CN101454308B - 制备杂环衍生物的方法 - Google Patents
制备杂环衍生物的方法 Download PDFInfo
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- CN101454308B CN101454308B CN200780019578XA CN200780019578A CN101454308B CN 101454308 B CN101454308 B CN 101454308B CN 200780019578X A CN200780019578X A CN 200780019578XA CN 200780019578 A CN200780019578 A CN 200780019578A CN 101454308 B CN101454308 B CN 101454308B
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- 125000000623 heterocyclic group Chemical group 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title 1
- -1 nitro, hydroxy Chemical group 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 13
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 239000005864 Sulphur Substances 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 abstract description 5
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 4
- 239000005557 antagonist Substances 0.000 abstract description 3
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical class NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 150000007529 inorganic bases Chemical class 0.000 abstract description 2
- 238000010979 pH adjustment Methods 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- 239000000203 mixture Substances 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000002585 base Substances 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- PTVZQOAHCSKAAS-UHFFFAOYSA-N 4-methyl-3-thiosemicarbazide Chemical compound CNC(=S)NN PTVZQOAHCSKAAS-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 150000003851 azoles Chemical class 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- ZTWKABXDEIGASN-UHFFFAOYSA-N 4-[5-(3-chloropropylsulfanyl)-4-methyl-1,2,4-triazol-3-yl]pyridazine Chemical compound CN1C(SCCCCl)=NN=C1C1=CC=NN=C1 ZTWKABXDEIGASN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VWRZVBBBJDQJAZ-UHFFFAOYSA-N C[n]1c(S)nnc1-c1ccnnc1 Chemical compound C[n]1c(S)nnc1-c1ccnnc1 VWRZVBBBJDQJAZ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- JUSIWJONLKBPDU-UHFFFAOYSA-N pyridazine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NN=C1 JUSIWJONLKBPDU-UHFFFAOYSA-N 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 1
- HNTZKNJGAFJMHQ-UHFFFAOYSA-N 2-methylpyridine-3-carboxylic acid Chemical compound CC1=NC=CC=C1C(O)=O HNTZKNJGAFJMHQ-UHFFFAOYSA-N 0.000 description 1
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 0 CC(*1*)=**=C1NC Chemical compound CC(*1*)=**=C1NC 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical class ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
本发明涉及新颖的方法，该方法用于制备合成多种化合物的式(I)的关键中间体，所述多种化合物为D3受体的有效和特异性拮抗剂，其中X可以为氮或硫；Het指芳基或杂芳基；每个可以被1-4个选自下列的基团J取代：卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、-C(O)R1、硝基、羟基、-NR2R3、氰基或基团Z；R1为C1-C4烷基、-OR3或-NR3R4；R2为氢或C1-C6烷基；R3为氢或C1-C6烷基；R为H、C1-C6烷基、芳基、苄基；每个可以被1-4个基团J取代；所述方法根据下述方案1进行，其中步骤a表示在碱性条件下化合物(IIA)与3-氨基硫脲衍生物反应，然后用无机碱和1-丙基磷酸酐处理，并最后用无机酸调节pH以得到式(II)化合物。
方案1
Description
本发明涉及新颖的方法，该方法用于制备合成多种化合物的关键中间体，其中所述化合物为D3受体的有效的和特异性的拮抗剂。
本发明涉及制备式(I)的三唑衍生物的新颖的方法：
其中
X为氮；
Het指芳基或杂芳基；每个可以被1-4个选自下列的基团J取代：
卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、-C(O)R1、硝基、羟基、-NR2R3、氰基或基团Z；
R1为C1-C4烷基、-OR3或-NR3R4；
R2为氢或C1-C6烷基；
R3为氢或C1-C6烷基；
R为H、C1-C6烷基、芳基、苄基；每个可以被1-4个基团J取代；
所述方法根据下述方案1进行：
方案1
其中
步骤a是指在碱性条件下化合物(IIA)与3-氨基硫脲衍生物反应，然后用无机碱和1-丙基磷酸酐(n-propane phosphonic cyclic anhydride)处理，并最后用无机酸调节pH以得到式(II)化合物。
本文作为基团或基团的一部分所用的术语C1-C6烷基是指直链或支链的含有1-6个碳原子的烷基；这些基团的实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基。
术语卤素是指氟、氯、溴或碘原子。
术语卤代C1-C6烷基是指具有一个或多个碳原子的烷基，且其中该烷基的至少一个氢原子被卤素取代，例如三氟甲基等。
术语C1-C6烷硫基(thioalkyl)可以为直链或支链的烷硫基，例如甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、仲丁硫基、叔丁硫基等。
术语C2-C6链烯基定义为含有一个或多个双键且具有2-6个碳原子的直链或支链烃基，例如乙链烯基、2-丙链烯基、3-丁链烯基、2-丁链烯基、2-戊链烯基、3-戊链烯基、3-甲基-2-丁链烯基或3-己链烯基等。
术语C1-C6烷氧基可以为直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、丙-2-氧基、丁氧基、丁-2-氧基或甲基丙-2-氧基等。
术语卤代C1-C6烷氧基可以为上述定义的C1-C6烷氧基，其被至少一个卤素(优选氟)取代，如OCHF2或OCF3。
术语C2-C6炔基定义为含有一个或多个三键且具有2-6个碳原子的直链或支链烃基，包括乙炔基、丙炔基、1-丁炔基、1-戊炔基、3-甲基-1-丁炔基等。
术语芳基指芳香碳环基团，如苯基、联苯基或萘基。
术语杂芳基指5-10元并具有至少一个选自氮、氧和硫的杂原子、并且含有至少一个碳原子的芳香杂环，其包括单环和二环体系。
示例性的杂芳基包括(但不限于)呋喃基、苯并呋喃基、噻吩基(thiophenyl)、苯并噻吩基、吡咯基、吲哚基、异吲哚基、氮杂吲哚基、吡啶基、喹啉基、异喹啉基、
唑基、异
唑基、苯并
唑基、吡唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、噌啉基、酞嗪基、三唑基、四唑基、喹唑啉基和苯并二氧杂环戊链烯基(benzodioxolyl)。
根据上述定义，术语5-6元杂环指5-6单环杂环，其为饱和、不饱和或芳香的，且其含有1-4个杂原子，所述杂原子独立地选自氮、氧和硫，且其中氮和硫杂原子可任选被氧化，且氮杂原子可任选被季铵化。杂环包括上述定义的杂芳基。杂环可以通过任何杂原子或碳原子连接。因此，该术语包括(但不限于)吗啉基、吡啶基、吡嗪基、吡唑基、噻唑基、三唑基、咪唑基、
二唑基、
唑基、异
唑基、吡咯烷酮基、吡咯烷基、哌啶基、乙内酰脲基(hydantoinyl)、戊内酰胺基(valerolactamyl)、环氧乙烷基、环氧丙烷基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢嘧啶基、四氢噻吩基、四氢噻喃基(tetrahydrothiopyranyl)等。
式(I)化合物可以用于(但不限于)制备式(IA)的D3拮抗剂，如WO2005/080382所公开的：
其中
●G选自：苯基、吡啶基、苯并噻唑基、吲唑基；
●p为0-5的整数；
●R1独立地选自：卤素、羟基、氰基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-4烷酰基；或相应于基团R5；
●R2为氢或C1-4烷基；
●R3为C1-4烷基；
●R4为氢或苯基、杂环基、5-或6-元杂芳基、或8-11元双环基团，任何这些基团任选被1、2、3或4个选自下述的取代基取代：卤素、氰基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C1-4烷酰基；
●R5为选自下述的基团：异
唑基、-CH2-N-吡咯基、1，1-二氧代-2-异噻唑烷基、噻吩基、噻唑基、吡啶基、2-吡咯烷酮基，且该基团任选被一个或两个选自下述的取代基取代：卤素、氰基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C1-4烷酰基；
且当R1为氯且p为1时，该R1不出现在相对于与该分子其它部分的连接键的邻位；且当R1相应于R5时，p为1。
式(I)化合物，作为制备其它化合物的中间体，可以方便地被官能化，如WO2005/080382中所述。实例在本发明的实验部分描述。
WO2005/080382中描述了使用1-羟基苯并三唑(HOBt)和1，3-二环己基碳二亚胺(DCC)制备式(I)化合物。
在工业级别中该反应试剂的缺点概括如下：HOBt及其副产物具有爆炸性，且DCC及其副产物总是很难完全除去。
本发明的方法通过使用1-丙基磷酸酐(T3P)作为缩合试剂解决了上述问题。
T3P首次被H.Wissmann(Angew.Chem.，1980，92，129)于1980年用于合成肽，并在有机合成中逐渐获得重要性，因为其与其它常用缩合试剂(如DCC)相比具有更小的毒性和更高的安全性。
该反应试剂不产生任何水不溶性的副产物。在本发明的方法中，T3P以在乙酸乙酯中的50％溶液形式使用，且不需要分离中间体肼-硫代酰胺(hydrazine-carbothiamide)。类似地，T3P以在DMF(二甲基甲酰胺)中的50％溶液形式使用，并可用在本发明的方法中。
本发明的方法如下更详细的描述：
起始物质，杂环羧酸，通常是市售的，或其可以通过文献中已知的方法制备，可以方便地将1当量的起始物质溶于适当的溶剂(例如，二甲基甲酰胺；乙酸乙酯；乙腈和四氢呋喃以及其它极性非质子溶剂)中，然后用稍过量的3-氨基硫脲的衍生物(1.10当量)如4-甲基的衍生物处理。然后在室温下加入有机碱(如，三乙胺、二异丙基乙基胺和可能其它的脂肪族或芳香族胺)。
然后可以在温度0-40℃下滴加1-丙基磷酸酐(50％w/w的乙酸乙酯溶液)。当在约0℃加入时，然后将温度在低于15℃下保持20-60分钟。然后于20℃搅拌所得混合物2-16小时。
然后用适合的无机碱水溶液稀释该混合物直到达到碱性pH。所述适合的碱选自：碳酸钾、碳酸钠、氢氧化钠、氢氧化钾。
然后分离所得两相混合物(当观察到时)，且弃去上层有机层。然后将水层加热至50-90℃(内部温度)维持半小时至几小时直到反应完全。
冷却至20℃后，然后缓慢加入适合的无机酸(如HCl 37％)视需要调节pH(4至8)。
然后通常将混悬液搅拌2-16小时，然后过滤固体，用纯净水洗涤，然后在真空箱中于40-60℃干燥至干。从没有被含磷衍生物污染的水性混合物中分离终产物。
实施例
除另有说明，在所述实施例中：
所有温度为℃。红外光谱于FT-IR仪器上检测。通过将溶于乙腈的样品直接加入到质谱仪上，以正离子电喷雾(ES+)离子化方式分析化合物。质子核磁共振(1H-NMR)光谱于400MHz记录，化学位移以自Me4Si(作为内标)的低场(d)ppm记录，且记作单峰(s)、宽单峰(bs)、二重峰(d)、双二重峰(dd)、三重峰(t)、四重峰(q)或多重峰(m)。经过硅胶(Merck AG Darmstaadt，德国)进行柱色谱。在文本中使用下述缩写：T3P＝1-丙基磷酸酐，EtOAc＝乙酸乙酯，DIPEA＝N，N-二异丙基乙基胺。
实施例1
制备4-甲基-5-(4-甲基-1，3-
唑-5-基)-2，4-二氢-3H-1，2，4-三唑-3-硫酮
将4-甲基-1，3-
唑-5-羧酸(市售)(12.9g，101.5mmol)溶于DMF(60mL)中，然后用4-甲基-3-氨基硫脲(11.61g，1.10当量)处理。然后于20℃加入DIPEA(31,0mL，1.75当量)。在冰浴冷却下，滴加EtOAc(90mL)中的T3P 50％w/w溶液，温度低于15℃保持20分钟。然后于20℃搅拌所得混合物6小时。
用NaOH 4M(120.0mL)稀释该混合物。分离所得两相混合物，并弃去上层有机层。用额外的NaOH 4M(60mL)调节水层(pH＝8)至pH＝11，然后于70℃(内部温度)加热30分钟。冷却过夜后，缓慢加入HCl 37％直到pH＝5。
搅拌混悬液8小时，然后过滤固体并用水(60mL)洗涤，在真空箱中于40℃干燥过夜。
产率：10.48g，53.4mmol，53％的理论产率
1H NMR(DMSO-d6，600MHz，δppm)：14.11(bs，1H)，8.60(s，1H)，3.61(s，3H)，2.33(s，3H)
MH+＝197
实施例2
制备5-(2，4-二甲基-1，3-噻唑-5-基)-4-甲基-2，4-二氢-3H-1，2，4-三唑-3-硫
酮
将2，4-二甲基-1，3-
唑-5-羧酸(市售)(5g，31.8mmol)和4-甲基-3-氨基硫脲(3.68g，1.10当量)溶于DMF(15mL)中。然后于20℃加入DIPEA(10.0mL，1.80当量)。冰浴冷却下，滴加T3P 50％w/w的EtOAc溶液(35mL，1.50当量)，保持温度低于10℃。然后于20℃搅拌所得混合物2小时。
用水(20mL)稀释该混合物，然后加入NaOH 4M(20.0mL)。弃去有机相，且将水层于70℃(内部温度)加热90分钟。冷却至50℃后，缓慢加入HCl 37％直到pH＝6.5。
将混悬液冷却至5℃，并过滤固体然后用水洗涤，然后在真空箱中于40℃干燥过夜。
产率：5.45g，24.4mmol，77％的理论产率
1H NMR(DMSO-d6，600MHz，δppm)：14.02(bs，1H)，3.39(s，3H)，2.69(s，3H)，2.34(s，3H)
MH+＝227
实施例3
制备4-甲基-5-(2-甲基-3-吡啶基)-2，4-二氢-3H-1，2，4-三唑-3-硫酮
将2-甲基烟酸(市售)(5g，36.5mmol)和4-甲基-3-氨基硫脲(4.22g，1.10当量)溶于EtOAc(15mL)中。然后于20℃加入DIPEA(14.5mL，2.28当量)。冰浴冷却下，滴加T3P 50％w/w的EtOAc溶液(32.5mL，1.50当量)，保持温度低于15℃。然后于20℃搅拌所得混合物90分钟。用水(10mL)稀释该混合物，然后加入NaOH 4M(18.5mL)。弃去有机层，并将剩余的水层于70℃(内部温度)加热2小时45分钟。冷却至环境温度后，得到混悬液，其pH为约7.5-8.0。
缓慢加入HCl 37％直到pH＝5。
过滤固体，然后在真空箱中于40℃干燥过夜。
产率：7.04g，34.1mmol，93％的理论产率
1H NMR(DMSO-d6，600MHz，δppm)：14.01(bs，1H)，8.66(dd，1H)，7.96(dd，1H)，7.42(dd，1H)，3.29(s，3H)，2.42(s，3H)
MH+＝207
实施例4
制备4-甲基-5-(4-哒嗪基)-2，4-二氢-3H-1，2，4-三唑-3-硫酮
将4-哒嗪羧酸(市售)(5g，40.3mmol)和4-甲基-3-氨基硫脲(4.66g，1.10当量)溶于DMF(15mL)中，然后于20℃加入DIPEA(12.5mL，1.78当量)。冰浴冷却下，滴加T3P 50％w/w的EtOAc溶液(36mL，1.50当量)，保持温度低于20℃。然后于20℃搅拌所得混合物30分钟。
用水(20mL)稀释该混合物，然后加入NaOH 4M(20.0mL)。弃去有机层，且将剩余的水相于70℃(内部温度)加热5小时。冷却至环境温度后，得到混悬液，其pH为约7.5-8.0。缓慢加入HCl 37％直到pH＝5。
过滤固体，并用水(20mL，3次)洗涤，然后在真空箱中于40℃干燥过夜。
产率：6.37g，33.0mmol，82％的理论产率
1H NMR(DMSO-d6，600MHz，δppm)：14.29(bs，1H)，9.58(d，1H)，9.47(d，1H)，8.09(d，1H)，3.64(s，3H)
MH+＝194
实施例5
制备5-(2，4-二甲基-1，3-
唑-5-基)-4-甲基-2，4-二氢-3H-1，2，4-三唑-3-硫酮
搅拌下，将4-甲基-3-氨基硫脲(4.5g，42.8mmol)溶于DMF(12.5mL，2.5vol)中。加入市售的2，4-二甲基-1，3-
唑-5-甲酸(5g，35.4mmol)和DIPEA(15.5mL，89mmol)。用冰水浴将混合物冷却至5℃，且在15分钟内滴加T3P50％w/w的乙酸乙酯溶液(45.5mL，76.4mmol)，保持温度低于10℃。加入后，使混合物达到环境温度，并在氮气下搅拌2小时。搅拌下用22.5mL的水和22.5mL的NaOH 32％w/w溶液稀释该混合物(最终pH＝12)。分液后，弃去上层有机层，且将水层加热至70℃(65℃内部)。随时监测混合物的pH，且视需要调节pH至12。总共维持加热3小时。
冷却至环境温度后，加入2.5mL的HCl 37％w/w溶液直到pH为8。开始沉淀固体，并搅拌该混悬液过夜。
过滤混合物，用22.5mL水洗涤滤饼，且在真空箱中于40℃干燥收集到的固体5小时。
产量：4.28g；57％的理论产率(theoretical)
1H-NMR
600MHz，DMSO-d6：2.26(3H，s)，2.48(3H，s)，3.59(3H，s)，14.07(1H，br.s.)
MH+[211]
实施例6
制备4-甲基-5-(4-哒嗪基)-2，4-二氢-3H-1，2，4-三唑-3-硫酮的衍生物：4-{5-[(3-氯丙基)硫基]-4-甲基-4H-1，2，4-三唑-3-基}哒嗪
将4-甲基-5-(4-哒嗪基)-2，4-二氢-3H-1，2，4-三唑-3-硫酮(5g；1当量，0.026mmol)和K2CO3325筛目(mesh)(1.2当量，4.3g)混悬于丙酮(17.5mL)和甲醇(7.5mL)的混合物中。将混悬液加热至40℃，且一次加入所有的1-溴-3-氯丙烷(1.1当量，2.8mL)。于40℃搅拌该混悬液3小时，然后冷却至环境温度。加入乙酸乙酯(25mL)，且将混合物蒸馏至约20mL。用乙酸乙酯(20mL)稀释该混合物，且用水(每次15mL)洗涤。溶液经Na2SO4干燥；过滤并蒸发至约20mL。搅拌下经30分钟将所得溶液冷却至环境温度，然后再搅拌30分钟。这段时间中，从溶液中析出部分产物。经30分钟滴加庚烷(40mL)，然后搅拌所得混悬液至少6小时。过滤该混悬液，并用EtOAc/庚烷1/2(15mL)混合物洗涤滤饼。标题化合物4-{5-[(3-氯丙基)硫基]-4-甲基-4H-1，2，4-三唑-3-基}哒嗪，在烘箱中于40℃干燥直到重量恒定不变。
产率：61％的理论产率(th)，4.27g
MS：[MH]+270
NMR(DMSO-d6，600MHz；δppm)：9.61(dd，1H)；9.43(dd，1H)；8.07(dd，1H)；3.78(t，2H)；3.73(s，3H)；3.31(t，2H)；2.17(m，2H)
说明书中引用的所有的出版物，包括但不限于专利和专利申请，在此并入作为参考，如同每篇出版物的内容通过全篇引用被具体地和分别地并入到本文中。
应该理解本发明包括本文上述的特定和优选组的组合。
说明书和权利要求书是该申请的部分，该申请可以用作任何以后申请的优先权基础。所述以后申请的权利要求书可以涉及本文所述的任何特点或特点的组合。它们可以采用产物、组合物、方法或用途权利要求的形式，且可以包括例如但不限于下述权利要求书。
Claims (1)
1.制备式(I)的三唑衍生物的方法：
其中
X为氮；
Het指杂芳基；每个可以被1-4个选自下列的基团J取代：
卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、-C(O)R1、硝基、羟基、-NR2R3或氰基；
R1为C1-C4烷基、-OR3或-NR3R4；
R2为氢或C1-C6烷基；
R3为氢或C1-C6烷基；
R为H、C1-C6烷基、苄基；每个可以被1-4个基团J取代；
其中，杂芳基指5-10元并具有至少一个选自氮、氧和硫的杂原子，并且含有至少一个碳原子的芳香杂环，其包括单环和二环体系；
所述方法根据下述方案1进行：
方案1
其中
步骤a是指在碱性条件下化合物(IIA)与3-氨基硫脲衍生物反应，然后用无机碱和1-丙基磷酸酐处理，并最后用无机酸调节pH以得到式(I)化合物。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0607899.2A GB0607899D0 (en) | 2006-04-03 | 2006-04-03 | Process for preparing heterocyclic derivatives |
| GB0607899.2 | 2006-04-03 | ||
| PCT/EP2007/053118 WO2007113261A1 (en) | 2006-04-03 | 2007-03-30 | Process for preparing heterocyclic derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101454308A CN101454308A (zh) | 2009-06-10 |
| CN101454308B true CN101454308B (zh) | 2013-05-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200780019578XA Expired - Fee Related CN101454308B (zh) | 2006-04-03 | 2007-03-30 | 制备杂环衍生物的方法 |
Country Status (18)
| Country | Link |
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| US (2) | US20070232808A1 (zh) |
| EP (1) | EP2007747B1 (zh) |
| JP (1) | JP5167242B2 (zh) |
| KR (1) | KR101411124B1 (zh) |
| CN (1) | CN101454308B (zh) |
| AU (1) | AU2007233744B2 (zh) |
| BR (1) | BRPI0710049A2 (zh) |
| CA (1) | CA2648089A1 (zh) |
| CR (1) | CR10351A (zh) |
| EA (1) | EA017304B1 (zh) |
| ES (1) | ES2443219T3 (zh) |
| GB (1) | GB0607899D0 (zh) |
| IL (1) | IL194389A0 (zh) |
| MA (1) | MA30354B1 (zh) |
| MX (1) | MX2008012876A (zh) |
| NO (1) | NO20084414L (zh) |
| WO (1) | WO2007113261A1 (zh) |
| ZA (1) | ZA200808107B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| MD3995C2 (ro) * | 2009-05-11 | 2010-07-31 | Государственный Университет Молд0 | Utilizare a di(µ-Ofenoxi)-di{[2-(4-aminobenzensulfamido)-5-etil-1,3,4-tiadiazol]-3,5-dibromosalicilidentiosemicarbazonato(-1)-cupru} în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar |
| IT201700041723A1 (it) | 2017-04-14 | 2018-10-14 | Italfarmaco Spa | Nuovi inibitori selettivi di HDAC6 |
| CN106866657A (zh) * | 2017-04-25 | 2017-06-20 | 成都倍特药业有限公司 | 一种麦角新碱的制备方法 |
| US9862675B1 (en) | 2017-07-05 | 2018-01-09 | King Fahd University Of Petroleum And Minerals | Method of N-formylating amines with a phosphonic anhydride |
| US20230286970A1 (en) | 2020-08-07 | 2023-09-14 | Italfarmaco S.P.A. | Novel oxadiazole-based selective hdac6 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020032238A1 (en) * | 2000-07-08 | 2002-03-14 | Henning Priepke | Biphenylcarboxylic acid amides, the preparation thereof and the use thereof as medicaments |
| DE10033337A1 (de) * | 2000-07-08 | 2002-01-17 | Boehringer Ingelheim Pharma | Biphenylcarbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel |
| AU1697502A (en) * | 2000-10-20 | 2002-04-29 | Rhodia Acetow Gmbh | Highly compressed filter tow bales |
| PT2060570E (pt) | 2004-02-23 | 2012-05-07 | Glaxo Group Ltd | Derivados de azabiciclo(3.1.0)-hexano úteis como moduladores dos receptores d3 da dopamina |
| GB0517193D0 (en) | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Novel use |
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2006
- 2006-04-03 GB GBGB0607899.2A patent/GB0607899D0/en not_active Ceased
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2007
- 2007-03-30 CN CN200780019578XA patent/CN101454308B/zh not_active Expired - Fee Related
- 2007-03-30 CA CA002648089A patent/CA2648089A1/en not_active Abandoned
- 2007-03-30 JP JP2009503555A patent/JP5167242B2/ja not_active Expired - Fee Related
- 2007-03-30 EP EP07727590.7A patent/EP2007747B1/en active Active
- 2007-03-30 ES ES07727590.7T patent/ES2443219T3/es active Active
- 2007-03-30 BR BRPI0710049-3A patent/BRPI0710049A2/pt not_active Application Discontinuation
- 2007-03-30 KR KR1020087026730A patent/KR101411124B1/ko not_active IP Right Cessation
- 2007-03-30 AU AU2007233744A patent/AU2007233744B2/en not_active Ceased
- 2007-03-30 WO PCT/EP2007/053118 patent/WO2007113261A1/en active Application Filing
- 2007-03-30 US US11/693,757 patent/US20070232808A1/en not_active Abandoned
- 2007-03-30 EA EA200870405A patent/EA017304B1/ru not_active IP Right Cessation
- 2007-03-30 MX MX2008012876A patent/MX2008012876A/es active IP Right Grant
-
2008
- 2008-09-22 ZA ZA200808107A patent/ZA200808107B/xx unknown
- 2008-09-25 IL IL194389A patent/IL194389A0/en unknown
- 2008-10-07 CR CR10351A patent/CR10351A/es unknown
- 2008-10-21 NO NO20084414A patent/NO20084414L/no not_active Application Discontinuation
- 2008-10-23 MA MA31326A patent/MA30354B1/fr unknown
-
2009
- 2009-10-29 US US12/608,184 patent/US7838680B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| Abdellah Ech-Chahad, et al..An expeditious hydroxyamidation of carboxylic acids.《Tetrahedron Letters》.2005,第46卷第5113-5115页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0710049A2 (pt) | 2011-08-02 |
| EA200870405A1 (ru) | 2009-04-28 |
| MA30354B1 (fr) | 2009-04-01 |
| EP2007747A1 (en) | 2008-12-31 |
| EA017304B1 (ru) | 2012-11-30 |
| US7838680B2 (en) | 2010-11-23 |
| US20100048895A1 (en) | 2010-02-25 |
| GB0607899D0 (en) | 2006-05-31 |
| JP2009532428A (ja) | 2009-09-10 |
| KR101411124B1 (ko) | 2014-06-25 |
| ES2443219T3 (es) | 2014-02-18 |
| MX2008012876A (es) | 2008-10-13 |
| CA2648089A1 (en) | 2007-10-11 |
| JP5167242B2 (ja) | 2013-03-21 |
| US20070232808A1 (en) | 2007-10-04 |
| KR20080108328A (ko) | 2008-12-12 |
| ZA200808107B (en) | 2009-10-28 |
| WO2007113261A1 (en) | 2007-10-11 |
| AU2007233744A1 (en) | 2007-10-11 |
| IL194389A0 (en) | 2009-08-03 |
| NO20084414L (no) | 2008-10-28 |
| AU2007233744B2 (en) | 2012-09-06 |
| EP2007747B1 (en) | 2013-11-20 |
| CN101454308A (zh) | 2009-06-10 |
| CR10351A (es) | 2008-10-29 |
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