WO2017191619A2 - A process for the preparation of a salt of sacubitril and valsartan - Google Patents
A process for the preparation of a salt of sacubitril and valsartan Download PDFInfo
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- WO2017191619A2 WO2017191619A2 PCT/IB2017/052672 IB2017052672W WO2017191619A2 WO 2017191619 A2 WO2017191619 A2 WO 2017191619A2 IB 2017052672 W IB2017052672 W IB 2017052672W WO 2017191619 A2 WO2017191619 A2 WO 2017191619A2
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- sodium
- process according
- sacubitril
- valsartan
- group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/30—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 doubly-bound oxygen atoms
- C07C233/31—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 doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
Definitions
- the present invention provides a process for the preparation of a salt of sacubitril and valsartan. Specifically, the present invention provides a process for the preparation of a sodium salt of sacubitril and valsartan.
- U.S. Patent No. 5,399,578 provides processes for the preparation of valsartan of Formula II.
- FORMULA II PCT Publication No. WO 2007/056546 describes a dual-acting compound, such as a supramolecular complex, comprising: (a) an angiotensin receptor antagonist; (b) a neutral endopeptidase inhibitor (NEPi); and optionally (c) a pharmaceutically acceptable cation.
- a dual-acting compound such as a supramolecular complex, comprising: (a) an angiotensin receptor antagonist; (b) a neutral endopeptidase inhibitor (NEPi); and optionally (c) a pharmaceutically acceptable cation.
- the present invention provides a simple, industrially viable, and cost effective process for the preparation of a salt of sacubitril and valsartan. Specifically, the present invention provides a process for the preparation of a sodium salt of sacubitril and valsartan.
- the sodium salt of sacubitril and valsartan produced by following the process disclosed herein is non-hygroscopic, has better yield, purity, and flowability.
- the sodium salt of sacubitril and valsartan produced by following the process disclosed herein is also easy to handle and is found to be stable.
- Figure 1 depicts an X-ray Powder Diffraction (XRPD) pattern of a sodium salt of sacubitril and valsartan as prepared according to the Example 1.
- XRPD X-ray Powder Diffraction
- ambient temperature refers to the temperature in the range of25°C to 35°C.
- treating includes combining, mixing, triturating, suspending, contacting, or a combination thereof.
- stable refers to a salt of sacubitril and valsartan, which does not convert to any other polymorphic form upon storage at 30°C ⁇ 2°C and 75% ⁇ 5% relative humidity and for which the chromatographic purity does not decrease on storage.
- An aspect of the present invention provides a process for the preparation of a sodium salt of sacubitril and valsartan, wherein the process comprises treating sacubitril and valsartan with a sodium salt of an organic acid.
- Sacubitril is prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,217,996 or J. Med. Chem. 1995, 38, 1689-1700.
- Valsartan is prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,399,578.
- the sodium salt of an organic acid is selected from the group consisting of sodium 2-ethyl hexanoate, sodium octanoate, sodium formate, sodium acetate, sodium propionate, sodium butyrate, sodium valerate, sodium caproate, sodium oxalate, sodium lactate, sodium malate, sodium citrate, sodium benzoate, sodium succinate, and a mixture thereof.
- the treatment of sacubitril and valsartan with the sodium salt of an organic acid is carried out in a solvent.
- the solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, aliphatic hydrocarbons, polar aprotic solvents, and mixtures thereof.
- aromatic hydrocarbons include toluene or benzene.
- ketones include acetone or methyl ethyl ketone.
- esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate.
- ethers include methyl i-butyl ether or tetrahydrofuran.
- alkanols include primary, secondary, and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol.
- halogenated hydrocarbons include dichloromethane, chloroform, or 1,2- dichloroethane.
- aliphatic hydrocarbons include n-pentane, n-hexane, n- heptane, cyclohexane, or cycloheptane.
- polar aprotic solvents include N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulphoxide, acetonitrile, or N- methylpyrrolidone .
- Sacubitril and valsartan are treated with the sodium salt of an organic acid at a temperature of about 10°C to about 60°C, for example, at about 20°C to about 55°C.
- Sacubitril and valsartan are treated with the sodium salt of an organic acid for about 1 hour to about 7 hours, for example, for about 2 hours to about 5 hours.
- the sodium salt of sacubitril and valsartan may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
- the sodium salt of sacubitril and valsartan is present in the form of supramolecular complex, co-crystal, chelate, mixed co-crystal, co-precipitate, solid dispersion, chelate, clathrate, co-crystal complex, clathrate, or a combination thereof. Further, the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or ⁇ - ⁇ stacking.
- the sodium salt of sacubitril and valsartan is characterized by an XRPD pattern as depicted in Figure 1.
- the sodium salt of sacubitril and valsartan prepared by the present invention is found to be stable.
- XRPD of the sample was determined by using a PANalytical ® instrument; Model X'pert PRO; Detector: X'celerator ® .
- Example 1 Preparation of a sodium salt of sacubitril and valsartan.
- Sacubitril (10 g) was added to methyl-i-butyl ether (40 mL) at 20°C to obtain a mixture.
- Valsartan (10.59 g) was added to the mixture and the reaction mixture was stirred at 20°C to 25°C for 10 minutes.
- Sodium-2-ethylhexanoate (12.12 g) was added to the reaction mixture at 20°C.
- the reaction mixture was heated to 55°C and then stirred for 5 hours at 55°C to 57°C.
- the reaction mixture was cooled to 20°C to 25°C and the mixture was stirred for 1 hour.
- the solvents were recovered at 40°C to 45 °C and methyl t- butyl ether (10 mL) was added to the reaction mixture at 40°C.
Abstract
The present invention provides a process for the preparation of a salt of sacubitril and valsartan. Specifically, the present invention provides a process for the preparation of a sodium salt of sacubitril and valsartan.
Description
A PROCESS FOR THE PREPARATION OF A SALT OF SACUBITRIL AND
VALSARTAN
Field of the Invention
The present invention provides a process for the preparation of a salt of sacubitril and valsartan. Specifically, the present invention provides a process for the preparation of a sodium salt of sacubitril and valsartan.
Background of the Invention
U.S. Patent No. 5,217,996, PCT Publication Nos. WO 2008/031567, WO 2008/083967, WO 2009/090251, WO 2012/025502, WO 2012/025501, WO 2013/026773, and WO 2014/032627 provide processes for the preparation of sacubitril of Formula I or salts thereof.
FORMULA I
U.S. Patent No. 5,399,578 provides processes for the preparation of valsartan of Formula II.
FORMULA II
PCT Publication No. WO 2007/056546 describes a dual-acting compound, such as a supramolecular complex, comprising: (a) an angiotensin receptor antagonist; (b) a neutral endopeptidase inhibitor (NEPi); and optionally (c) a pharmaceutically acceptable cation.
Summary of the Invention
The present invention provides a simple, industrially viable, and cost effective process for the preparation of a salt of sacubitril and valsartan. Specifically, the present invention provides a process for the preparation of a sodium salt of sacubitril and valsartan. The sodium salt of sacubitril and valsartan produced by following the process disclosed herein is non-hygroscopic, has better yield, purity, and flowability. The sodium salt of sacubitril and valsartan produced by following the process disclosed herein is also easy to handle and is found to be stable.
Brief Description of the Drawing
Figure 1 depicts an X-ray Powder Diffraction (XRPD) pattern of a sodium salt of sacubitril and valsartan as prepared according to the Example 1.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to the temperature in the range of25°C to 35°C.
The term "treating," "reacting," or "converting," includes combining, mixing, triturating, suspending, contacting, or a combination thereof.
The term "stable," as used herein, refers to a salt of sacubitril and valsartan, which does not convert to any other polymorphic form upon storage at 30°C±2°C and 75% ±5% relative humidity and for which the chromatographic purity does not decrease on storage.
An aspect of the present invention provides a process for the preparation of a sodium salt of sacubitril and valsartan, wherein the process comprises treating sacubitril and valsartan with a sodium salt of an organic acid.
Sacubitril is prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,217,996 or J. Med. Chem. 1995, 38, 1689-1700.
Valsartan is prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,399,578.
The sodium salt of an organic acid is selected from the group consisting of sodium 2-ethyl hexanoate, sodium octanoate, sodium formate, sodium acetate, sodium propionate, sodium butyrate, sodium valerate, sodium caproate, sodium oxalate, sodium lactate, sodium malate, sodium citrate, sodium benzoate, sodium succinate, and a mixture thereof.
The treatment of sacubitril and valsartan with the sodium salt of an organic acid is carried out in a solvent.
The solvent is selected from the group consisting of water, aromatic hydrocarbons, ketones, esters, ethers, alkanols, halogenated hydrocarbons, aliphatic hydrocarbons, polar aprotic solvents, and mixtures thereof. Examples of aromatic hydrocarbons include toluene or benzene. Examples of ketones include acetone or methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, or n-butyl acetate. Examples of ethers include methyl i-butyl ether or tetrahydrofuran. Examples of alkanols include primary, secondary, and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, 1-propanol, 2-propanol, or butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, or 1,2- dichloroethane. Examples of aliphatic hydrocarbons include n-pentane, n-hexane, n- heptane, cyclohexane, or cycloheptane. Examples of polar aprotic solvents include N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulphoxide, acetonitrile, or N- methylpyrrolidone .
Sacubitril and valsartan are treated with the sodium salt of an organic acid at a temperature of about 10°C to about 60°C, for example, at about 20°C to about 55°C.
Sacubitril and valsartan are treated with the sodium salt of an organic acid for about 1 hour to about 7 hours, for example, for about 2 hours to about 5 hours.
The sodium salt of sacubitril and valsartan may be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
The sodium salt of sacubitril and valsartan is present in the form of supramolecular complex, co-crystal, chelate, mixed co-crystal, co-precipitate, solid dispersion, chelate, clathrate, co-crystal complex, clathrate, or a combination thereof. Further, the salt is
linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
The sodium salt of sacubitril and valsartan is characterized by an XRPD pattern as depicted in Figure 1.
The sodium salt of sacubitril and valsartan prepared by the present invention is found to be stable.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
Methods
XRPD of the sample was determined by using a PANalytical® instrument; Model X'pert PRO; Detector: X'celerator®.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLE
Example 1: Preparation of a sodium salt of sacubitril and valsartan.
Sacubitril (10 g) was added to methyl-i-butyl ether (40 mL) at 20°C to obtain a mixture. Valsartan (10.59 g) was added to the mixture and the reaction mixture was stirred at 20°C to 25°C for 10 minutes. Sodium-2-ethylhexanoate (12.12 g) was added to the reaction mixture at 20°C. The reaction mixture was heated to 55°C and then stirred for 5 hours at 55°C to 57°C. The reaction mixture was cooled to 20°C to 25°C and the mixture was stirred for 1 hour. The solvents were recovered at 40°C to 45 °C and methyl t- butyl ether (10 mL) was added to the reaction mixture at 40°C. The solvents were recovered under 680 mm Hg to 710 mm of Hg at 40°C to 45°C. N-pentane (50 mL) was added to the reaction mixture and then stirred for 1 hour at 20°C to 25 °C. The solid obtained was filtered and dried under 680 mm Hg to 710 mm of Hg at 35°C to 40°C to obtain the solid compound.
Weight = 15 g
An X-ray Powder Diffraction (XRPD) pattern of the resulting solid compound is depicted in Figure 1.
Claims
1. A process for the preparation of a sodium salt of sacubitril and valsartan, wherein the process comprises treating sacubitril and valsartan with a sodium salt of an organic acid.
2. The process according to claim 1, wherein the sodium salt of an organic acid is selected from the group consisting of sodium 2-ethyl hexanoate, sodium octanoate, sodium formate, sodium acetate, sodium propionate, sodium butyrate, sodium valerate, sodium caproate, sodium oxalate, sodium lactate, sodium malate, sodium citrate, sodium benzoate, sodium succinate, and a mixture thereof.
3. The process according to claim 1, wherein treatment of the sacubitril and the valsartan with the sodium salt of an organic acid is carried out in a solvent.
4. The process according to claim 3, wherein the solvent is selected from the group consisting of water, an aromatic hydrocarbon, a ketone, an ester, an ether, an alkanol, a halogenated hydrocarbon, an aliphatic hydrocarbon, a polar aprotic solvent, and a mixture thereof.
5. The process according to claim 4, wherein the aromatic hydrocarbon is selected from the group consisting of toluene and benzene.
6. The process according to claim 4, wherein the ketone is selected from the group consisting of acetone and methyl ethyl ketone.
7. The process according to claim 4, wherein the ester is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
8. The process according to claim 4, wherein the ether is selected from the group consisting of methyl i-butyl ether, and tetrahydrofuran.
9. The process according to claim 4, wherein the alkanol is selected from the group consisting of primary, secondary, and tertiary alcohols having from one to six carbon atoms.
10. The process according to claim 4, wherein the halogenated hydrocarbon is selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane.
11. The process according to claim 4, wherein the aliphatic hydrocarbon is selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, and cycloheptane.
12. The process according to claim 4, wherein the polar aprotic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
13. The process according to claim 1, wherein the treatment of sacubitril and valsartan with the sodium salt of the organic acid is performed at a temperature of about 10°C to about 60°C.
14. The process according to claim 1, wherein the sodium salt of sacubitril and valsartan is prepared in the form of a supramolecular complex, co-crystal, chelate, mixed co-crystal, co-precipitate, solid dispersion, chelate, clathrate, co-crystal complex, clathrate, or a combination thereof.
15. The process according to claim 14, wherein the sodium salt of sacubitril and valsartan is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
16. The process according to claim 1, wherein the sodium salt of sacubitril and valsartan is characterized by an XRPD pattern as depicted in Figure 1.
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| IN201611015864 | 2016-05-06 | ||
| IN201611015864 | 2016-05-06 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020039386A1 (en) | 2018-08-23 | 2020-02-27 | Novartis Ag | New pharmaceutical use for the treatment of heart failure |
| WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR057882A1 (en) * | 2005-11-09 | 2007-12-26 | Novartis Ag | DOUBLE ACTION COMPOUNDS OF ANGIOTENSIN RECEPTOR BLOCKERS AND NEUTRAL ENDOPEPTIDASE INHIBITORS |
| KR20100087002A (en) * | 2007-11-12 | 2010-08-02 | 노파르티스 아게 | Liquid compositions comprising valsartan |
| WO2017042700A1 (en) * | 2015-09-07 | 2017-03-16 | Sun Pharmaceutical Industries Limited | Solid forms of valsartan and sacubitril |
-
2017
- 2017-05-08 WO PCT/IB2017/052672 patent/WO2017191619A2/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020039386A1 (en) | 2018-08-23 | 2020-02-27 | Novartis Ag | New pharmaceutical use for the treatment of heart failure |
| WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
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| WO2017191619A3 (en) | 2017-12-14 |
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