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
- Publication number
- 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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- WO
- WIPO (PCT)
- Prior art keywords
- sodium
- process according
- sacubitril
- valsartan
- group
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 32
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 title claims abstract description 32
- 229960003953 sacubitril Drugs 0.000 title claims abstract description 32
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title claims abstract description 32
- 229960004699 valsartan Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 title abstract description 8
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 25
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- 239000013522 chelant Substances 0.000 claims description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical group COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 claims description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- 238000005411 Van der Waals force Methods 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 150000003138 primary alcohols Chemical class 0.000 claims description 2
- 150000003333 secondary alcohols Chemical class 0.000 claims description 2
- 235000019265 sodium DL-malate Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 229960003885 sodium benzoate Drugs 0.000 claims description 2
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 229960001790 sodium citrate Drugs 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- UDWXLZLRRVQONG-UHFFFAOYSA-M sodium hexanoate Chemical compound [Na+].CCCCCC([O-])=O UDWXLZLRRVQONG-UHFFFAOYSA-M 0.000 claims description 2
- 239000001540 sodium lactate Substances 0.000 claims description 2
- 229940005581 sodium lactate Drugs 0.000 claims description 2
- 235000011088 sodium lactate Nutrition 0.000 claims description 2
- 239000001394 sodium malate Substances 0.000 claims description 2
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 claims description 2
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 claims description 2
- 229940039790 sodium oxalate Drugs 0.000 claims description 2
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 claims description 2
- 239000004324 sodium propionate Substances 0.000 claims description 2
- 235000010334 sodium propionate Nutrition 0.000 claims description 2
- 229960003212 sodium propionate Drugs 0.000 claims description 2
- 229940074404 sodium succinate Drugs 0.000 claims description 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 2
- LHYPLJGBYPAQAK-UHFFFAOYSA-M sodium;pentanoate Chemical compound [Na+].CCCCC([O-])=O LHYPLJGBYPAQAK-UHFFFAOYSA-M 0.000 claims description 2
- 239000007962 solid dispersion Substances 0.000 claims description 2
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000002792 enkephalinase inhibitor Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229940127282 angiotensin receptor antagonist Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
Classifications
-
- 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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
| WO2020039386A1 (en) | 2018-08-23 | 2020-02-27 | Novartis Ag | New pharmaceutical use for the treatment of heart failure |
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| 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 |
| WO2009064681A2 (en) * | 2007-11-12 | 2009-05-22 | Novartis Ag | Liquid compositions comprising valsartan |
| WO2017042700A1 (en) * | 2015-09-07 | 2017-03-16 | Sun Pharmaceutical Industries Limited | Solid forms of valsartan and sacubitril |
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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 |
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