MXPA99002150A - Process to prepare pharmaceutical compounds - Google Patents
Process to prepare pharmaceutical compoundsInfo
- Publication number
- MXPA99002150A MXPA99002150A MXPA/A/1999/002150A MX9902150A MXPA99002150A MX PA99002150 A MXPA99002150 A MX PA99002150A MX 9902150 A MX9902150 A MX 9902150A MX PA99002150 A MXPA99002150 A MX PA99002150A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- alkyl
- carbon atoms
- hydrogen
- substituted
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 348
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 332
- 229910052739 hydrogen Inorganic materials 0.000 claims description 256
- 239000001257 hydrogen Substances 0.000 claims description 256
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims description 151
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 104
- 125000003118 aryl group Chemical group 0.000 claims description 80
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 78
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- -1 OR18 Chemical group 0.000 claims description 9
- 101700023211 nhr-65 Proteins 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000006307 alkoxy benzyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000004429 atoms Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000006498 halo alkoxy benzyl group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- BMAZFNRVUOBMEH-UHFFFAOYSA-N [4-[tert-butyl(dimethyl)silyl]oxyphenyl]methyl-triphenylphosphanium Chemical compound C1=CC(O[Si](C)(C)C(C)(C)C)=CC=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BMAZFNRVUOBMEH-UHFFFAOYSA-N 0.000 claims description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 4
- 150000001336 alkenes Chemical class 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-BJUDXGSMSA-N (11)6C Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 claims description 3
- 229910006069 SO3H Inorganic materials 0.000 claims description 3
- 102100007636 TMEM106C Human genes 0.000 claims description 3
- 101710025031 TMEM106C Proteins 0.000 claims description 3
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- 101700021218 CAT Proteins 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N Cesium Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 150000001345 alkine derivatives Chemical class 0.000 claims 2
- 241000689227 Cora <basidiomycete fungus> Species 0.000 claims 1
- 108020005497 Nuclear hormone receptors Proteins 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- PSNOPSMXOBPNNV-VVCTWANISA-N Cryptophycin 1 Chemical class C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 150000001720 carbohydrates Chemical class 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000014633 carbohydrates Nutrition 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 125000004430 oxygen atoms Chemical group O* 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004434 sulfur atoms Chemical group 0.000 description 3
- OOWSDKUFKGVADH-UHFFFAOYSA-N 1-diphenylphosphoryloxy-2,3,4,5,6-pentafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 OOWSDKUFKGVADH-UHFFFAOYSA-N 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 108010006226 cryptophycin Proteins 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- TUVXGJSVOKWYPS-UHFFFAOYSA-N C(C)(=O)OCC.[Li] Chemical compound C(C)(=O)OCC.[Li] TUVXGJSVOKWYPS-UHFFFAOYSA-N 0.000 description 1
- 101700067048 CDC13 Proteins 0.000 description 1
- 101710018145 CLTC Proteins 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N-diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101710019691 Olfr1 Proteins 0.000 description 1
- 101700049711 SYCP3 Proteins 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N Sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N TFA trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 101710008831 UQCRC1 Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001946 anti-microtubular Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N aziridine Chemical group C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002118 epoxides Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 150000002829 nitrogen Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000000737 periodic Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004437 phosphorous atoms Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000002269 spontaneous Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- WGYONVRJGWHMKV-UHFFFAOYSA-M tetrabutylazanium;benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1.CCCC[N+](CCCC)(CCCC)CCCC WGYONVRJGWHMKV-UHFFFAOYSA-M 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003553 thiiranes Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Abstract
This invention provides novel cryptophycin compounds and a process for preparing cryptophycin compounds.
Description
PROCESS FOR PREPARING PHARMACEUTICAL COMPOUNDS
DESCRIPTION OF THE INVENTION
This invention relates to the fields of pharmaceutical and organic chemistry, and provides a process for preparing cryptophycin compounds as antimicrotubule agents. The cryptophycin compounds may be useful for the treatment of cancer and neoplasms, and are thus useful pharmaceutical agents. The literature describes a protocol for cyclizing certain cryptophycin compounds. Barro, R.A .; Hemscheidt, T .; Liang, J; Paik, S .; Moore, R.E .; Tius, M.A. J. Am. Chem. Soc. 1995, 117, 2479. This three step sequence (hereinafter "synthetic Barrow sequence") began with the conversion of the trichloroethyl ester to the corresponding carboxylic acid using zinc and acetic acid. The conversion of the crude product to the amino carboxylate was achieved with the trifluoroacetic acid, followed by a basic aqueous treatment. In the final step, the closure of the ring was achieved in the presence of
REF.29497 pentafluorophenyldiphenylphosphinate (FDPP) in N, N-dimethylforma ida to provide the desired product 3 (3 is illustrated below in Scheme 1 to provide additional clarification) (61% after chromatography). In contrast, the currently claimed process provides a shorter process (two steps) which is more adaptable for the large-scale or commercial preparation of the macrocyclic core of cryptophycin derivatives. The claimed process can reduce the reagent expense, as well as minimize the potential problems of the waste stream, associated with the use of certain reagents in the Barrow synthetic sequence. In addition, purification by means of the claimed process can be achieved without chromatography, which is expensive and difficult to implement on a large scale. The presently claimed invention provides a process for the preparation of a compound of the formula II
wherein Ar is selected from the group consisting of phenyl, any "simple substituted aromatic group, simple substituted aromatic, substituted heteroaromatic, unsubstituted heteroaromatic group, heterocyclic group, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 atoms carbon, alkynyl of 2 to 12 carbon atoms, NR51R52, COR52, OR53, and the Formula Ar '
"
R51 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R52 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms;
R53 is selected from the group consisting of alkyl of 1 to 12 carbon atoms; R54 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) - (R57'R57"R57" '), simple unsubstituted, aromatic substituted simple aromatic group, heterocyclic, phenyl, halogen, 4- (tert-butyldimethylsiloxy) -benzyltriphenylphosphonium, COOR57, P03H, SO3H, S02R58, N (R59) R60, NHOR61, NHCHR61 ',
CM, N02, halogen, OR, 6e2 CH2 (O) R 6c2 '-CH20C (O) Ry °,
CHZN'ÍR * '3) R D', COR1 (alkyl of 1 to 6 carbon atoms) OR100, R »'
and SR63; R, 95 is selected from the group consisting of -R NH3;
R and R, 96 are each independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, -R97NH3, and -R99NR "rR99"; R97 is selected from the group consisting of alkyl of 1 to 6 carbon atoms;
R98 is selected from the group consisting of alkyl of 1 to 6 carbon atoms; R 99 is alkyl of 1 carbon atoms; R99 'and R99"are each independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R100 is selected from the group consisting of hydrogen, and Si (R101R102R103); RJ is alkyl of 1 to 6 carbon atoms; R 102 is alkyl of 1 to 6 carbon atoms; R - is alkyl of 1 to 6 carbon atoms; R104- is selected from the group consisting of
C (O) (alkyl of 1 to 6 carbon atoms) N (R106) (R59) R60,
C (O) (C 1-6 alkyl) N +, fused bicyclic, and NHR105N (R106) (R59) R60; R105 is selected from the group consisting of
C (O) (alkyl of 1 to 6 carbon atoms), alkyl of
1 to 6 carbon atoms; R106 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms; C (O) OR107; RJ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, CR 108
R109 RH0 R is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R109 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R110 is selected from the group consisting of hydrogen and alkyl of 1 to carbon atoms; R111 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and C (0) OR107; R55 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms C (R57'R57"R57" '), a single unsubstituted aromatic group, simple substituted aromatic, phenyl, COOR57, P03H, S03TT, S02R58,
NR59R60, NHOR61, NHCHR61 ', CN, N02, halogen, OR62, and SR63;
R56 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, C (R57 'R57"R57"'), a single unsubstituted aromatic group, simple substituted aromatic, phenyl, COOR57, P03H, S03H, S02R58 ,
, 59t-, 60 NHOR, NHCHRbi, (alkyl of 1 to 6 carbon atoms) NR and R CN, N02, halogen, OR1 CR, 1104 OR, 6b2 and
SR63; R > 57 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms; R57 '- is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms;
R57"is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; R 57 'is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; of the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms: R59 - is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC); R60 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R61 is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 'and fluorenylmethoxycarbonyl (FMOC); is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 'fluorenylmethoxycarbonyl (FMOC), R62 is selected from hydrogen, and alkyl from 1 carbon atoms, R62' is selected from hydrogen, OH, OR, and alkyl from 1 to 6 carbon atoms;
R63 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R64 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, CH2NR66R67; R65 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2, fluorenylmethoxycarbonyl (FMOC); R65 'is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2 and fluorenylmethoxycarbonyl (FMOC); R66 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms and fluorenylmethoxycarbonyl (FMOC); R67 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R3 is a lower alkyl group; R4 is hydrogen or OH; R5 is hydrogen or OH; R4 and R5 can be taken together to form a second bond between C3 and C4; R6 is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl, a heteroaromatic group of B ring, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, substituted cycloalkyl of 3 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, a group of the formula III '
and a group of formula III
R7 is selected from the group consisting of NR51R52,
R. 5O3JN, R, 5O 1J-pR52, OR, 53, H and a lower alkylamino group; R 51
R 52 are independently selected from the group consisting of alkyl of 1 to 3 carbon atoms; R53 is alkyl of 1 to 3 carbon atoms; R8 is hydrogen or a lower alkyl group; or R7 and R8 can form a cyclopropyl ring; R9 is selected from the group consisting of hydrogen, a lower alkyl group, an unsaturated lower alkyl group, lower alkyl- (cycloalkyl of 3 to 5 carbon atoms) and benzyl; R10 is hydrogen or a lower alkyl group; R 11 is selected from the group consisting of hydrogen, OH, a lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, OR16, halo, NR18'R19 ', N02, OP03H2, 0R19phenyl, SCH2phenyl, CONH2, C02H, P03H2, S02R23, and ZZ; RJ is selected from the group consisting of hydrogen, aryl, alkyl of 1 to 6 carbon atoms, C (0) R90 and fluorenylmethoxycarbonyl (EMOC); R1 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and C (O) R90 '; R19 is alkyl of 1 to 6 carbon atoms, C (0) R90"and fluorenylmethoxycarbonyl (FMOC);
R19 'is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and C (0) R90"'; R 90 R * R 90 'and R90'" are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, OR91 'and aryl; R91 'is selected from the group consisting of alkyl of 1 to 6 carbon atoms, aryl, and hydrogen; R23 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R30 is hydrogen or alkyl of 1 to 6 carbon atoms; or R30 can be taken together with N with carbon 11 to form a cyclic ring of three to seven members;
R is hydrogen or n is 0, 1, or 2; is O, 1, or 2; p is 0, 1, or 2; X is selected from the group consisting of O, C, S, NH, and alkylamino; And it is selected from the group consisting of C, O, NH,
S, SO, S02 and alkylamino;
Z is selected from the group consisting of - (CH2) n-,
- (CH2) p-0- (CH2) m- and cycloalkyl of 3 to 5 carbon atoms; ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; which comprises contacting a compound of formula III
with a solvent and a catalyst of formula IV
IV wherein M is selected from the group consisting of hydrogen, sodium, lithium, potassium and cesium; Xcat is selected from the group consisting of oxygen, nitrogen, and sulfur; Ycat is selected from the group consisting of oxygen, nitrogen, and sulfur; R cat is selected from the group consisting of alkyl of 1 to 6 carbon atoms and aryl; R cat2 is selected from the group consisting of alkyl of 1 to 6 carbon atoms and aryl. In addition, the present invention provides a new cryptophycin compound of formula III
wherein Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic group, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocycle, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, carbon, alkynyl of 2 to 12 carbon atoms, NR 51tR-, 52 COR 52 OR- the
Formula Ar '
R51 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R52 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R53 is selected from the group consisting of alkyl of 1 to 12 carbon atoms; R54 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) - (R57'R57"R57" '), a simple unsubstituted aromatic group, an aromatic group simple substituted, a heterocyclic group, phenyl, halogen, 4- (tert-butyldimethylsiloxy) -benzyltriphenylphosphonium, COOR57, P03H, S03H,, S02R58, N (R59) R60, NHOR61, NHCHR61 ', CN, N02, halogen, OR62, CH2 (O) Re-CH2 OC (O) R "CH2N (R, 96 ^ R96 COR100, (at which 1 to 6 carbon atoms) OR 100 f? T"
R, 953 is selected from a group consisting of -R98NH3; R96 and R96 'are each independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, -R97NH3, and -R99NR99'R99"; R97 is selected from the group consisting of alkyl of 1 to 6 carbon atoms; carbon: R98 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, R99 is alkyl of 1 to 6 carbon atoms, R99 'and R99"are each independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; to 6 carbon atoms; R100 is selected from the group consisting of hydrogen, and Si (R101R102R103); R101 is alkyl of 1 to 6 carbon atoms; R102 is alkyl of 1 to 6 carbon atoms;
R is alkyl of 1 to 6 carbon atoms; R 104 is selected from the group consisting of
C (O) (C 1-6 alkyl) N (R 10 6) (R59) R60, C (O) (C 1-6 alkyl) N +, fused bicyclic, and NHR105N (R106) (R59) R60; R1 is selected from the group consisting of
C (0) (alkyl of 1 to 6 carbon atoms), alkyl of 1 to 6 carbon atoms; R 106 is selected from the group consisting of hydrogen, alkyl of 1 carbon atoms, R 107 is selected from the group consisting of hydrogen, alkyl of 1 carbon atoms, j- p l 08 p l 09-p l l 0
R 1 08 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R109 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R 110 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R111 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and
C (0) 0R107; R55 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, C (R R R), a simple unsubstituted aromatic group, a simple substituted aromatic group, phenyl,
COOR57 P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61 ', CN,
N02, halogen, OR ^ and SR, 6"3 R" is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, C (R5 'R57"R57'"), a simple unsubstituted aromatic group, a simple substituted aromatic group, phenyl, COOR57, P03H, SO3H, S02R58, NR59R60, NHOR61, NHCHR61 ', (alkyl of 1 to 6 carbon atoms) NR59R60, CN, N02, halogen, OR104, CR104, OR62 and SR63; R 57 is selected from the group consisting of hydrogen, and alkyl of 1 to 12 carbon atoms; R57 'is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; R57"is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; R57 '___ is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; R58 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms;
R59 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC); Rc is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R61 - is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 ', and fluorenylmethoxycarbonyl (FMOC); R 61 'is selected from the group consisting of hydrogen, OR, 64, CH2NHR65, NHRe and fluorenylmethoxycarbonyl (FMOC); R62 is selected from hydrogen, and alkyl of 1 to 6 carbon atoms; R62 'is selected from hydrogen, OH, OR62, and alkyl of 1 to 6 carbon atoms; R 63 is selected from hydrogen and alkyl of 1 carbon atoms; R64 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms,
CH2NR66R67; R65 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2, and fluorenylmethoxycarbonyl (FMOC);
R65 'is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2, and fluorenylmethoxycarbonyl (FMOC); R66 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, and fluorenylmethoxycarbonyl (FMOC); R67 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R3 is a lower alkyl group; R4 is hydrogen or OH; R5 is hydrogen or OH; R4 and R5 can be taken together to form a second bond between C12 and C? 4; R6 is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohyd or ibencyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl, a heteroaromatic group with a B ring, a substituted heteroaromatic group, a B ring, alkyl of 1 to 6 carbon atoms, carbon, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, alkyl of 1 to 6 carbon atoms substituted, a group of formula III '
and a group of the formula III_
R7 is selected from the group consisting of NR51R52,
R53NR51R52, OR53, H and a lower alkyl group; R51 and
R52 are independently selected from the group consisting of alkyl of 1 to 3 carbon atoms; R53 is alkyl of 1 to 3 carbon atoms; R8 is hydrogen or a lower alkyl group; or R7 and R8 can form a cyclopropyl ring; R9 is selected from the group consisting of hydrogen, a lower alkyl group, an unsaturated lower alkyl group, (lower alkyl) - (cycloalkyl of 3 to 5 carbon atoms), and benzyl; R 10 is hydrogen or a lower alkyl group; RJ is selected from the group consisting of hydrogen, OH, a lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R15, R16 and R17 are each independently selected from the group consisting of hydrogen, OR18, halo, NR18'R19 ', N02, 0P03H2, OR19phenyl, SCH2phenyl, CONH2, C02H, S02R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, alkyl of 1 to 6 carbon atoms, C (0) R90 and fluorenylmethoxycarbonyl (FMOC); R 18 'is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and
C (O) R 90 '; R19 is alkyl of 1 to 6 carbon atoms, C (0) R90"and fluorenylmethoxycarbonyl (FMOC), R19 'is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and
C (0) R90"'; R90, R90', R90 '' 'are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, OR91' and aryl;
R is selected from the group consisting of alkyl of 1 to 6 carbon atoms, aryl, and hydrogen; R23 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R30 is hydrogen or alkyl of 1 to 6 carbon atoms; or R30 can be taken together with the N at carbon atom 11 to form a cyclic ring of three to seven members;
R50 is hydrogen or n is 0, 1, or 2; m is 0, 1 or 2; p is O, 1 6 2; X is selected from the group consisting of O, C, S, NH, and alkylamino; And it is selected from the group consisting of C, O, NH,
S, SO, S02 and alkylamino; Z is selected from the group consisting of the group of
- (CH) "-, - (CH2) p-0- (CH2) m- and cycloalkyl of 3 to 5 carbon atoms; ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; or a pharmaceutically acceptable salt or a solvate thereof. As used herein, the term "simple alkyl" will refer to alkyl of 1 to 7 carbon atoms, wherein the alkyl may be saturated, unsaturated, branched, or straight chain. Examples include, but are not limited to, methyl, ethyl n-propyl, isopropyl, n-butyl, propenyl, ethenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, butyl groups methylated, pentyl, ter-pentyl, sec- ^ pentyl, methylated pentyl groups and the like. The term "alkenyl" refers to an alkyl group, as defined above having one to three double bonds. The term "alkynyl" refers to an alkyl group, as defined above, having at least one triple bond. It is especially preferred that the alkynyl only have one triple bond. The term alkyl of 1 to n 'carbon atoms, wherein n' is an integer of 1 to 12 means an alkyl group having one to the indicated number of carbon atoms. The alkyl of 1 to n 'carbon atoms may be straight or branched chain.
As used herein, the term "alkyl of 1 to 6 carbon atoms of B ring" refers to saturated, unsaturated, branched and straight chain alkyl wherein the alkyl group of 1 to 6 carbon atoms of the B ring it may include up to three (3) different carbon substituents. Such substituents other than carbon are more preferably selected from the group consisting of OH, SCH2phenyl, NH2, CO, CONH2, C02H, P03H2, S02R21 wherein R21 is selected from hydrogen and alkyl of 1 to 3 carbon atoms; As used herein, the term "alkyl linker of 1 to 6 carbon atoms" refers to an alkyl group of 1 to 6 carbon atoms having from zero to three substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms. to 6 carbon atoms, NH2 and amino acid. As used herein, the term "amino acid" means an organic acid that contains an amino group. The term includes the amino acids of natural and synthetic origin, therefore, the amido group may be, but is not required to be, coupled to the carbon together with the acid. The term will be referred to, but will not be limited to (CH2) 2NH2COOH, (CH2) 3NH2COOC (CH3) 3, CH2NH2COOC (CH3) 3, CH2CH (NH2) CH2COOH, "CH2CH (NH2) CH2C00C (CH3) 3 / y As used herein, the term "carbohydrate" refers to a class of substituents consisting of carbon, hydrogen and oxygen, wherein hydrogen and oxygen are in the same proportions as water or almost the same proportions as The term "carbohydrate" further refers to an aldehyde or ketone-alcohol or a compound which after hydrolysis produces an aldehyde or ketone.The term "carbohydrate" is as commonly understood by the person skilled in the art. For example, the term refers but is not limited in any way to, C 2 H 2 20 n and C 6 H 0 005. As used herein, the term
"Amino-sugar" refers to a carbohydrate group containing one to three amino substituents in any available position on the carbohydrate molecule. As used herein, the term
"saccharide" refers to carbohydrate subunits to form disaccharides or polysaccharides. The term means, for example, but is by no means limited to lactose, maltose, sucrose, fructose, starch, and the like.
As used herein, the term "substituted phenyl" refers to a phenyl group with one to three different hydrocarbon substituents which may be independently selected from the group consisting of simple alkyl, chlorine, bromine, fluorine and iodine. As used herein, the term "substituted benzyl" will refer to a benzyl group with one to three hydrocarbon substituents, which may be independently selected from a group consisting of simple alkyl, chlorine, bromine, fluorine and iodine, wherein such substituents may be attached at any available carbon atom. As used herein, the term
"B-ring heterocyclic group" refers to aromatic or unsaturated rings which contain one or more substituents other than carbon, selected from the group consisting of oxygen, nitrogen and sulfur. The especially preferred ring B heterocyclic groups are selected from, but are not limited to, the group consisting of
R20 is selected from hydrogen and alkyl of 1 to 6 carbon atoms, wherein R20 is selected from hydrogen and alkyl of 1 to 6 carbon atoms. It is especially preferred that the "B ring heteroaromatic group" refers to a substituent selected from the group consisting of:
As used herein, "cycloalkyl" refers to a saturated CC cycloalkyl group, wherein such a group may include from zero to three substituents of the group consisting of alkyl of 1 to three carbon atoms, halo, and OR22 wherein R22 is selected from hydrogen and alkyl of 1 to 3 carbon atoms. Such substituents can be attached at any available carbon atom. It is especially preferred that the cycloalkyl refers to the substituted or unsubstituted cyclohexyl; As used herein, "lower alkoxy group" means any alkyl group of one to five carbon atoms attached to an oxygen atom. As used herein, "lower alkyl group" means an alkyl group of 1 to 5 carbon atoms and includes linear and non-linear hydrocarbon chains, including, for example, but not limited to methyl, ethyl, propyl, isopropyl, butyl , isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, ter-pentyl, sec-pentyl, and methylated pentyl groups. As used herein, "allyl substituted alkene" means any alkene having from one to seven carbon atoms, which contains an alkyl substitution thereon. As used herein, the term "unsaturated lower alkyl" means a lower alkyl group as defined above, wherein one to two double bonds are present in the unsaturated lower alkyl substituent. A preferred unsaturated lower alkyl is -CH2-CH = CH2. The term "(lower alkyl) - (cycloalkyl of 3 to 5 carbon atoms)" refers to C-C alkyl substituted with a cycloalkyl group of 3 to 5 carbon atoms. A group (lower alkyl) - (cycloalkyl of 3 to 5 carbon atoms) is -CH2-cyclopropyl; where the group is linked to the core structure of cryptophycin in R9 via CH2. As used herein, "epoxide ring" means a three-membered ring whose main chain or backbone consists of two carbon atoms and one oxygen atom. As used herein, "aziridine ring" means a three-membered ring whose main chain consists of two carbon atoms and one nitrogen atom. As used in the present "sulfur ring" it means a three-membered ring whose main chain consists of two carbon atoms and one sulfur atom. As used in this"episulfide ring" means a three-membered ring whose main chain consists of two carbon atoms and one sulfur atom. As used herein, "sulfate group" means a five-membered ring consisting of a carbon-carbon-oxygen-sulfur-oxygen backbone with two additional oxygen atoms connected to the sulfur atom. As used herein, "cyclopropyl ring" means a three-membered ring whose main chain consists of three carbon atoms. As used herein, "monoalkyl phosphate ring" means a five-membered ring consisting of a carbon-carbon-oxygen-phosphorus-oxygen backbone with two additional oxygen atoms, one of which has an alkyl group lower, connected to the phosphorus atom. As used herein, "simple unsubstituted group" refers to the common aromatic rings having 4n + 2 p-electrons in a monocyclic conjugate system, for example, but not limited to: furyl, pyrrolyl, thienyl, pyridyl and the like , or a bicyclic conjugate system, for example but not limited to indolyl or naphthyl. As used herein, "simple substituted aromatic group" refers to a phenyl group substituted with a simple group, selected from the group consisting of halogen and a lower alkyl group. As used herein, the term
"Bicyclic fused" refers to two linked ring systems which are optionally, independently saturated, unsaturated or aromatic. Such groups include but are not limited in any way to the naphthyl groups, which fuse an unsaturated ring with an aromatic ring, the groups having a heterocyclic group fused with a heteroaromatic group, and a heterocyclic group fused with an aromatic group. The bicyclic fused is optionally substituted with one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms and halogen. As used herein, "heteroaromatic group" refers to aromatic rings which contain one or more atoms other than carbon, independently selected from the group consisting of oxygen, nitrogen, and sulfur. It is more preferred that the heteroaromatic group have from three to eight members in the ring. It is especially preferred that the number of different carbon members be from one to three. As used herein, the term "heterocyclic" refers to saturated or unsaturated rings that contain one or more atoms other than carbon, and independently selected from the group consisting of oxygen, nitrogen, and sulfur. It is more preferred that the heterocyclic group have from three to eight members in the ring. It is especially preferred that the number of different carbon members be from one to three. As used herein, "halogen" or "halo" refers to those members of the periodic table group historically known as halogens. Halogenation methods include, but are not limited to, the addition of hydrogen halides, high temperature substitution, photohalogenation, etc., and such methods are known to the person skilled in the art. Especially preferred halogens are chlorine, bromine, fluorine and iodine. For some purposes within the scope of this invention, chlorine, bromine and fluorine are especially preferred halogens. The compounds of the formula III are particularly useful for the preparation of cryoficin compounds. The starting material corresponding to a compound of the formula I as illustrated in Scheme I, can be prepared using the descriptions available to the person skilled in the art. See Barrow, id. The processes for the preparation of compound 2 as illustrated in Scheme 1 'used trifluoroacetic acid (TFA); however, the expert will recognize that alternative agents can be used in this process. Similarly, the basic treatment uses sodium hydroxide; however, the expert will appreciate that other basic agents may also be effective. The processes for preparing the compounds of this invention are more preferably completed in the presence of a solvent. The person skilled in the art can select the appropriate solvents using the known methodologies. Without intending to limit the scope of the present invention, some preferred solvents are provided for expert guidance, including, but not limited to, a solvent selected from the group consisting of toluene, N, N-di-ethylformamide, ethyl acetate, tetrahydrofuran, and acetonitrile. The reaction time is related to the initial materials and to the operating temperature. The optimal reaction time for a given process is, as always, a commitment that is determined by considering the desired performance goals, which is favored by short reaction times, and maximum performance, which is favored by the times of prolonged reaction. The process of this invention can be further illustrated by the following Scheme 1 ':
And more particularly, Scheme 1:
catalyst Tolueno, ta 'J Í' Ís ^
As illustrated above, the catalyst is more preferably selected from the group consisting of alkyl and aryl substituted metal carboxylates., carboxylic acids, and other bifunctional compounds according to formula IV. Especially preferred catalysts are selected from the group consisting of 2-hydroxypyridine, tetrabutylammonium cyanide, and sodium benzoate / n-tetrabutyl-NHS04. The following are provided to further illustrate the advantages of the claimed process: As shown in Table 1, 2- hydroxypyridine (entries 2-4) and tetrabutylammonium benzoate (entry 5) have been shown to significantly accelerate the macrolactamization process In contrast, ring closure was very slow when the reaction was allowed to stir at room temperature without catalyst (inlet 1.) Although not listed in Table 1, tetrabutylammonium cyanide (NaBu NCN + NaCN) also promoted macrolactamization of 2. As shown in Table 1, 2 and 3 refer to the structures of Scheme 1 where Ar is phenyl.
Table 1
Table 1 (continuation;
Example 1
Cryptophycin- 51
Compound 1 (as illustrated by Scheme 1 above) (10.2 g, 11.2 mmol) was cooled to 0 ° C and dissolved in trifluoroacetic acid (TFA) (50 mL). The resulting solution was stirred at 0 ° C for 30 minutes and then concentrated under reduced pressure. The resulting syrup was diluted with toluene (250 ml) and washed with 1 N sodium hydroxide (2 x 100 ml) using brine (50 ml) to break the emulsions. The aqueous extracts were back extracted with fresh toluene (1 x 50 ml) and the organic phases were combined and dried (magnesium sulfate). TLC analysis (thin layer chromatography) did not indicate traces of the initial compound 1. The filtered solution of the amino 2 ester was diluted to 500 ml and 2-hydroxypyridine (5.34, 56.2 mmol) was added. The resulting pale yellow light solution was allowed to stir at room temperature for 14 hours. The reaction mixture became turbid so that the suspension was diluted with CH2C12 (250 ml) to ensure the solubility of the product. The sample was washed with aqueous sodium hydrogen carbonate
(NaHCO 3) saturated (3 x 100 mL) and brine (1 x 100 mL). The aqueous extracts were back extracted with methylene chloride (1 x 100 mL) and the organic extracts were combined, dried over magnesium sulfate (MgSO4), and concentrated to a thick syrup. A solution of lithium ethyl acetate (100 ml, 1: 1 v / v) was added and the solution was cooled to 0 ° C. Spontaneous crystallization occurred after 30 minutes. The mixture was filtered, and the filtrate was concentrated and induced to crystallize two additional times. Harvests harvested were combined to give 5.04 g (69%) of compound 3 (LSN 354504) as a white powder. HPLC (85:15 CH3CH / H20, 0.05% TFA in the organic and aqueous phases, flow 1 ml / minute, wavelength: 225 nm, column: Zorbax SB-C18) Rt = 6.9 minutes, 95% pure, XH NMR (300 MHz, CDC13) d 7.32-7.17 (M, 8H); 7.04 (dd, 1H, J = 2.2, 8.4); 6.82 (d, 1H, J = 8.5); 6.76 (m, 1H); 6.39 (d, 1H, J = 15.9); 5.99 (dd, 1H, J = 8.8, 15.8); 5.73 (dd, 1H, J = 2.3, 16.4); 5.50 (d, 1H, J = 7.8); 5.03 (m, 1H); 4.83 (dd, 1H, J = 3.3, 9.9); 4.73 (ABq, 1H, J = 6.4); 3.86 (s, 3H); 3.39 (dd, 1H, J = 8.6, 13.5); 3.10 (m, 2H); 2.53 (m, 2H); 2.36 (m, 1H); 1.62 (, 3H); 1.21 (s, 3H); 1.14 (s, 3H); 1.11 (d, 3H, J = 6.9); 0.71 (app.t, 6H), J = 6.0).
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (13)
1. A compound of Formula III characterized in that Ar is selected from the group consisting of phenyl, any simple substituted aromatic group, simple substituted aromatic, substituted heteroaromatic, unsubstituted heteroaromatic group, heterocyclic group, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, carbon, alkynyl of 2 to 12 carbon atoms, NR51R52, COR52, OR53, and the Formula Ar '' R 51 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R52 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R53 is selected from the group consisting of alkyl of 1 to 12 carbon atoms; R 54 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) - (R57'R57"R57 '"), aromatic group * unsubstituted, simple, substituted aromatic simple, heterocyclic, phenyl, halogen, 4- (tert-butyldimethylsiloxy) -benzyltriphenylphosphonium, COOR57, P03H, S03H, S02R58, N (R59) R60, NHOR61, NHCHR61 ', CN, N02, halogen, OR 'CH2 (O) R 62' • CH20C (0) R, CH2N (R96) R96 'CORa (alkyl of 1 carbon atoms) OR 100 R "« 9 and SR63; R95 is selected from the group consisting of -R98NH3; R96 and R96 'are each independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, -R97NH3, and -R99NR391, R99"; R97 is selected from the group consisting of alkyl of 1 to 6 carbon atoms; R98 is selected from the group consisting of alkyl of 1 to 6 carbon atoms; is alkyl of 1 to 6 carbon atoms, R99 'and R99"are each independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R100 is selected from the group consisting of hydrogen, and Si (R101R10? R103); R101 is alkyl of 1 to 6 carbon atoms; R102 is alkyl of 1 to 6 carbon atoms; R103 is alkyl of 1 to 6 carbon atoms; R104 is selected from the group consisting of C (O) (alkyl of 1 to 6 carbon atoms) N (R106) (R59) R60, C (O) (C 1-6 alkyl) N ', fused bicyclic, and NHR105N (R106) (R59) R60; R105 is selected from the group consisting of C (0) (alkyl of 1 to 6 carbon atoms), alkyl of 1 to 6 carbon atoms; RJ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms; C (O) OR107; R107 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, CR108 R 108 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R 109 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R110 is selected from the group consisting of hydrogen and alkyl of 1 to carbon atoms; R 111 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and C (0) OR107; R 55 is selected from the group consisting of hydrogen, alkyl of 16 carbon atoms C (R57'R57 'rR57' "), a simple unsubstituted, aromatic substituted simple aromatic group, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61 ', CN, N02, halogen, OR62, and SR63; R 56 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, C (R57 'R57"R57"'), a single unsubstituted aromatic group, simple substituted aromatic, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61 ', (alkyl of 1 to 6 carbon atoms) NR59R60, CN, N02, halogen, OR104, CR104, OR62, and SR **; R57 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms: R 57 'is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms: R 57' is selected from the group consisting of hydrogen, halogen, and alkyl of 3 to 12 carbon atoms: R 57 'is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; R58 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms; R 59 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC); R60 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R61 - is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 'and fluorenylmethoxycarbonyl (FMOC); R61 'is selected from the group consisting of hydrogen, OR 64 CHzNHR65, NHRC fluorenylmethoxycarbonyl (FMOC); R62 is selected from hydrogen, and alkyl of 1 to 6 carbon atoms; R62 'is selected from hydrogen, OH, OR62, and alkyl of 1 to 6 carbon atoms; R63 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R 64 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, CH2NR66R67; R65 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2, fluorenylmethoxycarbonyl (FMOC); R65 'is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2 and fluorenylmethoxycarbonyl (FMOC); R6e is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms and fluorenylmethoxycarbonyl (FMOC); R67 is selected from the group consisting of nitrogen and alkyl of 1 to 6 carbon atoms; R3 is a lower alkyl group; R4 is hydrogen or OH; R5 is hydrogen or OH; R4 and R5 can be taken together to form a second bond between Ci3 and C? 4; R < is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl, a heteroaromatic group of B ring, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl from 3 to 8 carbon atoms substituted, alkyl of 1 to 6 carbon atoms substituted, a group of the formula III ' and a group of formula III III R7 is selected from the group consisting of NR51R52, R53NR51R52, OR53, H and a lower alkyl group; R51 and R52 are independently selected from the group consisting of alkyl of 1 to 3 carbon atoms; R53 is alkyl of 1 to 3 carbon atoms; R8 is hydrogen or a lower alkyl group; or R7 and R8 can form a cyclopropyl ring; R9 is selected from the group consisting of hydrogen, a lower alkyl group, an unsaturated lower alkyl group, lower alkyl- (cycloalkyl of 3 to 5 carbon atoms) and benzyl; R10 is hydrogen or a lower alkyl group; R11 is selected from the group consisting of hydrogen, OH, a lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, OR16, halo, NR18'R19 ', N02, 0P03H2, OR19phenyl, SCH2phenyl, CONH2, C02H, P03H2, S02R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, alkyl of 1 to 6 carbon atoms, C (0) R90 and fluorenylmethoxycarbonyl (EMOC); R18 'is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and C (0) R90 '; R is alkyl of 1 to 6 carbon atoms, C (0) R and fluorenylmethoxycarbonyl (FMOC); R19 'is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and C (Q) R90 '"; R90, R90' and R90" 'are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, OR91' and aryl; R91 'is selected from the group consisting of alkyl of 1 to 6 carbon atoms, aryl, and hydrogen; R23 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R30 is hydrogen or alkyl of 1 to 6 carbon atoms; or R30 can be taken together with N with carbon 11 to form a cyclic ring of three to seven members; OR R 50 is hydrogen or n is 0, 1, or 2 m O s, 1, or 2 p is 0, 1, or 2 X is selected from the group consisting of O, C, S, NH and alkylamino; And it is selected from the group consisting of C, O, NH, S, SO, S02 and alkylamino; Z is selected from the group consisting of - (CH2) n-, - (CH2) p-0- (CH2) m- and cycloalkyl of 3 to 5 carbon atoms; ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1, characterized in that the compound of the Formula III is defined as follows: characterized in that Ar is phenyl or any simple substituted or unsubstituted aromatic or heteroaromatic group, alkyl of 1 to 12 carbon atoms, alkene of 1 to 12 carbon atoms, alkyne of 1 to 12 carbon atoms, NR51R52, OR53, Formula Ar ' R51 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R52 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R53 is selected from the group consisting of alkyl of 1 to 12 carbon atoms; R54 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, simple aromatic, phenyl, COOR57, P03H, S03H, S02R58, NR, 5"9Rt-, 60, NHOR0 1, NHCHRb i, CN, N02, ha l or geno,, and SR63; R55 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, simple aromatic, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61 ', CN, N02, halogen, OR62, and SR63; R56 is selected from the group consisting of hydrogen, alkyl of 1 to carbon atoms, simple aromatic, phenyl, COOR57, P03H, S03H, S02R58, NR59R6 C \ NHOR61, NHCHR61 '(at l of 1 to 6 carbon atoms) NR "Rbü I CN, N02, halogen, 0 £, .1J 04 CR 1 04 OR 62 SR, 6 * 3. R 57 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms; R = is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms; R 59 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and fluorenylmethoxycarbonyl (FMOC); R 60 is selected from the group qμe consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R61 is selected from the group consisting of hydroge.no, OR64, CH2NHR65, NHR 65, and fluorenylmethoxycarbonyl (FMOC); R61 'is selected from the group consisting of hydrogen, 0R64, CH2NHR65, NHR 65, and fluorenylmethoxycarbonyl (FMOC); R 62 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R 63 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R64 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, CH2NR6 6R67; R65 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2, and fluorenylmethoxycarbonyl (FMOC); R66 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms and fluorenylmethoxycarbonyl (FMOC); R67 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R3 is a lower alkyl group; R4 is hydrogen or OH; R5 is hydrogen or OH; R4 and R5 can be taken together to form a second bond between Ci3 and CX4; R6 is selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxyibeiyl, or dihaloalkoxybenzyl, a heteroaromatic group of ring B, substituted heteroaromatic, alkyl of 1 to 6 carbon atoms of B ring, 3-cycloalkyl 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, alkyl of 1 to 6 carbon atoms substituted, a group of formula III ' and a group of formula III ' R7 is hydrogen or a lower alkyl group; R8 is hydrogen or a lower alkyl group; R9 is hydrogen or a lower alkyl group; R10 is hydrogen or a lower alkyl group; R11 is selected from the group consisting of hydrogen, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, OR18, halo, NR18'R19 ', N02, OP04H2, OR19phenyl, SCH2phenyl, CONH2, C02H, P03H2, S02R23, and ZZ; R 18 is selected from the group consisting of hydrogen, aryl, and alkyl of 1 to 6 carbon atoms; R18 'is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R19 is alkyl of 1 to 6 carbon atoms; R19 'is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R23 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R30 is hydrogen or alkyl of 1 to 6 carbon atoms; R50 is hydrogen or n is 0, 1, or 2; p is 0, 1, or 2; m is 0, 1, or 2; q is 2, 3, or 4; X is O, NH or alkylamino; Y is C, O, NH, S, SO, S02 or alkylamino; Z is selected from the group consisting of (CH2) n-, - (CH2) p-0- (CH2) m- and cycloalkyl of 3 to 5 carbon atoms; ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1, characterized in that Ar is selected from the group consisting of phenyl, aromatic, or simple substituted aromatic.
4. A compound according to claim 2, characterized in that Ar is a phenyl ring substituted with parafluoro.
5. A compound according to claim 1, characterized in that R 30 is hydrogen, R 7 and R 8 are each methyl, X is O, Y is O, and R, 50 is a group of the formula
6. A compound according to claim 1, characterized in that R 30 is hydrogen, one of R 7 and R 8 is methyl, X is O, Y is O, O -r - ^^ T. and R is a group of the formula
7. A process for the preparation of a compound of formula II characterized in that: Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic group, simple substituted aromatic, substituted heteroaromatic, unsubstituted heteroaromatic group, heterocyclic group, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 atoms of carbon, alkynyl of 2 to 12 carbon atoms, NR51R52, COR52, OR53, and the Formula Ar ' R is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R52 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R53 is selected from the group consisting of alkyl of 1 to 12, carbon atoms; R54 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) - (R57'R57"R57" '), simple unsubstituted, aromatic substituted simple aromatic group, heterocyclic, phenyl, halogen, 4- (tert-butyldimethylsiloxy) -benzyltriphenylphosphonium, COOR57, P03H, S03H, S02R58, N (R59) R60, NHOR61, NHCHR61 ', CN, N02 / halogen, OR62, CH2 (0) R62' , -CH20C (0) R95, CH2N (R96) R96 ', COR100, (alkyl having 1 to 6 carbon atoms) OR100, and SR * R, 915 is selected from the group consisting of -R NH3; R and R are each independently selected from. group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, -R97NH3, and -R99NR "'R" "; R 97 is selected from the group consisting of alkyl of 1 to 6 carbon atoms; a group consisting of alkyl of 1 to 6 carbon atoms, R 99 is alkyl of 1 to 6 carbon atoms, R, 9> 9 and R 99 'are each independently selected from the group consisting of hydrogen and alkyl from 1 to 6 carbon atoms, R100 - is selected from the group consisting of hydrogen, and Si (R101R102R103): R 101 is alkyl of 1 to 6 carbon atoms, R, 1i0? 2"is alkyl of 1 to 6 atoms of carbon; R103- is alkyl of 1 to 6 carbon atoms; R104 is selected - from the group consisting of C (0) (alkyl of 1 to 6 carbon atoms) N (R106) (R59) R60, C (O) (C 1-6 alkyl) N +, fused bicyclic, and NHR105N (R106) (R59) R60; R105 is selected from the group consisting of C (O) (alkyl of 1 to 6 carbon atoms), alkyl of 1 to 6 carbon atoms; R106 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, C (0) OR107; R 107 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, nlOßnlOSpHO RJ is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R 109 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R 110 is selected from the group consisting of hydrogen and alkyl of 1 to carbon atoms; R55 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms C (R5 'R- R- a single unsubstituted, simple substituted aromatic aromatic group, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61', CN, N02, halogen, OR62, and SR63; selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, C (R57 'R57"R57'"), a single unsubstituted aromatic group, simple substituted aromatic, phenyl, COOR57, P03H, SO3H, S02R58, NR59R60, NHOR61, NHCHR61 ', (alkyl of 1 to 6 carbon atoms) NR59R60, CN, N02, halogen, OR104, CR104, OR62, and SR63; R57 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms; R 57 'is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; R57"is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; R57 '" is selected from the group consisting of hydrogen, halogen, and alkyl of 1 to 12 carbon atoms; R58 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms; R59 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC); R60 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R61 _ is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR 65 'and f-luorenylmethoxycarbonyl (FMOC); R61 '- is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR 65' and f ^ Luorenylmethoxycarbonyl (FMOC); R62 is selected from hydrogen, and alkyl of 1 to 6 carbon atoms; R62 'is selected from hydrogen, OH, OR62, and alkyl of 1 to 6 carbon atoms; R63 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R64 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, CH2NR66R67; R65 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2, and fluorenylmethoxycarbonyl (FMOC); R65 'is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2, and fluorenylmethoxycarbonyl (FMOC); R66 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms and fluorenylmethoxycarbonyl (FMOC); R67 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R3 is a lower alkyl group; R4 is hydrogen or OH; R5 is hydrogen or OH; R4 and R5 can be taken together to form a second bond between C3 and C4; R6 is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzene, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl, a heteroaromatic group of ring B, substituted heteroaromatic, alkyl of 1 to 6 carbon atoms of B ring, cycloalkyl of 3 at 8 carbon atoms, substituted cycloalkyl of 3 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, a group of formula III ' and a group of formula III III R7 is selected from the group consisting of NR51R52, R53NR51R52, OR53, H and a lower alkyl group; R51 and R52 are independently selected from the group consisting of alkyl of 1 to 3 carbons atoms > do not; R53 is alkyl of 1 to 3 carbon atoms; R8 is hydrogen or a lower alkyl group; or R7 and R8 can form a cyclopropyl ring; R9 is selected from the group consisting of hydrogen, a lower alkyl group, an unsaturated lower alkyl group, lower alkyl- (cycloalkyl of 3 to 5 carbon atoms), and benzyl; R10 is hydrogen or a lower alkyl group; R 11 is selected from the group consisting of hydrogen, OH, a lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, OR16, halo, NR18'R19 ', N02, 0P03H2, OR19phenyl, SCH2phenyl, CONH2, C02H, P03H2, SO ^ R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, alkyl of 1 to 6 carbon atoms, C (0) R90 and fluorenylmethoxycarbonyl (EMOC); R18 'is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and C (0) R90 '; R19 is alkyl of 1 to 6 carbon atoms, C (O) R90"and fluorenylmethoxycarbonyl (FMOC), R19 'is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and C (0) R 90"'; R 90 R 90' Rs R 90 'are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, OR91' and aryl; R91 'is selected from the group consisting of consists of alkyl of 1 to 6 carbon atoms, aryl, and hydrogen, R23 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, R30 is hydrogen or alkyl of 1 to 6 carbon atoms; R30 can be taken together with N with carbon 11 to form a cyclic ring of three to seven members; R50 is hydrogen or .A n is 0, 1, or 2; m is 0, 1, or 2; p e s 0, 1, or 2; X is selected from the group consisting of O, C, S, NH, and alkylamino; And it is selected from the group consisting of C, O, NH, S, SO, S02 and alkylamino; Z is selected from the group consisting of - (CH2) n-, - (CH2) P-0- (CH2) m- and cycloalkyl of 3 to 5 carbon atoms; ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; which comprises contacting a compound of formula III with a solvent a catalyst of formula IV wherein M is selected from the group consisting of hydrogen, sodium, lithium, potassium, and cesium; Xcat is selected from the group consisting of oxygen, nitrogen, and sulfur; Ycat is selected from the group consisting of oxygen, nitrogen, and sulfur; Rcatl is selected from the group consisting of alkyl of 1 to 6 carbon atoms and aryl; R cat2 is selected from the group consisting of alkyl of 1 to 6 carbon atoms and aryl.
8. A process according to claim 7, characterized in that the solvent is selected from the group consisting of toluene, N, N-dimethyl ormamide, ethyl acetate, tetrahydrofuran and acetonitrile. 61
9. A process according to claim 7, wherein the compound of Formula II is defined as follows: characterized in that Ar is phenyl or any simple substituted or unsubstituted aromatic or heteroaromatic group, alkyl of 1 to 12 carbon atoms, alkene of 1 to 12 carbon atoms, alkyne of 1 to 12 carbon atoms, NR51R52, OR53, the Formula Ar ' R 51 is selected from the group qμe consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R52 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R53 is selected from the group consisting of alkyl of 1 to 12 carbon atoms; R54 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, simple aromatic, phenyl, COOR57, P03H, SOs ?, S02R58, NRD yR, NHOR, 61, NHCHR01, CN, N02, has loo geno, OR 62, SR * R 55 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, a simple aromatic group, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61 ', CN, N02, halogen, OR62, and SR63; R56 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, a simple aromatic group, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61 ', CN, N02, halogen, OR62, and SR63; R57 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms; R58 is selected from the group consisting of hydrogen and alkyl of 1 to 12 carbon atoms; R- is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and fluorenylmethoxycarbonyl (FMOC); R 60 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R61 is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 and f-luorenylmethoxycarbonyl (FMOC); R61 's is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR? 5 and fluorenylmethoxycarbonyl (FMOC); R62 is selected from hydrogen, and alkyl of 1 to 6 carbon atoms; R63 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R 64 is selected from the group consisting of hydrogen, alkyl of 1 to < carbon atoms, CH2NR66R67; R65 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms, NH2, and fluorenylmethoxycarbonyl (FMOC); R6e is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms and fluorenylmethoxycarbonyl (FMOC); R is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R3 is a lower alkyl group; R4 is hydrogen or OH; R5 is hydrogen or OH; R4 and R5 can be taken together to form a second bond between C13 and C? 4; R6 is selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl, a heteroaromatic group of ring B, heteroaromatic substituted, alkyl of 1 to 6 carbon atoms of ring B, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, alkyl of 1 to 6 carbon atoms substituted, a group of formula III ' and a group of the formula III R7 is hydrogen or a lower alkyl group; R8 is hydrogen or a lower alkyl group; R9 is hydrogen or a lower alkyl group; R10 is hydrogen or a lower alkyl group; R11 is selected from the group consisting of hydrogen, OH, a simple alkyl group, phenyl, substituted phenyl, benzyl, and substituted benzyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, OR18, halo, NR18'R19 ', N02, OP04H2, OR19phenyl, SCH2phenyl, CONH2, C02H, P03H2, S02R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, and alkyl of 1 to 6 carbon atoms; R18 '- is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R19 &ss alkyl of 1 to 6 carbon atoms; R19 'is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R23 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R30 is hydrogen or alkyl of 1 to 6 carbon atoms; R is hydrogen or; n is 0, 1, or 2; p is 0, 1, or 2; m is 0, 1, or 2; q is 2, 3, or 4; X is 0, NH or alkylamino; Y is C, O, NH, S, SO, S02 or alkylamino; Z is selected from the group consisting of - (CH2) n-, - (CH2) P-0- (CH2) m- and cycloalkyl of 3 to 5 carbon atoms; ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group.
10. A process according to claim 7, characterized in that the solvent is toluene.
11. A process according to claim 7, characterized in that Ar is aromatic or substituted aromatic.
12. A process according to claim 7, characterized in that R30 is hydrogen, R7 and R8 are each methyl, X is O, Y is O, and R is a group of the formula
13. A process according to claim 7, characterized in that R30 is hydrogen, upo of R7 and R8 is methyl, X is O, Y is O, , 5O eß a group of_ the formula
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US025437 | 1987-03-13 | ||
| US60025437 | 1996-09-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99002150A true MXPA99002150A (en) | 2000-12-06 |
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