ITMI20100984A1 - PROCEDURE FOR THE PREPARATION OF OXADIAZOLIS - Google Patents
PROCEDURE FOR THE PREPARATION OF OXADIAZOLIS Download PDFInfo
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- ITMI20100984A1 ITMI20100984A1 IT000984A ITMI20100984A ITMI20100984A1 IT MI20100984 A1 ITMI20100984 A1 IT MI20100984A1 IT 000984 A IT000984 A IT 000984A IT MI20100984 A ITMI20100984 A IT MI20100984A IT MI20100984 A1 ITMI20100984 A1 IT MI20100984A1
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- 238000000034 method Methods 0.000 title claims description 39
- 238000002360 preparation method Methods 0.000 title claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- 125000002015 acyclic group Chemical group 0.000 claims description 3
- 150000003950 cyclic amides Chemical class 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- -1 piperidine compound Chemical class 0.000 description 4
- 150000005071 1,2,4-oxadiazoles Chemical class 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- JHRDEHLFNLLCQS-UHFFFAOYSA-N n'-hydroxy-2-methylpropanimidamide Chemical compound CC(C)C(N)=NO JHRDEHLFNLLCQS-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 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
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 1
- PCJFEVUKVKQSSL-UHFFFAOYSA-N 2h-1,2,4-oxadiazol-5-one Chemical compound O=C1N=CNO1 PCJFEVUKVKQSSL-UHFFFAOYSA-N 0.000 description 1
- LGMIMRBZBZTNJS-UHFFFAOYSA-N 3-[1-(3-propan-2-yl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]propan-1-ol Chemical compound CC(C)C1=NOC(N2CCC(CCCO)CC2)=N1 LGMIMRBZBZTNJS-UHFFFAOYSA-N 0.000 description 1
- DBIMLJDSPUCGGY-UHFFFAOYSA-N 3-piperidin-4-ylpropan-1-ol Chemical compound OCCCC1CCNCC1 DBIMLJDSPUCGGY-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- OHZZTXYKLXZFSZ-UHFFFAOYSA-I manganese(3+) 5,10,15-tris(1-methylpyridin-1-ium-4-yl)-20-(1-methylpyridin-4-ylidene)porphyrin-22-ide pentachloride Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Mn+3].C1=CN(C)C=CC1=C1C(C=C2)=NC2=C(C=2C=C[N+](C)=CC=2)C([N-]2)=CC=C2C(C=2C=C[N+](C)=CC=2)=C(C=C2)N=C2C(C=2C=C[N+](C)=CC=2)=C2N=C1C=C2 OHZZTXYKLXZFSZ-UHFFFAOYSA-I 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“PROCEDIMENTO PER LA PREPARAZIONE DI OSSADIAZOLI” "PROCEDURE FOR THE PREPARATION OF OXADIAZOLS"
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione riguarda un procedimento per la preparazione di intermedi a struttura 1,2,4-ossadiazolica, utili nella preparazione di composti biologicamente attivi. The present invention relates to a process for the preparation of intermediates having a 1,2,4-oxadiazole structure, useful in the preparation of biologically active compounds.
STATO DELLA TECNICA STATE OF THE TECHNIQUE
Molti composti organici contenenti l’anello 1,2,4-ossadiazolico hanno mostrato elevata attività biologica nei settori più svariati. Si citano in particolare i composti di formula (A) Many organic compounds containing the 1,2,4-oxadiazole ring have shown high biological activity in the most varied sectors. In particular, the compounds of formula (A)
dove X è -NH- oppure -0-; E e G sono residui alchilici o arilici variamente sostituiti; oppure il gruppo EX- rappresenta un gruppo eterociclico saturo, opzionalmente sostituito, contenente un azoto legato all’ossadiazolo. In particolare, derivati 1,2,4-ossadiazolici 5-0-sostituiti aventi proprietà fungicida e insetticida sono descritti in WO 95/05368, WO 99/31072 e WO 2009/158257; recentemente, composti a struttura 1,2,4 ossadiazolica 5 -V- sostituita, impiegati nel trattamento di obesità e diabete, sono stati descritti in WO 2008/081204, WO 2008/081205 e WO 2009/034388. where X is -NH- or -0-; E and G are variously substituted alkyl or aryl residues; or the EX- group represents a saturated heterocyclic group, optionally substituted, containing a nitrogen linked to oxadiazole. In particular, 5-0-substituted 1,2,4-oxadiazole derivatives having fungicidal and insecticidal properties are described in WO 95/05368, WO 99/31072 and WO 2009/158257; recently, compounds with 1,2,4 oxadiazole 5 -V-substituted structure, used in the treatment of obesity and diabetes, have been described in WO 2008/081204, WO 2008/081205 and WO 2009/034388.
L’introduzione dell’eteroatomo X in posizione 5 in un nucleo 1,2,4-ossadiazolico, avviene generalmente mediante reazione di sostituzione da parte di un nucleofilo ossigenato, come un alcol, oppure azotato, come ad esempio una ammina o una idrazina, su un composto di formula (B) The introduction of the heteroatom X in position 5 in a 1,2,4-oxadiazole nucleus generally occurs by means of a substitution reaction by an oxygenated nucleophile, such as an alcohol, or nitrogenous, such as an amine or a hydrazine, on a compound of formula (B)
dove Y rappresenta un gruppo uscente, ad esempio un atomo di cloro o il gruppo triclorometile (G è come prima definito). where Y represents a leaving group, for example a chlorine atom or the trichloromethyl group (G is as defined above).
Un composto di formula (B), dove Y è un atomo di cloro, può essere ottenuto ad esempio per reazione di un l,2,4-ossadiazol-5-one con pentacloruro di fosforo (PC15). Detto l,2,4-ossadiazol-5-one a sua volta può essere preparato ad esempio mediante acilazione di un’ammidossima con una opportuna anidride e successiva ciclizzazione dell’intermedio così ottenuto, come riportato in WO 95/05368. L’ammidossima può essere preparata mediante metodi noti, ad esempio per reazione deiridrossilammina con un opportuno nitrile. A compound of formula (B), where Y is a chlorine atom, can be obtained for example by the reaction of 1, 2,4-oxadiazol-5-one with phosphorus pentachloride (PC15). Said 2,4-oxadiazol-5-one in turn can be prepared for example by acylation of an amidoxime with a suitable anhydride and subsequent cyclization of the intermediate thus obtained, as reported in WO 95/05368. Amidoxime can be prepared by known methods, for example by reaction of hydroxylamine with a suitable nitrile.
Un composto di formula (B), dove Y è il gruppo triclorometile, può essere preparato secondo quanto descritto in /. Org. Chem. 2002, 67, 6253-6255, mediante acilazione con l’anidride tricloroacetica di una ammidossima e ciclizzazione dell’intermedio risultante. A compound of formula (B), where Y is the trichloromethyl group, can be prepared as described in /. Org. Chem. 2002, 67, 6253-6255, by acylation with trichloroacetic anhydride of an amidoxime and cyclization of the resulting intermediate.
Sia in termini di preparazione che di reattività ed efficienza, l’impiego di un composto di formula (B) dove Y è un gruppo triclorometile è da preferirsi rispetto a un composto di formula (B) dove Y è un cloro. Both in terms of preparation and reactivity and efficiency, the use of a compound of formula (B) where Y is a trichloromethyl group is to be preferred over a compound of formula (B) where Y is a chlorine.
Nella preparazione di un composto di formula (A), dove X è -NH-oppure un eterociclo saturo, come prima definito, pur impiegando una ammina come nucleofilo ed un 1,2,4-ossadiazolo, ad esempio di formula (B), dove Y come gruppo uscente è un gruppo triclorometile, la reazione di sostituzione non è di facile applicazione su scala industriale. Ad esempio, in US 3,574,222 è stato riportato che le sostituzioni con ammine semplici su composti di formula (B), dove Y è triclorometile, avvengono in condizioni di reazione piuttosto drastiche e in molti casi anche con basse rese. In molti casi sono stati necessari alte temperature d’esercizio e larghissimi eccessi delhammina, utilizzata anche come solvente, per portare a completezza la reazione. In the preparation of a compound of formula (A), where X is -NH- or a saturated heterocycle, as defined above, while using an amine as nucleophile and a 1,2,4-oxadiazole, for example of formula (B), where Y as the leaving group is a trichloromethyl group, the substitution reaction is not easy to apply on an industrial scale. For example, in US 3,574,222 it has been reported that the substitutions with simple amines on compounds of formula (B), where Y is trichloromethyl, occur under rather drastic reaction conditions and in many cases also with low yields. In many cases, high operating temperatures and very large excesses of hammine, also used as a solvent, were required to complete the reaction.
Questo metodo è evidentemente poco efficiente, difficilmente scalabile e a volte inattuabile industrialmente, anche a causa degli elevati costi associati alle materie prime e alle condizioni di reazione utilizzate. Inoltre, qualora l’ammina fosse un composto solido e/o molto costoso, il procedimento sarebbe inattuabile. This method is obviously not very efficient, difficult to scale and sometimes industrially impracticable, also due to the high costs associated with the raw materials and the reaction conditions used. Furthermore, if the amine were a solid and / or very expensive compound, the procedure would be impracticable.
Verosimilmente, per queste ragioni sono state ricercate vie di sintesi alternative per la preparazione di un composto di formula (I), qui riportati in Schema. Ad esempio, in WO 2008/081204, WO 2008/081205 e WO 2009/034388 non sono impiegati i composti di formula (B) per l’introduzione del ciclo etero aromatico 1,2,4-ossadiazolico, come evidente dallo Schema qui sotto riportato Probably, for these reasons, alternative synthesis routes have been sought for the preparation of a compound of formula (I), reported here in the Scheme. For example, in WO 2008/081204, WO 2008/081205 and WO 2009/034388 the compounds of formula (B) are not used for the introduction of the 1,2,4-oxadiazole hetero-aromatic cycle, as evident from the Scheme below. reported
dove R1?R2, R3e R4sono come definiti in WO 2008/081204 e WO 2008/081205. where R1? R2, R3 and R4 are as defined in WO 2008/081204 and WO 2008/081205.
Tuttavia la sintesi riportata nello Schema, che dall’ intermedio alchilpiperidinico di partenza di formula (IVa) porta a un composto di formula (I), soffre di alcune limitazioni fondamentali per un processo di produzione da usare su scala industriale. In particolare, la sintesi non è convergente e prevede la complessa formazione del ciclo 1,2,4-ossadiazolico a partire dalla costosa alchilpiperidina di formula (IVa). Non da ultimo, detta via sintetica fa uso del bromuro di cianogeno, un gas molto tossico e pericoloso, specialmente per l’uso su scala industriale. However, the synthesis reported in the Scheme, which leads from the starting alkylpiperidine intermediate of formula (IVa) to a compound of formula (I), suffers from some fundamental limitations for a production process to be used on an industrial scale. In particular, the synthesis is not convergent and involves the complex formation of the 1,2,4-oxadiazole cycle starting from the expensive alkylpiperidine of formula (IVa). Last but not least, this synthetic route makes use of cyanogen bromide, a very toxic and dangerous gas, especially for use on an industrial scale.
Esiste quindi la necessità di un metodo alternativo e più vantaggioso per preparare derivati 1,2,4-ossadiazolici, in particolare per la preparazione di un composto piperidinico di formula (I), e di intermedi utili nella sua sintesi. Tale metodo dovrebbe inoltre permettere di effettuare in maniera efficiente la preparazione di 1,2,4-ossadiazli 5 -N- sostituiti mediante l’impiego di reagenti più sicuri, essere scalabile industrialmente e fornire il prodotto desiderato con alte rese. There is therefore a need for an alternative and more advantageous method for preparing 1,2,4-oxadiazole derivatives, in particular for the preparation of a piperidine compound of formula (I), and of intermediates useful in its synthesis. This method should also allow to efficiently carry out the preparation of 1,2,4-oxadiazli 5 -N-substituted through the use of safer reagents, be industrially scalable and provide the desired product with high yields.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
È stato qui trovato un metodo vantaggioso per preparare un composto 1,2,4-ossadiazolico 5-N- sostituito di formula (II) An advantageous method has been found here for preparing a 5-N-substituted 1,2,4-oxadiazole compound of formula (II)
dove T, W, Wi ed R sono come qui definiti, mediante un procedimento comprendente la reazione di un composto di formula (III) where T, W, Wi and R are as defined herein, by a process comprising the reaction of a compound of formula (III)
dove Rè come qui definito, con un composto di formula (IV) where R is as defined here, with a compound of formula (IV)
dove W, Wj e Q sono come qui definiti, in condizioni di reazione blande che non prevedono l’eccesso di un composto di formula (IV) o alte temperature di reazione. Le rese ottenute nelle condizioni di reazione impiegate sono sorprendentemente molto elevate ed i reagenti impiegati sicuri e di facile manipolazione. Questo rende il procedimento dell’ invenzione vantaggioso su scala industriale. where W, Wj and Q are as defined here, under mild reaction conditions that do not involve the excess of a compound of formula (IV) or high reaction temperatures. The yields obtained under the reaction conditions used are surprisingly very high and the reagents used are safe and easy to handle. This makes the process of the invention advantageous on an industrial scale.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Oggetto dell’invenzione è un procedimento per la preparazione di un composto di formula (II), o un suo sale, come singolo isomero o una loro miscela, The subject of the invention is a process for the preparation of a compound of formula (II), or a salt thereof, as a single isomer or a mixture thereof,
dove where is it
il gruppo R è un gruppo CrC6alchile o arile; the R group is a CrC6alkyl or aryl group;
T è assente oppure è -NH-; T is absent or it is -NH-;
W e Wj, uguali o diversi, sono indipendentemente idrogeno, un gruppo CrC14alchile opzionalmente sostituito, un gruppo arile opzionalmente sostituito, un gruppo eteroarile opzionalmente sostituito, un gruppo aril-C1C14alchile opzionalmente sostituito o un gruppo eteroaril C1C14alchile opzionalmente sostituito; oppure W e W1?presi insieme all’atomo di azoto a cui sono uniti, formano un anello eterociclico saturo opzionalmente sostituito; comprendente la reazione di un composto di formula (III) W and Wj, equal or different, are independently hydrogen, an optionally substituted CrC14alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aryl-C1C14alkyl group or an optionally substituted C1C14alkyl heteroaryl group; or W and W1? taken together with the nitrogen atom to which they are joined, they form an optionally substituted saturated heterocyclic ring; comprising the reaction of a compound of formula (III)
dove R è come sopra definito, con un composto di formula (IV) o un suo sale, come singolo isomero o una loro miscela, where R is as defined above, with a compound of formula (IV) or a salt thereof, as a single isomer or a mixture thereof,
dove where is it
Q è idrogeno oppure NH2;e W e Wi sono come prima definiti; in presenza di un solvente, preferibilmente polare aprotico; e, se desiderato, la conversione di un composto di formula (II) in un suo sale o la conversione del sale nel composto libero. Q is hydrogen or NH2; and W and Wi are as defined above; in the presence of a solvent, preferably polar aprotic; and, if desired, the conversion of a compound of formula (II) into a salt thereof or the conversion of the salt into the free compound.
Un gruppo CrC6alchile, che può essere lineare o ramificato, è ad esempio metile, etile, propile, isopropile o tert-butile. A CrC6alkyl group, which can be linear or branched, is for example methyl, ethyl, propyl, isopropyl or tert-butyl.
Un gruppo o un residuo CrC14alchile, che può essere lineare o ramificato, è ad esempio un gruppo CrC6alchile, in particolare un gruppo CrC4alchile, preferibilmente metile, etile, propile, isopropile o tert-butile. A CrC14alkyl group or residue, which can be linear or branched, is for example a CrC6alkyl group, in particular a CrC4alkyl group, preferably methyl, ethyl, propyl, isopropyl or tert-butyl.
Un gruppo arile è ad esempio fenile o naftile, preferibilmente fenile. An aryl group is for example phenyl or naphthyl, preferably phenyl.
Un gruppo eteroarile può essere ad esempio un gruppo etero monociclico o biciclico, contenente uno o più, preferibilmente 1, 2 o 3, eteroatomi scelti indipendentemente tra ossigeno, zolfo e azoto, preferibilmente tale gruppo è scelto tra piridile, tienile o pirazinile. A heteroaryl group can be, for example, a monocyclic or bicyclic hetero group, containing one or more, preferably 1, 2 or 3, heteroatoms independently selected from oxygen, sulfur and nitrogen, preferably this group is selected from pyridyl, thienyl or pyrazinyl.
Un gruppo aril-CrC14alchile è ad esempio un gruppo aril-CrCe alchile, preferibilmente benzile o feniletile, più preferibilmente benzile. An aryl-CrC14alkyl group is for example an aryl-CrCe alkyl group, preferably benzyl or phenylethyl, more preferably benzyl.
Un gruppo eteroaril-CrC14alchile è ad esempio un gruppo eteroaril-Cr C6alchile, dove la porzione eteroarilica e alchilica sono ad esempio come sopra definite. A heteroaryl-CrC14alkyl group is for example a heteroaryl-CrC6alkyl group, where the heteroaryl and alkyl moieties are for example as defined above.
Un anello eterociclico saturo è ad esempio un anello pirrolidinico, piperidinico o morfolinico. A saturated heterocyclic ring is for example a pyrrolidine, piperidine or morpholine ring.
Un gruppo o un residuo alchilico, un gruppo arilico o eteroarilico, come sopra definito, possono essere sostituto da uno o più, preferibilmente uno o due sostituenti indipendentemente scelti tra alogeno ad esempio fluoro o cloro, idrossi, nitro e ciano. An alkyl group or residue, an aryl or heteroaryl group, as defined above, can be replaced by one or more, preferably one or two substituents independently selected from halogen, for example fluorine or chlorine, hydroxy, nitro and cyano.
Un gruppo eterociclico saturo, come sopra definito, può essere sostituto da uno o più, preferibilmente uno o due sostituenti indipendentemente scelti tra alogeno ad esempio fluoro o cloro, idrossi, nitro, ciano e CrC14alchile lineare o ramificato opzionalmente sostituito da idrossi. A saturated heterocyclic group, as defined above, can be replaced by one or more, preferably one or two substituents independently selected from halogen, for example fluorine or chlorine, hydroxy, nitro, cyano and linear or branched CrCl 14 alkyl optionally substituted by hydroxy.
Un solvente può essere ad esempio scelto nel gruppo comprendente un solvente polare aprotico, ad esempio un’ammide aciclica o ciclica, ad esempio dimetilformammide, dimetilacetammide oppure N-metilpirrolidone, preferibilmente dimetilacetammide; acetonitrile; dimetilsolfossido; un etere, ad esempio tetraidrofurano o diossano; un solvente clorurato, ad esempio, diclorometano, dicloroetano, cloroformio o clorobenzene; un estere, ad esempio acetato di metile o acetato di etile; un C3-C12chetone, ad esempio acetone, metiletilchetone o metilisobutilchetone; oppure una miscela di due o più, preferibilmente di due o tre di detti solventi; preferibilmente un solvente polare aprotico. A solvent can for example be selected from the group comprising an aprotic polar solvent, for example an acyclic or cyclic amide, for example dimethylformamide, dimethylacetamide or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile; dimethyl sulfoxide; an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example methyl acetate or ethyl acetate; a C3-C12 ketone, for example acetone, methylethyl ketone or methylisobutyl ketone; or a mixture of two or more, preferably two or three of said solvents; preferably an aprotic polar solvent.
Un composto di formula (III) può essere fatto reagire nella forma di una sua soluzione in un solvente come sopra definito in una concentrazione tra circa 1 e circa 15 M, preferibilmente tra circa 5 e circa 12 M. A compound of formula (III) can be reacted in the form of a solution thereof in a solvent as defined above in a concentration between about 1 and about 15 M, preferably between about 5 and about 12 M.
La reazione di un composto di formula (III) con un composto di formula (IV), o un suo sale, può essere condotta ad una temperatura compresa tra circa 0°C e 70°C, preferibilmente tra circa 20 e 40°C. The reaction of a compound of formula (III) with a compound of formula (IV), or a salt thereof, can be carried out at a temperature comprised between about 0 ° C and 70 ° C, preferably between about 20 and 40 ° C.
La conversione di un composto di formula (II) in un suo sale e la conversione del sale in un composto libero possono essere effettuate in accordo a metodi noti. The conversion of a compound of formula (II) into a salt thereof and the conversion of the salt into a free compound can be carried out according to known methods.
Ultimata la reazione, il composto di formula (II), o un suo sale, può essere eventualmente isolato. Once the reaction is completed, the compound of formula (II), or a salt thereof, can optionally be isolated.
Se desiderato, un singolo isomero di un composto di formula (II) può essere isolato da una miscela di suoi isomeri in accordo a metodi noti. If desired, a single isomer of a compound of formula (II) can be isolated from a mixture of its isomers according to known methods.
In accordo ad un aspetto preferito dell’ invenzione, un composto di formula (IV) è un composto di formula (IVa), o un suo sale, sia come singolo isomero, che una loro miscela, avente la seguente struttura According to a preferred aspect of the invention, a compound of formula (IV) is a compound of formula (IVa), or a salt thereof, either as a single isomer or a mixture thereof, having the following structure
dove R5 è idrogeno o CrC6alchile. where R5 is hydrogen or CrC6alkyl.
In accordo ad un ulteriore aspetto dell’invenzione la reazione tra un composto di formula (III), come prima definito, con un composto di formula (IVa) o un suo sale, sia come singolo isomero, che come una loro miscela, fornisce un composto di formula (Ila), o un suo sale, sia come singolo isomero, o una loro miscela, avente la seguente formula According to a further aspect of the invention, the reaction between a compound of formula (III), as defined above, with a compound of formula (IVa) or a salt thereof, either as a single isomer or as a mixture thereof, provides a compound of formula (IIa), or a salt thereof, either as a single isomer, or a mixture thereof, having the following formula
dove R ed R5 sono come prima definiti. where R and R5 are defined as above.
I composti di formula (III) e (IV) sono noti o sono ottenibili con metodi noti. In particolare, un composto di formula (IVa), come sopra definito, è presente in commercio o può essere preparato secondo quanto riportato in WO 2008/081204. The compounds of formula (III) and (IV) are known or can be obtained with known methods. In particular, a compound of formula (IVa), as defined above, is commercially available or can be prepared according to what is reported in WO 2008/081204.
Un composto di formula (Ila), come sopra definito, può essere utilizzato come intermedio in un metodo per la preparazione di un composto di formula (I), o un suo sale, sia come singolo isomero che una loro miscela, A compound of formula (IIa), as defined above, can be used as an intermediate in a method for the preparation of a compound of formula (I), or a salt thereof, either as a single isomer or a mixture thereof,
dove R e R5sono come prima definiti; R6è idrogeno, alogeno o CrC6alchile; R7è -S02Ra, dove Ra è CrC4alchile, oppure -CONHRb, dove Rb è idrogeno, oppure CrC4alchile opzionalmente sostituito da idrossi, in accordo al procedimento riportato in WO 2008/081204 e WO 2008/081205; o con tecniche note. where R and R5 are defined as above; R6 is hydrogen, halogen or CrC6alkyl; R7 is -S02Ra, where Ra is CrC4alkyl, or -CONHRb, where Rb is hydrogen, or CrC4alkyl optionally substituted by hydroxy, according to the process reported in WO 2008/081204 and WO 2008/081205; or with known techniques.
Un alogeno è ad esempio cloro o fluoro. A halogen is for example chlorine or fluorine.
Un gruppo CrC4alchile è preferibilmente metile, etile, propile, isopropile o tert-butile. A CrC4alkyl group is preferably methyl, ethyl, propyl, isopropyl or tert-butyl.
Un isomero di un composto di formula (I), (II) o (IV), in particolare di formula (IVa), può essere ad esempio un suo isomero ottico. An isomer of a compound of formula (I), (II) or (IV), in particular of formula (IVa), can be, for example, an optical isomer thereof.
Un ulteriore aspetto dell’ invenzione è quindi un procedimento per la preparazione di un composto di formula (I), o un suo sale, sia come singolo isomero o miscela di isomeri, come prima definito, comprendente l’uso di un composto di formula (Ila), o un suo sale, sia come singolo isomero o miscela di isomeri, ottenuto in accordo al procedimento dell’ invenzione. A further aspect of the invention is therefore a process for the preparation of a compound of formula (I), or a salt thereof, either as a single isomer or mixture of isomers, as defined above, comprising the use of a compound of formula ( 11a), or a salt thereof, either as a single isomer or a mixture of isomers, obtained according to the process of the invention.
Un sale di un composto di formula (I), (II) o (IV) è ad esempio un sale farmaceuticamente accettabile, tipicamente il cloridrato, bromidrato, fumarato, citrato o succinato. A salt of a compound of formula (I), (II) or (IV) is for example a pharmaceutically acceptable salt, typically the hydrochloride, hydrobromide, fumarate, citrate or succinate.
È stato qui sorprendentemente trovato un o procedimento per la preparazione di un composto (III) ad alta resa e purezza chimica. A process for the preparation of a compound (III) with high chemical yield and purity has been surprisingly found here.
In accardo ad un suo ulteriore aspetto, l’invenzione fornisce un procedimento per la preparazione di un composto (III), come sopra definito, comprendente la reazione di una ammidossima di formula (V), In addition to its further aspect, the invention provides a process for the preparation of a compound (III), as defined above, comprising the reaction of an amidoxime of formula (V),
dove R è come prima definito, con tricloroacetil cloruro, in presenza di un solvente. where R is as defined above, with trichloroacetyl chloride, in the presence of a solvent.
Un solvente può essere scelto tra un solvente polare aprotico, quale un’ammide aciclica o ciclica, ad esempio dimetilformammide, dimetilacetammide, o N-metilpirrolidone, preferibilmente dimetilacetammide; acetonitrile; dimetilsolfossido; un etere, ad esempio tetraidrofurano o diossano; un solvente clorurato, ad esempio, diclorometano, dicloroetano, cloroformio o clorobenzene; un estere, ad esempio acetato di etile o di metile; un C3-C12chetone, ad esempio acetone, metiletilchetone, metilisobutilchetone; un solvente apolare come toluene; oppure una miscela di due o più, preferibilmente di due o tre di detti solventi; preferibilmente esso è un solvente apolare. A solvent can be selected from an aprotic polar solvent, such as an acyclic or cyclic amide, for example dimethylformamide, dimethylacetamide, or N-methylpyrrolidone, preferably dimethylacetamide; acetonitrile; dimethyl sulfoxide; an ether, for example tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an ester, for example ethyl or methyl acetate; a C3-C12 ketone, for example acetone, methylethyl ketone, methylisobutyl ketone; a non-polar solvent such as toluene; or a mixture of two or more, preferably two or three of said solvents; preferably it is a non-polar solvent.
La reazione può essere condotta ad una temperatura compresa tra circa 20°C e 100°C, preferibilmente tra circa 60 e 80°C. The reaction can be carried out at a temperature comprised between about 20 ° C and 100 ° C, preferably between about 60 and 80 ° C.
Il tricloroacetil cloruro non è mai stato impiegato prima nella preparazione di un composto (III). Questo è un reagente disponibile in commercio ed è più economico della corrispondente anidride. E’ stato qui sorprendentemente trovato che, nonostante il tricloroacetil cloruro sia più reattivo e meno stabile della corrispondente anidride, le rese ottenute nella preparazione di un composto (III) in accordo alla presente invenzione e la sua purezza chimica, valutata per HPLC, sono superiori a quelle ottenibili in accordo ai precedimenti noti, ad esempio descritti in /. Org. Chem. 2002, 67, 6253-6255 e in US 3,574,222. Trichloroacetyl chloride has never been used before in the preparation of a compound (III). This is a commercially available reagent and is cheaper than the corresponding anhydride. It has been surprisingly found here that, although trichloroacetyl chloride is more reactive and less stable than the corresponding anhydride, the yields obtained in the preparation of a compound (III) according to the present invention and its chemical purity, evaluated by HPLC, are higher. to those obtainable according to the known precedents, for example described in /. Org. Chem. 2002, 67, 6253-6255 and in US 3,574,222.
Ciò permette l’impiego diretto di un composto (III) nella preparazione di un composto (II), o un suo sale, senza che sia necessaria alcuna sua purificazione, evitando così le purificazioni cromatografiche o per distillazione, altrimenti necessarie nei procedimenti noti nell’arte per la preparazione di un composto (II). This allows the direct use of a compound (III) in the preparation of a compound (II), or a salt thereof, without any purification thereof being necessary, thus avoiding the chromatographic or distillation purifications, otherwise necessary in the procedures known in the art for the preparation of a compound (II).
L’ammidossima (V) è un composto noto e può essere preparata con metodi noti, ad esempio per reazione dell’idrossilammina su un opportuno nitrile. Amidoxime (V) is a known compound and can be prepared with known methods, for example by reaction of hydroxylamine on a suitable nitrile.
In accordo ad un ulteriore aspetto, la presente invenzione fornisce un procedimento per la preparazione di un composto di formula (I) oppure (II), o un loro sale, sia come singolo isomero o miscela di isomeri, come prima definito, comprendente l’uso di un composto (III), o un suo sale, sia come singolo isomero o miscela di isomeri, ottenuto in accordo al procedimento dell’invenzione. According to a further aspect, the present invention provides a process for the preparation of a compound of formula (I) or (II), or a salt thereof, either as a single isomer or a mixture of isomers, as defined above, comprising the use of a compound (III), or a salt thereof, either as a single isomer or a mixture of isomers, obtained according to the process of the invention.
I seguenti esempi illustrano l’invenzione. The following examples illustrate the invention.
Esempio 1: Sintesi dell’isobutirroammidossima (V, R = isopropile) Example 1: Synthesis of isobutyroamide oxime (V, R = isopropyl)
L’isobutirronitrile (104 g, 1,50 mol) viene disciolto in metanolo (300 mi), quindi trattato con una soluzione al acquosa al 50% di idrossilammina (100 g, 1,51 mol) e la soluzione ottenuta è scaldata a 50°C per 18 ore, quindi a riflusso del solvente per 4 ore. La miscela di reazione viene quindi concentrata a pressione ridotta, diluita con toluene e coevaporata a pressione ridotta. Si riprende il residuo con toluene a caldo e si raffredda lentamente la soluzione ottenendo un’abbondante precipitato. Il solido è filtrato e lavato con toluene ottenendo 138 g di isobutirroammidossima con una resa del 90%. The isobutyronitrile (104 g, 1.51 mol) is dissolved in methanol (300 ml), then treated with a 50% aqueous solution of hydroxylamine (100 g, 1.51 mol) and the resulting solution is heated to 50 ° C for 18 hours, then under reflux of the solvent for 4 hours. The reaction mixture is then concentrated under reduced pressure, diluted with toluene and coevaporated under reduced pressure. The residue is taken up with hot toluene and the solution is slowly cooled, obtaining an abundant precipitate. The solid is filtered and washed with toluene obtaining 138 g of isobutyroamide oxime with a yield of 90%.
Esempio 2: Sintesi del 3-isopropil-5-triclorometil-l,2,4-ossadiazolo (III, R = isopropile) Example 2: Synthesis of 3-isopropyl-5-trichloromethyl-1,2-oxadiazole (III, R = isopropyl)
L’isobutirroammidossima (V, R = isopropile) (138 g, 1,35 mol) viene sospesa in toluene (600 mi), e la miscela ottenuta è scaldata fino a 75°C. il tricloroacetil cloruro (491 g, 2,70 mol) è quindi addizionato per lento gocciolamento alla miscela di reazione. A fine aggiunta la miscela di reazione è scaldata a riflusso per 30 minuti quindi raffreddata fino a 30°C e trattata con acqua. Si mantiene la miscela in agitazione per 30 minuti quindi si separano le fasi e la fase organica è lavata in successione prima con una soluzione acquosa al 5% di NaHC03e poi con acqua. La fase organica è concentrata a pressione ridotta e fornisce 255 g di composto di formula (II, R = isopropile) con una resa dell’ 82%. The isobutyroamidoxime (V, R = isopropyl) (138 g, 1.35 mol) is suspended in toluene (600 ml), and the mixture obtained is heated up to 75 ° C. the trichloroacetyl chloride (491 g, 2.70 mol) is then added by slow dripping to the reaction mixture. At the end of the addition, the reaction mixture is heated under reflux for 30 minutes then cooled to 30 ° C and treated with water. The mixture is kept under stirring for 30 minutes, then the phases are separated and the organic phase is washed in succession first with a 5% aqueous solution of NaHC03 and then with water. The organic phase is concentrated at reduced pressure and provides 255 g of formula compound (II, R = isopropyl) with a yield of 82%.
Esempio 3: Sintesi del 3-[l-(3-isopropil-l,2,4 ossadiazol-5-il)-piperidin-4-il]-propanolo (Ila, R = isopropile, Rs= H) Example 3: Synthesis of 3- [1- (3-isopropyl-1, 2,4 oxadiazol-5-yl) -piperidin-4-yl] -propanol (IIa, R = isopropyl, Rs = H)
Il composto (III), preparato come in Esempio 2, (100 g, 0,435 mol) viene disciolto in dimetilacetammide (42 mi), e alla soluzione si addiziona il 3-piperidin-4-il-propanolo (IVa, R5= H) (41,7 g, 0,29 mol) e la miscela ottenuta è mantenuta in agitazione per 48 ore a 28°C. Si diluisce la soluzione con toluene e acqua e si mantiene la sospensione in agitazione per 30 minuti quindi si separano le fasi e quella organica è ulteriormente lavata con acqua. La fase organica è quindi estratta con HC1 al 15% e la fase acquosa acida mescolata con toluene (200 mi). Sulla miscela bifasica si gocciola lentamente una soluzione di NaOH al 30% fino a pH 12, mantenendo la temperatura sotto i 30°C. Si separano le fasi e quella organica è lavata con acqua e poi con una soluzione di NH4C1 diluito. La fase organica è concentrata a pressione ridotta e fornisce 55,3 g di composto di formula (Ila, R = isopropile, R5= H) con una resa del 75%. Compound (III), prepared as in Example 2, (100 g, 0.435 mol) is dissolved in dimethylacetamide (42 ml), and 3-piperidine-4-yl-propanol (IVa, R5 = H) is added to the solution (41.7 g, 0.29 mol) and the obtained mixture is kept under stirring for 48 hours at 28 ° C. The solution is diluted with toluene and water and the suspension is kept under stirring for 30 minutes, then the phases are separated and the organic one is further washed with water. The organic phase is then extracted with 15% HCl and the acidic aqueous phase mixed with toluene (200 ml). A 30% NaOH solution is slowly dropped onto the biphasic mixture up to pH 12, keeping the temperature below 30 ° C. The phases are separated and the organic one is washed with water and then with a diluted NH4C1 solution. The organic phase is concentrated under reduced pressure and gives 55.3 g of compound of formula (IIa, R = isopropyl, R5 = H) with a yield of 75%.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3574222A (en) * | 1965-12-29 | 1971-04-06 | Mallinckrodt Chemical Works | Preparation of 5-amino-1,2,4-oxadiazoles |
| WO2006017409A2 (en) * | 2004-08-03 | 2006-02-16 | Merck & Co., Inc. | 1,3-disubstituted heteroaryl nmda/nr2b antagonists |
| WO2007099326A1 (en) * | 2006-03-02 | 2007-09-07 | Astrazeneca Ab | Quinoline derivatives |
| WO2008070692A2 (en) * | 2006-12-06 | 2008-06-12 | Smithkline Beecham Corporation | Bicyclic compounds and use as antidiabetics |
| WO2008148710A2 (en) * | 2007-06-08 | 2008-12-11 | F. Hoffmann-La Roche Ag | Aryloxazole, aryloxadiazole and benzimidazole derivatives as modulators of somatostatins receptor activity |
| WO2010123975A1 (en) * | 2009-04-22 | 2010-10-28 | Resverlogix Corp. | Novel anti-inflammatory agents |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69422379T2 (en) | 1993-08-13 | 2000-05-11 | Zeneca Ltd | THIADIAZOLE DERIVATIVES AND THEIR USE AS FUNGICIDES OR INSECTICIDES |
| AU1631699A (en) | 1997-12-18 | 1999-07-05 | E.I. Du Pont De Nemours And Company | Cyclohexylamine arthropodicides and fungicides |
| AR064736A1 (en) | 2007-01-04 | 2009-04-22 | Prosidion Ltd | GPCR AGONISTS |
| JP2010514828A (en) | 2007-01-04 | 2010-05-06 | プロシディオン・リミテッド | Piperidine GPCR agonist |
| US20100286112A1 (en) | 2007-09-10 | 2010-11-11 | Oscar Barba | Compounds for the treatment of metabolic disorders |
| TW201002202A (en) | 2008-06-27 | 2010-01-16 | Du Pont | Fungicidal pyridines |
| GB0812648D0 (en) * | 2008-07-10 | 2008-08-20 | Prosidion Ltd | Compounds |
-
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3574222A (en) * | 1965-12-29 | 1971-04-06 | Mallinckrodt Chemical Works | Preparation of 5-amino-1,2,4-oxadiazoles |
| WO2006017409A2 (en) * | 2004-08-03 | 2006-02-16 | Merck & Co., Inc. | 1,3-disubstituted heteroaryl nmda/nr2b antagonists |
| WO2007099326A1 (en) * | 2006-03-02 | 2007-09-07 | Astrazeneca Ab | Quinoline derivatives |
| WO2008070692A2 (en) * | 2006-12-06 | 2008-06-12 | Smithkline Beecham Corporation | Bicyclic compounds and use as antidiabetics |
| WO2008148710A2 (en) * | 2007-06-08 | 2008-12-11 | F. Hoffmann-La Roche Ag | Aryloxazole, aryloxadiazole and benzimidazole derivatives as modulators of somatostatins receptor activity |
| WO2010123975A1 (en) * | 2009-04-22 | 2010-10-28 | Resverlogix Corp. | Novel anti-inflammatory agents |
Non-Patent Citations (4)
| Title |
|---|
| G. ADEMBRI ET AL.: "Thermal Behaviour of 3-Phenyl-1,2,4-oxadiazol-5-ylhydrazines", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, 1981, XP009143719 * |
| G.D. DIANA ET AL.: "Oxadiazoles as Ester Bioisosteric replacements in Compounds Related to Disoxaril. Antirhinovirus Activity", JOURNAL OF MEDICAL CHEMISTRY, vol. 37, 1994, pages 2421 - 2436, XP002619407 * |
| S. BUSCEMI, A. PACE, I. PIBIRI, N. VIVONA: "Competing Ring-Photoisomerization Pathways in the 1,2,4-Oxadiazole Series. An Unprecedented Ring-Degenerate Photoisomerization", JOURNAL OF ORGANIC CHEMISTRY, vol. 67, 2002, pages 6253 - 6255, XP002619406 * |
| YURUGI S ET AL: "STUDIES ON THE SYNTHESES OF N-HETEROCYCLIC COMPOUNDS. III. HYPOCHOLESTEROLEMIC 1,2,4-OXADIAZOLE DERIVATIVES", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 21, no. 8, 1 January 1973 (1973-01-01), pages 1641 - 1650, XP001091336, ISSN: 0009-2363 * |
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