IV 38 g, yield 83%, chromatographic purity 99.3%.

The eutectic obtained in Example 1 was taken in parallel, and the moisture content of the eutectic was measured by Karl Fischer moisture meter to be 0.15 wt.% to 0.30 wt.%, which was far from satisfying at least one water in the eutectic. The mass percentage requirement of the molecule proves that the eutectic molecular composition does not contain crystal water. As shown in FIG. 1 , the NMR of the eutectic obtained in this example represents 2.2 ppm of two hydrogens of the sulcatalymethylene group, and the integral thereof is 1.98; the 1.80 ppm represents the methyl group in the acetic acid. 3 hydrogens with an integral of 1.48, so the ratio of Shakubi to acetate is 1.98/2:1.48/3=2:1 according to the integral ratio, ie the mole of Shakubi and acetic acid in the eutectic The ratio is 2:1.

In addition, the content of acetic acid in the eutectic was 6.58 wt.% by gas chromatography headspace method, which was consistent with the theoretical percentage content (6.55 wt.%) of 2 molecules of acetic acid in the eutectic IV, which indirectly proved the eutectic IV contains 2 molecules of acetic acid.

Table 2 below shows the sodium ion content data of the eutectic obtained in Example 1 by atomic emission spectrometry (ICP). Samples 1 and 2 are two samples randomly obtained from the eutectic obtained in Example 1, respectively. The samples were measured in parallel 3 times. The results show that the average content of sodium ions in the eutectic obtained in Example 1 was 3.69 wt.%, and the molar ratio of the sulbac and the sodium ions was calculated to be 4:3.

Table 2 Statistical table of parallel test results of ICP atomic emission spectrometry

The powder X-ray diffraction spectrum of the eutectic obtained in this example is shown in Fig. 2, wherein the 2θ angle of the characteristic peak and the relative diffraction intensity are shown in Table 3 below:

Table 3 shows the characteristic peak parameters of the X-ray diffraction pattern of the eutectic obtained in Example 1.

2θ angle (°)	Relative diffraction intensity (%)
5.32	40.8
10.60	83.2
10.96	24.6
12.35	18.8
14.85	18.8
15.90	15.3
16.95	14.1
17.19	15.5
17.53	25.4
18.80	8.2
19.45	14.1
19.93	62.3
20.32	21.7
20.80	100.0
21.62	13.9
21.95	11.9
22.22	25.4
26.95	16.5

27.33	12.6
27.66	13.8

The eutectic obtained in this example has a melting point of 118-120 ° C and a DCS peak of 119.01 ° C, as shown in FIG. 3 .

Table 4 is a comparison table of the hygroscopicity of the product obtained in the comparative example and the sample obtained in Example 1. It can be seen from the table that the eutectic obtained in the present application has little change in quality after being placed in a room temperature and high humidity environment, and the sand bank in the comparative example It is 20% heavier than the sodium salt and shows strong hygroscopicity.

Table 4 Comparative table of hygroscopicity of the product obtained in Example 1 and the product obtained in Example 1 (expressed by weight of compound, ambient temperature 25 ° C, relative humidity 75%)

Example 2: Preparation of LCZ696 from eutectic IV

The eutectic IV (64 g, 142 mmol) prepared by the method described in Example 1 was dissolved in a mixed solvent of 60 mL of isopropyl acetate and 1220 mL of acetone, and the mixture was heated to 50-55 ° C, stirred and dissolved, and then valsartan (63 g) was added. 145 mmol), then 142 g of an aqueous sodium hydroxide solution (10%, 355 mmol) was added dropwise at this temperature, and the mixture was kept at 40 to 45 ° C for 2 hours, and then cooled to room temperature (25 to 30 ° C) for 2 hours. After the end of the heat preservation, the temperature was raised to 40±3° C., 600 mL of isopropyl acetate was added dropwise, and the mixture was immersed at 40±3° C. for 0.5 hour. At the end of the heat preservation, 760 mL of solvent was removed under reduced pressure at a temperature of 35 ± 5 °C. After the completion, the temperature was raised to 40±3° C., 920 mL of isopropyl acetate was added dropwise, and the temperature was maintained at 40±3° C. for 0.5 hour. At the end of the heat preservation, 1200 mL of solvent was decompressed under reduced pressure of 35±5° C., and then the temperature was raised to 40±3° C., 1200 mL of isopropyl acetate was added dropwise, and the mixture was kept for 0.5 hour. Then, the temperature was controlled at 35 ± 5 ° C, and 1200 mL of solvent was removed under reduced pressure. After the release, cool down to 20-25 ° C for 3 hours. The end of the thermal crystallization is completed, and the mixture is filtered under reduced pressure to obtain a wet product. The wet product was dried under reduced pressure at 35 ° C for 12 hours in an oven to obtain 116 g of LCZ696 finished product, the yield was 85%, and the HPLC purity was 99.94%. The X-ray powder diffraction and DSC data of the obtained LCZ696 are shown in Fig. 4 and Fig. 5, which are consistent with the data reported by Novartis, and the crystal form is consistent with that reported by Novartis.

The data of the components of the obtained LCZ696 are shown in the following table:

	Shakubi content	Valsartan content	Sodium ion content	Moisture content
Theoretical value	42.8%	45.3%	7.2%	4.7%
Measured value	42.7%	45.2%	7.3%	4.8%

Claims (10)

1. a eutectic as shown in Formula IV,

   
2. A crystalline form of a eutectic as shown in Formula IV, characterized in that the powder X-ray diffraction spectrum of the eutectic having the crystalline form has the following characteristic peak represented by 2θ angle: 5.3 ° ± 0.2 °, 10.6°±0.2°, 19.9±0.2°, 20.8±0.2°;

   Preferably, the powder X-ray diffraction spectrum of the eutectic having the crystalline form has the following characteristic peaks represented by 2θ angles: 5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 10.9 ° ± 0.2 °, 17.5 ± 0.2 ° , 19.9 ± 0.2 °, 20.3 ± 0.2 °, 20.8 ± 0.2 °, 22.2 ± 0.2 °;

   More preferably, the powder X-ray diffraction spectrum of the eutectic having the crystalline form has the following characteristic peaks represented by 2θ angles: 5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 10.9 ° ± 0.2 °, 12.3 ° ± 0.2°, 14.8°±0.2°, 15.9°±0.2°, 16.9°±0.2°, 17.1°±0.2°, 17.5°±0.2°, 18.8°±0.2°, 19.4°±0.2°, 19.9°±0.2° 20.3°±0.2°, 20.8°±0.2°, 21.6°±0.2°, 21.9°±0.2°, 22.2°±0.2°, 26.9°±0.2°, 27.3±0.2°, 27.7°±0.2°.
3. The crystal form according to claim 2, wherein the eutectic having the crystal form has a melting range of 118 to 120 ° C and a DSC peak temperature of 119.01 ° C.
4. A method for preparing a eutectic having the crystalline form according to claim 2 or 3, comprising the steps of: dissolving the shakubic acid in methylene chloride, adding sodium acetate, and incubating the reaction at 30 to 35 ° C, The filtrate was then filtered and collected, and the filtrate was added dropwise to n-heptane and crystallized.
5. The production method according to claim 4, wherein the reaction time is 0.5 to 2 hours, preferably 1 hour.
6. The preparation method according to claim 4 or 5, wherein the filtrate is added to n-heptane at 0 to 5 ° C;

   Preferably, the crystallization is carried out in the range of 0 to 5 ° C;

   Preferably, the step of crystallizing further comprises the step of filtering and/or drying the crystal.
7. The preparation method according to any one of claims 4 to 6, wherein the molar ratio of the sulbacb to sodium acetate is 1: (1.0 to 1.2), preferably 1:1.1;

   Preferably, the ratio of the mole number of the sirolimus to the volume of methylene chloride is 1 mol: (1 ~ 2) L, preferably 1 mol: 1.5 L;

   Preferably, the volume ratio of the dichloromethane to n-heptane is 1: (5-15), preferably 1:10.
8. Use of the eutectic according to claim 1 in the preparation of LCZ696.
9. Use of a eutectic having a crystalline form according to claim 2 or 3 in the preparation of LCZ696.
10. The use according to claim 9, wherein the preparation of LCZ696 is carried out by dissolving a eutectic having the crystalline form according to claim 2 or 3 in a mixed solvent of isopropyl acetate and acetone, After warming and dissolving, valsartan is added, and then an aqueous solution of sodium hydroxide is added dropwise. After the dropwise addition, a part of the solvent is distilled off, and then isopropyl acetate is added, and the solvent is distilled off and the isopropyl acetate is added repeatedly. ~ 3 times, followed by cooling and crystallization, filtration and drying to obtain LCZ696;

    More preferably, the molar ratio of the eutectic to valsartan is 1:0.95 to 1.10, more preferably 1:1.05;

    More preferably, the molar ratio of the eutectic to sodium hydroxide is 1:2.25 to 3.00, more preferably 2.5;

    More preferably, the crystallization is carried out at a temperature of 20 to 30 ° C, preferably 25 ° C;

    More preferably, the evaporation solvent is carried out using vacuum distillation;

    More preferably, the step of distilling off the solvent is carried out at a temperature of 35 ± 5 ° C; when the isopropyl acetate is added, the temperature of the reaction system is 40 ± 3 ° C;

    More preferably, the step of maintaining the heat is further included after the step of evaporating the solvent and adding isopropyl acetate, and more preferably the holding time is 0.5 hours.

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