WO2007005450A2 - Improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted heterocycles - Google Patents
Improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted heterocycles Download PDFInfo
- Publication number
- WO2007005450A2 WO2007005450A2 PCT/US2006/025130 US2006025130W WO2007005450A2 WO 2007005450 A2 WO2007005450 A2 WO 2007005450A2 US 2006025130 W US2006025130 W US 2006025130W WO 2007005450 A2 WO2007005450 A2 WO 2007005450A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally substituted
- alkyl
- formula
- compound
- heterocyclic ring
- Prior art date
Links
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 125000003884 phenylalkyl group Chemical group 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical group 0.000 claims description 31
- 239000003054 catalyst Substances 0.000 claims description 27
- -1 cyclic ester Chemical class 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical class C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 14
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 10
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 10
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 10
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 6
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 claims description 5
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 claims description 5
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 claims description 5
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 claims description 5
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 5
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 5
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 5
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 5
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims description 5
- ONJRTQUWKRDCTA-UHFFFAOYSA-N 2h-thiochromene Chemical compound C1=CC=C2C=CCSC2=C1 ONJRTQUWKRDCTA-UHFFFAOYSA-N 0.000 claims description 5
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 5
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 5
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 5
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012964 benzotriazole Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 125000005179 haloacetyl group Chemical group 0.000 claims description 5
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 5
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 5
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 5
- 125000000232 haloalkynyl group Chemical group 0.000 claims description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 5
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000005554 pyridyloxy group Chemical group 0.000 claims description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 5
- 229930192474 thiophene Natural products 0.000 claims description 5
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004440 haloalkylsulfinyl group Chemical group 0.000 claims 2
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 claims 2
- 239000000543 intermediate Substances 0.000 abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Chemical group 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000003444 phase transfer catalyst Substances 0.000 description 3
- 150000004714 phosphonium salts Chemical group 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- WXVRAHOQLYAQCR-UHFFFAOYSA-N 1-benzofuran-7-ol Chemical compound OC1=CC=CC2=C1OC=C2 WXVRAHOQLYAQCR-UHFFFAOYSA-N 0.000 description 2
- BYRJSCNPUHYZQE-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyridin-2-one Chemical compound OC1=CC=C(C(F)(F)F)C=N1 BYRJSCNPUHYZQE-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 0 *c1cc(OP(O*)(OS)=O)cc(*)c1O Chemical compound *c1cc(OP(O*)(OS)=O)cc(*)c1O 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 229910052801 chlorine Chemical group 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Definitions
- This invention is in the field of chemical processes; more specifically, an improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted heterocycles.
- R 1 , R 2 , R 3 , and R 4 are independently selected from halogen or alkyl, R 5 is an optionally substituted heterocyclic ring group and x is 2, 3, 4, 5 or 6; are useful insecticides and have been described in U.S. Patent 5,922,880 the disclosure of which is incorporated herein by reference. Disadvantages of processes to produce these compounds include less than optimal yields, less than optimal cycle times and high catalyst loadings.
- novel intermediates are compounds represented by formula I:
- R 3 , R 4 , R 5 and x are as defined above, and R 7 and R 8 are independently selected from hydrogen, alkyl, aryl or R and R may be taken together with an alkyl or aryl to form a cyclic ester.
- R 3 and R 4 are independently selected from halogen;
- R 5 is an optionally substituted heterocyclic ring group, provided that
- R 5 is not an optionally substituted dihydrobenzofuran
- R 7 and R 8 are independently selected from hydrogen, alkyl, aryl or R 7 and R taken together with an alkyl or aryl, forming a cyclic ester
- x is 2, 3, 4, 5 or 6;
- R 5 is as defined above;
- R 9 and R 10 are independently selected from halogen, hydroxyl or -OSO 2 R 11 wherein R 11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
- R 5 , R 10 and x are as defined above;
- R 3 , R 4 , R 7 and R 8 are as defined above;
- the "about” range shall be not more than 10% of the absolute value of an end point or 10% of the range recited, whichever is less.
- alkyl As used in this specification and unless otherwise indicated the substiruent terms "alkyl”, “alkenyl”, “alkoxy”, and “haloalkyl”, used alone or as part of a larger moiety, includes straight or branched chains of at least one or two carbon atoms, as appropriate to the substituent, and preferably up to 12 carbon atoms, more preferably up to ten carbon atoms, most preferably up to seven carbon atoms, wherein
- alkenyl has at least one carbon to carbon double bond.
- Halogen refers to fluorine, bromine, iodine, or chlorine.
- ambient temperature refers to a temperature in the range of about 20° C to about 30° C.
- DMAC meaning N,N-dimethylacetamide
- DMF meaning N 5 N- dimethylforrnarnide
- THF tetrahydrofuran.
- Glymes refers to a class of solvents comprised of monoglyme, diglyme, triglyme, tetraglyme, and polyglyme.
- the present invention relates to a process for preparing a compound of formula I:
- R 3 and R 4 are independently selected from halogen
- R 5 is an optionally substituted heterocyclic ring group, provided that
- R 5 is not an optionally substituted dihydrobenzofuran
- R 7 and R 8 are independently selected from hydrogen, alkyl, aryl or R 7 and R 8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6;
- R 9 and R 10 are independently selected from halogen, hydroxyl or -OSO 2 R 11 wherein R 11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
- R 5 , R 10 and x are as defined above;
- R 3 , R 4 , R 7 and R 8 are as defined above;
- the reacting of step a) can be conducted in the presence of a catalyst; at elevated temperature.
- the catalyst can be polyethylene glycol, triethylamine, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
- the catalyst can be present in a concentration of from about 0.1 % by weight to about 15% by weight.
- the elevated temperature can be in the range of 30°C to 12O 0 C.
- the reaction of step b) can be conducted in the presence of a solvent; in the presence of a catalyst; at elevated temperature.
- the solvent can be tetrahydrofuran, toluene, xylene, acetone, acetonitrile, 1,2-dichloroethane, triethylamine, p-dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof.
- the catalyst can be polyethylene glycol, triethylamine, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
- the catalyst can be present in a concentration of from about 0.1% by weight to about 20% by weight.
- the elevated temperature can be in the range of 30°C to HO 0 C.
- R >3 and A r R>4 are independently selected from halogen;
- R 5 is an optionally substituted heterocyclic ring group, provided that R 5 is not an optionally substituted dihydrobenzofuran;
- R and R are independently selected from hydrogen, alkyl, aryl or R and R 8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6;
- R 10 is selected from halogen, hydroxyl or -OSO 2 R 1 * wherein R 11 is alkyl or aryl; and R 3 , R 4 , R 7 , R 8 and x are as defined above;
- R 5 is as defined above;
- the reacting can be conducted in the presence of a solvent; in the presence of a catalyst; at elevated temperature.
- the solvent can be tetrahydrofuran, toluene, xylene, 1,2-dichloroethane, triethylamine, /?-dioxane, N,N-dimethylacetamide, N 5 N- dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof.
- the catalyst can be polyethylene glycol, triethylamine, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof.
- the catalyst can be present in a concentration of from about 0.1% by weight to about 20% by weight.
- the elevated temperature can be in the range of 30°C to l lO°C.
- R 3 and R 4 are independently selected from halogen
- R 5 is an optionally substituted heterocyclic ring group, provided that R 5 is not an optionally substituted dihydrobenzofuran;
- R 7 and R 8 are independently selected from hydrogen, alkyl, aryl or R 7 and R 8 taken together with an alkyl or aryl, forming a cyclic ester; and
- x is 2, 3, 4, 5 or 6.
- R 5 is an optionally substituted heterocyclic ring group, provided that R 5 is not an optionally substituted dihydrobenzofuran;
- R 10 is selected from halogen, hydroxyl or -OSO 2 R 11 wherein R is alkyl or aryl; and x is 2, 3, 4, 5 or 6.
- the heterocyclic ring in the optionally substituted heterocyclic ring group is preferably selected from the group consisting of isoxazole, thiazole, 1,3,4- thiadiazole, pyrrole, furan, thiophene, pyrazole, imidazole, 1,2,3-triazole, 1,2,4- triazole, 1,2,3,4-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, indole, benzofuran, thianaphthalene, indazole, benzimidazole, benzotriazole, benzisoxazole, benzoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, quinazole, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, pyrazoline, phthalimide, diox
- the optional substituent on the optionally substituted heterocyclic ring group is preferably selected from the group consisting of halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, alkylsulfonyl, haloalkylsulfmyl, haloalkylsulfonyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, amino, dimethylamino, acetamido, acetyl, haloacetyl, formyl, carboxyl, methoxycarbonyl, cycloalkyl, (alkyl)aminocarbonyl, [di(alkyl)amino]carbonyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, optionally
- R 3 and R 4 are halogen
- R 7 and R 8 are ethyl
- R 5 is benzofuran wherein R 9 and R 10 are halogen II
- dialkyl 4-hydroxybenzenephosphate (C)' for example diethyl 4-hydroxybenzenephosphate
- a halogenating agent for example sulfurylchloride
- step (a) of Example 1 benzo[b]furan-7-ol (A) is reacted with a 1,4- dihaloalkane (B), for example 1,4-dihalobutane, in the presence of abase and a catalyst at elevated temperature to form a l-(benzo[2,3-b]furan-7-yloxy)-4- haloalkane, a compound of formula II, for example l-(benzo[2,3-b]furan-7-yloxy)-
- B 1,4- dihaloalkane
- step (b) of Example 1 dialkyl 3,5-dihalo-4-hydroxybenzenephosphate, a compound of formula (C), for example diethyl 3,5-dihalo-4- hydroxybenzenephosphate, is reacted with a l-(benzo[2,3-b]furan-7-yloxy)-4- haloalkane, a compound of formula II, for example l-(benzo[2,3-b]furan-7-yloxy)-
- R 5 is a substituted wherein R 9 and R 10 are halogen II pyridine; Y is CF 3
- step (a) of Example 2 substituted pyridin-2-ol (A), for example 5- (trifluoromethyl)pyridin-2-ol, is reacted with a 1,4-dihaloalkane (B), for example 1 ,4-dihalobutane, in the presence of a base and a catalyst at elevated temperature to form a 1 -(substituted pyridin-2-yloxy)-4-haloalkane, a compound of formula II, for example l-((5-trifluoromethyl)pyridin-2-yloxy)-4-halobutane.
- A for example 5- (trifluoromethyl)pyridin-2-ol
- B 1,4-dihaloalkane
- B 1,4-dihalobutane
- dialkyl 3,5-dihalo-4-hydroxybenzenephosphate (C) for example diethyl 3,5-dihalo-4-hydroxybenzenephosphate
- C dialkyl 3,5-dihalo-4-hydroxybenzenephosphate
- a 1- (substituted pyridin-2-yloxy)-4-haloalkane a compound of formula II, for example l-((5-trifluoromethyl)pyridin-2-yloxy)-4-halobutane
- a compound of formula II for example l-((5-trifluoromethyl)pyridin-2-yloxy)-4-halobutane
- R 3 and R 4 are halogen from halogen, hydroxyl or -OSO 2 R 11 , where R 11 is alkyl or aryl
- A 1,4-disubstitutedalkane
- A 1,4-disubstitutedbutane
- a dialkyl 4-(4-substitutedalkoxy)-3,5- dihalobenzenephosphate, a compound of formula III, for example diethyl 4-(4- substitutedbutoxy)-3,5-dihalobenzenephosphate is reacted with benzo[b]furan-7-ol (A) in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4-[4-(benzo[2,3-b]furan-7-yloxy)alkoxy]-3,5-dihalobenzenephosphate, a compound of formula I, for example diethyl 4-[4-(benzo[2,3-b]furan-7- yloxy)butoxy]-3,5-dihalobenzenephosphate.
- a dialkyl 4-(4-substitutedalkoxy)-3,5- dihalobenzenephosphate, a compound of formula III, for example diethyl 4-(4- substitutedbutoxy)-3,5-dihalobenzenephosphate is reacted with substituted pyridin- 2-ol (A), for example 5-(trifluoromethyl)pyridin-2-ol, in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4- ⁇ 4- [(substituted)pyridin-2-yloxy]alkoxy ⁇ -3,5-dihalobenzenephosphate, a compound of formula I, for example diethyl 4- ⁇ 4-[(5-trifluoromethyl)pyridin-2-yloxy]butoxy ⁇ - 3 ,5-dihalobenzenephosphate.
- A substituted pyridin- 2-ol
- A for example 5-(trifluoromethyl)pyridin-2-ol
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Abstract
An improved process is described for preparing (disubstitutedpropenyl) phenylalkyl substituted heterocycles. This improved process is focused on steps to produce key intermediates, namely compounds of formula I; where R3, R4, R5, R7, R8 and x are defined herein.
Description
Improved Process for Preparing (Disubstitutedpropenyl) Phenylalkyl
Substituted Heterocycles
This application claims the benefit of U.S. Provisional Application No. 60/695,261, filed June 30, 2005.
Field of the Invention:
This invention is in the field of chemical processes; more specifically, an improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted heterocycles.
Background:
(Disubstitutedpropenyl) phenylalkyl substituted heterocycles, such as:
wherein R1, R2, R3, and R4 are independently selected from halogen or alkyl, R5 is an optionally substituted heterocyclic ring group and x is 2, 3, 4, 5 or 6; are useful insecticides and have been described in U.S. Patent 5,922,880 the disclosure of which is incorporated herein by reference. Disadvantages of processes to produce these compounds include less than optimal yields, less than optimal cycle times and high catalyst loadings.
Summary of the Invention The present invention improves the process for preparing
(disubstitutedpropenyl) phenylalkyl substituted heterocycles through the efficient preparation of novel intermediates thereto. The novel intermediates are compounds represented by formula I:
wherein R3, R4, R5 and x are as defined above, and R7 and R8 are independently selected from hydrogen, alkyl, aryl or R and R may be taken together with an alkyl or aryl to form a cyclic ester.
As a result of the present invention, overall yield, cycle times and catalyst loading are improved for the production of (disubstitutedpropenyl) phenylalkyl substituted heterocycles. Specifically, it has now been found that a compound of formula I:
I wherein
R3 and R4 are independently selected from halogen; R5 is an optionally substituted heterocyclic ring group, provided that
R5 is not an optionally substituted dihydrobenzofuran; R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6;
can be prepared in excellent yield and purity by a process comprising:
a) reacting a compound of formula (A):
HO-R5 Formula (A)
wherein R5 is as defined above;
with a compound of formula (B):
R9^(CH2)X \ R
Formula (B) wherein
R9 and R10 are independently selected from halogen, hydroxyl or -OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
in the presence of a base to form a compound of formula II:
°^R
Formula II
wherein
R5, R10 and x are as defined above; and
b) reacting a compound of formula II with a compound of formula (G):
Formula (CJ
wherein R3, R4, R7 and R8 are as defined above;
in the presence of a base to form a compound of formula I.
Definitions The modifier "about" is used herein to indicate that certain preferred operating ranges, such as ranges for molar ratios for reactants, material amounts, and temperature, are not fixedly determined. The meaning will often be apparent to one of ordinary skill. For example, a recitation of a temperature range of about 120° C to about 135° C in reference to, for example, an organic chemical reaction would be interpreted to include other like temperatures that can be expected to favor a useful reaction rate for the reaction, such as 105° C or 150° C. Where guidance from the experience of those of ordinary skill is lacking, guidance from the context is lacking, and where a more specific rule is not recited below, the "about" range shall be not more than 10% of the absolute value of an end point or 10% of the range recited, whichever is less.
As used in this specification and unless otherwise indicated the substiruent terms "alkyl", "alkenyl", "alkoxy", and "haloalkyl", used alone or as part of a larger moiety, includes straight or branched chains of at least one or two carbon atoms, as appropriate to the substituent, and preferably up to 12 carbon atoms, more preferably up to ten carbon atoms, most preferably up to seven carbon atoms, wherein
"alkenyl" has at least one carbon to carbon double bond. "Halogen", "halide" or "halo" refers to fluorine, bromine, iodine, or chlorine. The term "ambient temperature" refers to a temperature in the range of about 20° C to about 30° C.
Certain solvents, catalysts, and the like are known by their acronyms. These include the acronyms "DMAC" meaning N,N-dimethylacetamide, "DMF" meaning N5N- dimethylforrnarnide, "THF" meaning tetrahydrofuran. The term "glymes" refers to a class of solvents comprised of monoglyme, diglyme, triglyme, tetraglyme, and polyglyme.
Detailed Description of the Invention
The present invention relates to a process for preparing a compound of formula I:
I wherein
R3 and R4 are independently selected from halogen;
R5 is an optionally substituted heterocyclic ring group, provided that
R5 is not an optionally substituted dihydrobenzofuran;
R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6;
said process comprising:
a) reacting a compound of formula (A):
HO-R
Formula (A)
wherein R5 is as defined above;
with a compound of formula (B):
R9^(CH2)X \
K
Formula (B) wherein
R9 and R10 are independently selected from halogen, hydroxyl or -OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
in the presence of a base to form a compound of formula II:
Formula II
wherein R5, R10 and x are as defined above; and
reacting a compound of formula II with a compound of formula (CJ :
wherein
R3, R4, R7 and R8 are as defined above;
in the presence of a base to form a compound of formula I.
The reacting of step a) can be conducted in the presence of a catalyst; at elevated temperature. The catalyst can be polyethylene glycol, triethylamine, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1 % by weight to about 15% by weight. The elevated temperature can be in the range of 30°C to 12O0C.
The reaction of step b) can be conducted in the presence of a solvent; in the presence of a catalyst; at elevated temperature. The solvent can be tetrahydrofuran, toluene, xylene, acetone, acetonitrile, 1,2-dichloroethane, triethylamine, p-dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof. The catalyst can be polyethylene glycol, triethylamine, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1% by weight to about 20% by weight. The elevated temperature can be in the range of 30°C to HO0C.
Another embodiment of the present invention is a process for preparing a compound of formula I:
wherein
R >3 and A r R>4 are independently selected from halogen;
R5 is an optionally substituted heterocyclic ring group, provided that R5 is not an optionally substituted dihydrobenzofuran;
R and R are independently selected from hydrogen, alkyl, aryl or R and R8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6;
said process comprising:
reacting a compound of formula III:
Formula III
wherein R10 is selected from halogen, hydroxyl or -OSO2R1 * wherein R11 is alkyl or aryl; and R3, R4, R7, R8 and x are as defined above;
with a compound of formula (A):
HO-R5 Formula (A)
wherein R5 is as defined above;
in the presence of a base to form a compound of formula I.
The reacting can be conducted in the presence of a solvent; in the presence of a catalyst; at elevated temperature. The solvent can be tetrahydrofuran, toluene, xylene, 1,2-dichloroethane, triethylamine, /?-dioxane, N,N-dimethylacetamide, N5N- dimethylformamide, glymes, methyl isobutyl ketone, dimethylsulfoxide or mixtures thereof. The catalyst can be polyethylene glycol, triethylamine, pyridine, phase transfer catalysts such as quaternary ammonium salts or quaternary phosphonium salts or mixtures thereof. The catalyst can be present in a concentration of from about 0.1% by weight to about 20% by weight. The elevated temperature can be in the range of 30°C to l lO°C.
Another embodiment of the present invention is a compound of formula I:
Formula I wherein R3 and R4 are independently selected from halogen;
R5 is an optionally substituted heterocyclic ring group, provided that R5 is not an optionally substituted dihydrobenzofuran; R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6.
Yet another embodiment of the present invention is a compound of formula II:
R10— (CH2)xX 5 Q-R
Formula II
wherein
R5 is an optionally substituted heterocyclic ring group, provided that R5 is not an optionally substituted dihydrobenzofuran; R10 is selected from halogen, hydroxyl or -OSO2R11 wherein R is alkyl or aryl; and x is 2, 3, 4, 5 or 6.
The heterocyclic ring in the optionally substituted heterocyclic ring group is preferably selected from the group consisting of isoxazole, thiazole, 1,3,4- thiadiazole, pyrrole, furan, thiophene, pyrazole, imidazole, 1,2,3-triazole, 1,2,4- triazole, 1,2,3,4-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, indole, benzofuran, thianaphthalene, indazole, benzimidazole, benzotriazole, benzisoxazole, benzoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, quinazole, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, pyrazoline, phthalimide, dioxane, dioxolane and benzodioxolane. The optional substituent on the optionally substituted heterocyclic ring group is preferably selected from the group consisting of halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, alkylsulfonyl, haloalkylsulfmyl, haloalkylsulfonyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, amino, dimethylamino, acetamido, acetyl, haloacetyl, formyl, carboxyl, methoxycarbonyl, cycloalkyl, (alkyl)aminocarbonyl, [di(alkyl)amino]carbonyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, optionally substituted benzyloxy, and optionally substituted pyridyloxy, wherein the optional substitutent is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy or haloalkoxy.
The following examples illustrate processes for preparing comounds of formulae I, II and III.
(Q' (C)
R3 and R4 are halogen
R7 and R8 are ethyl
a') Halogenating Agent/Base/-20°C to 20°C/2-4 hours a)Base/Catalyst/30°C to 120°C/4-8 hours b) Base/CatalysiySolvent/30°C to 70°C/22-26 hours
In the first step (a') of Example 1, dialkyl 4-hydroxybenzenephosphate (C)', for example diethyl 4-hydroxybenzenephosphate, is reacted with a halogenating agent, for example sulfurylchloride, in the presence of a base at reduced temperature
to form dialkyl 3,5-dihalo-4-hydroxybenzenephosphate (C), for example diethyl 3,5- dihalo-4-hydroxybenzenephosphate.
In step (a) of Example 1, benzo[b]furan-7-ol (A) is reacted with a 1,4- dihaloalkane (B), for example 1,4-dihalobutane, in the presence of abase and a catalyst at elevated temperature to form a l-(benzo[2,3-b]furan-7-yloxy)-4- haloalkane, a compound of formula II, for example l-(benzo[2,3-b]furan-7-yloxy)-
4-halobutane.
In step (b) of Example 1, dialkyl 3,5-dihalo-4-hydroxybenzenephosphate, a compound of formula (C), for example diethyl 3,5-dihalo-4- hydroxybenzenephosphate, is reacted with a l-(benzo[2,3-b]furan-7-yloxy)-4- haloalkane, a compound of formula II, for example l-(benzo[2,3-b]furan-7-yloxy)-
4-halobutane, in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4-[4-(benzo[2,3-b]furan-7-yloxy)alkoxy]-3,5- dihalobenzenephosphate, a compound of formula I, for example diethyl 4-[4- (benzo[2,3-b]furan-7-yloxy)butoxy]-3,5-dihalobenzenephosphate.
Example 2
a)Base/Catalyst/30°C to 120°C/4-8 hours b) Base/Catalyst/Solvent/30°C to 70"C/22-26 hours
In step (a) of Example 2, substituted pyridin-2-ol (A), for example 5- (trifluoromethyl)pyridin-2-ol, is reacted with a 1,4-dihaloalkane (B), for example 1 ,4-dihalobutane, in the presence of a base and a catalyst at elevated temperature to form a 1 -(substituted pyridin-2-yloxy)-4-haloalkane, a compound of formula II, for example l-((5-trifluoromethyl)pyridin-2-yloxy)-4-halobutane.
In step (b) of Example 2, dialkyl 3,5-dihalo-4-hydroxybenzenephosphate (C), for example diethyl 3,5-dihalo-4-hydroxybenzenephosphate, is reacted with a 1- (substituted pyridin-2-yloxy)-4-haloalkane, a compound of formula II, for example l-((5-trifluoromethyl)pyridin-2-yloxy)-4-halobutane, in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4- {4-
[(substiruted)pyridin-2-yloxy]alkoxy}-3,5-dihalobenzenephosphate, a compound of formula I, for example diethyl 4-{4-[(5-trifluoromethyl)pyridin-2-yloxy]butoxy}- 3 ,5-dihalobenzenephosphate.
Example 3
(C) wherein R9 and R10 are independently selected
R3 and R4 are halogen from halogen, hydroxyl or -OSO2R11, where R11 is alkyl or aryl
a) Base/Catalyst/30°C to 100°C /4-48 hours b)Base/Catalyst/Solvent/30°C to 110°C/4-26 hours
In the first step (a) of Example 3 , dialkyl 3 ,5-dihalo-4- hydroxybenzenephosphate, a compound of formula (C), for example diethyl 3,5- dihalo-4-hydroxybenzenephosphate, is reacted with a 1,4-disubstitutedalkane (A), for example 1,4-disubstitutedbutane, in the presence of a base and a catalyst at elevated temperature to form dialkyl 4-(4-substitutedalkoxy)-3,5- dihalobenzenephosphate, a compound of formula III, for example diethyl 4-(4- substitutedbutoxy)-3,5-dihalobenzenephosphate.
In step (b) of Example 3, a dialkyl 4-(4-substitutedalkoxy)-3,5- dihalobenzenephosphate, a compound of formula III, for example diethyl 4-(4- substitutedbutoxy)-3,5-dihalobenzenephosphate, is reacted with benzo[b]furan-7-ol (A) in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4-[4-(benzo[2,3-b]furan-7-yloxy)alkoxy]-3,5-dihalobenzenephosphate, a compound of formula I, for example diethyl 4-[4-(benzo[2,3-b]furan-7- yloxy)butoxy]-3,5-dihalobenzenephosphate.
Example 4
substituted
a)Base/Catalysfr/Solvent/30oC to 110°C/4-26 hours
In step (a) of Example 4, a dialkyl 4-(4-substitutedalkoxy)-3,5- dihalobenzenephosphate, a compound of formula III, for example diethyl 4-(4- substitutedbutoxy)-3,5-dihalobenzenephosphate, is reacted with substituted pyridin- 2-ol (A), for example 5-(trifluoromethyl)pyridin-2-ol, in the presence of a base, a solvent and a catalyst at elevated temperature to form a dialkyl 4-{4- [(substituted)pyridin-2-yloxy]alkoxy}-3,5-dihalobenzenephosphate, a compound of
formula I, for example diethyl 4-{4-[(5-trifluoromethyl)pyridin-2-yloxy]butoxy}- 3 ,5-dihalobenzenephosphate.
While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations of the preferred embodiments may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly this invention includes all modifications encompassed within the spirit and scope as defined by the following claims.
Claims
1. A process for preparing a compound of formula I:
I wherein
R3 and R4 are independently selected from halogen;
R5 is an optionally substituted heterocyclic ring group, provided that
R5 is not an optionally substituted dihydrobenzofuran;
R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6;
said process comprising:
a) reacting a compound of formula (A):
HO-R-
Formula (A)
wherein R5 is as defined above;
with a compound of formula (B):
R9^(CH2)χ \
JV
Formula (B) wherein
R9 and R10 are independently selected from halogen, hydroxyl or -OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6;
in the presence of a base to form a compound of formula II:
R10— (CH2)xX
R5
Formula II
wherein
R5, R10 and x are as defined above; and
b) reacting a compound of formula II with a compound of formula (C):
Formula (C)
wherein R3, R4, R7 and R8 are as defined above;
in the presence of a base to form a compound of formula I.
2. The process of claim 1 wherein the reacting of step a) is conducted in the presence of a catalyst.
3. The process of claim 1 wherein the reacting of step a) is conducted at elevated temperature.
4. The process of claim 1 wherein the reacting of step b) is conducted in the presence of a solvent.
5. The process of claim 1 wherein the reacting of step b) is conducted in the presence of a catalyst.
6. The process of claim 1 wherein the reacting of step b) is conducted at elevated temperature.
7. The process of claim 1 wherein the heterocyclic ring in the optionally substituted heterocyclic ring group is selected from the group consisting of isoxazole, thiazole, 1,3,4-thiadiazole, pyrrole, furan, thiophene, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1, 2,3 ,4-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1 ,3, 5-triazine, indole, benzofuran, thianaphthalene, indazole, benzimidazole, benzotriazole, benzisoxazole, benzoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, quinazole, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, pyrazolone, phthalimide, dioxane, dioxolane and benzodioxolane.
8. The process of claim 7 wherein the optional substituent on the optionally substituted heterocyclic ring group is selected from the group consisting of halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfmyl, alkylsulfonyl, haloalkylsulfmyl, haloalkylsulfonyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, amino, dimethylamino, acetamido, acetyl, haloacetyl, formyl, carboxyl, methoxycarbonyl, cycloalkyl, (alkyl)aminocarbonyl, [di(alkyl)amino]carbonyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, optionally substituted benzyloxy, and optionally substituted pyridyloxy, wherein the optional substitutent is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy or haloalkoxy.
9. A process for preparing a compound of formula I:
I wherein
R3 and R4 are independently selected from halogen;
R5 is an optionally substituted heterocyclic ring group, provided that
R5 is not an optionally substituted dihydrobenzofuran;
R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6;
said process comprising:
reacting a compound of formula III:
Formula III
wherein R10 is selected from halogen, hydroxyl or -OSO2R11 wherein R is alkyl or aryl; and R3, R4, R7, R8 and x are as defined above;
with a compound of formula (A):
HO-R5 Formula (A)
wherein R5 is as defined above;
in the presence of a base to form a compound of formula I.
10. The process of claim 9 wherein the reacting is conducted in the presence of a solvent.
11. The process of claim 9 wherein the reacting is conducted in the presence of a catalyst.
12. The process of claim 9 wherein the reacting is conducted at elevated temperature.
13. The process of claim 9 wherein the heterocyclic ring in the optionally substituted heterocyclic ring group is selected from the group consisting of isoxazole, thiazole, 1,3,4-thiadiazole, pyrrole, furan, thiophene, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1, 2,3 ,4-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1, 3 ,5-triazine, indole, benzofuran, thianaphthalene, indazole, benzimidazole, benzotriazole, benzisoxazole, benzoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, quinazole, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, pyrazoline, phthalimide, dioxane, dioxolane and benzodioxolane.
14. The process of claim 13 wherein the optional substituent on the optionally substituted heterocyclic ring group is selected from the group consisting of halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, amino, dimethylamino, acetamido, acetyl, haloacetyl, formyl, carboxyl, methoxycarbonyl, cycloalkyl, (alkyl)aminocarbonyl, [di(alkyl)amino]carbonyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, optionally substituted benzyloxy, and optionally substituted pyridyloxy, wherein the optional substitutent is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy or haloalkoxy.
15. A compound of formula I:
Formula I wherein
R3 and R4 are independently selected from halogen;
R is an optionally substituted heterocyclic ring group wherein the heterocyclic ring in the optionally substituted heterocyclic ring group is selected from the group consisting of isoxazole, thiazole, 1,3,4-thiadiazole, pyrrole, furan, thiophene, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3,4-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, indole, benzofuran, thianaphthalene, indazole, benzimidazole, benzotriazole, benzisoxazole, benzoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, quinazole, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, pyrazolone, phthalimide, dioxane, dioxolane and benzodioxolane;
R7 and R8 are independently selected from hydrogen, alkyl, aryl or R7 and R8 taken together with an alkyl or aryl, forming a cyclic ester; and x is 2, 3, 4, 5 or 6.
16. The compound of claim 15 wherein the optional substituent on the optionally substituted heterocyclic ring group is selected from the group consisting of halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfmyl, alkylsulfonyl, haloalkylsulfmyl, haloalkylsulfonyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, amino, dimethylamino, acetamido, acetyl, haloacetyl, formyl, carboxyl, methoxycarbonyl, cycloalkyl, (alkyl)aminocarbonyl, [di(alkyl)amino]carbonyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, optionally substituted benzyloxy, and optionally substituted pyridyloxy, wherein the optional substitutent is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy or haloalkoxy.
17. A compound of formula II:
R is an optionally substituted heterocyclic ring group wherein the heterocyclic ring in the optionally substituted heterocyclic ring group is selected from the group consisting of isoxazole, thiazole, 1,3,4-thiadiazole, pyrrole, furan, thiophene, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3,4-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, indole, benzofuran, thianaphthalene, indazole, benzimidazole, benzotriazole, benzisoxazole, benzoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, quinazole, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, pyrazoline, phthalimide, dioxane, dioxolane and benzodioxolane;
R10 is selected from halogen, hydroxyl Or-OSO2R11 wherein R11 is alkyl or aryl; and x is 2, 3, 4, 5 or 6.
18. The compound of claim 17 wherein the optional substituent on the optionally substituted heterocyclic ring group is selected from the group consisting of halogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfmyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, amino, dimethylamino, acetamido, acetyl, haloacetyl, formyl, carboxyl, methoxycarbonyl, cycloalkyl, (alkyl)aminocarbonyl,
[di(alkyl)amino]carbonyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, optionally substituted benzyloxy, and optionally substituted pyridyloxy, wherein the optional substituted is selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy or haloalkoxy.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69526105P | 2005-06-30 | 2005-06-30 | |
| US60/695,261 | 2005-06-30 |
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| Publication Number | Publication Date |
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| WO2007005450A2 true WO2007005450A2 (en) | 2007-01-11 |
| WO2007005450A3 WO2007005450A3 (en) | 2007-03-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2006/025130 WO2007005450A2 (en) | 2005-06-30 | 2006-06-28 | Improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted heterocycles |
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| Country | Link |
|---|---|
| TW (1) | TW200726759A (en) |
| WO (1) | WO2007005450A2 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4225474A (en) * | 1977-02-04 | 1980-09-30 | Argus Chemical Corp. | Organophosphonate coester stabilizers |
| US4471048A (en) * | 1981-07-10 | 1984-09-11 | Ciba Geigy Ag | Photographic material |
| US5147864A (en) * | 1988-12-19 | 1992-09-15 | American Cyanamid Company | Bis-arylphosphate ester antagonists of platelet activating factor |
-
2006
- 2006-06-28 WO PCT/US2006/025130 patent/WO2007005450A2/en active Application Filing
- 2006-06-29 TW TW095123565A patent/TW200726759A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4225474A (en) * | 1977-02-04 | 1980-09-30 | Argus Chemical Corp. | Organophosphonate coester stabilizers |
| US4471048A (en) * | 1981-07-10 | 1984-09-11 | Ciba Geigy Ag | Photographic material |
| US5147864A (en) * | 1988-12-19 | 1992-09-15 | American Cyanamid Company | Bis-arylphosphate ester antagonists of platelet activating factor |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200726759A (en) | 2007-07-16 |
| WO2007005450A3 (en) | 2007-03-29 |
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