WO2017033212A1 - Preparation of sacubitril and salt thereof and novel compounds used in the process - Google Patents
Preparation of sacubitril and salt thereof and novel compounds used in the process Download PDFInfo
- Publication number
- WO2017033212A1 WO2017033212A1 PCT/IS2016/050012 IS2016050012W WO2017033212A1 WO 2017033212 A1 WO2017033212 A1 WO 2017033212A1 IS 2016050012 W IS2016050012 W IS 2016050012W WO 2017033212 A1 WO2017033212 A1 WO 2017033212A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenylphenylmethyl
- amino
- ethyl ester
- oxopropyl
- carboxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 115
- 150000003839 salts Chemical class 0.000 title claims abstract description 71
- 229960003953 sacubitril Drugs 0.000 title claims abstract description 37
- 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 35
- 150000001875 compounds Chemical class 0.000 title claims description 38
- 238000002360 preparation method Methods 0.000 title description 25
- 239000011541 reaction mixture Substances 0.000 claims description 69
- 150000001412 amines Chemical class 0.000 claims description 49
- 238000002329 infrared spectrum Methods 0.000 claims description 43
- 239000002253 acid Substances 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- 238000001757 thermogravimetry curve Methods 0.000 claims description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 26
- 229960004699 valsartan Drugs 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 21
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 21
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 20
- 229940014800 succinic anhydride Drugs 0.000 claims description 20
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 16
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 16
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 claims description 14
- ZRRNJJURLBXWLL-REWJHTLYSA-N (2r,3r,4r,5s)-6-(octylamino)hexane-1,2,3,4,5-pentol Chemical compound CCCCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO ZRRNJJURLBXWLL-REWJHTLYSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 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 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 8
- RUJHATQMIMUYKD-UHFFFAOYSA-N 2-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C(CCN)=CC=CC2=C1 RUJHATQMIMUYKD-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 229960002510 mandelic acid Drugs 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- 239000004310 lactic acid Substances 0.000 claims description 7
- 235000014655 lactic acid Nutrition 0.000 claims description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 7
- 239000011976 maleic acid Substances 0.000 claims description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- 235000006408 oxalic acid Nutrition 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 6
- NTOIKDYVJIWVSU-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-UHFFFAOYSA-N 0.000 claims description 6
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 235000002906 tartaric acid Nutrition 0.000 claims description 6
- 239000011975 tartaric acid Substances 0.000 claims description 6
- 229960001367 tartaric acid Drugs 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 150000003892 tartrate salts Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 72
- 239000000047 product Substances 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 31
- 238000002441 X-ray diffraction Methods 0.000 description 29
- -1 amine salts Chemical class 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 102000003729 Neprilysin Human genes 0.000 description 11
- 108090000028 Neprilysin Proteins 0.000 description 11
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- 150000007524 organic acids Chemical class 0.000 description 10
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000012916 structural analysis Methods 0.000 description 8
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- 150000007522 mineralic acids Chemical class 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
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- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 1
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- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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Classifications
-
- 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
- C07C233/45—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/03—Monoamines
- C07C211/07—Monoamines containing one, two or three alkyl groups, each having the same number of carbon atoms in excess of three
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention generally relates to methods of preparing a compound, in particular a pharmaceutical compound and more specifically a NEP inhibitor.
- the invention also relates to pharmaceutical compositions comprising such compounds, processes, starting materials and intermediates for preparing such compounds.
- Neprilysin neutral endopeptidase, EC 3.4.24.11) (NEP), is a(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester is an endothelial membrane bound Zn 2+ metallopeptidase found in many organs and tissues, including the brain, kidneys, lungs, gastrointestinal tract, heart, and the peripheral vasculature.
- NEP degrades and inactivates a number of endogenous peptides, such as enkephalins, circulating bradykinin, angiotensin peptides, and natriuretic peptides, the latter of which have several effects including, for example, vasodilation and natriure sis/diuresis, as well as inhibition of cardiac hypertrophy and ventricular fibrosis.
- endogenous peptides such as enkephalins, circulating bradykinin, angiotensin peptides, and natriuretic peptides, the latter of which have several effects including, for example, vasodilation and natriure sis/diuresis, as well as inhibition of cardiac hypertrophy and ventricular fibrosis.
- NEP plays an important role in blood pressure homeostasis and cardiovascular health.
- the present invention is related to the preparation of the NEP inhibitor sacubitril (Formula I).
- Sacubitril is (2R,4S)- 5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, also named N-(3-carboxy-l- oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester.
- sacubitril for treating cardiovascular disorders is described in U.S. Patent No. 5,217,996.
- Sacubitril is useful as a neutral endopeptidase (NEP) inhibitor, e.g. as inhibitors of the ANF-degrading enzyme in mammals, which prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals by inhibiting the degradation thereof to less active metabolites.
- NEP neutral endopeptidase
- sacubitril is useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase EC 3.4.24.11, particularly cardiovascular disorders, such as hypertension, renal insufficiency including edema and salt retention, pulmonary edema and congestive heart failure.
- U.S. Patent No. 7,468,390 discloses pharmaceutical composition of valsartan or a pharmaceutically acceptable salt thereof with sacubitril or a pharmaceutically acceptable salt thereof.
- a major drawback of the process disclosed in U.S. Patent No. 5,217,996 is that it involves using a diasteromeric mixture of (45)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester with a ratio of 80:20.
- the compound upon treatment with succinic anhydride, gives N-(3-carboxy (/)butoxy-l-oxopropyl)-(45)-(p- phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester.
- the (S,R) and (S,S) isomers must then be separated by column chromatography.
- the present invention relates to a process for preparing sacubitril, more specifically, a process for synthesizing the compound of formula I:
- the present invention also provides novel salts of sacubitril and its crystalline form.
- the invention thus provides amine salts of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester with the general formula (III):
- the invention provides crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt compound of formula (III):
- the amine salt can comprise an amine with the general formula NR : R 2 R 3 , wherein at least one of the groups R 1 , R 2 , R 3 is not hydrogen or a C1-C6 alkyl group.
- the amine salt of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester can also be an amine salt that is not one of tert-butylamine, isopropylamine, cyclohexylamine, n-propylamine and dicyclohexylamine.
- the amine salt is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-octyl-D-glucamine salt of formula Ill-b:
- the amine salt is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester phenyl ethyl salt of formula Ill-b:
- the amine salt is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester naphtyl ethyl amine salt of formula Ill-d:
- the present invention is in part based on the use of novel (4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester to synthesize sacubitril.
- Using of diastereomerically pure chiral isomer allows a substantially optically pure of sacubitril or salt thereof to be obtained, providing numerous advantages over presently known synthesis routes.
- substantially pure refers to at least about 95% purity, more preferably at least about 96% and most preferably at least about 98% purity or at least about 99% purity.
- U.S. Patent No. 8,877,938 uses about 95% pure Sacubitril for the preparation of Trisodium Sacubtril-valsartan hemipentahydrate. In contrast, it is possible to provide substantially pure sacubitril having purity more than 99.5% according to the present invention.
- the term "about” refers to a range of values ⁇ 10% of a specified value. For example, the phrase "about 95” includes ⁇ 10% of 95 and 95 as such.
- the present invention also provides process for preparing pure sacubitril which has purity more than 95% including more than 96%, more than 97%, more than 98%, more than 99% and up to 99.5% or more.
- the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (II).
- the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (III).
- R 1 , R 2 and R 3 are independently hydrogen or alkyl group; and XA is acid.
- the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising:
- one or more of R 1 , R 2 and R 3 is not H or a C1-C6 alkyl group.
- the amine salt according to formula (III) can preferably comprise an amine of formula NR : R 2 R 3 wherein R 1 , R 2 and R 3 are independently hydrogen or alkyl groups, with the provisio that at least one of the groups is not H or a C1-C6 alkyl group.
- the amine in Scheme III is n-octyl-D-glucamine.
- the amine is phenyl ethyl amine.
- the amine is naphtyl ethyl amine. It can be convenient to perform the reaction of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with an amine in a suitable organic solvent.
- the solvent can be a polar solvent, more preferably a non-aqueous polar solvent.
- the solvent is a non-protic non-aqueous polar solvent.
- Preferred polar solvents can include tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide.
- the solvent is acetone.
- reaction can be performed in an aqueous solution, which eliminates the need to use organic solvents that can be toxic and costly to remove.
- the reaction of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with t-butyl amine proceeds to completion in high yield using only water as solvent.
- Yet another advantage of the invention is the possibility to perform the reaction of N-(3-carboxy-l-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester with an amine in the absence of any additional solvent, which is particularly feasible for amines that are in a liquid state at or near room temperature.
- reaction involves mixing the ethyl ester with a neat amine, as for example manifested by the reaction of t-butyl amine with N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
- Conversion of the amine salt from step (b) to pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester can be conveniently performed by reacting the addition salt with an acid, such as hydrochloric acid or other suitable organic or inorganic acids.
- the present invention also provides a process of preparing compound of formula (I) illustrated by the following scheme (IV).
- R 1 , R 2 and R 3 are independently hydrogen or alkyl group; and XA is acid.
- one or more of R 1 , R 2 and R 3 is a group that is not H or a C1-C6 alkyl group.
- the amine salt according to formula (III) can preferably comprise an amine that independently contains hydrogen or alkyl groups, with the provisio that at least one of the groups is not H or a C1-C6 alkyl group.
- the amine in Scheme IV is n-octyl-D-glucamine.
- the amine is phenyl ethyl amine.
- the amine is naphtyl ethyl amine.
- the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)- 4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of amine;
- the amine is preferably an amine with formula NR : R 2 R 3 , wherein R 1 , R 2 and R 3 can be selected from H or an alkyl group.
- R 1 , R 2 and R 3 can be selected from H or an alkyl group.
- one or more of R 1 , R 2 and R 3 is not a C1-C6 alkyl group.
- the amine is selected from n-octyl-D-glucamine, phenyl ethyl amine and naphthyl ethyl amine.
- the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme
- the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of pyridine; b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I from the reaction mixture.
- the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (VI).
- the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine;
- step a) in the above scheme comprises reacting N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine, without the addition or inclusion of a solvent.
- the product amine salt of formula (III) can be isolated directly from the reaction mixture.
- reaction of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine can also be performed in an aqueous solution.
- the product amine salt can be washed using a suitable organic solvent, such as acetone or other polar solvent.
- the present invention further provides a process of preparing compound of formula (I) illustrated by the following scheme (VII).
- the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of with /-butyl amine to form N-(3-carboxy- l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester with /-butyl amine salt;
- the invention further provides novel salts of sacubitril.
- the invention provides novel N-(3-carboxy- l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salts, specifically novel N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt.
- the invention also provides N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt, N-(3 -carboxy- 1- oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt and N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
- the invention further provides crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester t-butyl amine salt.
- the compound is characterized by:
- At least one such as a least 2, at least 3, at least 4, at least5, at least 6, at least , at least 7, at least 8, at least 9, or all ofX-ray diffraction peaks with 2-theta values 4.11, 8.06, 9.88, 15.70, 16.16, 17.63, 17.78, 19.76, 20.23, and 23.10; and/or
- the powder x-ray diffraction pattern can have 2-theta values that show a slight deviation from the above recited values.
- the N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt of the invention is characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2-theta values 4.11+1- 0.1°, 8.06+/- 0.1°, 9.88+/- 0.1°, 15.70+/- 0.1°, 16.16+/- 0.1°, 17.63+/- 0.1°, 17.78+/- 0.1°, 19.76+/- 0.1°, 20.23+/- 0.1°
- the N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt is characterized by powder X-ray diffraction peaks with 2-theta values 4.11+/- 0.1°, 8.06+/- 0.1°, 9.88+/- 0.1°, 15.70+/- 0.1°, 16.16+/- 0.1°, 17.63+/- 0.1°, 17.78+/- 0.1°, 19.76+/- 0.1°, 20.23+/- 0.1° and 23.10 +/- 0.1 0 and a differential scanning calorimetric thermogram with an endothermic peak at about 133.7+/- 3°C.
- the invention also provides crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt that is characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2- theta values 4.40+/- 0.1°, 8.68+/- 0.1°, 10.37+/- 0.1°, 10.68+/- 0.1°, 12.81+/- 0.1°, 13.36+/- 0.1°, 14.48+/- 0.1°, 16.81+/- 0.1°, 16.99+/- 0.1°, 18.12+/-0.1°, 18.87+/-0.1 0 , 19.00+/-0.1 0 , 19.37+/-0.1 0 ,
- crystalline crystalline N-(3 -carboxy- 1-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt that is characterized by X-ray diffraction spectrum as shown in FIG. 4.
- the compound can also, or additionally, be characterized by a differential scanning calorimetric thermogram with an endothermic peak at about 126.7+/- 3°C, and an IR spectrum as shown in FIG. 5.
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl phenyl ethyl amine salt that is characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2-theta values 7.53+/- 0.1°, 8.36+/- 0.1°, 8.55+/- 0.1°, 10.93+/- 0.1°, 15.13+/- 0.1°, 15.96+/- 0.1°, 16.80+/- 0.1°, 17.36+/- 0.1°, 17.68+/- 0.1°, 18.82+/- 0.1°, 19.40+/-0.1 0 , 20.58+/-0.1 0 , 22.01+/-0.1 0 , 23.11+/-0.1
- crystalline crystalline N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt that is characterized by X-ray diffraction spectrum as shown in as shown in FIG. 7.
- the compound can also, or additionally, be characterized by a differential scanning calorimetric thermogram with an endothermic peak at about 128.7+/- 3°C, and an IR spectrum as shown in FIG. 8.
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl naphthyl ethyl amine salt that is characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2-theta values 3.76+/- 0.1°, 6.84+/- 0.1°, 7.17+/- 0.1°, 8.39+/- 0.1°, 9.20+/- 0.1°, 11.07+/- 0.1°, 13.70+/- 0.1°, 14.29+/- 0.1°, 15.11+/- 0.1°, 16.10+/- 0.1°, 16.79+/-0.1 0 , 17.75+/-0.1 0 , 18.01+/-0.1°, 18.45+/-0.1 0 ,
- crystalline crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt that is characterized by X-ray diffraction spectrum as shown in as shown in FIG. 10.
- the compound can also, or additionally, be characterized by a differential scanning calorimetric thermogram with an endothermic peak at about 138.1+/- 3°C, and an IR spectrum as shown in FIG. 11.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising N-(3-carboxy-l-oxopropyl)-(4S)- (p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester salt thereof prepared by any of the processes described herein.
- the composition comprises N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt.
- the composition comprises N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt.
- the composition comprises N- (3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt.
- the composition comprises N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
- the present invention further provides a process of preparing trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester - valsartan hemipentahydrate comprising: i) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester amine salt with valsartan;
- aqueous base such as an aqueous sodium hydroxide solution
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt can be any amine salt as disclosed herein.
- the amine salt can be a t-butyl salt, an n-octyl- d-glucamine salt, a phenyl ethyl amine salt, or a naphtyl ethyl amine salt of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester.
- Included in the present invention is also a process of preparaing trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester - valsartan hemipentahydrate comprising - treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester /-butyl amine salt with valsartan in presence of aqueous sodium hydroxide solution, and
- the advantage of the above process is that the preparation of sacubitril from sacubitril amine salt can be avoided, since the addition salt can directly be used for making the complex with valsartan. Furthermore, the amine salts are crystalline solid materials while sacubitril is oily. Hence, the handling of the addition salt is easy, making it convenient for a direct reaction with valsartan to generate sacubitril-valsartan hemipentahydrate complex.
- FIG. 1 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt by X-ray diffraction (XRD), as obtained by the process of the invention.
- XRD X-ray diffraction
- FIG. 2 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester t-butyl amine salt, as obtained by the process of the invention.
- IR Infrared Spectrum
- FIG. 3 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt, as obtained by the process of the invention.
- DSC Differential Scanning Calorimetry
- FIG. 4 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt by X-ray diffraction (XRD), as obtained by the process of the invention.
- XRD X-ray diffraction
- FIG. 5 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt, as obtained by the process of the invention.
- IR Infrared Spectrum
- FIG. 6 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt, as obtained by the process of the invention.
- DSC Differential Scanning Calorimetry
- FIG. 7 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester phenyl ethyl amine salt by X-ray diffraction (XRD), as obtained by the process of the invention.
- XRD X-ray diffraction
- FIG. 8 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt, as obtained by the process of the invention.
- IR Infrared Spectrum
- FIG. 10 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester naphthyl ethyl amine salt by X-ray diffraction (XRD), as obtained by the process of the invention.
- XRD X-ray diffraction
- FIG. 11 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt, as obtained by the process of the invention.
- IR Infrared Spectrum
- FIG. 12 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt, as obtained by the process of the invention.
- DSC Differential Scanning Calorimetry
- the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (II).
- the first step of the synthesis is to treat (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof with succinic anhydride.
- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof can be obtained by preparing (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester illustrated by the following scheme.
- XA is a chiral acid, preferably a chiral organic acid.
- the chiral acid can typically be selected from the group consisting of mandelic acid (2-hydroxy-2-phenylacetic acid), tartaric acid (2,3-dihydroxybutanedioic acid), di-p-toluyl tartaric acid (2,3-bis[(4- methylbenzoyl)oxy]butanedioic acid), dibenzoyl tartaric acid (2,3-dibenzoyloxybutanedioic acid), camphor sulfonic acid ((7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl)methanesulfonic acid) and the like.
- the compound of formula II can also be produced by the synthetic routes illustrated in the following scheme.
- X " is the anion of the organic or inorganic acid, and XA is any chiral acid, preferably a chiral organic acid.
- the salt of (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester may be first treated with base depending on the conjugated acid of the acid addition salt. If it is a strong conjugate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid and the like, the acid addition salt is treated with base before treatment with the chiral organic acid.
- a strong conjugate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid and the like
- the acid addition salt does not need to be treated with base before treatment with the chiral organic acid.
- the salt of compound II is (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate.
- Crystalline (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate may be characterized by at least one of
- Treatment of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof with succinic anhydride may be carried out in base, more preferably in an organic base.
- the base neutralizes the salt as well as maintains the basic condition of the reaction which enhances reaction rate.
- organic bases examples include but are not limited to triethylamine, tributylamine, diisopropylethylamine, diethylamine, tert-butyl amine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine and pyridine.
- the base is pyridine, TEA, t-butyl amine, sodium carbonate, sodium bicarbonate or sodium acetate.
- the salt is preferably selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
- the salt is preferably selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester is present in the form of tartrate salt.
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt is isolated from the reaction mixture.
- Standard work-up procedures s known in the art can be employed. These typically include removal of solvents, preferably by evaporation, separating the reaction mixture into organic and aqueous layers by liquid-liquid extraction, and purification by filtration and recrystallization.
- the solvent in the mixture may be first removed, preferably by evaporation under reduced pressure. Then, the solvent can be distilled from reaction mixture, for example under vacuum or partial vacuum.
- the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (V).
- step a) in scheme (II) is carried out in the presence of pyridine.
- the present invention provides a method of preparing N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of pyridine;
- the present invention provides a process of preparing substantially pure compound of formula (I) illustrated by the following scheme (III).
- R 1 , R 2 and R 3 are independently hydrogen or alkyl group; and XA is acid.
- the present invention also provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with amine;
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof is treated with amine.
- the amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
- step b) the amine salt can be isolated from the reaction mixture using standard work-up procedures s known in the art or described in the present application.
- step c isolated N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt is treated with acid, including inorganic acid or organic acids, to neutralize the amine salt, resulting in substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
- acid with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
- organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid and the like.
- the acid is hydrochloric acid.
- the amine used in step a) of scheme (III) is /-butyl amine.
- the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (VI).
- the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)- 4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: e) treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine;
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester obtained by the process described in the present application may have a purity > 99%, such as >99.1%, >99.2%, >99.3%, >99.4% and >99.5%.
- the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (IV).
- R 1 , R 2 and R 3 are independently hydrogen or alkyl group; and XA is acid.
- the first step a) of the synthesis is to treat (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof with succinic anhydride in the presence of amine. It is within the skilled person in the art to determine which amine can be used. In general, any amine which is able to neutralize the salt can be used. Preferably, the amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, t-butyl amine.
- the salt may be selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
- the salt may be selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
- the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)- 4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising:
- step b N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt of formula III is isolated from the reaction mixture.
- Standard work-up procedures s known in the art can be employed.
- step c isolated N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester amine salt is treated with acid, including inorganic acid or organic acids, to neutralize the amine, leading to formation of free N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester of formula I.
- acid with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
- organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid and the like.
- the amine used in step a) of scheme (IV) is t-butyl amine salt.
- the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of with /-butyl amine to form N-(3-carboxy- l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester with /-butyl amine salt;
- the inventors have discovered that N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester obtained by the process described in the present application may have a purity > 99%, such as >99.1%, >99.2%, >99.3%, >99.4% and >99.5%.
- the invention further provides novel crystalline forms of sacubitril salts.
- the invention provides N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt and crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt.
- Crystalline N-(3-carboxy- l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt can be characterized by
- the N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt is characterized by at least one of X-ray diffraction peaks with 2-theta values 4.11, 8.06, 9.88, 15.70, 16.16, 17.63, 17.78, 19.76, 20.23 and 23.10 and a differential scanning calorimetric thermogram with an endothermic peak at about 133.7+/- 3°C.
- FIG. 1 and Table 1 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt by X-ray diffraction (XRD), as obtained by the invention.
- XRD X-ray diffraction
- FIG. 2 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester t-butyl amine salt, as obtained by the process of the invention.
- IR Infrared Spectrum
- N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt may have an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 2.
- substantially similar means an analytical spectrum, such as XRD pattern, IH-NMR spectrum, FT-IR spectrum, Raman spectrum, TGA thermogram, etc., which resembles the reference spectrum to a great degree in both the peak locations and their intensity.
- FIG. 3 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt, as obtained by the process of the invention.
- DSC Differential Scanning Calorimetry
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt may have a differential scanning calorimetric thermogram substantially similar to a differential scanning calorimetric thermogram as depicted in Fig. 3.
- the invention further provides N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt and crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt.
- Crystalline N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D- glucamine salt can be characterized by an X-ray diffraction pattern substantially as shown in Table 2 and FIG. 4 herein.
- the compound can also be characterized by
- the N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt is characterized by at least one of X-ray diffraction peaks with 2-theta values 4.40, 8.68, 10.37, 10.68, 12.81, 13.36, 14.48, 16.81, 16.99, 18.12, 18.87, 19.00, 19.37, 19.85, 20.81, 21.32, 21.50 and 22.51; and a differential scanning calorimetric thermogram with an endothermic peak at about 126.7+/- 3°C.
- Table 2 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt by X-ray diffraction (XRD), as obtained by the invention.
- XRD X-ray diffraction
- FIG.5 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt, as obtained by the process of the invention.
- IR Infrared Spectrum
- n- Octhyl-D-glucamine salt can have an IR spectrum substantially similar to an IR spectrum as depicted in FIG.5.
- FIG.6 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt, as obtained by the process of the invention.
- DSC Differential Scanning Calorimetry
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt can have a differential scanning calorimetric thermogram substantially similar to a differential scanning calorimetric thermogram as depicted in FIG.6.
- the invention further provides N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester phenyl ethyl amine salt and crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt.
- Crystalline N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt can be characterized by an X-ray diffraction pattern substantially as shown in Table 3 and FIG. 7.
- the compound can also be characterized by
- a. at least one of X-ray diffraction peaks with 2-theta values 7.53, 8.36, 8.55, 10.93, 15.13, 15.96, 16.80, 17.36, 17.68, 18.82, 19.40, 20.58, 22.01, 23.11, 24.30, 24.90, 25.88, 26.45, 28.08, 28.66, 28.96 and 29.34°; or
- the N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt is characterized by at least one of X-ray diffraction peaks with 2-theta values 7.53, 8.36, 8.55, 10.93, 15.13, 15.96, 16.80, 17.36, 17.68, 18.82, 19.40, 20.58, 22.01, 23.11, 24.30, 24.90, 25.88, 26.45, 28.08, 28.66, 28.96 and 29.34° and a differential scanning calorimetric thermogram with an endothermic peak at about 128.7+/- 3°C.
- FIG. 7 and Table 3 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt by X-ray diffraction (XRD), as obtained by the invention.
- XRD X-ray diffraction
- FIG.8 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt, as obtained by the process of the invention.
- IR Infrared Spectrum
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt may have an IR spectrum substantially similar to an IR spectrum as depicted in FIG. 8.
- FIG. 9 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt, as obtained by the process of the invention.
- DSC Differential Scanning Calorimetry
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester phenyl ethyl amine salt may have a differential scanning calorimetric thermogram substantially similar to a differential scanning calorimetric thermogram as depicted in FIG. 9.
- Crystalline N-(3-carboxy-l-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt as obtained by the invention can be characterized by X-ray diffraction pattern substantially as shown in Table 4 and FIG. 10.
- the compound can also be characterized by
- a. at least one of X-ray diffraction peaks with 2-theta values 3.76, 6.84, 7.17+, 8.39, 9.20, 11.07, 13.70, 14.29, 15.11, 16.10, 16.79, 17.75, 18.01, 18.45, 18.90, 19.92, 20.29, 20.44, 21.31, 21.67, 22.31, 22.54, 25.14, 25.39, 26.23, 27.00, 27.93 and 30.03°; and/or
- the N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt is characterized by at least one of X-ray diffraction peaks with 2-theta values 3.76, 6.84, 7.17+, 8.39, 9.20, 11.07, 13.70, 14.29, 15.11, 16.10, 16.79, 17.75, 18.01, 18.45, 18.90, 19.92, 20.29, 20.44, 21.31, 21.67, 22.31, 22.54, 25.14, 25.39, 26.23, 27.00, 27.93 and 30.03 and a differential scanning calorimetric thermogram with an endothermic peak at about 138.1+/- 3°C.
- FIG. 10 and Table 4 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt by X-ray diffraction (XRD), as obtained in the example of the invention.
- XRD X-ray diffraction
- FIG. 11 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt, as obtained by the process of the invention.
- IR Infrared Spectrum
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt may have an IR spectrum substantially similar to an IR spectrum as depicted in FIG. 11.
- FIG. 12 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt, as obtained by the process of the invention.
- DSC Differential Scanning Calorimetry
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester naphthyl ethyl amine salt may have a differential scanning calorimetric thermogram substantially similar to a differential scanning calorimetric thermogram as depicted in FIG. 12.
- a process of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester comprising the steps of:
- salt is selected from the list of tartaric acid, dibenzoyl tartaric acid, di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
- R 1 , R 2 and R 3 are independently hydrogen or alkyl group; and XA is acid.
- step d) has purity more than 95% including more than 96%, more than 97%, more than 98%, more than 99% and up to 99.5% or more.
- amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
- step a) is performed using water as a solvent.
- step a) is performed without addition of a solvent.
- R 1 , R 2 and R 3 are independently hydrogen or alkyl group; and XA is acid.
- salt is selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
- amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
- step a) is performed using water as a solvent.
- step a) is performed without addition of a solvent.
- a crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt characterized by at least one of the following:
- a pharmaceutical composition comprising a compound according to any of clauses 28 to 43.
- a pharmaceutical composition comprising N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester salt thereof prepared by a process according to any one of clauses 1 to 27.
- amine is an amine with formula NR3 ⁇ 4 2 R 3 , with the provisio that at least one of the substituents R 1 , R 2 , R 3 is not H or a C1-G5 alkyl group.
- Example 1 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid
- Example 2 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(- )-tartrate salt.
- the final product is characterized a powder X-ray diffraction (XRD) pattern as shown in Figure 1.
- XRD powder X-ray diffraction
- Example 5 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid
- Example 6 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(- )-tartrate salt.
- Example 8 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt without the use of solvent.
- Example 9 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt in the absence of organic solvent.
- Example 10 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt using t-butyl amine as solvent and base.
- Example 11 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt.
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester 2.5g
- Reaction mixture was stirred for 2-3 hours.
- Product was filtered and washed with acetone (5ml). After drying 2.2g (75%) product was isolated.
- the HPLC purity of the product is more than 99%.
- Example 12 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt.
- Example 13 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl- D-Glucamine salt 25g was dissolved in dichloromethane (250ml) and solution was stirred for 10-15 minutes. To this solution water (150ml) was added and then slowly added hydrochloric acid (20%, 50ml). Reaction mixture was stirred for 15-20minutes. Organic layer was separated and aqueous layer extracted with dichloromethane (2 X 100ml). Combined organic layer washed with water (2 X 100ml). Organic layer was dried over sodium sulfate. After removing solvent under vacuum 13g (89%) oily product was obtained. The HPLC purity of the product is 99.5%.
- Example 14 Preparation of trisodium sacubitril- valsartan hemipentahydrate.
- Example 15 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester phenyl ethyl amine salt.
- Example 16 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt (25g) was dissolved in dichloromethane (250ml) and solution was stirred for 10-15 minutes. To this solution water (150ml) was added and then slowly added hydrochloric acid (20%, 50ml). Reaction mixture was stirred for 15-20minutes. Organic layer was separated and aqueous layer extracted with dichloromethane (2 X 100ml). Combined organic layer washed with water (2 X 100ml). Organic layer was dried over sodium sulfate. After removing solvent under vacuum 17g (90%) oily product was obtained. The HPLC purity of the product is 99.5%.
- Example 17 Preparation of trisodium sacubitril- valsartan hemipentahydrate.
- Example 18 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
- Example 19 Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
- N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt (20g) was dissolved in dichloromethane (200ml) and solution was stirred for 10-15 minutes. To this solution water (100ml) was added and then slowly added hydrochloric acid (20%, 40ml). Reaction mixture was stirred for 15-20minutes. Organic layer was separated and aqueous layer extracted with dichloromethane (2 X 75ml). Combined organic layer washed with water (2 X 75ml). Organic layer was dried over sodium sulfate. After removing solvent under vacuum 13.3g (94%) oily product was obtained. The HPLC purity of the product is 99.5%.
- Example 20 Preparation of trisodium sacubitril- valsartan hemipentahydrate.
Abstract
The invention provides a process for preparing sacubitril. The present invention also provides a novel salt of sacubitril and its crystalline form. The invention further provides crystalline N-(3-carboxy-1- oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salts. Also provided is a a method of preparing N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester.
Description
PREPARATION OF SACUBITRIL AND SALT THEREOF AND NOVEL COMPOUNDS
USED IN THE PROCESS
Field
The invention generally relates to methods of preparing a compound, in particular a pharmaceutical compound and more specifically a NEP inhibitor. The invention also relates to pharmaceutical compositions comprising such compounds, processes, starting materials and intermediates for preparing such compounds.
Introduction
Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is a(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester is an endothelial membrane bound Zn2+ metallopeptidase found in many organs and tissues, including the brain, kidneys, lungs, gastrointestinal tract, heart, and the peripheral vasculature. NEP degrades and inactivates a number of endogenous peptides, such as enkephalins, circulating bradykinin, angiotensin peptides, and natriuretic peptides, the latter of which have several effects including, for example, vasodilation and natriure sis/diuresis, as well as inhibition of cardiac hypertrophy and ventricular fibrosis. Thus, NEP plays an important role in blood pressure homeostasis and cardiovascular health.
The present invention is related to the preparation of the NEP inhibitor sacubitril (Formula I). Sacubitril is (2R,4S)- 5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, also named N-(3-carboxy-l- oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester.
Sacubitril
The use of sacubitril for treating cardiovascular disorders is described in U.S. Patent No. 5,217,996. Sacubitril is useful as a neutral endopeptidase (NEP) inhibitor, e.g. as inhibitors of the ANF-degrading enzyme in mammals, which prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals by inhibiting the degradation thereof to less active metabolites. In particular, sacubitril is useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase EC 3.4.24.11, particularly cardiovascular disorders, such as hypertension, renal insufficiency including edema and salt retention, pulmonary edema and congestive heart failure.
U.S. Patent No. 8,877,938 discloses trisodium sacubtril-valsartan hemipentahydrate in crystalline form, a dual- acting compound where the angiotensin receptor blocker and neutral endopeptidase inhibitor are linked via non- covalent bonding.
U.S. Patent No. 7,468,390 discloses pharmaceutical composition of valsartan or a pharmaceutically acceptable salt thereof with sacubitril or a pharmaceutically acceptable salt thereof.
U.S. patent No. 5,217,996 discloses synthesis of sacubitril isolated as sodium salt. Processes for preparing sacubitril is presented by the following Scheme I:
TFA
(I)
Scheme I
A major drawback of the process disclosed in U.S. Patent No. 5,217,996 is that it involves using a diasteromeric mixture of (45)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester with a ratio of 80:20. The compound, upon treatment with succinic anhydride, gives N-(3-carboxy (/)butoxy-l-oxopropyl)-(45)-(p- phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester. The (S,R) and (S,S) isomers must then be
separated by column chromatography. Subsequently, separated N-(3carboxy (/)butoxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester is treated with trifluroacetic acid (TFA) to obtain sacubitril of compound of formula I. This process cannot be easily scaled up as it involves column chromatography for product separation, which requires specialized equipment that is relatively expensive and time-consuming to operate. Furthermore, chiral separation of unwanted (S,S) isomer is carried out just one step before obtaining final product, which has impact on the overall yield.
Summary
The present invention relates to a process for preparing sacubitril, more specifically, a process for synthesizing the compound of formula I:
(I)
The present invention also provides novel salts of sacubitril and its crystalline form. The invention thus provides amine salts of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester with the general formula (III):
In a particular example, the invention provides crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt compound of formula (III):
In general, the amine salt can comprise an amine with the general formula NR:R2R3, wherein at least one of the groups R1, R2, R3 is not hydrogen or a C1-C6 alkyl group. The amine salt of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester can also be an amine salt that is not one of tert-butylamine, isopropylamine, cyclohexylamine, n-propylamine and dicyclohexylamine.
In one embodiment, the amine salt is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-octyl-D-glucamine salt of formula Ill-b:
Ill-b
In another embodiment, the amine salt is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester phenyl ethyl salt of formula Ill-b:
III-c
In another embodiment, the amine salt is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester naphtyl ethyl amine salt of formula Ill-d:
III-d
The present invention is in part based on the use of novel (4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester to synthesize sacubitril. Using of diastereomerically pure chiral isomer allows a substantially optically pure of sacubitril or salt thereof to be obtained, providing numerous advantages over presently known synthesis routes.
As used herein, "substantially pure" refers to at least about 95% purity, more preferably at least about 96% and most preferably at least about 98% purity or at least about 99% purity.
U.S. Patent No. 8,877,938 uses about 95% pure Sacubitril for the preparation of Trisodium Sacubtril-valsartan hemipentahydrate. In contrast, it is possible to provide substantially pure sacubitril having purity more than 99.5% according to the present invention. As used herein, the term "about" refers to a range of values ± 10% of a specified value. For example, the phrase "about 95" includes ± 10% of 95 and 95 as such.
The present invention also provides process for preparing pure sacubitril which has purity more than 95% including more than 96%, more than 97%, more than 98%, more than 99% and up to 99.5% or more.
In particular, the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (II).
(II) (1)
Scheme (II)
The present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)- 4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising:
a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I from the reaction mixture.
The present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (III).
Scheme (III)
wherein R1, R2 and R3 are independently hydrogen or alkyl group; and XA is acid.
In particular, the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising:
a) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with amine;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt from the reaction mixture;
c) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with acid;
d) isolating substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I.
In some preferred embodiments, one or more of R1, R2 and R3 is not H or a C1-C6 alkyl group. Thus the amine salt according to formula (III) can preferably comprise an amine of formula NR:R2R3 wherein R1, R2 and R3 are independently hydrogen or alkyl groups, with the provisio that at least one of the groups is not H or a C1-C6 alkyl group.
In one embodiment, the amine in Scheme III is n-octyl-D-glucamine. In another embodiment, the amine is phenyl ethyl amine. In another embodiment, the amine is naphtyl ethyl amine.
It can be convenient to perform the reaction of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with an amine in a suitable organic solvent. Preferably the solvent can be a polar solvent, more preferably a non-aqueous polar solvent. In some preferred embodiments, the solvent is a non-protic non-aqueous polar solvent. Preferred polar solvents can include tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide. In a preferred embodiment, the solvent is acetone.
However, the inventors have also discovered that the reaction can be performed in an aqueous solution, which eliminates the need to use organic solvents that can be toxic and costly to remove. For example, the reaction of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with t-butyl amine proceeds to completion in high yield using only water as solvent.
Yet another advantage of the invention is the possibility to perform the reaction of N-(3-carboxy-l-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester with an amine in the absence of any additional solvent, which is particularly feasible for amines that are in a liquid state at or near room temperature. This means that the reaction involves mixing the ethyl ester with a neat amine, as for example manifested by the reaction of t-butyl amine with N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
The possibility of running the reaction in the absence of an organic solvent, or even without the use of any solvent at all, leads to reduced cost of the process, increased productivity on industrial scale and environmental advantage, since there is no need to remove and discard toxic organic solvents. Conversion of the amine salt from step (b) to pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester can be conveniently performed by reacting the addition salt with an acid, such as hydrochloric acid or other suitable organic or inorganic acids.
The present invention also provides a process of preparing compound of formula (I) illustrated by the following scheme (IV).
Scheme (IV)
wherein R1, R2 and R3 are independently hydrogen or alkyl group; and XA is acid.
In some preferred embodiments, one or more of R1, R2 and R3 is a group that is not H or a C1-C6 alkyl group. Thus the amine salt according to formula (III) can preferably comprise an amine that independently contains hydrogen or alkyl groups, with the provisio that at least one of the groups is not H or a C1-C6 alkyl group.
In one embodiment, the amine in Scheme IV is n-octyl-D-glucamine. In another embodiment, the amine is phenyl ethyl amine. In another embodiment, the amine is naphtyl ethyl amine.
The present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)- 4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of amine;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt of formula III from the reaction mixture;
c) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with acid;
d) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I.
The amine is preferably an amine with formula NR:R2R3, wherein R1, R2 and R3can be selected from H or an alkyl group. Preferably, one or more of R1, R2 and R3 is not a C1-C6 alkyl group. Even more preferably, the amine is selected from n-octyl-D-glucamine, phenyl ethyl amine and naphthyl ethyl amine.
The present invention provides a process of preparing compound of formula (I) illustrated by the following scheme
(II) (1)
Scheme (V)
In particular, the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of pyridine;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I from the reaction mixture.
The present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (VI).
Scheme (VI)
In particular the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt from the reaction mixture;
c) treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt with acid;
d) isolating substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I.
The reaction of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine can be performed in a suitable organic solvent.
It can however be convenient to perform the reaction of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine in the absence of a solvent. Thus, in one embodiment according to the invention, step a) in the above scheme comprises reacting N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine, without the addition or inclusion of a solvent. The product amine salt of formula (III) can be isolated directly from the reaction mixture.
Alternatively, the reaction of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine can also be performed in an aqueous solution.
The product amine salt can be washed using a suitable organic solvent, such as acetone or other polar solvent.
The present invention further provides a process of preparing compound of formula (I) illustrated by the following scheme (VII).
Scheme (VII)
In particular, the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of with /-butyl amine to form N-(3-carboxy- l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester with /-butyl amine salt;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt from the reaction mixture;
c) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt with acid;
d) isolating substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I.
Included in the invention is also the novel use of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof to produce sacubitril.
The invention further provides novel salts of sacubitril. In particular, the invention provides novel N-(3-carboxy- l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salts, specifically novel N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt. The invention also provides N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt, N-(3 -carboxy- 1- oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt
and N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
The invention further provides crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester t-butyl amine salt. Preferably, the compound is characterized by
a. at least one, such as a least 2, at least 3, at least 4, at least5, at least 6, at least , at least 7, at least 8, at least 9, or all ofX-ray diffraction peaks with 2-theta values 4.11, 8.06, 9.88, 15.70, 16.16, 17.63, 17.78, 19.76, 20.23, and 23.10; and/or
b. a differential scanning calorimetric thermogram with a endothermic peak at about 133.7°C or 133.7+/- 3°C.
It should be appreciated and is well known to the skilled person that the powder x-ray diffraction pattern can have 2-theta values that show a slight deviation from the above recited values. Thus, in one embodiment, the N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt of the invention is characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2-theta values 4.11+1- 0.1°, 8.06+/- 0.1°, 9.88+/- 0.1°, 15.70+/- 0.1°, 16.16+/- 0.1°, 17.63+/- 0.1°, 17.78+/- 0.1°, 19.76+/- 0.1°, 20.23+/- 0.1° and 23.10 +/- 0.1°, and a differential scanning calorimetric thermogram with an endothermic peak at about 133.7+/- 3°C. More preferably, the N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt is characterized by powder X-ray diffraction peaks with 2-theta values 4.11+/- 0.1°, 8.06+/- 0.1°, 9.88+/- 0.1°, 15.70+/- 0.1°, 16.16+/- 0.1°, 17.63+/- 0.1°, 17.78+/- 0.1°, 19.76+/- 0.1°, 20.23+/- 0.1° and 23.10 +/- 0.10 and a differential scanning calorimetric thermogram with an endothermic peak at about 133.7+/- 3°C.
The invention also provides crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt that is characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2- theta values 4.40+/- 0.1°, 8.68+/- 0.1°, 10.37+/- 0.1°, 10.68+/- 0.1°, 12.81+/- 0.1°, 13.36+/- 0.1°, 14.48+/- 0.1°, 16.81+/- 0.1°, 16.99+/- 0.1°, 18.12+/-0.1°, 18.87+/-0.10, 19.00+/-0.10, 19.37+/-0.10, 19.85+/-0.10, 20.81+/-0.10, 21.32+/-0.10, 21.50+/-0.10 and 22.51+/-0.10. Also provided is crystalline crystalline N-(3 -carboxy- 1-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt that is characterized by X-ray diffraction spectrum as shown in FIG. 4. The compound can also, or additionally, be characterized by a differential scanning calorimetric thermogram with an endothermic peak at about 126.7+/- 3°C, and an IR spectrum as shown in FIG. 5.
Further provided is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl phenyl ethyl amine salt that is characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2-theta values 7.53+/- 0.1°, 8.36+/- 0.1°, 8.55+/- 0.1°, 10.93+/- 0.1°, 15.13+/- 0.1°, 15.96+/- 0.1°, 16.80+/- 0.1°, 17.36+/- 0.1°, 17.68+/- 0.1°, 18.82+/- 0.1°, 19.40+/-0.10, 20.58+/-0.10, 22.01+/-0.10, 23.11+/-0.1°, 24.30+/-0.10, 24.90+/-0.10, 25.88+/-0.10, 26.45+/- 0.1°, 28.08+/-0.10, 28.66+/-0.10, 28.96+/-0.10 and 29.34+/-0.10. Also provided is crystalline crystalline N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl
amine salt that is characterized by X-ray diffraction spectrum as shown in as shown in FIG. 7. The compound can also, or additionally, be characterized by a differential scanning calorimetric thermogram with an endothermic peak at about 128.7+/- 3°C, and an IR spectrum as shown in FIG. 8.
Further provided is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl naphthyl ethyl amine salt that is characterized by at least one, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or all of X-ray diffraction peaks with 2-theta values 3.76+/- 0.1°, 6.84+/- 0.1°, 7.17+/- 0.1°, 8.39+/- 0.1°, 9.20+/- 0.1°, 11.07+/- 0.1°, 13.70+/- 0.1°, 14.29+/- 0.1°, 15.11+/- 0.1°, 16.10+/- 0.1°, 16.79+/-0.10, 17.75+/-0.10, 18.01+/-0.1°, 18.45+/-0.10, 18.90+/-0.10, 19.92+/-0.10, 20.29+/-0.10, 20.44+/- 0.1°, 21.31+/-0.10, 21.67+/-0.10, 22.31+/-0.10, 22.54+/-0.10, 25.14+/-0.10, 25.39+/-0.10, 26.23+/-0.10, 27.00+/- 0.1°, 27.93+/-0.1° and 30.03+/-0.1°. Also provided is crystalline crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt that is characterized by X-ray diffraction spectrum as shown in as shown in FIG. 10. The compound can also, or additionally, be characterized by a differential scanning calorimetric thermogram with an endothermic peak at about 138.1+/- 3°C, and an IR spectrum as shown in FIG. 11.
The present invention also provides a pharmaceutical composition comprising N-(3-carboxy-l-oxopropyl)-(4S)- (p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester salt thereof prepared by any of the processes described herein. In one embodiment, the composition comprises N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt. In another embodiment, the composition comprises N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt. In another embodiment, the composition comprises N- (3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt. In another embodiment, the composition comprises N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
The present invention further provides a process of preparing trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester - valsartan hemipentahydrate comprising: i) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester amine salt with valsartan;
ii) treating the reaction mixture with an aqueous base, such as an aqueous sodium hydroxide solution, and
iii) isolating trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester - valsartan hemipentahydrate from the resulting reaction mass.
The N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt can be any amine salt as disclosed herein. For example, the amine salt can be a t-butyl salt, an n-octyl- d-glucamine salt, a phenyl ethyl amine salt, or a naphtyl ethyl amine salt of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester.
Included in the present invention is also a process of preparaing trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester - valsartan hemipentahydrate comprising
- treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester /-butyl amine salt with valsartan in presence of aqueous sodium hydroxide solution, and
- isolating trisodium N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester - valsartan hemipentahydrate from reaction mass.
The advantage of the above process is that the preparation of sacubitril from sacubitril amine salt can be avoided, since the addition salt can directly be used for making the complex with valsartan. Furthermore, the amine salts are crystalline solid materials while sacubitril is oily. Hence, the handling of the addition salt is easy, making it convenient for a direct reaction with valsartan to generate sacubitril-valsartan hemipentahydrate complex.
The above features along with additional details of the invention, are described further in the examples below, which are intended to further illustrate the invention but are not intended to limit its scope in any way.
Brief Description of the Drawings
The skilled person will understand that the drawings, described below, are for illustration purposes only. The drawings are not intended to limit the scope of the present teachings in any way.
FIG. 1 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt by X-ray diffraction (XRD), as obtained by the process of the invention.
FIG. 2 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester t-butyl amine salt, as obtained by the process of the invention.
FIG. 3 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt, as obtained by the process of the invention.
FIG. 4 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt by X-ray diffraction (XRD), as obtained by the process of the invention.
FIG. 5 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt, as obtained by the process of the invention.
FIG. 6 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt, as obtained by the process of the invention.
FIG. 7 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester phenyl ethyl amine salt by X-ray diffraction (XRD), as obtained by the process of the invention.
FIG. 8 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt, as obtained by the process of the invention.
FIG. 9 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt, as obtained by the process of the invention.
FIG. 10 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester naphthyl ethyl amine salt by X-ray diffraction (XRD), as obtained by the process of the invention.
FIG. 11 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt, as obtained by the process of the invention.
FIG. 12 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt, as obtained by the process of the invention.
Description of Various Embodiments
In the following, exemplary embodiments of the invention will be described, referring to the figures. These examples are provided to provide further understanding of the invention, without limiting its scope.
In the following description, a series of steps are described. The skilled person will appreciate that unless required by the context, the order of steps is not critical for the resulting configuration and its effect. Further, it will be apparent to the skilled person that irrespective of the order of steps, the presence or absence of time delay between steps, can be present between some or all of the described steps.
As used herein, including in the claims, singular forms of terms are to be construed as also including the plural form and vice versa, unless the context indicates otherwise. Thus, it should be noted that as used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.
The present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (II).
(ID (1)
Scheme (II)
The first step of the synthesis is to treat (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof with succinic anhydride.
Compound of formula II
According to the present invention, (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof can be obtained by preparing (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester illustrated by the following scheme.
The chiral acid can typically be selected from the group consisting of mandelic acid (2-hydroxy-2-phenylacetic acid), tartaric acid (2,3-dihydroxybutanedioic acid), di-p-toluyl tartaric acid (2,3-bis[(4- methylbenzoyl)oxy]butanedioic acid), dibenzoyl tartaric acid (2,3-dibenzoyloxybutanedioic acid), camphor sulfonic acid ((7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl)methanesulfonic acid) and the like.
The compound of formula II can also be produced by the synthetic routes illustrated in the following scheme.
wherein X" is the anion of the organic or inorganic acid, and XA is any chiral acid, preferably a chiral organic acid.
The salt of (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester may be first treated with base depending on the conjugated acid of the acid addition salt. If it is a strong conjugate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid and the like, the acid addition salt is treated with base before treatment with the chiral organic acid. On the other hand, in case of acid addition salt of weak conjugate acid, such as mandelic acid, acetic acid, succinic acid, propionic acid, crotonic acid, lactic acid, formic acid, glutaric acid, adipic acid, benzoic acid and the like, the acid addition salt does not need to be treated with base before treatment with the chiral organic acid.
Preferably, the salt of compound II is (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate.
Crystalline (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate may be characterized by at least one of
a) powder X-ray diffraction peaks with 2-theta 5.59, 8.63, 11.13, 14.82, 16.22, 16.82, 18.45, 19.86, 20.73 and 21.29, and/or
b) a differential scanning calorimetric thermogram with a endothermic peak at about 177°C.
Treatment of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof with succinic anhydride may be carried out in base, more preferably in an organic base. The base neutralizes the salt as well as maintains the basic condition of the reaction which enhances reaction rate.
Examples of organic bases that may be used include but are not limited to triethylamine, tributylamine, diisopropylethylamine, diethylamine, tert-butyl amine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine and pyridine. Preferably, the base is pyridine, TEA, t-butyl amine, sodium carbonate, sodium bicarbonate or sodium acetate.
Most preferably, treatment of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof with succinic anhydride is carried out in the presence of pyridine.
If the compound of formula II is present in the form of salt, the salt is preferably selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid. Preferably, (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester is present in the form of tartrate salt.
In the follow step, N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt is isolated from the reaction mixture. Standard work-up procedures s known in the art can be employed. These typically include removal of solvents, preferably by evaporation, separating the reaction mixture into organic and aqueous layers by liquid-liquid extraction, and purification by filtration and recrystallization. For example, the solvent in the mixture may be first removed, preferably by evaporation under reduced pressure. Then, the solvent can be distilled from reaction mixture, for example under vacuum or partial vacuum.
Thus, the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (V).
(ID (1)
Scheme (V)
Preferably, step a) in scheme (II) is carried out in the presence of pyridine. Thus, the present invention provides a method of preparing N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of pyridine;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I from the reaction mixture.
The present invention provides a process of preparing substantially pure compound of formula (I) illustrated by the following scheme (III).
Scheme (III)
wherein R1, R2 and R3 are independently hydrogen or alkyl group; and XA is acid.
It has been surprisingly found that the purity of sacubitril of compound of formula (I) was about 90%, which after formation of t-butyl amine salt of compound of formula (III) increases to about 98.5% and when it converted back to sacubitril of formula (I) purity increased to about 99.5%.
Thus, the present invention also provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising:
a) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with amine;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt from the reaction mixture;
c) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with acid;
d) isolating substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I.
For example, in step a) N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof is treated with amine. Preferably, the amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
In step b) the amine salt can be isolated from the reaction mixture using standard work-up procedures s known in the art or described in the present application.
In step c), isolated N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt is treated with acid, including inorganic acid or organic acids, to neutralize the amine salt, resulting in substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
Representative examples acid with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid and the like. Preferbly, the acid is hydrochloric acid.
Preferably, the amine used in step a) of scheme (III) is /-butyl amine. Thus, the present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (VI).
Scheme (VI)
The present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)- 4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: e) treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with /-butyl amine;
f) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt from the reaction mixture;
g) treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt with acid;
h) isolating substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I.
N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester obtained by the process described in the present application may have a purity > 99%, such as >99.1%, >99.2%, >99.3%, >99.4% and >99.5%.
The present invention provides a process of preparing compound of formula (I) illustrated by the following scheme (IV).
Scheme (IV)
wherein R1, R2 and R3 are independently hydrogen or alkyl group; and XA is acid.
The first step a) of the synthesis is to treat (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof with succinic anhydride in the presence of amine. It is within the skilled person in the art to determine which amine can be used. In general, any amine which is able to neutralize the salt can be used. Preferably, the amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, t-butyl amine.
When (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester treated is in the form of salt, the salt may be selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid,
mandelic acid and camphor sulfonic acid. Preferably, (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(-)-tartrate is used.
The present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)- 4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising:
a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of amine;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt of formula III from the reaction mixture;
c) treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with acid;
d) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I.
In step b), N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt of formula III is isolated from the reaction mixture. Standard work-up procedures s known in the art can be employed.
In the following step c), isolated N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester amine salt is treated with acid, including inorganic acid or organic acids, to neutralize the amine, leading to formation of free N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester of formula I.
Representative examples acid with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid and the like.
Preferably, the amine used in step a) of scheme (IV) is t-butyl amine salt. Thus, the present invention provides a method of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I, comprising: a) treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of with /-butyl amine to form N-(3-carboxy- l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester with /-butyl amine salt;
b) isolating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt from the reaction mixture;
c) treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt with acid;
d) isolating substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I.
The inventors have discovered that N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester obtained by the process described in the present application may have a purity > 99%, such as >99.1%, >99.2%, >99.3%, >99.4% and >99.5%.
Amine salts of sacubitril
The invention further provides novel crystalline forms of sacubitril salts.
Specifically, the invention provides N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt and crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt. Crystalline N-(3-carboxy- l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt can be characterized by
a. at least one of X-ray diffraction peaks with 2-theta values 4.11, 8.06, 9.88, 15.70, 16.16, 17.63, 17.78, 19.76, 20.23, and 23.10; or
b. a differential scanning calorimetric thermogram with a endothermic peak at about 133.7+/- 3°C.
Preferably, the N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt is characterized by at least one of X-ray diffraction peaks with 2-theta values 4.11, 8.06, 9.88, 15.70, 16.16, 17.63, 17.78, 19.76, 20.23 and 23.10 and a differential scanning calorimetric thermogram with an endothermic peak at about 133.7+/- 3°C.
FIG. 1 and Table 1 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt by X-ray diffraction (XRD), as obtained by the invention.
Table 1
: Pos. |°2Th.| \ Height [cts] i FWHW[°2Th.] d-spacing [A] i Rel. Int. [%] i
4.1078 410.42 0.0964 21.51072 6.74
8.0644 6090.33 0.0827 10.96369 100.00
8.7982 22.60 0.1653 10.05094 0.37
9.8756 1132.71 0.1033 8.95662 18.60
12.3426 215.42 0.1929 7.17139 3.54
12.6862 253.39 0.1653 6.97795 4.16
13.0629 488.94 0.1102 6.77755 8.03
13.9659 112.50 0.1378 6.34130 1.85
15.1536 534.27 0.1653 5.84685 8.77
15.7054 917.86 0.0620 5.64266 15.07
16.1609 1766.25 0.1102 5.48464 29.00
16.3355 819.84 0.0689 5.42641 13.46
16.5690 625.34 0.1696 5.35044 10.27
16.8372 342.84 0.1378 5.26582 5.63
17.6350 3201.64 0.0758 5.02934 52.57
17.7819 3417.88 0.1240 4.98814 56.12
19.0064 597.75 0.0964 4.66944 9.81
19.4116 958.71 0.1378 4.57288 15.74
19.6255 1180.38 0.0895 4.52351 19.38
19.7636 1502.09 1.5007 4.49221 24.66
20.2346 3372.32 0.1033 4.38870 55.37
21.4348 592.60 0.1929 4.14560 9.73
21.6570 796.92 0.1240 4.10357 13.09
22.0551 519.89 0.1102 4.03039 8.54
23.1051 1089.48 0.0689 3.84955 17.89
23.7847 231.85 0.2480 3.74107 3.81
24.5794 873.26 0.0964 3.62189 14.34
25.6517 338.44 0.1102 3.47286 5.56
26.0697 457.99 0.1102 3.41813 7.52
26.3150 460.21 0.1102 3.38682 7.56
27.3954 489.90 0.1102 3.25566 8.04
28.6540 314.32 0.3031 3.11545 5.16
29.1971 150.45 0.2204 3.05873 2.47
31.7402 182.28 0.2204 2.81923 2.99
FIG. 2 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester t-butyl amine salt, as obtained by the process of the invention. Thus, N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt may have an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 2.
The term "substantially similar" as used herein means an analytical spectrum, such as XRD pattern, IH-NMR spectrum, FT-IR spectrum, Raman spectrum, TGA thermogram, etc., which resembles the reference spectrum to a great degree in both the peak locations and their intensity.
FIG. 3 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt, as obtained by the process of the invention. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt may have a differential scanning calorimetric thermogram substantially similar to a differential scanning calorimetric thermogram as depicted in Fig. 3.
The invention further provides N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt and crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt. Crystalline N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D- glucamine salt can be characterized by an X-ray diffraction pattern substantially as shown in Table 2 and FIG. 4 herein. The compound can also be characterized by
a. at least one of X-ray diffraction peaks with 2-theta values 4.40+/- 0.1°, 8.68+/- 0.1°, 10.37+/- 0.1°,
10.68+/- 0.1°, 12.81+/- 0.1°, 13.36+/- 0.1°, 14.48+/- 0.1°, 16.81+/- 0.1°, 16.99+/- 0.1°, 18.12+/-0.1°, 18.87+/-0.10, 19.00+/-0.10, 19.37+/-0.10, 19.85+/-0.10, 20.81+/-0.10, 21.32+/-0.10, 21.50+/-0.10 and 22.51+/-0.10; and/or
b. a differential scanning calorimetric thermogram with a endothermic peak at about 126.7+/- 3°C.
Preferably, the N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt is characterized by at least one of X-ray diffraction peaks with 2-theta values 4.40, 8.68, 10.37, 10.68, 12.81, 13.36, 14.48, 16.81, 16.99, 18.12, 18.87, 19.00, 19.37, 19.85, 20.81, 21.32, 21.50 and 22.51; and a differential scanning calorimetric thermogram with an endothermic peak at about 126.7+/- 3°C.
FIG. 4 and Table 2 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt by X-ray diffraction (XRD), as obtained by the invention.
Table 2
31.6734 2.82502 317.58 38.84 1.88
33.9008 2.64433 301.67 73.79 1.79
FIG.5 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt, as obtained by the process of the invention. Thus, N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n- Octhyl-D-glucamine salt can have an IR spectrum substantially similar to an IR spectrum as depicted in FIG.5.
FIG.6 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt, as obtained by the process of the invention. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-glucamine salt can have a differential scanning calorimetric thermogram substantially similar to a differential scanning calorimetric thermogram as depicted in FIG.6.
The invention further provides N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester phenyl ethyl amine salt and crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt. Crystalline N-(3- carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt can be characterized by an X-ray diffraction pattern substantially as shown in Table 3 and FIG. 7. The compound can also be characterized by
a. at least one of X-ray diffraction peaks with 2-theta values 7.53, 8.36, 8.55, 10.93, 15.13, 15.96, 16.80, 17.36, 17.68, 18.82, 19.40, 20.58, 22.01, 23.11, 24.30, 24.90, 25.88, 26.45, 28.08, 28.66, 28.96 and 29.34°; or
b. a differential scanning calorimetric thermogram with a endothermic peak at about 128.7+/- 3°C.
Preferably, the N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt is characterized by at least one of X-ray diffraction peaks with 2-theta values 7.53, 8.36, 8.55, 10.93, 15.13, 15.96, 16.80, 17.36, 17.68, 18.82, 19.40, 20.58, 22.01, 23.11, 24.30, 24.90, 25.88, 26.45, 28.08, 28.66, 28.96 and 29.34° and a differential scanning calorimetric thermogram with an endothermic peak at about 128.7+/- 3°C.
FIG. 7 and Table 3 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt by X-ray diffraction (XRD), as obtained by the invention.
Table 3
11.5324 7.67335 104.18 22.65 3.44
13.6109 6.50586 158.16 17.19 5.22
13.9791 6.33533 119.22 25.92 3.93
15.1252 5.85777 1268.19 112.02 41.84
15.9593 5.55344 675.94 73.48 22.30
16.8022 5.27670 637.02 56.27 21.02
17.3649 5.10698 1601.76 119.72 52.85
17.6772 5.01744 781.35 95.56 25.78
18.8174 4.71592 836.88 136.47 27.61
19.4004 4.57549 974.06 72.80 32.14
20.5835 4.31509 2992.80 264.36 98.74
22.0133 4.03795 972.80 99.15 32.10
23.1074 3.84918 2134.06 290.00 70.41
24.2992 3.66302 1172.99 111.58 38.70
24.9010 3.57584 378.50 82.30 12.49
25.8822 3.44246 219.10 71.46 7.23
26.4536 3.36939 221.01 72.08 7.29
27.1339 3.28644 172.30 37.46 5.68
28.0837 3.17741 341.31 37.11 11.26
28.6552 3.11533 369.33 60.23 12.19
28.9580 3.08343 392.05 53.28 12.93
29.3381 3.04435 246.34 40.17 8.13
31.5401 2.83665 178.14 67.78 5.88
33.2018 2.69838 103.29 33.69 3.41
30.4801 2.93284 218.80 47.57 1.30
31.1487 2.87139 426.85 81.21 2.53
31.6734 2.82502 317.58 38.84 1.88
33.9008 2.64433 301.67 73.79 1.79
FIG.8 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt, as obtained by the process of the invention. Thus, N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt may have an IR spectrum substantially similar to an IR spectrum as depicted in FIG. 8.
FIG. 9 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt, as obtained by the process of the invention. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester phenyl ethyl amine salt may have a differential scanning calorimetric thermogram substantially similar to a differential scanning calorimetric thermogram as depicted in FIG. 9.
Further provided is N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphtyl ethyl amine salt and crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester naphtyl ethyl amine salt. Crystalline N-(3-carboxy-l-oxopropyl)-
(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt as obtained by the invention can be characterized by X-ray diffraction pattern substantially as shown in Table 4 and FIG. 10. The compound can also be characterized by
a. at least one of X-ray diffraction peaks with 2-theta values 3.76, 6.84, 7.17+, 8.39, 9.20, 11.07, 13.70, 14.29, 15.11, 16.10, 16.79, 17.75, 18.01, 18.45, 18.90, 19.92, 20.29, 20.44, 21.31, 21.67, 22.31, 22.54, 25.14, 25.39, 26.23, 27.00, 27.93 and 30.03°; and/or
b. a differential scanning calorimetric thermogram with a endothermic peak at about 138.1+/- 3°C.
Preferably, the N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt is characterized by at least one of X-ray diffraction peaks with 2-theta values 3.76, 6.84, 7.17+, 8.39, 9.20, 11.07, 13.70, 14.29, 15.11, 16.10, 16.79, 17.75, 18.01, 18.45, 18.90, 19.92, 20.29, 20.44, 21.31, 21.67, 22.31, 22.54, 25.14, 25.39, 26.23, 27.00, 27.93 and 30.03 and a differential scanning calorimetric thermogram with an endothermic peak at about 138.1+/- 3°C.
FIG. 10 and Table 4 shows structural analysis of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt by X-ray diffraction (XRD), as obtained in the example of the invention.
Table 4
27.0010 3.30231 357.37 77.70 9.15
27.9371 3.19375 384.14 83.52 9.84
30.0271 2.97604 401.90 87.39 10.29
32.3275 2.76933 213.25 69.55 5.46
33.1696 2.70093 144.32 47.07 3.70
34.3333 2.61200 143.69 54.68 3.68
36.5056 2.46141 131.34 28.56 3.36
38.6560 2.32929 221.34 54.14 5.67
FIG. 11 shows an Infrared Spectrum (IR) of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt, as obtained by the process of the invention. Thus, N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt may have an IR spectrum substantially similar to an IR spectrum as depicted in FIG. 11.
FIG. 12 shows results of Differential Scanning Calorimetry (DSC) of N-(3-carboxy-l-oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt, as obtained by the process of the invention. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester naphthyl ethyl amine salt may have a differential scanning calorimetric thermogram substantially similar to a differential scanning calorimetric thermogram as depicted in FIG. 12.
Particular embodiments of the present invention include:
1. A process of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester comprising the steps of:
a) Treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride;
b) Isolating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I from the reaction mixture;
(II) (1) 2. The process of clause 1 step a), wherein compound of formula II is present in the form of salt then salt is selected from the list of tartaric acid, dibenzoyl tartaric acid, di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
3. The process of clause 1 step a) or clause 2, wherein salt is tartrate salt.
4. The process of clause 1, wherein reaction is carried out in presence of base.
5. The process of clause 1 or 4, wherein base is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
6. The process of any of the preceding clauses, wherein the base is pyridine.
7. A process of preparing substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester of compound of formula (I) comprising the steps of:
a) Treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with amine;
b) Isolating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt from the reaction mixture;
c) Treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with acid;
d) Isolating substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester of formula I.
wherein R1, R2 and R3 are independently hydrogen or alkyl group; and XA is acid.
8. The process of clause 7, wherein the compound of formula I isolated in step d) has purity more than 95% including more than 96%, more than 97%, more than 98%, more than 99% and up to 99.5% or more.
9. The process of clause 7, wherein amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
10. The process of clause 8 and 9, wherein amine is /-butyl amine.
11. The process of clause 7 or clause 8, wherein the base is an amine NR¾2R3 with the provisio that at least one of the substituents R1, R2 or R3 is not H or a C1-C6 alkyl.
12. The proceass of clause 11, wherein the base is selected from the group consisting of n-Octyl-D-glucamine, phenyl ethyl amine and naphthyl ethyl amine.
13. The process of any one of the clauses 7 to 12, wherein step a) is performed using water as a solvent.
14. The process of any one of the clauses 7 to 12, wherein step a) is performed without addition of a solvent.
15. The process of any one of the clauses 7 to 14, wherein acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid, acetic acid, succinic acid, proponic acid, lactic acid, and formic acid.
16. The process of clause 15, wherein acid is hydrochloric acid.
A process of preparing substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester of compound of formula (I) comprising the steps of:
a) Treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of amine;
b) Isolating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt of formula III from the reaction mixture;
c) Treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with acid;
d) Isolating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula
18. The process of clause 17 step a), wherein compound of formula II is present in the form of salt then salt is selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
19. The process of clause 17 or 18, wherein amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
20. The process of any one of the clauses 17 to 19, wherein amine is /-butyl amine.
21. The process of clause 17 or 18, wherein the base is an amine with formula NR¾2R3 with the provisio that at least one of the substituents R1, R2 or R3 is not H or a C1-C6 alkyl.
22. The process of clause 17, 18 or 20, wherein the base is selected from the group consisting of n-Octyl-D- glucamine, phenyl ethyl amine and naphthyl ethyl amine.
23. The process of any one of the clauses 17 to 22, wherein step a) is performed using water as a solvent.
24. The process of any one of the clauses 17 to 22, wherein step a) is performed without addition of a solvent.
25. The process of any one of the clauses 17 to 24, wherein acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid, acetic acid, succinic acid, proponic acid, lactic acid, and formic acid.
26. The process of any one of the previous clauses 7 to 25, wherein substantially pure N-(3 -carboxy- 1-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I has a purity above 95%, preferably above 96%, more preferably above 97%, even more preferably above 98%, most preferably abo e 99%.
The process of any one of the previous clauses 7 to 25, wherein substantially pure N-(3 -carboxy- 1-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I has a purity above 99.5%.
N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t- butyl amine salt.
Crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt.
A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt characterized by at least one of the following:
a) Powder X-ray diffraction peaks with 2-theta values of 4.11, 8.06, 9.88, 15.70, 16.16, 17.63, 17.78, 19.76, 20.23 and 23.10 +/- 0.1°;
b) A differential scanning calorimetric thermogram with a endothermic peak at about 133.7°C +/- 3°C. The crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt of clause 29 or clause 30, further characterized by having an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 2.
N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n- octyl-D-glucamine salt.
Crystalline N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-octyl-D-glucamine of formula Ill-b.
Crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-octyl-D-glucamine salt characterized by at least one of the following:
a. 4.40, 8.68, 10.37, 10.68, 12.81, 13.36, 14.48, 16.81, 16.99, 18.12, 18.87, 19.00, 19.37, 19.85, 20.81, 21.32, 21.50 and 22.51 +/-0.10; and
b. a differential scanning calorimetric thermogram with an endothermic peak at about 126.7+/- 3°C.
Crystalline N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-octyl-D-glucamine salt of clause 33 or 34, further characterized by having an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 5.
N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine of formula III-c.
Crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt.
Crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt characterized by at least one of the following:
a. 7.53, 8.36, 8.55, 10.93, 15.13, 15.96, 16.80, 17.36, 17.68, 18.82, 19.40, 20.58, 22.01, 23.11, 24.30, 24.90, 25.88, 26.45, 28.08, 28.66, 28.96 and 29.34 +/- 0.1° and
b. a differential scanning calorimetric thermogram with an endothermic peak at about 128.7+/- 3°C.
39. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt of clause 37 or 38, further characterized by having an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 8.
40. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt of formula Ill-d.
41. Crystalline N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
42. Crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt characterized by at least one of the following:
a. 3.76, 6.84, 7.17+, 8.39, 9.20, 11.07, 13.70, 14.29, 15.11, 16.10, 16.79, 17.75, 18.01, 18.45,
18.90, 19.92, 20.29, 20.44, 21.31, 21.67, 22.31, 22.54, 25.14, 25.39, 26.23, 27.00, 27.93 and 30.03 +/- 0.1°; and/or
b. a differential scanning calorimetric thermogram with a endothermic peak at about 138.1+/- 3°C.
43. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt of clause 41 or 42, further characterized by having an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 11.
44. A pharmaceutical composition comprising a compound according to any of clauses 28 to 43.
45. Use of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof to prepare sacubitril or salt thereof.
46. Use of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(-)-tartrate salt to to prepare sacubitril or salt thereof.
47. A pharmaceutical composition comprising N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester salt thereof prepared by a process according to any one of clauses 1 to 27.
48. A process of preparang trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester - valsartan hemipentahydrate comprising,
- treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with valsartan in presence of aqueous sodium hydroxide solution, and
isolating trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester - valsartan hemipentahydrate from reaction mass;
wherein the amine is an amine with formula NR¾2R3, with the provisio that at least one of the substituents R1, R2, R3 is not H or a C1-G5 alkyl group.
49. The process of clause 48, wherein the amine is selected from the group consisting of n-octyl-D-glucamine, phenyl ethyl amine and naphthyl ethyl amine.
Examples
The present invention will now be exemplified by the following non-limiting examples.
Example 1: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid
To a suspension of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid (30g) in dichloromethane (450ml), pyridine (210ml) was added and reaction mixture was stirred for 10-15 minutes. Succinic anhydride (14.46g) was added to a reaction mixture under stirring and reaction mixture was stirred for about 8-10 hours. Solvent was distilled out from the reaction mixture and ethyl acetate (150ml) was added in to it. Reaction mixture was stirred for few minutes. Organic layer was separated and washed with dilute hydrochloric acid solution (IN, 100ml X 4times) followed by washing with brine solution (100 ml X 2 times). Organic layer was separated and dried over sodium sulfate. After removal of solvent by distillation oily product 35g (88.28%) having 90% HPLC purity was obtained.
Example 2 : Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(- )-tartrate salt.
To a suspension of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(-)-tartrate (30g) in dichloromethane (450ml), pyridine (210ml) was added and reaction mixture was stirred for 10-15 minutes. Succinic anhydride (9.76g) was added to a reaction mixture under stirring and reaction mixture was stirred for about 8-10 hours. Solvent was distilled out from the reaction mixture and ethyl acetate (150ml) was added in to it. Reaction mixture was stirred for few minutes. Organic layer was separated and washed with dilute hydrochloric acid solution (IN, 100ml X 4times) followed by washing with brine solution (100 ml X 2 times). Organic layer was separated and dried over sodium sulfate. After removal of solvent by distillation oily product 25g (93.5%) having 90% HPLC purity was obtained.
Example 3: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt
To a solution of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (25g) in acetone (250ml) was added /-butyl amine (4.44g) under stirring at 10-15°C. Reaction mixture was stirred for2-3 hours at 25-30°C. Solid product was filtered and washed with acetone (100ml). After drying 23g (78%) product was obtained. The HPLC purity of the product is 98.9%.
The final product is characterized a powder X-ray diffraction (XRD) pattern as shown in Figure 1. The XRD pattern shows the following main peaks as 2-theta values as indicated in the following table:
Table 5
Sr. No. 2-theta values
1 4.11
2 8.06
3 9.88
4 15.70
5 16.16
6 17.63
7 17.78
8 19.76
9 20.23
10 23.10
Example 4: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester
N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt (25g) was dissolved in dichloromethane (250ml) and solution was stirred for 10-15 minutes. To this solution water (150ml) was added and then slowly added hydrochloric acid (20%, 50ml). Reaction mixture was stirred for 15-20minutes. Organic layer was separated and aqueous layer extracted with dichloromethane (2 X 100ml). Combined organic layer washed with water (2 X 100ml). Organic layer was dried over sodium sulfate. After removing solvent under vacuum 20.5g (96.57%) oily product was obtained. The HPLC purity of the product is 99.5%.
Example 5: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid
To a suspension of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid (30g) in dichloromethane (450ml), /-butyl amine (210ml) was added and reaction mixture was stirred for 10-15 minutes. Succinic anhydride (14.46g) was added to a reaction mixture under stirring and reaction mixture was stirred for about 8-10 hours. Solvent was distilled out from the reaction mixture and ethyl acetate (150ml) was added in to it. Reaction mixture was stirred for few minutes. Organic layer was separated and washed with dilute hydrochloric acid solution (IN, 100ml X 4times) followed by washing with brine solution (100 ml X 2 times). Organic layer was separated and dried over sodium sulfate. After removal of solvent by distillation oily product 31.7g (80%) having 90% HPLC purity was obtained.
Example 6: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester from (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(- )-tartrate salt.
To a suspension of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(-)-tartrate (30g) in dichloromethane (450ml), /-butyl amine (210ml) was added and reaction mixture was stirred for 10-15 minutes. Succinic anhydride (9.76g) was added to a reaction mixture under stirring and reaction mixture was stirred for about 8-10 hours. Solvent was distilled out from the reaction mixture and ethyl acetate (150ml) was added in to it. Reaction mixture was stirred for few minutes. Organic layer was separated and washed with dilute hydrochloric
acid solution (IN, 100ml X 4times) followed by washing with brine solution (100 ml X 2 times). Organic layer was separated and dried over sodium sulfate. After removal of solvent by distillation oily product 24.3g (90.8%) having 90% HPLC purity was obtained. Example 7: Preparation of trisodium sacubitril- valsartan hemipentahydrate.
To a solution of sacubitril t-buty 1 amine salt (2g) in acetone (30ml) was added valsartan ( 1.8g) and reaction mixture was stirred for ten minutes to get clear solution. To this reaction mass sodium hydroxide solution (0.5g in 2ml water) was added slowly by maintaining reaction temperature in between 10-20°C and stireed reaction mixture for for one hour. Solvent was removed under vacuum and to get a residue. The residue was terturated in acetone(30ml). Product was filtered and washed with acetone (30ml). After drying 3.3g (71%) solid crystalline product was obtained.
Example 8: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt without the use of solvent.
To a round bottom flask containing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester (2.5g) was added /-butyl amine (0.44g). Formation of solid product was observed within few minutes after addition. Reaction mixture was kept on hold for 24 hours. 2.7g (92%) product was isolated. The HPLC purity of the product is more than 99%.
Example 9: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt in the absence of organic solvent.
To a round bottom flask containing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester (2.5g) was added /-butyl amine (0.44g) and water (25ml). Reaction mixture was stirred for 2-3 hours. Water was removed by distillation. After drying 2.5g (85%) product was isolated. The HPLC purity of the product is more than 99%.
Example 10: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt using t-butyl amine as solvent and base.
To a round bottom flask containing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester (2.5g) was added /-butyl amine (7.5ml). Reaction mixture was stirred for 2-3 hours. Product was filtered. After drying 2.4g (81.6%) product was isolated. The HPLC purity of the product is more than 99%.
Example 11: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester t-butyl amine salt.
To a round bottom flask containing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester (2.5g) was added /-butyl amine (7.5ml). Reaction mixture was stirred for 2-3 hours. Product was filtered and washed with acetone (5ml). After drying 2.2g (75%) product was isolated. The HPLC purity of the product is more than 99%.
Example 12: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester n-Octyl-D-Glucamine salt.
To a solution of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (25g) in acetone (250ml) was added n-Octyl-D-Glucamine (17.83g) under stirring at 10-15°C. Reaction mixture was stirred for 5-10 minutes at 25-30°C and then heated to reflux. At reflux temperature added water (5ml) in the reaction mixture. The reaction mixture was cooled to 10-20°C and stirred at this temperature for 2-3 hours. Solid product was filtered and washed with acetone (50ml). After drying 35g (82%) product was obtained. The HPLC purity of the product is 99%.
Example 13: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-Octyl- D-Glucamine salt (25g) was dissolved in dichloromethane (250ml) and solution was stirred for 10-15 minutes. To this solution water (150ml) was added and then slowly added hydrochloric acid (20%, 50ml). Reaction mixture
was stirred for 15-20minutes. Organic layer was separated and aqueous layer extracted with dichloromethane (2 X 100ml). Combined organic layer washed with water (2 X 100ml). Organic layer was dried over sodium sulfate. After removing solvent under vacuum 13g (89%) oily product was obtained. The HPLC purity of the product is 99.5%.
Example 14: Preparation of trisodium sacubitril- valsartan hemipentahydrate.
To a suspension of sacubitril n-Octyl-D-Glucamine salt (2g) in acetone (30ml) and water (10ml) was added valsartan (1.23 g) and reaction mixture was stirred for ten minutes. To this reaction mass sodium hydroxide solution (0.34g in 2ml water) was added slowly by maintaining reaction temperature in between 10-20°C and stirred reaction mixture for one hour. Insoluble n-Octyl-D-Glucamine was removed by filteration. Solvent was removed under vacuum and to get a residue. The residue was triturated in acetone (30ml). Product was filtered and washed with acetone (30ml). After drying 2g (75%) solid crystalline product was obtained.
Example 15: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester phenyl ethyl amine salt.
To a solution of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (25g) in acetone (250ml) was added phenyl ethyl amine (7.36g) under stirring at 10-15°C. Reaction mixture was stirred for 5-10 minutes at 25-30°C and then heated to reflux. At reflux temperature added water (5ml) in the reaction mixture. The reaction mixture was cooled to 10-20°C and stirred at this temperature for 2-3 hours. Solid product was filtered and washed with acetone (50ml). After drying 26g (80%) product was obtained. The HPLC purity of the product is 99%.
Example 16: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt (25g) was dissolved in dichloromethane (250ml) and solution was stirred for 10-15 minutes. To this solution water (150ml) was added and then slowly added hydrochloric acid (20%, 50ml). Reaction mixture was stirred for 15-20minutes. Organic layer was separated and aqueous layer extracted with dichloromethane (2 X 100ml). Combined organic layer washed with water (2 X 100ml). Organic layer was dried over sodium sulfate. After removing solvent under vacuum 17g (90%) oily product was obtained. The HPLC purity of the product is 99.5%.
Example 17: Preparation of trisodium sacubitril- valsartan hemipentahydrate.
To a solution of sacubitril phenyl ethyl amine salt (2g) in acetone (30ml) was added valsartan (1.64g) and reaction mixture was stirred for ten minutes. To this reaction mass sodium hydroxide solution (0.44g in 2ml water) was added slowly by maintaining reaction temperature in between 10-20°C and stirred reaction mixture for one hour. Solvent was removed under vacuum. The obtained residue was triturated in acetone (30ml). Product was filtered and washed with acetone (30ml). After drying 2.5g (72%) solid crystalline product was obtained.
Example 18: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
To a solution of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (20g) in acetone (200ml) was added naphthyl ethyl amine (8.3g) under stirring at 10-15°C. Reaction mixture was stirred for 5-10 minutes at 25-30°C and then heated to reflux. The reaction mixture was cooled to 10-
20°C and stirred at this temperature for 2-3 hours. Solid product was filtered and washed with acetone (40ml). After drying 20g (70.6%) product was obtained. The HPLC purity of the product is more than 99%.
Example 19: Preparation of N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester.
N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt (20g) was dissolved in dichloromethane (200ml) and solution was stirred for 10-15 minutes. To this solution water (100ml) was added and then slowly added hydrochloric acid (20%, 40ml). Reaction mixture was stirred for 15-20minutes. Organic layer was separated and aqueous layer extracted with dichloromethane (2 X 75ml). Combined organic layer washed with water (2 X 75ml). Organic layer was dried over sodium sulfate. After removing solvent under vacuum 13.3g (94%) oily product was obtained. The HPLC purity of the product is 99.5%.
Example 20: Preparation of trisodium sacubitril- valsartan hemipentahydrate.
To a solution of sacubitril naphthyl ethyl amine salt (10g) in acetone (150ml) was added valsartan (7.47g) and reaction mixture was stirred for ten minutes. To this reaction mass sodium hydroxide solution (2.2g in 10ml water) was added slowly by maintaining reaction temperature in between 10-20°C and stirred reaction mixture for one hour. Solvent was removed under vacuum. The obtained residue was triturated in acetone (30ml). Product was filtered and washed with acetone (150ml). After drying 13.2g (80%) solid crystalline product was obtained.
Claims
1. A process of preparing N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester comprising the steps of:
c) Treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride;
d) Isolating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula I from the reaction mixture;
(II) (1)
2. The process of claim 1 step a), wherein compound of formula II is present in the form of salt then salt is selected from the list of tartaric acid, dibenzoyl tartaric acid, di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
3. The process of claim 1 step a) or claim 2, wherein salt is tartrate salt.
4. The process of claim 1, wherein reaction is carried out in presence of base.
5. The process of claim 1 or 4, wherein base is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
6. The process of any of the preceding claims, wherein the base is pyridine.
7. A process of preparing substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester of compound of formula (I) comprising the steps of:
e) Treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I or salt thereof with amine;
f) Isolating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt from the reaction mixture;
g) Treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with acid;
h) Isolating substantially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester of formula I.
8. The process of claim 7, wherein the compound of formula I isolated in step d) has purity more than 95% including more than 96%, more than 97%, more than 98%, more than 99% and up to 99.5% or more.
9. The process of claim 7, wherein amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
10. The process of claim 8 and 9, wherein amine is /-butyl amine.
11. The process of claim 7 or claim 8, wherein the base is an amine NR¾2R3 with the provisio that at least one of the substituents R1, R2 or R3 is not H or a C1-C6 alkyl.
12. The proceass of claim 11, wherein the base is selected from the group consisting of n-Octyl-D-glucamine, phenyl ethyl amine and naphthyl ethyl amine.
13. The process of any one of the claims 7 to 12, wherein step a) is performed using water as a solvent.
14. The process of any one of the claims 7 to 12, wherein step a) is performed without addition of a solvent.
15. The process of any one of the claims 7 to 14, wherein acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid, acetic acid, succinic acid, proponic acid, lactic acid, and formic acid.
16. The process of claim 15, wherein acid is hydrochloric acid.
17. A process of preparing substancially pure N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester of compound of formula (I) comprising the steps of:
e) Treating (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of compound of formula II or salt thereof with succinic anhydride in presence of amine;
f) Isolating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt of formula III from the reaction mixture;
g) Treating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with acid;
h) Isolating N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula
wherein R1, R2 and R3 are independently hydrogen or alkyl group; and XA is acid.
18. The process of claim 17 step a), wherein compound of formula II is present in the form of salt then salt is selected from the list of tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid, mandelic acid and camphor sulfonic acid.
19. The process of claim 17 or 18, wherein amine is selected from triethylamine, dimethylamine, pyridine, piperidine, ammonia, diisopropylethylamine, /-butyl amine.
20. The process of any one of the claims 17 to 19, wherein amine is /-butyl amine.
21. The process of claim 17 or 18, wherein the base is an amine NR¾2R3 with the provisio that at least one of the substituents R1, R2 or R3 is not H or a C1-C6 alkyl.
22. The process of claim 17, 18 or 20, wherein the base is selected from the group consisting of n-Octyl-D- glucamine, phenyl ethyl amine and naphthyl ethyl amine.
23. The process of any one of the claims 17 to 22, wherein step a) is performed using water as a solvent.
24. The process of any one of the claims 17 to 22, wherein step a) is performed without addition of a solvent.
25. The process of any one of the claims 17 to 24, wherein acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid, acetic acid, succinic acid, proponic acid, lactic acid, and formic acid.
26. The process of any one of the previous claims 7 to 25, wherein substantially pure N-(3-carboxy-l-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I has a purity above 95%, preferably above 96%, more preferably above 97%, even more preferably above 98%, most preferably abo e 99%.
27. The process of any one of the previous claims 7 to 25, wherein substantially pure N-(3-carboxy-l-oxopropyl)- (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula I has a purity above 99.5%.
28. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t- butyl amine salt.
29. Crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt.
30. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt characterized by at least one of the following:
c) Powder X-ray diffraction peaks with 2-theta values of 4.11, 8.06, 9.88, 15.70, 16.16, 17.63, 17.78, 19.76, 20.23 and 23.10 +/- 0.1°;
d) A differential scanning calorimetric thermogram with a endothermic peak at about 133.7°C +/- 3°C.
31. The crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester t-butyl amine salt of claim 29 or claim 30, further characterized by having an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 2.
32. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n- octyl-D-glucamine salt.
33. Crystalline N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-octyl-D-glucamine salt.
34. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-octyl-D-glucamine salt characterized by at least one of the following:
a. 4.40, 8.68, 10.37, 10.68, 12.81, 13.36, 14.48, 16.81, 16.99, 18.12, 18.87, 19.00, 19.37, 19.85,
20.81, 21.32, 21.50 and 22.51 +/-0.10; and
b. a differential scanning calorimetric thermogram with an endothermic peak at about 126.7+/- 3°C.
35. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester n-octyl-D-glucamine salt of claim 33 or 34, further characterized by having an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 5.
36. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt.
37. Crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt.
38. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt characterized by at least one of the following:
a. 7.53, 8.36, 8.55, 10.93, 15.13, 15.96, 16.80, 17.36, 17.68, 18.82, 19.40, 20.58, 22.01, 23.11, 24.30, 24.90, 25.88, 26.45, 28.08, 28.66, 28.96 and 29.34 +/- 0.1° and
b. a differential scanning calorimetric thermogram with an endothermic peak at about 128.7+/-
3°C.
39. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester phenyl ethyl amine salt of claim 37 or 38, further characterized by having an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 8.
40. N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
41. Crystalline N-(3 -carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt.
42. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt characterized by at least one of the following:
a. 3.76, 6.84, 7.17+, 8.39, 9.20, 11.07, 13.70, 14.29, 15.11, 16.10, 16.79, 17.75, 18.01, 18.45, 18.90, 19.92, 20.29, 20.44, 21.31, 21.67, 22.31, 22.54, 25.14, 25.39, 26.23, 27.00, 27.93 and 30.03 +/- 0.1°; and/or
b. a differential scanning calorimetric thermogram with a endothermic peak at about 138.1+/- 3°C.
43. A crystalline N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester naphthyl ethyl amine salt of claim 41 or 42, further characterized by having an IR spectrum substantially similar to an IR spectrum as depicted in Fig. 11.
44. A pharmaceutical composition comprising a compound according to any of claims 28 to 43.
45. Use of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof to prepare sacubitril or salt thereof.
46. Use of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid D-(-)-tartrate salt to to prepare sacubitril or salt thereof.
47. A pharmaceutical composition comprising N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-(2R)-methylbutanoic acid ethyl ester salt thereof prepared by a process according to any one of claims 1 to 27.
48. A process of preparang trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester - valsartan hemipentahydrate comprising,
- treating N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester amine salt with valsartan in presence of aqueous sodium hydroxide solution, and
- isolating trisodium N-(3-carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester - valsartan hemipentahydrate from reaction mass;
wherein the amine is selected from the group consisting of n-octyl-D-glucamine, phenyl ethyl amine and naphthyl ethyl amine.
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WO2017191620A1 (en) * | 2016-05-06 | 2017-11-09 | Sun Pharmaceutical Industries Limited | A crystalline form of a salt of sacubitril and a process of its preparation |
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CN108794342A (en) * | 2017-04-28 | 2018-11-13 | 武汉朗来科技发展有限公司 | Ammonium carboxylate salt compound, its crystal form, amorphous substance and preparation method thereof |
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