CN105884644B - Neutral endopeptidase inhibitor salt dominant form and preparation method thereof - Google Patents
Neutral endopeptidase inhibitor salt dominant form and preparation method thereof Download PDFInfo
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Abstract
The advantageous form of the calcium salt of the compound 1 achieves the effects of improving the quantitative accuracy, simplifying the synthesis process, optimizing the production environment, controlling the quality of the final product and the like through the advantages of fluidity, stability, solubility and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an advantageous form of a neutral endopeptidase inhibitor salt and a preparation method thereof.
Background
The compound 1, a neutral endopeptidase inhibitor (NEPi), has the effects of promoting natriuresis and diuresis clinically.
The compound 2 is a medicine developed by Nowa company and used for resisting heart failure, and is a supermolecular complex (compound) formed by combining valsartan and the compound 1 through a non-covalent bond, and has double effects of angiotensin receptor blocking and neutral endopeptidase inhibition. The completed clinical experiment results show that the compound 2 has better clinical anti-heart failure effect than enalapril, and is a drug with great market potential for resisting heart failure.
In the disclosed method for synthesizing compound 2, the free acid of compound 1 can be used as the starting material, and the salt of compound 1 can also be used. However, because the free acid of the compound 1 is not easy to store and is inconvenient to feed, and the salt thereof shows more stable physicochemical properties, and is also beneficial to the operation and the accuracy of feeding, so that the compound is more suitable for production, the synthesis of the compound 2 by adopting the salt of the compound 1 in the production is a better choice, and the calcium salt is one of common salts.
Chinese patent ZL200680001733.0 discloses a method for preparing compound 2, wherein example 3 uses the calcium salt of compound 1 as an intermediate to prepare compound 2, but does not describe the form of the calcium salt of compound 1.
Chinese patent CN200780034141.3 discloses a preparation process route of compound 1 calcium salt, but does not disclose a specific preparation method, and the compound 1 calcium salt prepared by a conventional method is a mixed crystal, which is not beneficial to optimizing the whole preparation process of compound 2, although it can be used for subsequent production. In the production of medicines, the use of the dominant forms of the raw materials is beneficial to the improvement of the quantitative accuracy of the reaction, the simplification of the synthesis process, the optimization of the production environment, the control of the quality of the final product and the like.
Therefore, the finding of an advantageous form of compound 1 calcium salt suitable for the industrial production of compound 2 enables the compound to achieve the effects of improving the quantitative accuracy, simplifying the synthesis process, optimizing the production environment, controlling the quality of the final product and the like through the advantages of fluidity, stability, solubility and the like, and is a technical problem to be solved in the prior art.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an advantageous form of calcium salt of compound 1, which has the advantages of high dissolution speed, good fluidity, good stability and the like and is suitable for industrial production of compound 2.
The advantageous form of the calcium salt of compound 1 according to the present invention has an X-ray powder diffraction (XRD) pattern as shown in fig. 1 or fig. 2; it can be seen that the XRD spectrum of the dominant form of the calcium salt of compound 1 does not show a sharp absorption peak, and only non-sharp absorption occurs between 2 θ shift values of 10 ° to 30 °, and more specifically, the XRD spectrum of the dominant form of the calcium salt of compound 1 does not show non-sharp absorption between 2 θ shift values of 15 ° to 25 °, which meets the definition of amorphous in the art, and thus the dominant form of the calcium salt of compound 1 is amorphous.
The compound 1 calcium salt has the advantages that the DSC spectrogram shows that the melting point/decomposition temperature of the product is near 227 ℃, namely 227 +/-3 ℃; specifically, a DSC spectrogram has endothermic peaks at 56.0 +/-3 ℃, 126.7 +/-3 ℃, 205.2 +/-3 ℃ and 227.2 +/-3 ℃, and in the DSC spectrogram, 56.0 +/-3 ℃ and 126.7 +/-3 ℃ are solvent endothermic peaks, and because the advantageous form of the compound 1 calcium salt is amorphous, a person skilled in the art can understand that in the DSC spectrogram of the advantageous form of the compound 1 calcium salt, the solvent endothermic peaks can have larger displacement fluctuation or even lack due to the difference of solvent types and detection conditions; more specifically, the advantageous form of the calcium salt of the compound 1 has a DSC spectrum shown in figure 3;
the advantageous form of the calcium salt of compound 1 of the present invention may contain up to 10% of free moisture, for example, its TG spectrum may be as shown in fig. 4 or fig. 5;
comprehensive judgment shows that the advantageous form of the calcium salt of the compound 1 is amorphous, the moisture represented by the TG spectrogram is free water, and the moisture in the product is favorably removed by prolonging the drying time.
Experiments prove that the compound 1 calcium salt provided by the invention has better solubility than that of the prior art, and can be dissolved clearly more quickly in the using process. Specifically, because the production of the compound 2 has strict requirements on a solvent system and reaction conditions, the calcium salt of the compound 1 needs to be freely dissolved in the solvent system during production, and if the raw material is not completely dissolved, the subsequent reaction steps are greatly influenced. More specifically, the compound 1 calcium salt provided by the invention has an advantageous form that the free dissolution time of each 100g of the compound 1 calcium salt in a mixed solvent of isopropyl acetate and hydrochloric acid is less than 10 minutes, while the time required by the prior art product is more than 30 minutes, and the faster dissolution speed is beneficial to the industrial production of the compound 2. In addition, as the amorphous form, the stability and the fluidity of the amorphous form meet the requirements of industrial production on intermediates, and the amorphous form is also beneficial to the quantification of subsequent reactions. In conclusion, the advantageous form of the calcium salt of compound 1 is more suitable for the industrial production of compound 2 than the calcium salt of compound 1 of the prior art.
Another object of the present invention is to provide a process for the preparation of the advantageous form of the calcium salt of compound 1, as follows:
a process for the preparation of a predominant form of the calcium salt of compound 1, characterized in that it comprises the following steps:
(1) taking A-1 as a raw material, esterifying to obtain A-2, and reacting with succinic anhydride to obtain a compound 1 (A-3);
(2) dissolving the compound 1 in isopropyl acetate, dripping 1-1.2 equivalent of 1N sodium hydroxide aqueous solution, and stirring at the temperature lower than 45 ℃ to form salt;
(3) separating and combining the water phases;
(4) slowly dripping 0.15-0.25 g/mL calcium chloride solution into the water phase obtained in the step (2) at a constant speed at room temperature, wherein the dripping time is controlled within 20 min;
(5) keeping the temperature below 70 ℃ and stirring at the rotating speed of 150-250r/min for 0.5-24 hours, and then filtering and drying to obtain the advantageous form of the compound 1 calcium salt.
The purity of the calcium salt of the compound 1 can be further improved by repeating the above steps after the calcium salt of the compound 1 obtained above is acidified, and the form of the calcium salt of the compound 1 obtained is unchanged.
Specifically, in the above production step, the equivalent weight is calculated relative to the amount of A-2 in the above step (1).
In the step (2), the sodium hydroxide aqueous solution is added to make the compound 1 become a sodium salt, and 1 to 1.2 equivalents of 1N (1mol/L) of the sodium hydroxide aqueous solution is added to facilitate sufficient salt formation of the compound 1, and hydrolysis does not occur.
In the step (4), 0.15 to 0.25g/mL of calcium chloride solution is dropped to maintain the saturation of the solution system in a range favorable for precipitation in an amorphous form, and the amount of calcium chloride is preferably 0.5 to 1.0 equivalent.
In the step (5), the advantageous form can be prepared at the crystallization temperature below 70 ℃, for example, the temperature can be selected to be room temperature or 70 ℃, and the room temperature is 25 +/-5 ℃; stirring at the rotation speed of 150-250r/min is favorable for uniform precipitation of the product, and preferably, the rotation speed is 180 r/min.
The preparation method ensures that the calcium salt of the compound 1 is uniformly precipitated on the whole, the obtained calcium salt of the compound 1 has high purity and uniform shape, and the reaction yield and the reaction time are in better levels.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. provides the advantageous form of the calcium salt of the compound 1, which is amorphous and has the beneficial effects of high free speed, high purity, high stability, good fluidity and the like.
2. Provides a preparation method of the advantageous form of the calcium salt of the compound 1, and the method can realize the scale production of the advantageous form of the calcium salt of the compound 1.
Drawings
FIG. 1 XRD spectrum of predominant form of calcium salt of Compound 1 obtained in example 2
FIG. 2 XRD spectrum of predominant form of calcium salt of Compound 1 obtained in example 3
FIG. 3 DSC spectra of advantageous forms of calcium salt of Compound 1 obtained in example 2 and example 3
FIG. 4 TG spectrum of advantageous form of calcium salt of Compound 1 obtained in example 2
FIG. 5 TG spectrum of advantageous form of calcium salt of Compound 1 obtained in example 3
FIG. 6 HPLC chromatogram of the predominant form of calcium salt of Compound 1 obtained in example 2
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.
In the following examples:
the X-ray powder diffraction is detected by an X-ray diffractometer with an acute shadow (Empyrean), and the detection conditions comprise Cu target K α rays, voltage 40KV, current 40mA, emission slit 1/32 degrees, anti-scattering slit 1/16 degrees, anti-scattering slit 7.5mm, 2 theta range of 3-40 degrees, step size of 0.02 degree and residence time of 40s in each step.
The differential scanning calorimetry spectrogram is detected by adopting a DSC204F1 differential scanning calorimeter device of Germany NETZSCH company, and the detection conditions are as follows: atmosphere: n is a radical of220 mL/min; and (3) scanning procedure: the temperature was raised from room temperature to 250 ℃ at 10 ℃/min and the temperature rise curve was recorded.
The moisture content is detected by adopting a TG209 thermogravimetric analyzer of Germany NETZSCH company, and the detection conditions are as follows: atmosphere: n is a radical of220 mL/min; and (3) scanning procedure: room temperature-500 ℃, heating rate: 10 ℃/min.
Example 1
Preparation of Compound 1(A-3)
Dissolving A-1(15g) in 150ml of absolute ethanol at room temperature; heating to 60 ℃, slowly dripping 8.5ml of thionyl chloride, heating to 70 ℃ and reacting for 2 hours; distilling under reduced pressure to obtain white solid, adding 150ml n-heptane, removing half volume under reduced pressure, and pulping for 20min under ice bath; filtration and washing of the solid with n-heptane, followed by drying at 30 ℃ for 10 hours gave 13.4g of a white solid (A-2).
13.4g A-2 was added to a flask containing 250ml of isopropyl acetate (IPAC) at room temperature; adding 11.7g (16ml) of triethylamine and 4.9g of succinic anhydride in sequence, and reacting at normal temperature until A-2 is completely consumed; direct filtration, the filter cake washed with IPAC and 22g (A-3) of a pale yellow viscous liquid from the combined filtrates under reduced pressure were combined.
Example 2
Preparation of advantageous forms of the calcium salt (A-5) of Compound 1
22g A-3 prepared according to the method of example 1 was dissolved in 200ml IPAC at room temperature; dropwise adding 1.2 equivalent (relative to A-2) of sodium hydroxide aqueous solution (1N), and stirring at room temperature until full salification occurs; separating, and combining water layers (about 80 ml);
adding the aqueous solution containing A-4 into a 250ml two-mouth bottle at room temperature, slowly dropwise adding the calcium chloride aqueous solution (3.6g of calcium chloride is dissolved in 20ml of water) at a constant speed, stirring for 3 hours at the room temperature at a rotating speed of 180r/min after dropwise adding for 10 min; filtering, washing the filter cake with water, and vacuum drying at 30 deg.C for 6h to obtain 21g of advantageous form of calcium salt (A-5) of compound 1. The XRD spectrum, DSC spectrum and TG spectrum of the product are shown in figures 1, 3 and 4 respectively. The HPLC profile (fig. 6) shows that the purity was 98.6%.
Example 3
Preparation of advantageous forms of the calcium salt (A-5) of Compound 1.
22g A-3 prepared according to the method of example 1 was dissolved in 200ml IPAC; dropwise adding 1.1 equivalent (relative to A-2) of sodium hydroxide aqueous solution (1N) in ice bath, and stirring at 40 ℃ until full salification occurs; separating and combining water layers; after the temperature is raised to 70 ℃, slowly and uniformly dripping a calcium chloride aqueous solution (3.1g of calcium chloride is dissolved in 20ml of water) into the aqueous solution containing A-4, heating to 70 ℃ and stirring for 2 hours at the rotating speed of 180r/min after dripping for 8 min; cooling to 50 ℃, filtering, washing a filter cake with water, purging with nitrogen for 1h, and vacuum drying at 80 ℃ for 48h to obtain 18g (with the purity of 99.2%) of the compound 1 calcium salt (A-5) with the advantageous form. The XRD spectrum is shown in figure 2, the DSC spectrum is shown in figure 3, and the TG spectrum is shown in figure 5.
It can be seen that the stability of the dominant form is high, meeting the requirements of the art for intermediate quality; in addition, the drying time is prolonged, and the drying temperature is increased, so that the free water in the product can be removed.
Example 4
Preparation of advantageous forms of the calcium salt (A-5) of Compound 1
22g A-3 prepared according to the method of example 1 was dissolved in 200ml IPAC; dropwise adding 1 equivalent (relative to A-2) of sodium hydroxide aqueous solution (1N) in ice bath, and stirring at 35 ℃ until full salification occurs; separating and combining water layers; slowly and uniformly dripping a calcium chloride aqueous solution (3.3g of calcium chloride is dissolved in 20ml of water) into the aqueous solution containing A-4 at room temperature, heating to 60 ℃ after 15min of dripping, and stirring for 3 hours at a rotating speed of 200 r/min; cooling to 50 ℃, filtering, washing a filter cake with water, purging with nitrogen for 1h, and vacuum drying at 60 ℃ for 50h under reduced pressure to obtain 16g (with the purity of 99.3%) of the compound 1 calcium salt (A-5) with the advantage form.
The product obtained by detection is the same as that obtained in example 2.
Example 5
Preparation of advantageous forms of the calcium salt (A-5) of Compound 1
22g A-3 prepared according to the method of example 1 was dissolved in 200ml IPAC; dropwise adding 1.1 equivalent (relative to A-2) of sodium hydroxide aqueous solution (1N) in ice bath, and stirring at 40 ℃ until full salification occurs; separating and combining water layers; after the temperature is raised to 50 ℃, slowly and uniformly dripping a calcium chloride aqueous solution (3.1g of calcium chloride is dissolved in 20ml of water) into the aqueous solution containing A-4, and stirring for 5 hours at the rotating speed of 250r/min after dripping for 10 min; the mixture was filtered while hot, and the filter cake was washed with water, purged with nitrogen for 1 hour, and vacuum-dried at 80 ℃ for 56 hours under reduced pressure to obtain 21g (97.9% purity) of the advantageous form of calcium salt (A-5) of Compound 1.
The product obtained by detection is the same as that obtained in example 2.
Example 6
According to the process scheme of patent CN200780034141.3, compound 1 calcium salt (purity 99.3%) is prepared according to conventional reaction conditions.
100g of the proprietary product and the product prepared according to the method of example 2 and example 3, respectively, were taken to simulate the synthesis of compound 2, i.e. 1L of isopropyl acetate was added at room temperature, 2N (2mol/L) hydrochloric acid corresponding to 4 equivalents of compound 1 calcium salt was slowly added dropwise and the free clearing time was recorded as follows:
| sample (I) | Time of dissolution and clearing |
| CN200780034141.3 product | >30min |
| Example 2 | ≤10min |
| Example 3 | ≤10min |
It can be seen that the dissolution time of the product of the patent under the same conditions is far shorter than that of the product obtained by the prior art, and the difference of the dissolution time is more obvious in industrial mass production (such as production of 5 kg and above).
In further detection, the flow performance of the product is also obviously superior to that of CN200780034141.3 product.
Example 7
Stability detection
The calcium salt of compound 1 (purity 99.3%) obtained according to the process scheme of patent CN200780034141.3 in example 4, and the products obtained according to the methods of examples 2 and 3, were stored at 60 ℃ for 3 months with the following stability results:
| sample (I) | Purity (0 day) | Purity (3 months) |
| CN200780034141.3 product | 99.3％ | 94.9％ |
| Example 2 | 98.6％ | 97.5％ |
| Example 3 | 99.2％ | 98.0％ |
It can be seen that the storage stability of the product of the patent under the high temperature condition is obviously higher than that of the product of the prior art, and the product of the patent is more suitable for industrial production than the product of the prior art.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (8)
1. An advantageous form of the calcium salt of compound 1 of the formula wherein the XRD spectrum of the advantageous form of the calcium salt of compound 1 does not exhibit sharp absorption peaks;
and the XRD pattern of the advantageous form of the calcium salt of the compound 1 is shown in figure 1 or figure 2.
2. The dominant form of the calcium salt of compound 1 according to claim 1, characterized in that the DSC profile of the dominant form of the calcium salt of compound 1 has an endothermic peak at 227 ± 3 ℃.
3. The dominant form of the calcium salt of compound 1 according to claim 1 or 2, characterized in that the DSC profile of the dominant form of the calcium salt of compound 1 has endothermic peaks at 205.2 ± 3, 227.2 ± 3 ℃.
4. Advantageous form of the calcium salt of compound 1 according to claim 3, characterized in that the DSC diagram of the advantageous form of the calcium salt of compound 1 further has endothermic peaks at 56.0 ± 3, 126.7 ± 3 ℃.
5. The dominant form of the calcium salt of compound 1 according to claim 1 or 2, characterized in that the dominant form of the calcium salt of compound 1 has a DSC profile as shown in figure 3.
6. A process for the preparation of the advantageous form of the calcium salt of compound 1 according to any one of claims 1 to 5, characterized in that it comprises the following steps:
(1) taking A-1 as a raw material, esterifying to obtain A-2, and reacting with succinic anhydride to prepare a compound 1;
(2) dissolving the compound 1 in isopropyl acetate, dripping 1-1.2 equivalent of 1N sodium hydroxide aqueous solution, and stirring at the temperature lower than 45 ℃ to form salt;
(3) separating and combining the water phases;
(4) slowly dripping 0.15-0.25 g/mL calcium chloride solution into the water phase obtained in the step (2) at a constant speed at room temperature, wherein the dripping time is controlled within 20 min;
(5) keeping the temperature below 70 ℃ and stirring at the rotating speed of 150-250r/min for 0.5-24 hours, and then filtering and drying to obtain the advantageous form of the compound 1 calcium salt.
7. The process for the preparation of the advantageous form of the calcium salt of compound 1 according to claim 6, characterized in that the stirring time in step (5) is 2-5 hours.
8. Process for the preparation of the advantageous form of the calcium salt of Compound 1 according to any one of claims 6 or 7, characterized in that the temperature in step (5) is room temperature, the rotation speed is 180r/min and the stirring time is 2-5 hours.
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| CN106496055A (en) * | 2016-10-09 | 2017-03-15 | 杭州科巢生物科技有限公司 | A kind of key component sand storehouse of anti-heart failure new drug is than bent novel synthesis |
| CN107082746A (en) * | 2017-03-23 | 2017-08-22 | 广州隽沐生物科技有限公司 | A kind of preparation method of AHU sodium salts crystal formation |
| CN107188817A (en) * | 2017-05-22 | 2017-09-22 | 杭州瑞法康科技有限公司 | A kind of husky storehouse of high-purity is than novel crystal forms of bent half calcium salt monohydrate and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101098689A (en) * | 2005-11-09 | 2008-01-02 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药（湖北）有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098689A (en) * | 2005-11-09 | 2008-01-02 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药（湖北）有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
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