KR20010049559A - 신규한 방법 및 중간체 - Google Patents
신규한 방법 및 중간체 Download PDFInfo
- Publication number
- KR20010049559A KR20010049559A KR1020000033140A KR20000033140A KR20010049559A KR 20010049559 A KR20010049559 A KR 20010049559A KR 1020000033140 A KR1020000033140 A KR 1020000033140A KR 20000033140 A KR20000033140 A KR 20000033140A KR 20010049559 A KR20010049559 A KR 20010049559A
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- indole
- chloro
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims abstract description 59
- 239000000543 intermediate Substances 0.000 title abstract description 18
- -1 5-chloro-lH-indole-2-carbonyl Chemical group 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- VFHUJFBEFDVZPJ-UHFFFAOYSA-N 1h-indole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)N)=CC2=C1 VFHUJFBEFDVZPJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 163
- 239000000203 mixture Substances 0.000 claims description 49
- 239000012044 organic layer Substances 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 43
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- 239000000010 aprotic solvent Substances 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- FUQOTYRCMBZFOL-UHFFFAOYSA-N 5-chloro-1H-indole-2-carboxylic acid Chemical compound ClC1=CC=C2NC(C(=O)O)=CC2=C1 FUQOTYRCMBZFOL-UHFFFAOYSA-N 0.000 claims description 32
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 32
- 239000002002 slurry Substances 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 235000019439 ethyl acetate Nutrition 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000010410 layer Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000003586 protic polar solvent Substances 0.000 claims description 14
- 239000011261 inert gas Substances 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 239000012190 activator Substances 0.000 claims description 10
- 239000012465 retentate Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 238000002955 isolation Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 239000011260 aqueous acid Substances 0.000 claims description 7
- 230000003197 catalytic effect Effects 0.000 claims description 7
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 230000000717 retained effect Effects 0.000 claims description 5
- 229940062627 tribasic potassium phosphate Drugs 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical group [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- PITVZRMNFBGRFW-UHFFFAOYSA-N 5,6-dichloro-1h-indole-2-carboxylic acid Chemical compound ClC1=C(Cl)C=C2NC(C(=O)O)=CC2=C1 PITVZRMNFBGRFW-UHFFFAOYSA-N 0.000 claims description 2
- YDCGVASFVACWKF-NRFANRHFSA-N 5-chloro-1h-indole-2-carboxylic acid [1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1yl)-2-oxoethyl]amide Chemical class C1CC(O)CCN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=C(F)C=C1 YDCGVASFVACWKF-NRFANRHFSA-N 0.000 claims description 2
- KLLOIWZUJAJGPU-IBGZPJMESA-N 5-chloro-n-[(2s)-1-(3-hydroxyazetidin-1-yl)-1-oxo-3-phenylpropan-2-yl]-1h-indole-2-carboxamide Chemical compound C1C(O)CN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1 KLLOIWZUJAJGPU-IBGZPJMESA-N 0.000 claims description 2
- XCLXHRBTKOPLRH-IBGZPJMESA-N 5-chloro-n-[(2s)-1-(3-hydroxyiminoazetidin-1-yl)-1-oxo-3-phenylpropan-2-yl]-1h-indole-2-carboxamide Chemical compound C1C(=NO)CN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1 XCLXHRBTKOPLRH-IBGZPJMESA-N 0.000 claims description 2
- DJKMYENTBUQHNM-FQEVSTJZSA-N 5-chloro-n-[(2s)-1-(3-hydroxyiminopyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl]-1h-indole-2-carboxamide Chemical compound C1C(=NO)CCN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1 DJKMYENTBUQHNM-FQEVSTJZSA-N 0.000 claims description 2
- DVXQIHZTVBIXDY-NRFANRHFSA-N 5-chloro-n-[(2s)-1-(4-hydroxyiminopiperidin-1-yl)-1-oxo-3-phenylpropan-2-yl]-1h-indole-2-carboxamide Chemical compound C1CC(=NO)CCN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1 DVXQIHZTVBIXDY-NRFANRHFSA-N 0.000 claims description 2
- FTMFRKISBMECSW-SLFFLAALSA-N 5-chloro-n-[(2s)-1-[(3r,4s)-3,4-dihydroxypyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]-1h-indole-2-carboxamide Chemical compound C1[C@@H](O)[C@@H](O)CN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1 FTMFRKISBMECSW-SLFFLAALSA-N 0.000 claims description 2
- QMJHLMFORFSFQM-NRFANRHFSA-N 5-chloro-n-[(2s)-3-(2-fluorophenyl)-1-(4-hydroxypiperidin-1-yl)-1-oxopropan-2-yl]-1h-indole-2-carboxamide Chemical class C1CC(O)CCN1C(=O)[C@@H](NC(=O)C=1NC2=CC=C(Cl)C=C2C=1)CC1=CC=CC=C1F QMJHLMFORFSFQM-NRFANRHFSA-N 0.000 claims description 2
- JPXQQFCADYJMMN-UHFFFAOYSA-N 5-chloro-n-[2-(1,1-dioxo-1,3-thiazolidin-3-yl)-2-oxoethyl]-1h-indole-2-carboxamide Chemical compound C=1C2=CC(Cl)=CC=C2NC=1C(=O)NCC(=O)N1CCS(=O)(=O)C1 JPXQQFCADYJMMN-UHFFFAOYSA-N 0.000 claims description 2
- WAAVFJWSRFFSSW-BETUJISGSA-N 5-chloro-n-[2-[(3s,4r)-3,4-dihydroxypyrrolidin-1-yl]-2-oxoethyl]-1h-indole-2-carboxamide Chemical compound C1[C@@H](O)[C@@H](O)CN1C(=O)CNC(=O)C1=CC2=CC(Cl)=CC=C2N1 WAAVFJWSRFFSSW-BETUJISGSA-N 0.000 claims description 2
- TWYFEHONZYASQG-UHFFFAOYSA-N 5-chloro-n-[2-oxo-2-(1,3-thiazolidin-3-yl)ethyl]-1h-indole-2-carboxamide Chemical compound C=1C2=CC(Cl)=CC=C2NC=1C(=O)NCC(=O)N1CCSC1 TWYFEHONZYASQG-UHFFFAOYSA-N 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 229940111685 dibasic potassium phosphate Drugs 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- JNJCEALGCZSIGB-SECBINFHSA-N (2r)-2-hydroxy-4-phenylbutanoic acid Chemical compound OC(=O)[C@H](O)CCC1=CC=CC=C1 JNJCEALGCZSIGB-SECBINFHSA-N 0.000 abstract description 17
- 102000007390 Glycogen Phosphorylase Human genes 0.000 abstract description 7
- 108010046163 Glycogen Phosphorylase Proteins 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 241000124008 Mammalia Species 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 229920002527 Glycogen Polymers 0.000 abstract 1
- 102000009097 Phosphorylases Human genes 0.000 abstract 1
- 108010073135 Phosphorylases Proteins 0.000 abstract 1
- 229940096919 glycogen Drugs 0.000 abstract 1
- 208000024891 symptom Diseases 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000460 chlorine Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000009739 binding Methods 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007872 degassing Methods 0.000 description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000007942 carboxylates Chemical group 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229950009215 phenylbutanoic acid Drugs 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 241000208140 Acer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 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
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13999799P | 1999-06-18 | 1999-06-18 | |
| US60/139,997 | 1999-06-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20010049559A true KR20010049559A (ko) | 2001-06-15 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020000033140A Ceased KR20010049559A (ko) | 1999-06-18 | 2000-06-16 | 신규한 방법 및 중간체 |
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| US (1) | US6410750B1 (enExample) |
| EP (1) | EP1061074A1 (enExample) |
| JP (1) | JP3342471B2 (enExample) |
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| CN (1) | CN1283615A (enExample) |
| AU (1) | AU4089200A (enExample) |
| BR (1) | BR0002686A (enExample) |
| CA (1) | CA2311872A1 (enExample) |
| CZ (1) | CZ20002242A3 (enExample) |
| HU (1) | HUP0002285A3 (enExample) |
| ID (1) | ID26385A (enExample) |
| IL (1) | IL136726A0 (enExample) |
| IN (1) | IN188853B (enExample) |
| PL (1) | PL340866A1 (enExample) |
| RU (1) | RU2195450C2 (enExample) |
| TR (1) | TR200001781A2 (enExample) |
| YU (1) | YU38000A (enExample) |
| ZA (1) | ZA200002987B (enExample) |
Families Citing this family (2)
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|---|---|---|---|---|
| AR052864A1 (es) * | 2005-01-06 | 2007-04-11 | Schering Corp | Preparacion de cetoamidas |
| EP2714660B1 (en) * | 2011-05-31 | 2018-09-26 | Theravance Biopharma R&D IP, LLC | Neprilysin inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX9709874A (es) | 1995-06-06 | 1998-03-31 | Pfizer | N-(INDOL-2-CARBONIL) beta-ALANILAMIDAS SUSTITUIDAS Y DERIVADOS COMO INHIBIDORES DE GLUCOGENO FOSFORILASA, USO DE LOS MISMOS Y COMPOSICIONES QUE LOS CONTIENEN. |
| JP3314938B2 (ja) | 1995-06-06 | 2002-08-19 | ファイザー・インコーポレーテッド | グリコーゲンホスホリラーゼ抑制剤としての置換されたｎ−（インドール−２−カルボニル）−グリシンアミド類および誘導体 |
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2000
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- 2000-06-14 EP EP00305048A patent/EP1061074A1/en not_active Withdrawn
- 2000-06-15 JP JP2000179880A patent/JP3342471B2/ja not_active Expired - Fee Related
- 2000-06-16 TR TR2000/01781A patent/TR200001781A2/xx unknown
- 2000-06-16 YU YU38000A patent/YU38000A/sh unknown
- 2000-06-16 CN CN00118397A patent/CN1283615A/zh active Pending
- 2000-06-16 KR KR1020000033140A patent/KR20010049559A/ko not_active Ceased
- 2000-06-16 ID IDP20000495D patent/ID26385A/id unknown
- 2000-06-16 HU HU0002285A patent/HUP0002285A3/hu unknown
- 2000-06-16 CA CA002311872A patent/CA2311872A1/en not_active Abandoned
- 2000-06-16 AU AU40892/00A patent/AU4089200A/en not_active Abandoned
- 2000-06-16 CZ CZ20002242A patent/CZ20002242A3/cs unknown
- 2000-06-16 RU RU2000115273/04A patent/RU2195450C2/ru not_active IP Right Cessation
- 2000-06-19 BR BR0002686-7A patent/BR0002686A/pt not_active IP Right Cessation
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Also Published As
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| ID26385A (id) | 2000-12-21 |
| HUP0002285A2 (en) | 2001-03-28 |
| HU0002285D0 (en) | 2000-08-28 |
| IL136726A0 (en) | 2001-06-14 |
| TR200001781A2 (tr) | 2001-01-22 |
| CN1283615A (zh) | 2001-02-14 |
| CZ20002242A3 (cs) | 2002-01-16 |
| IN188853B (enExample) | 2002-11-16 |
| PL340866A1 (en) | 2001-01-02 |
| JP3342471B2 (ja) | 2002-11-11 |
| ZA200002987B (en) | 2001-12-14 |
| CA2311872A1 (en) | 2000-12-18 |
| AU4089200A (en) | 2000-12-21 |
| YU38000A (sh) | 2003-02-28 |
| EP1061074A1 (en) | 2000-12-20 |
| US6410750B1 (en) | 2002-06-25 |
| BR0002686A (pt) | 2001-08-21 |
| HUP0002285A3 (en) | 2002-09-30 |
| RU2195450C2 (ru) | 2002-12-27 |
| JP2001039949A (ja) | 2001-02-13 |
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