US20130310577A1 - Convergent synthesis of renin inhibitors and intermediates useful therein - Google Patents
Convergent synthesis of renin inhibitors and intermediates useful therein Download PDFInfo
- Publication number
- US20130310577A1 US20130310577A1 US13/939,983 US201313939983A US2013310577A1 US 20130310577 A1 US20130310577 A1 US 20130310577A1 US 201313939983 A US201313939983 A US 201313939983A US 2013310577 A1 US2013310577 A1 US 2013310577A1
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- United States
- Prior art keywords
- formula
- group
- optionally substituted
- alkyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 239000000543 intermediate Substances 0.000 title abstract description 20
- 239000002461 renin inhibitor Substances 0.000 title abstract 2
- 229940086526 renin-inhibitors Drugs 0.000 title abstract 2
- 238000003786 synthesis reaction Methods 0.000 title description 40
- 230000015572 biosynthetic process Effects 0.000 title description 38
- 238000000034 method Methods 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract 6
- 150000001875 compounds Chemical class 0.000 claims description 146
- 239000000203 mixture Substances 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 14
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 150000002466 imines Chemical class 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 108010031620 mandelonitrile lyase Proteins 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000012634 fragment Substances 0.000 claims description 5
- 229910052748 manganese Inorganic materials 0.000 claims description 5
- 230000003019 stabilising effect Effects 0.000 claims description 5
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 229910052738 indium Inorganic materials 0.000 claims description 4
- 229910052719 titanium Inorganic materials 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 229910052726 zirconium Inorganic materials 0.000 claims description 4
- 150000001923 cyclic compounds Chemical class 0.000 claims description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 238000011924 stereoselective hydrogenation Methods 0.000 claims 1
- 150000001299 aldehydes Chemical class 0.000 abstract description 26
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 17
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 abstract description 12
- 229960004601 aliskiren Drugs 0.000 abstract description 11
- 150000002596 lactones Chemical class 0.000 abstract description 4
- 0 [4*][C@@H]1C[C@@H](C)OC1=O Chemical compound [4*][C@@H]1C[C@@H](C)OC1=O 0.000 description 38
- -1 nitro, amino Chemical group 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 238000005859 coupling reaction Methods 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 230000008878 coupling Effects 0.000 description 15
- 238000010168 coupling process Methods 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- 239000000654 additive Substances 0.000 description 7
- 150000004696 coordination complex Chemical class 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 229940093499 ethyl acetate Drugs 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000011572 manganese Substances 0.000 description 3
- VLTMUXCHUMLSAB-YUMQZZPRSA-N methyl (2s,4s)-4-cyano-4-hydroxy-2-propan-2-ylbutanoate Chemical compound COC(=O)[C@H](C(C)C)C[C@H](O)C#N VLTMUXCHUMLSAB-YUMQZZPRSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- NISCTHRFELYLJB-OKUDJXLHSA-N COC(=O)[C@@H](C[C@@H](C#N)O[Si](C)(C)C(C)(C)C)C(C)C.COC(=O)[C@@H](C[C@H](O)C#N)C(C)C Chemical compound COC(=O)[C@@H](C[C@@H](C#N)O[Si](C)(C)C(C)(C)C)C(C)C.COC(=O)[C@@H](C[C@H](O)C#N)C(C)C NISCTHRFELYLJB-OKUDJXLHSA-N 0.000 description 2
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000002815 homogeneous catalyst Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- AQXXLBGKWDWVFE-ZETCQYMHSA-N methyl (2s)-3-methyl-2-(2-oxoethyl)butanoate Chemical compound COC(=O)[C@H](C(C)C)CC=O AQXXLBGKWDWVFE-ZETCQYMHSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 238000006478 transmetalation reaction Methods 0.000 description 2
- CTHQFCTWPIJSIM-BQBZGAKWSA-N (2s,4s)-5-oxo-4-propan-2-yloxolane-2-carbonitrile Chemical compound CC(C)[C@@H]1C[C@@H](C#N)OC1=O CTHQFCTWPIJSIM-BQBZGAKWSA-N 0.000 description 1
- GISRXNBOYCLUQZ-MLWJPKLSSA-N (3s)-5-(nitromethyl)-3-propan-2-yloxolan-2-one Chemical compound CC(C)[C@@H]1CC(C[N+]([O-])=O)OC1=O GISRXNBOYCLUQZ-MLWJPKLSSA-N 0.000 description 1
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- HKQZJXVIXAPOPZ-UHFFFAOYSA-N CC(C)(CN)C(N)=O Chemical compound CC(C)(CN)C(N)=O HKQZJXVIXAPOPZ-UHFFFAOYSA-N 0.000 description 1
- HIDMIFYVMIAMJO-STQMWFEESA-O CC(C)[C@H](C[C@@H](C#N)O[SH+](C)(C)C(C)(C)C)C(OC)=O Chemical compound CC(C)[C@H](C[C@@H](C#N)O[SH+](C)(C)C(C)(C)C)C(OC)=O HIDMIFYVMIAMJO-STQMWFEESA-O 0.000 description 1
- VMDZHGYJUMKEGZ-YCWVUKJASA-N CC(C)[C@H]1CC(C[N+](=O)[O-])OC1=O.C[N+](=O)[O-].[H]C(=O)C[C@H](C(=O)OC)C(C)C Chemical compound CC(C)[C@H]1CC(C[N+](=O)[O-])OC1=O.C[N+](=O)[O-].[H]C(=O)C[C@H](C(=O)OC)C(C)C VMDZHGYJUMKEGZ-YCWVUKJASA-N 0.000 description 1
- QMARHJPFBNDUEI-QIMKFJALSA-N COC(=O)[C@@H](C/C=C/Cl)C(C)C.S.[H]C(=O)C[C@H](C(=O)OC)C(C)C Chemical compound COC(=O)[C@@H](C/C=C/Cl)C(C)C.S.[H]C(=O)C[C@H](C(=O)OC)C(C)C QMARHJPFBNDUEI-QIMKFJALSA-N 0.000 description 1
- LDEPGHVWHKDPQY-VVHFHNIVSA-N COC(=O)[C@@H](C[C@@H](C#N)O[Si](C)(C)C(C)(C)C)C(C)C.[H]/C(=N\C)[C@H](C[C@H](C(=O)OC)C(C)C)O[Si](C)(C)C(C)(C)C Chemical compound COC(=O)[C@@H](C[C@@H](C#N)O[Si](C)(C)C(C)(C)C)C(C)C.[H]/C(=N\C)[C@H](C[C@H](C(=O)OC)C(C)C)O[Si](C)(C)C(C)(C)C LDEPGHVWHKDPQY-VVHFHNIVSA-N 0.000 description 1
- QFQOJUQJGMZNJO-VVHFHNIVSA-N COC(=O)[C@@H](C[C@@H](C#N)O[Si](C)(C)C(C)(C)C)C(C)C.[H]/C([C@H](C[C@H](C(=O)OC)C(C)C)O[Si](C)(C)C(C)(C)C)=[N+](/[H])[CH2-] Chemical compound COC(=O)[C@@H](C[C@@H](C#N)O[Si](C)(C)C(C)(C)C)C(C)C.[H]/C([C@H](C[C@H](C(=O)OC)C(C)C)O[Si](C)(C)C(C)(C)C)=[N+](/[H])[CH2-] QFQOJUQJGMZNJO-VVHFHNIVSA-N 0.000 description 1
- JWHVMVYLJJTLLE-HJIBXMCBSA-N COCCCOC1=C(OC)C=CC(C[C@@H](CCl)C(C)C)=C1.COCCCOC1=C(OC)C=CC(C[C@@H](CI)C(C)C)=C1 Chemical compound COCCCOC1=C(OC)C=CC(C[C@@H](CCl)C(C)C)=C1.COCCCOC1=C(OC)C=CC(C[C@@H](CI)C(C)C)=C1 JWHVMVYLJJTLLE-HJIBXMCBSA-N 0.000 description 1
- SFRQBEJFXDGRAB-RJVCVNDASA-M COCCCOC1=C(OC)C=CC(C[C@@H](CCl)C(C)C)=C1.COCCCOC1=C(OC)C=CC(C[C@@H](C[Mg]Cl)C(C)C)=C1 Chemical compound COCCCOC1=C(OC)C=CC(C[C@@H](CCl)C(C)C)=C1.COCCCOC1=C(OC)C=CC(C[C@@H](C[Mg]Cl)C(C)C)=C1 SFRQBEJFXDGRAB-RJVCVNDASA-M 0.000 description 1
- GTSSXKLRUQXNEQ-KYGXTCBDSA-N COCCCOC1=C(OC)C=CC(C[C@@H](CI)C(C)C)=C1.[Li]C[C@H](CC1=CC(OCCCOC)=C(OC)C=C1)C(C)C Chemical compound COCCCOC1=C(OC)C=CC(C[C@@H](CI)C(C)C)=C1.[Li]C[C@H](CC1=CC(OCCCOC)=C(OC)C=C1)C(C)C GTSSXKLRUQXNEQ-KYGXTCBDSA-N 0.000 description 1
- JPGJABOWMYPIMJ-XLXZRNDBSA-N COCCCOC1=C(OC)C=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)CCC(C)(C)C(N)=O)C(C)C)C(C)C)=C1 Chemical compound COCCCOC1=C(OC)C=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)CCC(C)(C)C(N)=O)C(C)C)C(C)C)=C1 JPGJABOWMYPIMJ-XLXZRNDBSA-N 0.000 description 1
- AEEWGZNMEJZRLU-CBAASYFYSA-N CS.[C-]#[N+][C@@H](O)C[C@H](C(=O)OC)C(C)C.[H]C(=O)C[C@H](C(=O)OC)C(C)C Chemical compound CS.[C-]#[N+][C@@H](O)C[C@H](C(=O)OC)C(C)C.[H]C(=O)C[C@H](C(=O)OC)C(C)C AEEWGZNMEJZRLU-CBAASYFYSA-N 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 238000006842 Henry reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021577 Iron(II) chloride Inorganic materials 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 108091007187 Reductases Proteins 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 229910019891 RuCl3 Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- IOPQYDKQISFMJI-UHFFFAOYSA-N [1-[2-bis(4-methylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(4-methylphenyl)phosphane Chemical group C1=CC(C)=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC(C)=CC=1)C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 IOPQYDKQISFMJI-UHFFFAOYSA-N 0.000 description 1
- BNZFLCOBBFGDJR-WXTPMGMXSA-N [C-]#[N+]C1C[C@@H](C(C)C)C(=O)O1.[C-]#[N+][C@@H](O)C[C@H](C(=O)OC)C(C)C Chemical compound [C-]#[N+]C1C[C@@H](C(C)C)C(=O)O1.[C-]#[N+][C@@H](O)C[C@H](C(=O)OC)C(C)C BNZFLCOBBFGDJR-WXTPMGMXSA-N 0.000 description 1
- JAENACQSJHCSME-VVHFHNIVSA-N [H]/C([C@H](C[C@H](C(=O)OC)C(C)C)O[Si](C)(C)C(C)(C)C)=[N+](/[H])[CH2-].[H]C(=O)[C@H](C[C@H](C(=O)OC)C(C)C)O[Si](C)(C)C(C)(C)C Chemical compound [H]/C([C@H](C[C@H](C(=O)OC)C(C)C)O[Si](C)(C)C(C)(C)C)=[N+](/[H])[CH2-].[H]C(=O)[C@H](C[C@H](C(=O)OC)C(C)C)O[Si](C)(C)C(C)(C)C JAENACQSJHCSME-VVHFHNIVSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000006241 alcohol protecting group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- FWXAUDSWDBGCMN-ZEQRLZLVSA-N chiraphos Chemical compound C=1C=CC=CC=1P([C@@H](C)[C@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 FWXAUDSWDBGCMN-ZEQRLZLVSA-N 0.000 description 1
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 150000004985 diamines Chemical group 0.000 description 1
- BVURNMLGDQYNAF-UHFFFAOYSA-N dimethyl(1-phenylethyl)amine Chemical compound CN(C)C(C)C1=CC=CC=C1 BVURNMLGDQYNAF-UHFFFAOYSA-N 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000007976 iminium ions Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical class [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- ZOIJCHWBSPXSQY-ABLWVSNPSA-N methyl (2s)-4-[tert-butyl(dimethyl)silyl]oxy-5-imino-2-propan-2-ylpentanoate Chemical compound COC(=O)[C@H](C(C)C)CC(C=N)O[Si](C)(C)C(C)(C)C ZOIJCHWBSPXSQY-ABLWVSNPSA-N 0.000 description 1
- LACIXVBZYVVDRB-ZEDZUCNESA-N methyl (2s)-4-[tert-butyl(dimethyl)silyl]oxy-5-imino-2-propan-2-ylpentanoate;triethylborane Chemical compound CCB(CC)CC.COC(=O)[C@H](C(C)C)CC(C=N)O[Si](C)(C)C(C)(C)C LACIXVBZYVVDRB-ZEDZUCNESA-N 0.000 description 1
- DILDDQLWBUOTET-STQMWFEESA-N methyl (2s,4s)-4-[tert-butyl(dimethyl)silyl]oxy-4-cyano-2-propan-2-ylbutanoate Chemical compound COC(=O)[C@H](C(C)C)C[C@@H](C#N)O[Si](C)(C)C(C)(C)C DILDDQLWBUOTET-STQMWFEESA-N 0.000 description 1
- GJCWMSMIVAUULE-STQMWFEESA-N methyl (2s,4s)-4-[tert-butyl(dimethyl)silyl]oxy-5-oxo-2-propan-2-ylpentanoate Chemical compound COC(=O)[C@H](C(C)C)C[C@@H](C=O)O[Si](C)(C)C(C)(C)C GJCWMSMIVAUULE-STQMWFEESA-N 0.000 description 1
- BHFJTVFRXXWPLV-JQTRYQTASA-N methyl (e,2s)-5-chloro-2-propan-2-ylpent-4-enoate Chemical compound COC(=O)[C@H](C(C)C)C\C=C\Cl BHFJTVFRXXWPLV-JQTRYQTASA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 150000003283 rhodium Chemical class 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910009112 xH2O Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- 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
- C07C231/16—Preparation of optical isomers
- C07C231/18—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/02—Lithium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the invention pertains to a convergent synthesis route for the preparation of certain 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives, or pharmaceutically acceptable salts thereof, such as the compound aliskiren.
- the invention particularly relates to a synthetic route that will introduce the nitrogen of the above mentioned compounds ultimately required for the amino-group at C-5, at a relative early stage of the synthesis.
- the invention further relates to novel intermediates useful in the manufacture of the above mentioned compounds.
- the 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives to which the methods of the present invention applies are any of those having renin inhibitory activity and, therefore, pharmaceutical utility, e.g., those disclosed in U.S. Pat. No. 5,559,111, WO 2006/061427, or WO 2006/095020.
- R 1 is halogen, C 1-6 halogenalkyl, C 1-6 alkoxy-C 1-6 alkoxy or C 1-6 alkoxy-C 1-6 alkyl;
- R 2 is halogen, C 1-6 alkyl or C 1-6 alkoxy;
- R 3 and R 4 are independently branched C 3-6 alkyl; and
- R 5 is C 1-12 cycloalkyl, C 1-12 alkyl, C 1-12 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkanoyloxy-C 1-6 alkyl, C 1-12 -aminoalkyl, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 dialkylamino-C 1-6 alkyl, C 1-6 alkanoylamino-C 1-6 alkyl, HO—(O)C—C 1-12 alkyl, C 1-6 alkyl-O—(O)C—C 1-6 alkyl, H 2 N—C(
- the structural parts referred to are an aromatic part typically satisfying the structural formula (5),
- R 1 is 3-methoxy-propoxy
- R 2 is methoxy
- R 3 are 2-propyl
- the Cl-group is transferred to the corresponding Grignard compound and subsequently transmetallated with CeCl 3 , prior to the coupling with an aldehyde part typically satisfying the structural formula (3)
- R 4 is 2-propyl, and Ph stands for phenyl.
- any reference to aliskiren is deemed to include reference to all pharmaceutically acceptable salts, and prodrugs thereof.
- a critical step in the process is the chemo- and stereoselective introduction of nitrogen so as to create the 5-amino group.
- the nitrogen is introduced after coupling of the described structural parts by substituting the obtained alcohol moiety using several, laborious steps. Moreover, some of these steps are difficult to perform at production scale.
- the invention now provides a novel route for coupling new nitrogen containing compounds of formula (7) and (8) to a compound of formula (2) (see below). Surprisingly, such coupling can be achieved with a much simpler nitrogen containing compound, in particular a compound not comprising a chiral auxiliary. It is an advantage of the new nitrogen containing compounds, that the desired coupling products can be obtained with a higher yield of the compound with the desired configuration at the C-5 stereogenic center.
- the invention provides a synthesis route to compounds of formula (1a).
- R groups have the above-indicated meaning.
- the synthesis route is based on a novel nitrogen-containing compound according to formula (7), or the corresponding lactone of formula (8), as described below.
- the invention provides a novel chiral aldehyde (10), as a precursor for the nitrogen-containing intermediates, and thus as an intermediate to facilitate the synthesis of the compounds concerned.
- the invention presents processes for the stereoselective conversion of the chiral aldehyde into the nitrogen containing compound.
- the invention provides the coupling of compounds of structure (2) with the nitrogen containing compounds of formula (7) and/or (8), under the appropriate conditions, resulting in compounds depicted by formula (9a) and/or (11a), with the configuration of the C-5 stereogenic center being undefined, optionally followed by a purifying step in order to obtain the desired configurational purity at the C-5 stereogenic center, or the coupling of compounds of structure (2) with the nitrogen containing compound of formula (7) and/or (8) is resulting in the compounds depicted by formula (9) and/or (11).
- the invention provides a synthesis route to compounds of formula (1), notably to aliskiren and closely related compounds.
- the overall synthetic route to compound (1) as an example of synthetic routes according to the invention, can be as follows:
- R 4 has the meaning given above with reference to formula (1). In the specific synthesis route to aliskiren, this represents a 2-propyl group.
- Nf is a group comprising a carbon atom directly bonded to a nitrogen atom, preferably Nf is a group resulting in the compounds depicted by formulae (7a) to (7h), and compounds depicted by formulae (8a) to (8h),
- R 4 , R 6 , and R 7 have the meaning given above, and Z is a N-protecting group;
- R 11 is an O-protecting group, e.g acetyl, trifluoroacetyl, trialkylsilyl, or benzyl, or groups as described in T. W. Greene and P. G. M.
- R 12 and R 13 are either the same or different fragments, chosen from the group of H, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 alkylaryl, or optionally substituted C 1-12 aryl, or they are joined together in a C 1-20 (hetero)cyclic structure;
- Ra + is a counter-cation;
- St is a group capable of stabilising the imine.
- the N-protecting group depicted as Z is preferably a group which can be easily removed in a latter stage of the synthesis, such as optionally substituted benzyl, para-methoxyphenyl, (2-pyridyl)sulfonyl or any group described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999;
- Ra + is a counter-cation, for example the one remaining after the partial reduction of the cyano group, e.g. Al(iBu) 2 + , as is depicted as example in Scheme 1 (when DiBAL-His used as reducing agent);
- St is a group capable of stabilising the imine, preferably the remaining group after partial reduction of the cyano group, e.g. B(R 10 ) 3 , if LiBH(R 10 ) 3 was used, R 10 being H or a C 1-6 alkyl group.
- Said catalyst can be a chiral organic compound, a chiral metal complex, or an enzyme, as described in by F. X. Chen and X. M. Feng in “Asymmetric synthesis of cyanohydrins” Current Organic Synthesis 2006, 3, 77-97, and references therein; and by P. Poechlauer, W.
- the nitrile containing compound of formula (7a) and (8a) can be converted to other nitrogen containing compounds according to formula (7b-g) and (8b-g) by using methods known in the art, for example by partial reduction as described above. Examples of various imine-type compounds, and applied conditions can be found in Bloch Chem. Rev. 1998, 98, 1407-1438; Friestad and Mathies Tetrahedron 2007, 63, 2541-2569 and references therein.
- the partial reduction can be followed by immediate hydrolysis to the corresponding aldehyde group resulting in the formation of compounds of formula (6a) or (6b),
- R 4 , R 6 , and R 7 have the meaning given above, and subsequent reaction to the imine, oxime or hydrazone compounds.
- the compounds according to formula (6a) and (6b) can be purified and isolated, or immediately converted to the corresponding nitrogen containing compounds of formula (7) and (8).
- the compounds according to formula (6a) and (6b) are converted without isolation to the corresponding nitrogen containing compounds of formula (7) and (8).
- said chiral compound is used in catalytic amounts, preferably less than 10 mol % compared to the amount of chiral aldehyde.
- Suitable examples of said chiral compounds are for example described by Boruwa et al. in Tetrahedron Asymmetry 2006, 17, 3315-3326 and references therein.
- the nitrogen containing compounds of formula (7) can be converted into the corresponding lactone compounds of formula (8) by using methods known in the art, in analogy with regular deprotection methods and ester synthesis, e.g. catalyzed by para-toluene sulfonic acid.
- R 6 is preferentially C 1-6 alkyl, more preferentially methyl.
- the lactone nitrile of formula (8a) in the diastereochemically desired configuration can be obtained by ring-closing the cyanohydrin of formula (7a) in the desired configuration, or by ring-closing both diastereomers of the cyanohydrin of formula (7a) with fixed configuration at C-2 stereogenic center, followed by epimerization of the C-4 steroegenic center to the thermodynamically preferred diastereomer, also being the desired diastereomer.
- Said epimerisation can be conducted by heating the lactone nitrile, optionally in a suitable solvent, and optionally in the presence of a base or other suitable additives.
- the diastereoisomer with the desired configuration can be separated from the other diastereoisomer making use of their different physical properties (e.g. preferential crystallization), or by means of classic or separating moving beds (SMB) chromatography.
- SMB separating moving beds
- Suitable examples of SMB chromatography can be found in Schulte and Strube J. Chromatogr. A 2001, 906, 399-416 and references therein.
- the lactone nitrile of formula (8a) in the diastereochemically desired configuration is obtained by ring-closing an optically pure cyanohydrin of formula (7a).
- the nitrogen-containing intermediates can be used in the synthesis of compounds of formula (1), as is depicted in the overall reaction scheme by reacting compound of formula (9a) or (11a), or a mixture thereof, with an appropriate amine, i.e. of a general formula H 2 N—R 5 , under conditions sufficient to form an amide bond, optionally followed by purification in order to obtain the desired configuration of the C-5 sterogenic center.
- an appropriate amine i.e. of a general formula H 2 N—R 5
- Suitable conditions for the amide bond formation are known to the person skilled in the art, and are for example described in Sandham (Tetrahedron Letters, 2000, 41, 10091-10094), referred to above.
- R 1 , R 2 , and R 3 and Re have the aforementioned meaning, which reaction results in the synthesis of a compound according to formula (9a) or (11a), or a mixture thereof.
- R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 have the previously given meanings.
- Said catalysts can be any metal complex, preferably transition metal complexes, more preferred metal complexes derived from group VII and group VIII of the periodic system, most preferred manganese or iron complexes are used, such as MnCl 2 , and FeCl 3 , Fe(acac) 3 , FeCl 2 .
- Suitable additives are Lewis acids, such as ZnCl 2 , CuCl; CuI, INCl 3 , TiCl 4 , alkali metal salts, such as LiCl; tertiary amines and tertiary diamines, such as Et 3 N,N-methylpyrrolidine, tetramethylendiamine (TMEDA); amides and ureas, such as N-methylpyrrolidinone (NMP) and 1,3-dimethyl-2-oxohexahydropyrimidine (DMPU); hexamethylphosphoric acid triamide (HMPA); tris(dialkylamino)phosphines, such as tris(dimethylamino)phosphine (HMPT).
- Lewis acids such as ZnCl 2 , CuCl; CuI, INCl 3 , TiCl 4
- alkali metal salts such as LiCl
- tertiary amines and tertiary diamines such as Et 3 N
- Said metal complexes or additives can be chiral to enhance the amount of compound of formula (9a) or (11a) or mixture thereof, with the desired configuration at the C-5 stereogenic center.
- Chiral metal complexes can be prepared beforehand or prepared in situ, by mixing the metal complex with an suitable chiral ligand.
- Suitable chiral ligands are known to the person skilled in the art, for example chiral amino alcohols, optionally alkylated at the amine functionality, such as ephedrine; chiral phosphor containing compounds, such as (3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a′]dinapthalen-4-yl)dimethylamine (MonoPhos), chiral bisphosphines, such as 2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl (BINAP).
- chiral amino alcohols optionally alkylated at the amine functionality
- chiral phosphor containing compounds such as (3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a′]dinapthalen-4-yl)dimethylamine (MonoPhos)
- chiral bisphosphines such
- Suitable chiral additives are any additive mentioned above with a stereogenic center or other form of chirality.
- Preferred are chiral amines and amine derivatives, such as N,N-dimethylamino acid methyl esters, N,N-dimethylmethylbenzylamine and chiral phosphor containing compounds, such as (3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a′]dinapthalen-4-yl)dimethylamine (MonoPhos).
- the Re group denotes preferably Cl, Br, I, or OR 9 , wherein R 9 is a group capable of making OR 9 a leaving group, such group being known to the person skilled in the art, for example R 9 is acetyl, trifluoroacetyl; CF 3 SO 2 , CH 3 SO 2 , CH 3 C 6 H 4 SO 2 , C(O)OCH 3 , or C(O)OC 4 H 9 , and this reaction is performed in the presence of a base, or metal complex.
- Suitable bases are any base capable of, optionally partly, deprotonating the carbon center with the nitro group directly attached to it, such as bases are known to the person skilled in the art, for example sodium hydride, sodium methoxide, n-butyllithium, sec-butyllithium, tertiar-butyllithium, KOtertiar-butyl, KOAc, KOH, NaOH, and so on.
- Suitable metal complexes are similar complexes as used for the synthesis of compounds of formula (7h) or (8h) or mixture thereof, as also described in Boruwa et al. in Tetrahedron Asymmetry 2006, 17, 3315-3326 and references therein.
- Said bases or metal complexes can be chiral to enhance the amount of compound of formula (9a) or (11a) or mixture thereof, with the desired configuration at the C-5 stereogenic center.
- Suitable chiral bases are for example alkali-metal amides, such as chiral lithium amides similar to those described in Cailleau et al. Org. Biomol. Chem. 2007, 5, 3922-3931 and references therein.
- the diastereoselectivity is influenced by the nature of the reagents of formula (7a-h), (8a-h) and (2), optionally, by the addition of a catalyst, base, and/or additive as described above.
- the diastereoselectivity can be increased by making use of the different physical properties of the diastereoisomers (e.g. preferential crystallization), or by means of classic or separating moving beds (SMB) chromatography as described above.
- this additional purification is performed in the presence of a suitable agent capable of racemising the C-5 center.
- the racemization could be done in the same vessel or by external loops.
- Said techniques to obtain a theoretical 100% yield of the desired enantiomer, or diastereomer using racemising techniques and techniques and/or reactions to take out the desired enantiomer or diastereomer from the reaction mixture are well known by the person skilled in the art. Said techniques are called dynamic kinetic resolution techniques, see for example described by Pelliessier, Tetrahedron 2003, 59, 8291-8327, and references therein.
- the said iminium compounds retain the stereochemistry from the cyanohydrin and lactone nitrile.
- TBDMSiCl stands for tert-butyldimethylsilyl chloride.
- DMF is dimethyl formamide
- RT is room temperature.
- the nitrogen-containing compound is the nitro-compound of formula (7h) or (8h), or mixture thereof.
- a possible sequence of the coupling of compound of formula (7h) and compound of formula (2), and the following steps producing compound of formula (1) are depicted in Scheme VI.
- R 1 , R 2 , R 3 , Re, R 4 , R 6 , R 7 , and R 8 have the previously given meanings.
- the coupling of this compound of formula (2a) can be performed with any of the compounds of formula (7), and formula (8), or a mixture thereof.
- the required chirality at C-7 of compound of formula (1) can then later be introduced through hydrogenation of the C ⁇ C double bond (as for example shown for compound of formula (14) in Scheme VII).
- Said hydrogenation can be performed with any reducing agent, e.g. NaBH 4 , BH 3 , LiAlH 4 ; or hydrogen gas, optionally in the presence of a catalyst.
- Said catalyst can be a well known heterogeneous catalyst, such as Pd on Carbon or any support, or can be a homogeneous catalyst, e.g. those based on late transition metals, such as Rh, Ru, Ir, or Pd.
- a chiral hydrogenation reagent, or a chiral catalyst is used.
- Said chiral catalyst can be any transition metal with a chiral ligand, or of any enzymatic origin, or the so-called organo-catalysts.
- Suitable chiral catalysts are for example heterogeneous Pd on Carbon with cinchonidine alkoloids, or homogeneous rhodium complexes with chiral ligands, or for example enzymes called reductases.
- Suitable chiral ligands for the homogeneous catalysts are known in the art, for example chiral phosphor-containing ligands such as BINAP, JosiPhos, ChiraPhos, MonoPhos.
- R 1 , R 2 , R 3 , Re, R 4 , and R 8 have the previously given meanings.
- Re in compound of formula (2a) is M(X)n with the meanings for M, X and n as given above, more preferably M is Ba.
- the coupling reaction of compound of (2a) with compound of formula (7) or compound of formula (8), or mixture thereof, is performed preferably according to as described above for the coupling of compound of formula (2) with compound of formula (7) or compound of formula (8), or mixture thereof.
- the nitrogen-containing compound of formula (7a) can be obtained in many different ways and is part of the invention.
- the following route depicted in Scheme VIII can be used:
- the nitrogen-containing compound of formula (7), or formula (8), or mixture thereof is obtained via a novel chiral aldehyde compound as depicted below in FIG. (10), allowing the enantioselective addition of HCN, or related reagents, or allowing the addition of nitromethane, as mentioned above.
- aldehyde intermediate provides a building-block for aliskiren, as can be used in the synthesis thereof, and then satisfies formula (10a):
- the chiral aldehyde of formula (10) exhibits a further advantage in that it introduces immediately the required nitrogen in a stereochemically desired way by catalytic addition of HCN, or related reagents, or the stereochemically desired addition of nitromethane, both approaches as discussed above in connection with the synthesis of the nitrogen-containing compounds of formula (7) and (8), or a mixture thereof.
- the aldehyde can be converted into compound of formula (8a), optionally via compound of formula (7a).
- Scheme X illustrates the HNL catalyzed addition of HCN to the chiral aldehyde (10) forming compound of formula (7a), followed by acid catalyzed lactonisation to compound of formula (8a).
- the chiral aldehyde itself can be obtained in various alternative ways, e.g. as depicted in the following Schemes XI (a) through XI (g); wherein, the specific compounds chosen are illustrative, and can be translated to the corresponding other aldehydes commensurate with the respective structural part of the compounds of formula (1).
- R in Scheme XI (g) denotes a H, C 1-6 alkyl, or Cl.
- the oxidation depicted in Scheme XI (g) could also be performed by ozonolysis.
- the chiral aldehyde can be synthesized using a chiral pool strategy, for which several options are available, e.g. from the required enantiomer of Valine or Carvone.
- the aforementioned compounds can be used in a convergent synthesis route to the compounds of formula (9) or (11), or a mixture thereof, and ultimately to the compounds of formula (1), preferably aliskiren.
- the compound of formula (9) can be converted into the desired end-product, such as a compound according to formula (1), by allowing it to react with the appropriate amine NH 2 —R 5 , optionally followed by hydrolysis of the amine protecting group.
- Such reactions have been described, e.g in WO 2007/039183 and WO 2006/131304. It will be apparent to the skilled person that in the event of the synthesis of aliskiren, this amine will satisfy formula (15), and be synthesized in a known manner.
- optionally substituted groups do mean all the groups possible which will not interfere with the aimed reaction and/or reactions afterwards.
- the compounds of formula (1) include salts, especially pharmaceutically acceptable salts.
- any reference to “compounds”, “precursors” and “intermediates” is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate, metabolic precursor such as ester or amide of the compound of formula (1), or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise.
- Different crystal forms may be obtainable and then are also included.
- Salts including pharmaceutically acceptable salts are known and described in U.S. Pat. No. 5,559,111, column 11 line 50 to column 12, line 35, and incorporated herein by reference.
- All the above-mentioned process steps can be carried out under reaction conditions that are known per se, preferably those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, preferably solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the H + form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about ⁇ 100° C. to about 190° C., preferably from approximately ⁇ 80° C.
- solvents or diluents preferably solvents or diluents that are inert towards the reagents used and dissolve them
- condensation or neutralizing agents for example ion exchangers, such as cation exchangers, e.g. in the H + form, depending on
- the solvents include those mentioned specifically or, for example, water; esters, such as lower alkyl-lower alkanoates, for example ethyl acetate; ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofurane or dioxane; liquid aromatic hydrocarbons, such as benzene or toluene; alcohols, such as methanol, ethanol or 1- or 2-propanol; nitriles, such as acetonitrile; halogenated hydrocarbons, e.g.
- reaction mixtures especially in order to isolate desired compounds or intermediates, follows customary procedures and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
- the invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
- reaction mixture was diluted with 1 L of MTBE and the aqueous layer was extracted several times with MTBE.
- the combined organic extracts (approximately 2.5 L) were stabilized with 0.5 mL of phosphoric acid (conc.) and concentrated under reduced pressure yielding 12.4 g of the title compound as a crude mixture which was used without further purification.
- the crude cyanohydrin (12.4 g) was diluted with 120 mL of toluene and 25 g of mol sieves 5 ⁇ were added. To this mixture, 250 mg of p-toluenesulfonic acid was added and, whilst stirring, the mixture was heated at 70° C. for 1 hour. After cooling to RT, the molecular sieves were filtered off and washed with toluene. The collected organic phase was washed with a saturated aqueous solution of sodium bicarbonate and dried over Na 2 SO 4 . After filtering off the Na 2 SO 4 , the organic phase was concentrated under reduced pressure yielding 10.7 g of crude lactone. Purification by flash column chromatography on silica gel yielded the title compound with >98% purity.
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Abstract
Description
- This application is a divisional of commonly owned U.S. application Ser. No. 12/810,220, filed Sep. 22, 2010 (now U.S. Pat. No. ______), which is the national phase application under 35 USC §371 of PCT/EP2008/009050, Dec. 19, 2008, which designated the US and claims benefit of EP Patent Application No. 07025093.1, filed Dec. 24, 2007, the entire contents of each of which are hereby incorporated by reference.
- The invention pertains to a convergent synthesis route for the preparation of certain 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives, or pharmaceutically acceptable salts thereof, such as the compound aliskiren. The invention particularly relates to a synthetic route that will introduce the nitrogen of the above mentioned compounds ultimately required for the amino-group at C-5, at a relative early stage of the synthesis. The invention further relates to novel intermediates useful in the manufacture of the above mentioned compounds. Particularly, the 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives to which the methods of the present invention applies are any of those having renin inhibitory activity and, therefore, pharmaceutical utility, e.g., those disclosed in U.S. Pat. No. 5,559,111, WO 2006/061427, or WO 2006/095020.
- The 2(S),4(S),5(S);7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives, or pharmaceutically acceptable salts thereof to which the invention pertains, satisfy the general formula (1).
- Herein R1 is halogen, C1-6halogenalkyl, C1-6alkoxy-C1-6alkoxy or C1-6alkoxy-C1-6alkyl; R2 is halogen, C1-6alkyl or C1-6alkoxy; R3 and R4 are independently branched C3-6alkyl; and R5 is C1-12cycloalkyl, C1-12alkyl, C1-12hydroxyalkyl, C1-6alkoxy-C1-6alkyl, C1-6alkanoyloxy-C1-6alkyl, C1-12-aminoalkyl, C1-6alkylamino-C1-6alkyl, C1-6dialkylamino-C1-6alkyl, C1-6alkanoylamino-C1-6alkyl, HO—(O)C—C1-12alkyl, C1-6alkyl-O—(O)C—C1-6alkyl, H2N—C(O)—C1-12alkyl, C1-6alkyl-HN—C(O)—C1-6alkyl, (C1-6alkyl)2—N—C(O)—C1-6alkyl; saturated, unsaturated, or partially saturated C1-12heterocyclyl bonded via a carbon atom, and which heterocyclyl is optionally substituted one or more times by C1-6alkyl, trifluoromethyl, nitro, amino, N-mono- or N,N-di-C1-6alkylated amino, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkoxycarbonylamino, C0-6alkylcarbonylamino, C1-6alkylcarbonyloxy, C1-12aryl, N-mono or N,N-di-C1-6alkylated carbamoyl, optionally esterified carboxyl, cyano, halogen, halo-C1-6alkoxy halo-C1-6alkyl, C1-12heteroaryl, saturated, unsaturated or partially saturated C1-6heterocyclyl, hydroxyl, nitro; or the salt of compound according to formula (1), especially pharmaceutically acceptable salt thereof.
- In the convergent synthesis of compounds according to formula (1), it is known to separately provide e.g. two synthons commensurate with the following structural parts and, in the course of the entire synthesis route, couple these and convert as necessary. A reference in this respect is Sandham et al. Tetrahedron Letters 2000, 41, 10091-10094.
- The structural parts referred to are an aromatic part typically satisfying the structural formula (5),
- wherein R1 is 3-methoxy-propoxy, R2 is methoxy, and R3 are 2-propyl, and the Cl-group is transferred to the corresponding Grignard compound and subsequently transmetallated with CeCl3, prior to the coupling with
an aldehyde part typically satisfying the structural formula (3), - wherein R4, is 2-propyl, and Ph stands for phenyl.
- The above more particularly pertains to the synthesis of compounds of formula (4), the fumaric acid salt of which is known as aliskiren, (2S,4S,5S,7S)-7-(3-(3-methoxypropoxy)-4-methoxybenzyl)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-8-methylnonanamide.
- In the present application, any reference to aliskiren is deemed to include reference to all pharmaceutically acceptable salts, and prodrugs thereof.
- For the synthesis of the aforementioned parts, and the resulting linked compounds, generally multistep processes are used. In typical cases, the yields of one or more of these steps are low, and the overall yield is further affected by the desire to ultimately obtain a diastereomerically pure compound.
- A critical step in the process is the chemo- and stereoselective introduction of nitrogen so as to create the 5-amino group. In the above routes of synthesis, the nitrogen is introduced after coupling of the described structural parts by substituting the obtained alcohol moiety using several, laborious steps. Moreover, some of these steps are difficult to perform at production scale.
- Coupling of the compound of formula (5) wherein R1 is 3-methoxy-propoxy, R2 is methoxy, and R3 are 2-propyl, with a nitrogen containing building block derived from the compound of formula (3) is Dondoni et al. Tetrahedron Letters 2001, 41, 4819-4823, wherein, prior to the coupling, the Cl-group of compound according to formula (5) is transferred to the corresponding Grignard compound and subsequently transmetallated with CeCl3.
- This route results, at best, in a very small excess of the desired diastereomer (55:45), only if additional measures are employed, such as the addition of a chelate complex-destroying agent. In general, the opposite of the desired diastereomer is obtained in excess. As indicated in the paper, a substantial dominance of the desired S-epimer could not be achieved.
- The invention now provides a novel route for coupling new nitrogen containing compounds of formula (7) and (8) to a compound of formula (2) (see below). Surprisingly, such coupling can be achieved with a much simpler nitrogen containing compound, in particular a compound not comprising a chiral auxiliary. It is an advantage of the new nitrogen containing compounds, that the desired coupling products can be obtained with a higher yield of the compound with the desired configuration at the C-5 stereogenic center.
- It would be advantageous to provide a convergent synthesis route for compounds of formula (1) which satisfies one or more of the following:
-
- a reduced number of steps;
- an improved overall yield;
- a relatively easy introduction of the “5-amino” group;
- providing a nitrogen-containing compound (preferably in a short and scalable route) that is capable of being coupled with the compound according to formula (2).
- By preference, it would be advantageous to achieve one or more of the following:
-
- an increased diastereomeric selectivity in the aforementioned coupling step;
- providing an enantiomerically enriched (most preferably pure) nitrogen-containing compound that is capable of being coupled with the compound according to formula (2), resulting in the coupling product with the desired stereochemical configuration, or at least so as to provide the 5(S) configuration in excess.
- In order to better address the foregoing, in one aspect, the invention provides a synthesis route to compounds of formula (1a).
- Herein, the R groups have the above-indicated meaning. The synthesis route is based on a novel nitrogen-containing compound according to formula (7), or the corresponding lactone of formula (8), as described below.
- In another aspect, the invention provides a novel chiral aldehyde (10), as a precursor for the nitrogen-containing intermediates, and thus as an intermediate to facilitate the synthesis of the compounds concerned. In another aspect, the invention presents processes for the stereoselective conversion of the chiral aldehyde into the nitrogen containing compound.
- In yet a further aspect, the invention provides the coupling of compounds of structure (2) with the nitrogen containing compounds of formula (7) and/or (8), under the appropriate conditions, resulting in compounds depicted by formula (9a) and/or (11a), with the configuration of the C-5 stereogenic center being undefined, optionally followed by a purifying step in order to obtain the desired configurational purity at the C-5 stereogenic center, or the coupling of compounds of structure (2) with the nitrogen containing compound of formula (7) and/or (8) is resulting in the compounds depicted by formula (9) and/or (11).
- In a still further aspect, the invention provides a synthesis route to compounds of formula (1), notably to aliskiren and closely related compounds.
- The overall synthetic route to compound (1), as an example of synthetic routes according to the invention, can be as follows:
- The abbreviations in this scheme, other than chemical elements have the following meaning:
-
- DiBAL-H is diisobutyl aluminum hydride;
- p-TsOH is para-toluene sulfonic acid;
- HNL is hydroxynitrile lyase;
- R1, R2, R3, R4, and R5 are as described for the compound according to formula (1);
- Re is a reactive moiety selected from F; Cl; Br; I; M(X)n, wherein X is F, Cl, Br, I, CN, C1-12alkyl, or C1-6alkoxy and M is a metal, preferably M is Mg, Ce, Li, Ba, Al, B, Cu, Zn, Mn, Ti, Zr, In and n is 0, 1, 2, 3, or 4; MM′(X)n(Y)n′, wherein M and M′ are a metal, preferably M and M′ are each independently Mg, Ce, Li, Ba, Al, B, Cu, Zn, Mn, Ti, Zr, In, where X and Y are each independently chosen from F, Cl, Br, I, or CN, C1-6alkoxy and n, n′ are each independently chosen from the values as described above; or Re is OR9, wherein R9 is a group capable of making OR9 a leaving group, such group being known to the person skilled in the art, for example R9 is acetyl, trifluoroacetyl; CF3SO2, CH3SO2, CH3C6H4SO2, C(O)OCH3, or C(O)OC4H9;
- R6 represents H, or optionally substituted C1-12alkyl, optionally substituted C1-12alkylaryl, or optionally substituted C1-12aryl;
- R7 represents H, or is an O-protecting group as described in J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; or in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999;
- or R6 forms with R7 an, optionally substituted C1-12(hetero)cyclic compound, as such protecting both the acid and alcohol group;
- R8 denotes H, or a group remaining after the reaction of the Nf group as it was present in compound of formula (8), or R8 represents a group, put on independently in an additional reaction step, making the moiety attached via the N-atom to the C-5 stereogenic center of the compound depicted by formula (11) inactive for reaction steps thereafter,
- With reference to the overall reaction Scheme I, the various novel intermediates and the various related reaction steps are separately discussed hereinafter.
- This can be a compound depicted by formula (7), or the corresponding lactone compound of formula (8):
- In these formulae, R4 has the meaning given above with reference to formula (1). In the specific synthesis route to aliskiren, this represents a 2-propyl group.
- R4, R6, and R7, have the meaning given above, and Nf is a group comprising a carbon atom directly bonded to a nitrogen atom, preferably Nf is a group resulting in the compounds depicted by formulae (7a) to (7h), and compounds depicted by formulae (8a) to (8h),
- wherein R4, R6, and R7, have the meaning given above, and
Z is a N-protecting group;
R11 is an O-protecting group, e.g acetyl, trifluoroacetyl, trialkylsilyl, or benzyl, or groups as described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999;
R12 and R13 are either the same or different fragments, chosen from the group of H, optionally substituted C1-12alkyl, optionally substituted C1-12alkylaryl, or optionally substituted C1-12aryl, or they are joined together in a C1-20(hetero)cyclic structure; Ra+ is a counter-cation; St is a group capable of stabilising the imine. - The N-protecting group depicted as Z is preferably a group which can be easily removed in a latter stage of the synthesis, such as optionally substituted benzyl, para-methoxyphenyl, (2-pyridyl)sulfonyl or any group described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999;
- Ra+ is a counter-cation, for example the one remaining after the partial reduction of the cyano group, e.g. Al(iBu)2 +, as is depicted as example in Scheme 1 (when DiBAL-His used as reducing agent);
- St is a group capable of stabilising the imine, preferably the remaining group after partial reduction of the cyano group, e.g. B(R10)3, if LiBH(R10)3 was used, R10 being H or a C1-6 alkyl group.
- The partial reduction of the nitrile group in the compounds depicted by formulae (7a) and (8a), resulting in compounds of formula (7e and f) and (8e and f), can be conducted in a variety of ways known to the skilled person, as described in Andreoli et al. J. Org. Chem. 1990, 55, 4199-4200; Masahiko et al. Synlett 1991, 7, 479-480; Zandbergen et al. Tetrahedron 1992, 48, 3977-3982; Cainelli et al. Tetrahedron 1993, 49, 3809-3826; Itsuno et al. J. Chem. Soc. Perkin Trans. 11991, 1767-1769; Ramachandran and Biaswas Org. Lett. 2007, 9, 3025-3027.
- The cyanohydrin compound of formula (7a) (Nf=CN) can be prepared by reacting the chiral aldehyde of formula (10) with a cyanide, preferably with HCN, NaCN, KCN, (R)3SiCN (with R selected from C1-6alkyl, C1-10alkylaryl, and C1-10aryl), optionally in the presence of a chiral catalyst. Said catalyst can be a chiral organic compound, a chiral metal complex, or an enzyme, as described in by F. X. Chen and X. M. Feng in “Asymmetric synthesis of cyanohydrins” Current Organic Synthesis 2006, 3, 77-97, and references therein; and by P. Poechlauer, W. Skranc, and M. Wubbolts in “The large-scale biocatalytic synthesis of enantiopure cyanohydrins” in Asymmetric Catalysis on Industrial Scale; H. U. Blaser and E. Schmidt, Eds. Wiley-VCH, 2004, pp 151-164. Preferably HCN, or (R)3SiCN in the presence of a suitable chiral catalyst is used. More preferred HCN and the enzyme HNL (hydroxynitrile lyase) are used. Suitable conditions for the synthesis of compound of formula (7a) are known by the person skilled in the art and are described in the references above, and references therein.
- The nitrile containing compound of formula (7a) and (8a) can be converted to other nitrogen containing compounds according to formula (7b-g) and (8b-g) by using methods known in the art, for example by partial reduction as described above. Examples of various imine-type compounds, and applied conditions can be found in Bloch Chem. Rev. 1998, 98, 1407-1438; Friestad and Mathies Tetrahedron 2007, 63, 2541-2569 and references therein. Optionally, the partial reduction can be followed by immediate hydrolysis to the corresponding aldehyde group resulting in the formation of compounds of formula (6a) or (6b),
- wherein R4, R6, and R7, have the meaning given above,
and subsequent reaction to the imine, oxime or hydrazone compounds. The compounds according to formula (6a) and (6b) can be purified and isolated, or immediately converted to the corresponding nitrogen containing compounds of formula (7) and (8). Preferably, the compounds according to formula (6a) and (6b) are converted without isolation to the corresponding nitrogen containing compounds of formula (7) and (8). - One example of such a preferred sequence (without isolation of compound of formula (6a) is depicted in Scheme II.
- The nitro analogue of compound of formula (7h, Nf=(H)C(H)NO2) can be prepared by addition of nitromethane to the chiral aldehyde of formula (10), the so-called Henry reaction, preferably in the presence of a chiral compound, said chiral compound can be an organic compound, a metal complex, or an enzyme. Preferably, said chiral compound is used in catalytic amounts, preferably less than 10 mol % compared to the amount of chiral aldehyde. Suitable examples of said chiral compounds are for example described by Boruwa et al. in Tetrahedron Asymmetry 2006, 17, 3315-3326 and references therein.
- The nitrogen containing compounds of formula (7) can be converted into the corresponding lactone compounds of formula (8) by using methods known in the art, in analogy with regular deprotection methods and ester synthesis, e.g. catalyzed by para-toluene sulfonic acid. For the lacton formation, R6 is preferentially C1-6alkyl, more preferentially methyl.
- The lactone nitrile of formula (8a) in the diastereochemically desired configuration can be obtained by ring-closing the cyanohydrin of formula (7a) in the desired configuration, or by ring-closing both diastereomers of the cyanohydrin of formula (7a) with fixed configuration at C-2 stereogenic center, followed by epimerization of the C-4 steroegenic center to the thermodynamically preferred diastereomer, also being the desired diastereomer. Said epimerisation can be conducted by heating the lactone nitrile, optionally in a suitable solvent, and optionally in the presence of a base or other suitable additives. Alternatively, the diastereoisomer with the desired configuration can be separated from the other diastereoisomer making use of their different physical properties (e.g. preferential crystallization), or by means of classic or separating moving beds (SMB) chromatography. Suitable examples of SMB chromatography can be found in Schulte and Strube J. Chromatogr. A 2001, 906, 399-416 and references therein.
- Preferably the lactone nitrile of formula (8a) in the diastereochemically desired configuration is obtained by ring-closing an optically pure cyanohydrin of formula (7a).
- It will be appreciated that the nitrogen-containing intermediates can be used in the synthesis of compounds of formula (1), as is depicted in the overall reaction scheme by reacting compound of formula (9a) or (11a), or a mixture thereof, with an appropriate amine, i.e. of a general formula H2N—R5, under conditions sufficient to form an amide bond, optionally followed by purification in order to obtain the desired configuration of the C-5 sterogenic center. Suitable conditions for the amide bond formation are known to the person skilled in the art, and are for example described in Sandham (Tetrahedron Letters, 2000, 41, 10091-10094), referred to above.
- More directly, the nitrogen-containing compounds of formula (7) or (8), or a mixture thereof, are reacting with a compound according to formula (2)
- wherein R1, R2, and R3 and Re have the aforementioned meaning,
which reaction results in the synthesis of a compound according to formula (9a) or (11a), or a mixture thereof. - Herein, R1, R2, R3, R4, R6, R7, and R8 have the previously given meanings.
- When compounds according to formula (7a-g) or compounds according to formula (8a-g), or a mixture thereof, are reacting with compound of formula (2) the Re group denotes preferably M(X)n, or MM′(X)n(Y)n′. Optionally, compounds according to formula (7a-g) or compounds according to formula (8a-g), or a mixture thereof, are reacting with compound according to formula (2) in the presence of a metal complex, preferably a metal complex used in catalytically amounts, and optionally in the presence of an additive. Said catalysts can be any metal complex, preferably transition metal complexes, more preferred metal complexes derived from group VII and group VIII of the periodic system, most preferred manganese or iron complexes are used, such as MnCl2, and FeCl3, Fe(acac)3, FeCl2.
- Suitable additives are Lewis acids, such as ZnCl2, CuCl; CuI, INCl3, TiCl4, alkali metal salts, such as LiCl; tertiary amines and tertiary diamines, such as Et3N,N-methylpyrrolidine, tetramethylendiamine (TMEDA); amides and ureas, such as N-methylpyrrolidinone (NMP) and 1,3-dimethyl-2-oxohexahydropyrimidine (DMPU); hexamethylphosphoric acid triamide (HMPA); tris(dialkylamino)phosphines, such as tris(dimethylamino)phosphine (HMPT).
- Said metal complexes or additives can be chiral to enhance the amount of compound of formula (9a) or (11a) or mixture thereof, with the desired configuration at the C-5 stereogenic center. Chiral metal complexes can be prepared beforehand or prepared in situ, by mixing the metal complex with an suitable chiral ligand. Suitable chiral ligands are known to the person skilled in the art, for example chiral amino alcohols, optionally alkylated at the amine functionality, such as ephedrine; chiral phosphor containing compounds, such as (3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a′]dinapthalen-4-yl)dimethylamine (MonoPhos), chiral bisphosphines, such as 2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl (BINAP).
- Suitable chiral additives are any additive mentioned above with a stereogenic center or other form of chirality. Preferred are chiral amines and amine derivatives, such as N,N-dimethylamino acid methyl esters, N,N-dimethylmethylbenzylamine and chiral phosphor containing compounds, such as (3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a′]dinapthalen-4-yl)dimethylamine (MonoPhos).
- When the compound according to formula (7h) or the compound according to formula (8h), or a mixture thereof, is reacting with compound of formula (2) the Re group denotes preferably Cl, Br, I, or OR9, wherein R9 is a group capable of making OR9 a leaving group, such group being known to the person skilled in the art, for example R9 is acetyl, trifluoroacetyl; CF3SO2, CH3SO2, CH3C6H4SO2, C(O)OCH3, or C(O)OC4H9, and this reaction is performed in the presence of a base, or metal complex. Suitable bases are any base capable of, optionally partly, deprotonating the carbon center with the nitro group directly attached to it, such as bases are known to the person skilled in the art, for example sodium hydride, sodium methoxide, n-butyllithium, sec-butyllithium, tertiar-butyllithium, KOtertiar-butyl, KOAc, KOH, NaOH, and so on. Suitable metal complexes are similar complexes as used for the synthesis of compounds of formula (7h) or (8h) or mixture thereof, as also described in Boruwa et al. in Tetrahedron Asymmetry 2006, 17, 3315-3326 and references therein.
- Said bases or metal complexes can be chiral to enhance the amount of compound of formula (9a) or (11a) or mixture thereof, with the desired configuration at the C-5 stereogenic center. Suitable chiral bases are for example alkali-metal amides, such as chiral lithium amides similar to those described in Cailleau et al. Org. Biomol. Chem. 2007, 5, 3922-3931 and references therein.
- With reference to producing a compound satisfying formula (1), it will be apparent that the corresponding compound of formula (9a) or (11a), or a mixture thereof, is formed with an undefined configuration at the C-5 stereogenic center (the carbon center with the HR8N moiety attached to it). It will be appreciated that the nitrogen-containing compounds of formula (7) or (8), or mixture thereof, employed in the synthesis of compound of formula (9a) or (11a), or mixture thereof, are able to react with a compound of formula (2) in a diastereoselective manner, due to a preferential direction of attack during the coupling reaction and the presence of neighbouring fixed stereogenic centers. The diastereoselectivity is influenced by the nature of the reagents of formula (7a-h), (8a-h) and (2), optionally, by the addition of a catalyst, base, and/or additive as described above. Optionally, the diastereoselectivity can be increased by making use of the different physical properties of the diastereoisomers (e.g. preferential crystallization), or by means of classic or separating moving beds (SMB) chromatography as described above. Optionally this additional purification is performed in the presence of a suitable agent capable of racemising the C-5 center. The racemization could be done in the same vessel or by external loops.
- In the case of the compound according to formula (7h) or the compound according to formula (8h), or a mixture thereof, reacting with compound of formula (2) the intermediate compound obtained of formula (12) or (13) or mixture thereof is in particular suitable for preferential crystallization and racemisation (in the presence of a suitable base).
- Said techniques to obtain a theoretical 100% yield of the desired enantiomer, or diastereomer using racemising techniques and techniques and/or reactions to take out the desired enantiomer or diastereomer from the reaction mixture, are well known by the person skilled in the art. Said techniques are called dynamic kinetic resolution techniques, see for example described by Pelliessier, Tetrahedron 2003, 59, 8291-8327, and references therein.
- The compounds of formula (2), with R1, R2, R3, as described above, and with Re is Cl can be made in known ways. References in this respect are Sandham et al. Tetrahedron Lett. 2000, 41, 10091-10094 and Sturm et al. Adv. Synth. Catal. 2003, 345, 160-164.
- The preparation of the corresponding Grignard reagent (Re=MgCl) is described by Sandham. The preparation of many other organometallic compounds can be performed by the transmetalation reaction of the appropriate metal salts with a magnesium or lithium organometallic compound of formula (2). These transmetallation procedure are known to persons skilled in the art.
- As a part of the invention, the coupling of the organometallic reagent according to formula (2) with the nitrogen containing compound of formula (7a) or formula (8a), or a mixture thereof, can be performed as depicted in the Scheme III:
- or for example by first reducing the cyanohydrin and the lactone nitrile to the corresponding iminium ions of formula (7e) and (8e), as depicted in Scheme IV.
- In Schemes III and IV, R1, R2, R3, Re, R4, R6, R7, R8, and Ra+ have the previously given meanings.
- The said iminium compounds retain the stereochemistry from the cyanohydrin and lactone nitrile.
- In the event of an organometallic coupling reaction of a compound according to formula (2) with any nitrogen-containing compound of formula (7), the hydroxyl group in compound according to formula (7) can be protected in various ways using known alcohol protecting groups, e.g. as depicted in Scheme V:
- Herein, the abbreviation TBDMSiCl stands for tert-butyldimethylsilyl chloride. DMF is dimethyl formamide, and RT is room temperature.
- Alternatively, the nitrogen-containing compound is the nitro-compound of formula (7h) or (8h), or mixture thereof. A possible sequence of the coupling of compound of formula (7h) and compound of formula (2), and the following steps producing compound of formula (1) are depicted in Scheme VI.
- Here, R1, R2, R3, Re, R4, R6, R7, and R8 have the previously given meanings.
- As an alternative, a variant of a compound of formula (2) is used that itself does not possess the desired chirality, yet. This refers to a compound of formula (2a), which has the advantage of being more reactive:
- The coupling of this compound of formula (2a) can be performed with any of the compounds of formula (7), and formula (8), or a mixture thereof. The required chirality at C-7 of compound of formula (1) can then later be introduced through hydrogenation of the C═C double bond (as for example shown for compound of formula (14) in Scheme VII). Said hydrogenation can be performed with any reducing agent, e.g. NaBH4, BH3, LiAlH4; or hydrogen gas, optionally in the presence of a catalyst. Said catalyst can be a well known heterogeneous catalyst, such as Pd on Carbon or any support, or can be a homogeneous catalyst, e.g. those based on late transition metals, such as Rh, Ru, Ir, or Pd. Optionally, a chiral hydrogenation reagent, or a chiral catalyst is used. Said chiral catalyst can be any transition metal with a chiral ligand, or of any enzymatic origin, or the so-called organo-catalysts. Suitable chiral catalysts, are for example heterogeneous Pd on Carbon with cinchonidine alkoloids, or homogeneous rhodium complexes with chiral ligands, or for example enzymes called reductases. Suitable chiral ligands for the homogeneous catalysts are known in the art, for example chiral phosphor-containing ligands such as BINAP, JosiPhos, ChiraPhos, MonoPhos.
- An alternative synthesis route to compound of formula (1) could for example satisfy the following reaction scheme VII (here shown for the reaction of compounds (2a) and (8e)):
- Herein, R1, R2, R3, Re, R4, and R8 have the previously given meanings.
- Preferably Re in compound of formula (2a) is M(X)n with the meanings for M, X and n as given above, more preferably M is Ba.
- The coupling reaction of compound of (2a) with compound of formula (7) or compound of formula (8), or mixture thereof, is performed preferably according to as described above for the coupling of compound of formula (2) with compound of formula (7) or compound of formula (8), or mixture thereof.
- The nitrogen-containing compound of formula (7a) can be obtained in many different ways and is part of the invention. For example the following route depicted in Scheme VIII can be used:
- The chiral lactone nitrile (8a), also being part of the invention can be made in various ways, e.g. according to Scheme IX:
- In Schemes VIII and IX the R groups have the meanings given above.
- Preferably, the nitrogen-containing compound of formula (7), or formula (8), or mixture thereof, is obtained via a novel chiral aldehyde compound as depicted below in FIG. (10), allowing the enantioselective addition of HCN, or related reagents, or allowing the addition of nitromethane, as mentioned above.
- This refers to a compound that is useful as a precursor for the nitrogen-containing compounds, and that is a novel compound, representing a conceptually different synthetic route, in the preparation of compounds of formula (1). The chiral aldehyde satisfies the following formula (10):
- With R4 and R6 as indicated above. More particularly, the aldehyde intermediate provides a building-block for aliskiren, as can be used in the synthesis thereof, and then satisfies formula (10a):
- The use of the chiral aldehyde of formula (10) or formula (10a) are representing a novel approach to the synthesis of compounds of formula (1), and particularly of aliskiren. It has an advantage in the sense that it introduces the desired stereochemistry at the C-2 stereogenic center atom of compounds of formula (1) without the use of stoichiometric amounts of relative expensive chiral auxiliaries as shown in Sandham et al. Tetrahedron Lett. 2000, 41, 10091-94.
- The chiral aldehyde of formula (10) exhibits a further advantage in that it introduces immediately the required nitrogen in a stereochemically desired way by catalytic addition of HCN, or related reagents, or the stereochemically desired addition of nitromethane, both approaches as discussed above in connection with the synthesis of the nitrogen-containing compounds of formula (7) and (8), or a mixture thereof. Thus, the aldehyde can be converted into compound of formula (8a), optionally via compound of formula (7a).
- By way of example, the following scheme (Scheme X) illustrates the HNL catalyzed addition of HCN to the chiral aldehyde (10) forming compound of formula (7a), followed by acid catalyzed lactonisation to compound of formula (8a).
- The chiral aldehyde itself can be obtained in various alternative ways, e.g. as depicted in the following Schemes XI (a) through XI (g); wherein, the specific compounds chosen are illustrative, and can be translated to the corresponding other aldehydes commensurate with the respective structural part of the compounds of formula (1).
- Wherein R in Scheme XI (g) denotes a H, C1-6 alkyl, or Cl. The oxidation depicted in Scheme XI (g) could also be performed by ozonolysis. Alternatively, the chiral aldehyde can be synthesized using a chiral pool strategy, for which several options are available, e.g. from the required enantiomer of Valine or Carvone.
- The various reaction steps are identified with reference to terminology and names commonly known in the art, and to the person skilled in the art are understandable as such.
- The aforementioned compounds can be used in a convergent synthesis route to the compounds of formula (9) or (11), or a mixture thereof, and ultimately to the compounds of formula (1), preferably aliskiren.
- The convergence, resulting in a compound of formula (9) or (11) or mixture thereof, comes when the intermediates representing the aromatic part are reacted with the nitrogen-containing intermediate. Other than in previous routes which lead to an excess of the desired diastereomer, at the convergence stage of this invention the critical 5-amino nitrogen is already present in the molecule. Moreover, provided that the preferred choices are made in the synthetic route from the aforementiond chiral aldehyde, the amino group is present in the desired stereomeric configuration.
- The compound of formula (9) can be converted into the desired end-product, such as a compound according to formula (1), by allowing it to react with the appropriate amine NH2—R5, optionally followed by hydrolysis of the amine protecting group. Such reactions have been described, e.g in WO 2007/039183 and WO 2006/131304. It will be apparent to the skilled person that in the event of the synthesis of aliskiren, this amine will satisfy formula (15), and be synthesized in a known manner.
- Thus, a straightforward convergent synthesis results, without undue complexity. The two aforementioned building blocks are provided, coupled and, subsequently, with one or two steps the desired end-product results.
- In the case of optionally substituted groups are mentioned or used in the invention, optionally substituted groups do mean all the groups possible which will not interfere with the aimed reaction and/or reactions afterwards.
- As mentioned above in respect of aliskiren, the compounds of formula (1) include salts, especially pharmaceutically acceptable salts. In view of the close relationship between the compounds and intermediates in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the compounds or salts thereof, any reference to “compounds”, “precursors” and “intermediates” is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate, metabolic precursor such as ester or amide of the compound of formula (1), or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise. Different crystal forms may be obtainable and then are also included.
- Salts, including pharmaceutically acceptable salts are known and described in U.S. Pat. No. 5,559,111, column 11 line 50 to column 12, line 35, and incorporated herein by reference.
- The following, in accordance with the knowledge of a person skilled in the art about possible limitations in the case of single reactions, applies in general to all processes mentioned in the foregoing description, or hereinafter in the Examples and Claims, while reaction conditions specifically mentioned above or below are preferred:
- All the above-mentioned process steps can be carried out under reaction conditions that are known per se, preferably those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, preferably solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about −100° C. to about 190° C., preferably from approximately −80° C. to approximately 150° C., for example at from −80 to −60° C., at room temperature, at from −20 to 40° C. or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.
- The solvents, from which those solvents that are suitable for any particular reaction may be selected, include those mentioned specifically or, for example, water; esters, such as lower alkyl-lower alkanoates, for example ethyl acetate; ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofurane or dioxane; liquid aromatic hydrocarbons, such as benzene or toluene; alcohols, such as methanol, ethanol or 1- or 2-propanol; nitriles, such as acetonitrile; halogenated hydrocarbons, e.g. as methylene chloride or chloroform; acid amides, such as dimethylformamide or dimethyl acetamide; bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2-one; carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride; cyclic, linear or branched hydrocarbons, such as cyclohexane, heptane or (iso)pentane; or mixtures of these, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning. Where required or desired, water-free or absolute solvents can be used.
- Where required, the working-up of reaction mixtures, especially in order to isolate desired compounds or intermediates, follows customary procedures and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like. The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ. In the process of the present invention those starting materials are preferably used which result in compounds of formula (1) which are described as being preferred. Special preference is given to reaction conditions that are identical or analogous to those mentioned in the Examples. The invention relates also to novel starting compounds and intermediates described herein, especially those leading to compounds mentioned as preferred herein.
- It is to be understood that the invention is not limited to the embodiments and formulae as described hereinbefore. It is also to be understood that in the claims the word “comprising” does not exclude other elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. “a” or “an”, “the”, this includes a plural of that noun unless something else is specifically stated.
- The invention will be illustrated with reference to the following, non-limiting Examples.
-
- A solution of the aromatic chloride (7.87 g, 25.0 mmol) and 1,2-dibromoethane (50 μL) in THF (24 mL) was added dropwise, under a nitrogen atmosphere, to an over-dried round bottomed flask containing a suspension of magnesium powder (670 mg, 27.5 mmol, 1.1 eq.) and few crystals of I2 in THF (1 mL). The temperature was maintained at 65-69° C. during the addition and for the following 2 hours, after which time the stirring was stopped and the mixture was allowed to reach room temperature overnight.
- After treatment with a saturated aqueous solution of NH4Cl, a sample of reaction mixture was analyzed by 1H-NMR and showed full consumption of the starting material. Before use, the titration of the grignard reagent was performed using sec-BuOH in the presence of 1,10-phenantroline. The titer was generally found to be 0.71-0.82 M.
-
- A solution of the aromatic chloride (9.5 g, 30.0 mmol) in acetone (30 mL) containing NaI (9.0 g, 60.0 mmol, 2 eq.) was stirred at room temperature for 5 days. A sample analyzed by 1H-NMR showed a ratio of 40:60 between starting material and product. The solvent was then removed and water was added. The aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over Na2SO4 and the solvent removed under reduced pressure. Acetone (30 mL) was added to the crude mixture, followed by NaI (9.0 g, 60.0 mmol, 2 eq.). The reaction mixture was stirred at 56° C. for extra 5 days. It was decided to stop the reaction when a ratio of 92:8 was reached. The work up was performed as previously described. The crude mixture was purified by flash column chromatography on silica gel affording the desired compound in 80.5% yield, as a light brown solid.
- 1H-NMR (400 MHz, CDCl3): δ 6.76-6.62 (m, 3H), 4.05 (t, J=6.5 Hz, 2H), 3.76 (s, 3H), 3.51 (t, J=6.1 Hz, 2H), 3.28 (s, 3H), 3.18-2.97 (m, 2H), 2.75-2.65 (m, 1H), 2.34-2.21 (m, 1H), 2.10-1.98 (m, 2H), 1.73-1.57 (m, 1H), 1.15-1.05 (m, 1H), 0.94 (d, J=6.5 Hz, 3H), 0.87 (d, J=6.9 Hz, 3H).
-
- In an oven-dried flask kept under a nitrogen atmosphere, the aromatic iodide (406.3 mg, 1.0 mmol) was dissolved in diethyl ether (2.5 mL) and the solution was cooled to −78° C. A pentane solution of t-BuLi (1.7 M, 0.7 mL, 1.2 eq.) was then added dropwise and the reaction mixture was stirred for 1 h at −78° C., after which time it was allowed to reach room temperature and it was stirred for an extra hour. A sample was quenched by the addition of an aqueous HCl solution (3 M), which was extracted with ethylacetate. The organic layer was dried over Na2SO4, the solvent was removed and the residue was analyzed by 1H-NMR, revealing full conversion of the starting material and presence of 73.0% of the hydrolysis compound related to the desired product.
-
- In a 1 ltr Schott-bottle with magnetic stirrer 18 g of (S,E)-methyl 5-chloro-2-isopropylpent-4-enoate (0.094 mol) was mixed with 680 ml of acetonitrile and 88 ml of water and it was stirred at 25° C. To this solution 39.6 g of NalO4 (0.184 mol) and 1.08 g of RuCl3xH2O were added at once. The temperature was maintained at 35° C. The progress of the reaction was followed by TLC (eluent: heptane/ethylacetate 3/2).
- When the reaction was finished the mixture was cooled to RT and the precipitate was filtered off and washed with ethylacetate. The organic liquid phase was successively washed once with 50 ml of a saturated aqueous solution of sodium thiosulfate, once with 50 ml of brine, once with 50 ml of a saturated aqueous solution of sodium bicarbonate and once with 40 ml of brine. The organic solution was dried over Na2SO4. After filtering off Na2SO4, the organic solvent was removed under reduced pressure yielding 18.4 g of crude aldehyde.
-
- The chiral aldehyde (10) (0.033 mol) was diluted with 345 ml of toluene and 500 mL of a (S)—HNL solution (pH=5.6) was added. The two phases were mixed by stirring and, at a temperature of 0° C., 20 mL of pure HCN (0.53 mol) was dosed over 5 minutes. The mixture was stirred for 3 hours at 0° C. The conversion of the aldehyde was >94% and the enantiomeric excess of the product was 94%.
- The reaction mixture was diluted with 1 L of MTBE and the aqueous layer was extracted several times with MTBE. The combined organic extracts (approximately 2.5 L) were stabilized with 0.5 mL of phosphoric acid (conc.) and concentrated under reduced pressure yielding 12.4 g of the title compound as a crude mixture which was used without further purification.
-
- The crude cyanohydrin (12.4 g) was diluted with 120 mL of toluene and 25 g of mol sieves 5 Å were added. To this mixture, 250 mg of p-toluenesulfonic acid was added and, whilst stirring, the mixture was heated at 70° C. for 1 hour. After cooling to RT, the molecular sieves were filtered off and washed with toluene. The collected organic phase was washed with a saturated aqueous solution of sodium bicarbonate and dried over Na2SO4. After filtering off the Na2SO4, the organic phase was concentrated under reduced pressure yielding 10.7 g of crude lactone. Purification by flash column chromatography on silica gel yielded the title compound with >98% purity.
- 1H-NMR (400 MHz, CDCl3): δ 5.11 (dd, J=8.4, 2.3 Hz, 1H), 2.84-2.74 (m, 1H), 2.62-2.41 (m, 2H), 2.31-2.16 (m, 1H), 1.10 (d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H).
-
- Imidazole (7.35 g, 108 mmol) was added at 0° C. to a solution of the crude hydroxyl nitrile (10 g) in DMF (180 mL), followed by TBDMSiCl (9.77 g, 64.8 mmol). The mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was poured over an ice-cold aqueous HCl solution (1 M, 80 mL). After the addition of diethyl ether (100 mL), the organic layer was separated and the aqueous layer was further extracted with diethyl ether (2×100 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over Na2SO4 and the solvent was then removed under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel.
- 1H-NMR (400 MHz, CDCl3): δ 4.26 (dd, J=9.2, 3.4 Hz, 1H), 3.50 (s, 3H), 2.37-2.29 (m, 1H), 2.08-1.96 (m, 1H), 1.86-1.68 (m, 2H), 0.81-0.68 (m, 15H), 0.00 (s, 3H), −0.08 (s, 3H).
-
- A solution of TBS-protected cyanohydrin (75 mg, 0.25 mmol) in pentane (2 mL) was cooled to −78° C. and kept under a nitrogen atmosphere. A pentane solution of DiBAL-H (1 M, 0.25 mL) was then added dropwise. The reaction mixture was stirred at −78° C. for extra 4 hours. The consumption of the starting material was followed by TLC and GC. The resulting metallo-imine was maintained at the same temperature and used without any further purification.
-
- A solution of TBS-protected cyanohydrin (75 mg, 0.25 mmol) in Et2O (2 mL) was cooled to −78° C. and kept under a nitrogen atmosphere. A THF solution of LiBEt3H (1 M, 0.25 mL) was then added dropwise. The consumption of the starting material was followed by TLC and GC. After stirring at the same temperature for 2 hours, MeOH (10 μL, 1 eq.) was added to the reaction mixture, which was then stirred for extra 30 minutes at room temperature. The development of a light turbidity was observed, probably due to the presence in solution of MeOLi. The resulting metallo-imine was analyzed and used without any further purification.
- Metallo-imine relevant peaks 1H-NMR (400 MHz, CDCl3): δ 9.48 (m, 1H), 7.54 (m, 1H), 4.34 (m, 1H), 3.63 (s, 3H), 2.19 (m, 2H), 0.60 (t, 9H), 0.14 (q, 6H).
-
- The crude solution of the previously obtained metallo-imine was treated with an aqueous HCl solution (1 M), which was extracted with diethyl ether. The organic layer was dried over Na2SO4, the solvent was removed under reduced pressure. Purification by flash column chromatography on silica gel yielded the title compound.
- 1H-NMR (400 MHz, CDCl3): 9.53 (d, J=1.5 Hz, 1H), 9.47 (d, J=1.9 Hz, 1H), 3.95-3.85 (m, 1H), 3.61 (s, 3H), 3.60 (s, 3H), 2.42-2.29 (m, 1H), 2.07-1.94 (m, 1H), 1.92-1.80 (m, 1H), 1.61-1.50 (m, 1H), 0.91-0.77 (m, 15H), 0.03-(−)0.04 (m, 6H).
-
- 363 mg (1.0 mmol, 1.03 eq) zinctriflate, 1 ml (18.5 mmol, 19 eq) nitromethane and 174 μl (1.0 mmol, 1.03 eq) diisopropylethylamine were placed in a dry schlenk vessel under Nitrogen. The yellow slurry was cooled in ice and 153.3 mg (0.97 mmol) (S)-methyl 2-isopropyl-4-oxobutanoate was added. The reaction mixture was stirred for 3 h, after which it was quenched with 2 ml 1 N ammonium chloride solution. After separation the water phase was extracted 3 times with 4 ml dichloromethane and the combined organic phases were washed with 4 ml brine and dried with Na2SO4, yielding 365 mg crude material after film evaporation, which contained still diisopropylethylamine according to NMR. The material was dissolved in 5 ml dichloromethane, washed 3 times with 1 ml 1 N HCl, dried with sodiumsulphate yielding 161 mg after removal of the solvent. Column separation (30/70 v/v ethylacetate/heptane) gave the pure target compound (3S)-3-isopropyl-5-(nitromethyl)dihydrofuran-2(3H)-one.
Claims (10)
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US81022010A | 2010-09-22 | 2010-09-22 | |
US13/939,983 US20130310577A1 (en) | 2007-12-24 | 2013-07-11 | Convergent synthesis of renin inhibitors and intermediates useful therein |
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WO2016057683A3 (en) * | 2014-10-07 | 2016-06-02 | Ann And Robert H. Lurie Children's Hospital Of Chicago | Novel anti-nodal antibodies and methods of using same |
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IT1402925B1 (en) * | 2010-12-10 | 2013-09-27 | Chemo Iberica Sa | ALISKIREN PRODUCTION PROCESS |
TW201202178A (en) * | 2010-06-04 | 2012-01-16 | Chemo Iberica Sa | Process for producing Aliskiren |
CN102432466B (en) * | 2011-09-22 | 2013-10-16 | 武汉武药制药有限公司 | Preparation method of aliskiren intermediate |
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US4886834A (en) * | 1986-03-17 | 1989-12-12 | Eisai Co., Ltd. | Diphenyl-methane compounds useful in the treatment of diseases caused by aggregation of platelets or formation of thrombus |
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CA2469130A1 (en) * | 2001-12-04 | 2003-06-12 | Elan Pharmaceuticals, Inc. | Peptide isosteres containing a heterocycle useful in the treatment of alzheimer's disease |
TW200633983A (en) * | 2004-12-10 | 2006-10-01 | Speedel Experimenta Ag | 5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyl-nonanamides |
GB0511686D0 (en) * | 2005-06-08 | 2005-07-13 | Novartis Ag | Organic compounds |
US8063105B2 (en) * | 2005-07-22 | 2011-11-22 | Merck Canada Inc. | Renin inhibitors |
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- 2008-12-19 ES ES08865851.3T patent/ES2442266T3/en active Active
- 2008-12-19 PT PT88658513T patent/PT2225200E/en unknown
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US4886834A (en) * | 1986-03-17 | 1989-12-12 | Eisai Co., Ltd. | Diphenyl-methane compounds useful in the treatment of diseases caused by aggregation of platelets or formation of thrombus |
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WO2016057683A3 (en) * | 2014-10-07 | 2016-06-02 | Ann And Robert H. Lurie Children's Hospital Of Chicago | Novel anti-nodal antibodies and methods of using same |
US9688750B2 (en) | 2014-10-07 | 2017-06-27 | Ann And Robert H. Lurie Children's Hospital Of Chicago | Anti-nodal antibodies and methods of using same |
US10494428B2 (en) | 2014-10-07 | 2019-12-03 | Ann & Robert H. Lurie Children's Hosp. of Chicago | Anti-nodal antibodies and methods of using same |
US10508147B2 (en) | 2014-10-07 | 2019-12-17 | Ann & Robert H. Lurie Children's Hospital | Anti-nodal antibodies and methods of using same |
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EP2225200A1 (en) | 2010-09-08 |
CN101952242A (en) | 2011-01-19 |
CN101952242B (en) | 2015-05-20 |
WO2009080773A1 (en) | 2009-07-02 |
US8563279B2 (en) | 2013-10-22 |
HK1153189A1 (en) | 2012-03-23 |
PT2225200E (en) | 2014-01-21 |
US20110008852A1 (en) | 2011-01-13 |
EP2225200B1 (en) | 2013-10-16 |
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