ES2684268T3 - Inhibidores de pirimidinil tirosina quinasa - Google Patents
Inhibidores de pirimidinil tirosina quinasa Download PDFInfo
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- ES2684268T3 ES2684268T3 ES13800042.7T ES13800042T ES2684268T3 ES 2684268 T3 ES2684268 T3 ES 2684268T3 ES 13800042 T ES13800042 T ES 13800042T ES 2684268 T3 ES2684268 T3 ES 2684268T3
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- optionally substituted
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- 125000000714 pyrimidinyl group Chemical group 0.000 title 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 6
- 125000005842 heteroatom Chemical group 0.000 abstract 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 3
- 229910052760 oxygen Inorganic materials 0.000 abstract 3
- 239000001301 oxygen Chemical group 0.000 abstract 3
- 229910052717 sulfur Chemical group 0.000 abstract 3
- 239000011593 sulfur Chemical group 0.000 abstract 3
- 125000001931 aliphatic group Chemical group 0.000 abstract 2
- 125000004429 atom Chemical group 0.000 abstract 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract 2
- 239000001257 hydrogen Substances 0.000 abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 2
- 125000002950 monocyclic group Chemical group 0.000 abstract 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 2
- 229920006395 saturated elastomer Polymers 0.000 abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 abstract 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- -1 -tert-butyl 4'-ethyl 3 - ((3-chloro-5- (trifluoromethyl) phenyl) amino) -2-oxo- [1,3'-bipiperidine] -1 ', 4' dicarboxylate Chemical compound 0.000 description 3
- WCTXJAXKORIYNA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 3-oxopiperidine-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O WCTXJAXKORIYNA-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- QPXNWTGYAKMATA-UHFFFAOYSA-N ethyl 3-oxopiperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1=O QPXNWTGYAKMATA-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WBIILFBKPWFGDS-KBPBESRZSA-N 1-O-tert-butyl 4-O-ethyl (3R,4S)-3-(2-oxopiperidin-1-yl)piperidine-1,4-dicarboxylate Chemical compound O=C1N(CCCC1)[C@H]1CN(CC[C@@H]1C(=O)OCC)C(=O)OC(C)(C)C WBIILFBKPWFGDS-KBPBESRZSA-N 0.000 description 1
- WBIILFBKPWFGDS-ZIAGYGMSSA-N 1-O-tert-butyl 4-O-ethyl (3S,4R)-3-(2-oxopiperidin-1-yl)piperidine-1,4-dicarboxylate Chemical compound O=C1N(CCCC1)[C@@H]1CN(CC[C@H]1C(=O)OCC)C(=O)OC(C)(C)C WBIILFBKPWFGDS-ZIAGYGMSSA-N 0.000 description 1
- RSTHZVHDEQOTTE-HNNXBMFYSA-N 1-o-tert-butyl 4-o-ethyl 5-[[(1s)-1-phenylethyl]amino]-3,6-dihydro-2h-pyridine-1,4-dicarboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C(=O)OCC)=C1N[C@@H](C)C1=CC=CC=C1 RSTHZVHDEQOTTE-HNNXBMFYSA-N 0.000 description 1
- RWAWMKWJDOUNKY-UHFFFAOYSA-N 1-piperidin-3-ylpiperidine Chemical compound C1CCCCN1C1CNCCC1 RWAWMKWJDOUNKY-UHFFFAOYSA-N 0.000 description 1
- OVENUGPMQDFGLE-UHFFFAOYSA-N 3-chloro-5-(trifluoromethyl)aniline Chemical compound NC1=CC(Cl)=CC(C(F)(F)F)=C1 OVENUGPMQDFGLE-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- DJLLJBLGCMFLSC-UHFFFAOYSA-N [dimethyl-(silylamino)silyl]methane Chemical compound C[Si](C)(C)N[SiH3] DJLLJBLGCMFLSC-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- JYFGIESQUYQLGM-UHFFFAOYSA-N ethyl 1-benzyl-3-oxopiperidine-4-carboxylate Chemical compound C1C(=O)C(C(=O)OCC)CCN1CC1=CC=CC=C1 JYFGIESQUYQLGM-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A61P37/08—Antiallergic agents
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
Un compuesto de fórmula I:**Fórmula** o una sal farmacéuticamente aceptable de este, en donde: cada R1 es independientemente hidrógeno, un grupo alifático C1-6 opcionalmente sustituido, un grupo heterocíclico monocíclico, de 3-7 miembros, opcionalmente sustituido, o un grupo heterociclilalquilo opcionalmente sustituido que tiene 3-7 átomos de carbono y 1-3 heteroátomos seleccionados independientemente de nitrógeno, oxígeno o azufre; o dos grupos R1 se toman junto con sus átomos interventores para formar un anillo heterocíclico monocíclico, saturado o parcialmente insaturado, de 3-7 miembros, opcionalmente sustituido que tiene 1-2 heteroátomos seleccionados independientemente de nitrógeno, oxígeno o azufre; en donde los grupos opcionalmente sustituidos pueden sustituirse con halógeno, -NO2, -CN, -OR, -SR, -N(R) 2, -C(O)R, -CO2 R, -N(R)C(O)OR, -C(O)N(R) 2, -OC(O)R, -N(R)C(O)R, -S(O)R, -S(O) 2 R, o -S(O) 2 N(R) 2; cada R es independientemente hidrógeno o un grupo alifático C1-6; o dos grupos R unidos al mismo nitrógeno se toman junto con sus átomos interventores para formar un anillo heterocíclico monocíclico, saturado o parcialmente insaturado, de 3-7 miembros, opcionalmente sustituido que tiene 1-2 heteroátomos, en donde cualquier segundo heteroátomo se selecciona independientemente de nitrógeno, oxígeno o azufre; El anillo A es**Fórmula** R2 es -Cl o -F; y R3 es -CF3, -OCF3, o -F.
Description
Los compuestos de la invención se sintetizan mediante una combinación adecuada de métodos sintéticos generalmente bien conocidos. Las técnicas útiles para sintetizar los compuestos de la invención son muy evidentes y accesibles para los expertos en la materia relevante. El análisis más adelante se ofrece para ilustrar algunos de los diversos métodos disponibles para usar en la obtención de los compuestos de la invención. Sin embargo, el análisis no está destinado a definir el alcance de las reacciones o las secuencias de reacciones que son útiles para preparar los compuestos de la presente invención.
Los compuestos de fórmula I pueden prepararse generalmente de acuerdo con el esquema 1.
8
10
otros métodos conocidos por un experto en la técnica, pueden aplicarse a todos los compuestos y subclases y especies de cada uno de estos compuestos, como se describe en la presente. Ejemplo 1 Síntesis de (3'R,4'S)-1'-terc-butil 4'-etil 2-oxo-[1,3'-bipiperidina]-1',4'-dicarboxilato
R: 98 % CH3OH, ta, 16 h tolueno, reflujo, 16 h
R: 86 % R: 88 %
R: 46 % R: 73 % ta, 2 h
R: 80 %
R: 92 %
THF, reflujo, 4 h
R: 88 %
Preparación del intermediario 3-oxopiperidina-4-carboxilato de etilo. El 1-bencil-3-oxopiperidina-4-carboxilato de etilo
10 1 (15,0 g, 50,5 mmol, 1,0 equiv) se hidrogenó en presencia del catalizador Pd/C 10 % (1,5 g) en H2 a presión atmosférica en MeOH (250 ml) durante 16 horas. El catalizador se filtró y el disolvente se concentró al vacío para producir 3-oxopiperidina-4-carboxilato de etilo 2 como un sólido de color amarillo claro (10,2 g, rendimiento: 98,0 %). ESI-MS (M+H)+: 172,1.1H NMR (400 MHz, DMSO-d6)δ:4,23 (q, 2H), 3,75 (s, 2H), 3,37 (s, 2H), 3,20-3,16 (m, 2H), 2,44 (t, 1H), 1,25 (t, 3H).
15 Preparación de 1-terc-butil 4-etil 3-oxopiperidina-1,4-dicarboxilato. El 3-oxopiperidina-4-carboxilato de etilo 2 (10,2 g, 60,0 mmol, 1,0 equiv) se disolvió en MeOH seco (200 ml) y se añadió Et3N (33,1 ml, 240 mmol, 4,0 equiv). La mezcla se agitó durante 1 hora y se añadió Boc2O (19,5 g, 90,0 mmol, 1,5 equiv) y se agitó durante 16 horas. El disolvente se concentró al vacío y el crudo se purificó mediante cromatografía en columna (sílice, éter de
20 petróleo/EtOAc =9:1) para producir el aceite amarillo claro 1-terc-butil 4-etil 3-oxopiperidina-1,4-dicarboxilato 3 (11,5 g, rendimiento: 86 %). ESI-MS (M+H-56)+: 216,0.1H NMR (400 MHz, CDCl3)δ:4,24 (q, 2H), 4,03 (s, 2H), 3,49 (t, 2H), 2,33 (t, 2H), 1,47 (s, 9H), 1,31 (t, 3H).
Preparación de (S)-1-terc-butil 4-etil 3-((1-feniletil)amino)-5,6-dihidro piridina-1,4-(2H)-dicarboxilato. En un matraz
25 seco equipado con una trampa de Dean-Stark y un condensador de reflujo, se disolvió 1-terc-butil 4-etil 3oxopiperidina-1,4-dicarboxilato 3 (10,0 g, 37,0 mmol, 1,1 equiv) en tolueno (100 ml). Se añadieron S-(-)-αmetilbenzilamina (4,9 g, 40,5 mmol, 1,1 equiv) y ácido p-toluenosulfónico monohidrato (0,7 g, 3,7 mmol, 0,1 equiv) y
20
5
10
15
20
25
30
Síntesis de trans-1'-terc-butil-4'-etil-3-yodo-2-oxo-[1,3'-bipiperidina]-1',4'-dicarboxilato. A la solución de trans-1'-tercbutil 4'-etil 2-oxo-[1,3'-bipiperidina]-1',4'-dicarboxilato 8 (141 mg, 2,58 mmol, 1,0 equiv) en tolueno seco (10 ml) a 0 °C, se añadieron sucesivamente TMEDA (0,89 g, 7,7 mmol, 3,0 equiv) y TMSCl (0,6 mg, 1,0 mmol, 2,0 equiv) en N2. Después de 0,5 horas, se añadió cuidadosamente I2 (0,98 g, 3,87 mmol, 1,5 equiv) en porciones pequeñas. La solución de reacción se agitó a 0 °C a temperatura ambiente durante 16 horas. La mezcla se diluyó con EtOAc (100 ml), se lavó con Na2S2O3 saturado (20 ml × 2) y salmuera (20 ml), se secó (Na2SO4), filtró y concentró al vacío. El producto crudo 9 (2,2 g, Y: 81 %) se usó directamente en la siguiente etapa sin purificación adicional. ESI-MS (M+H56)+: 424,9.1H NMR (400 MHz, CDCl3)δ: 4,78-4,73 (m, 1H), 4,19-4,04 (m, 4H), 3,55-3,30 (m, 4H), 3,24-3,16 (m, 2H), 2,73-2,60 (m, 1H), 2,22-2,14 (m, 2H), 1,96-1,78 (m, 2H), 1,70-1,60 (m, 1H),1,44 (s, 9H), 1,25 (t,J=7,2 Hz, 3H).
Síntesis de trans-1'-terc-butil 4'-etil 3-((3-cloro-5-(trifluorometil) fenil)amino)-2-oxo-[1,3'-bipiperidina]-1',4'dicarboxilato. Una solución 1,0 M de bis(trimetildisilil)amida de litio en THF (13 ml, 12 mmol, 2,0 equiv) se añadió mediante un embudo de adición a 10-15 °C a una solución de 3-cloro-5-(trifluorometil)anilina (15 g, 78 mmol, 1,2 equiv) en THF (13 ml). La mezcla se agitó a temperatura ambiente durante 20 min y se añadió una solución de trans1'-terc-butil-4'-etil-3-yodo-2-oxo-[1,3'-bipiperidina]-1',4'- dicarboxilato crudo 9 (3,7 g, 65 mmol, 1,0 equiv) en THF (13 ml) mediante un embudo de adición a 10-15 °C durante 30 min. Después de la adición, la reacción se agitó a la temperatura durante 30 min. Al terminar, la reacción se enfrió a 5 °C y se inactivó lentamente con agua (10 ml), manteniendo la temperatura por debajo de 20 °C. La reacción inactivada se extrajo con EtOAc (2 x 30 ml). Las capas orgánicas combinadas se lavaron con salmuera saturada (30 ml), se secaron (Na2SO4), filtraron y concentraron al vacío. El producto crudo resultante se purificó sobre gel de sílice eluyendo con un gradiente de 10 % a 75 % de EtOAc en heptanos para producir el producto deseado 10. ESI-MS (M+H-56)+: 463,1.1H NMR (400 MHz, CDCl3)δ:6,92 (s, 1H), 6,71-6,69 (m, 2H), 4,17-4,06 (m, 4H), 3,78-3,68 (m, 2H), 3,46-3,36 (m, 3H), 3,23-3,07 (m, 2H), 2,73-2,65 (m, 1H), 2,44-2,37 (m, 1H), 2,03-1,85 (m, 3H), 1,71-1,61 (m, 2H), 1,46 (s, 9H), 1,27-1,19 (m, 3H).
Síntesis del ácido trans-1'-(terc -butoxicarbonil)-3-((3-cloro-5-(trifluorometil) fenil) amino) -2-oxo-[1,3'-bipiperidina]-4'carboxílico. A una solución de trans-1'-terc-butil 4'-etil 3-((3-cloro-5-(trifluorometil)fenil)amino)-2-oxo-[1,3'bipiperidina]-1',4'-dicarboxilato 10 (180 mg, 0,33 mmol, 1,0 equiv) en EtOH (5 ml) se añadió NaOH (40 mg, 0,99 mmol, 3,0 equiv) y la solución se agitó a 80 °C durante 1 hora. El disolvente se concentró al vacío y el residuo se suspendió en agua (10 ml) y se ajustó a pH = 6 con HCl (4 N). El precipitado se filtró para producir el ácido (trans)-1'(terc-butoxicarbonil)-3-((3-cloro-5-(trifluorometil)fenil)amino)-2-oxo-[1,3'-bipiperidina]-4'-carboxílico 11 (150 mg, Y: 82 %) como un sólido amarillo que se usó en la próxima etapa sin purificación adicional. ESI-MS (M+H-85)+: 463,1.1H
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2016
- 2016-06-29 US US15/196,389 patent/US9944622B2/en not_active Expired - Fee Related
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2017
- 2017-03-07 AU AU2017201536A patent/AU2017201536B2/en not_active Ceased
- 2017-08-03 JP JP2017150480A patent/JP2017193583A/ja not_active Withdrawn
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2018
- 2018-03-05 US US15/911,546 patent/US10618887B2/en active Active
- 2018-08-16 CY CY181100861T patent/CY1120638T1/el unknown
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2019
- 2019-02-04 JP JP2019017850A patent/JP2019077728A/ja not_active Withdrawn
- 2019-05-17 AU AU2019203476A patent/AU2019203476B2/en not_active Ceased
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2020
- 2020-02-27 US US16/802,959 patent/US20210017155A1/en not_active Abandoned
- 2020-10-11 IL IL277951A patent/IL277951A/en unknown
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2021
- 2021-02-08 JP JP2021018127A patent/JP2021073298A/ja active Pending
- 2021-02-08 JP JP2021018128A patent/JP2021073299A/ja active Pending
- 2021-04-21 AU AU2021202412A patent/AU2021202412A1/en not_active Abandoned
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2022
- 2022-08-08 US US17/883,202 patent/US20230174511A1/en not_active Abandoned
- 2022-11-25 AU AU2022275504A patent/AU2022275504A1/en not_active Abandoned
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2023
- 2023-01-16 JP JP2023004462A patent/JP2023052415A/ja active Pending
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2024
- 2024-08-23 US US18/813,750 patent/US20240417389A1/en active Pending
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