AU6051998A - Novel solid-phase synthesis techniques for preparing multiple analogous compounds - Google Patents
Novel solid-phase synthesis techniques for preparing multiple analogous compoundsInfo
- Publication number
- AU6051998A AU6051998A AU60519/98A AU6051998A AU6051998A AU 6051998 A AU6051998 A AU 6051998A AU 60519/98 A AU60519/98 A AU 60519/98A AU 6051998 A AU6051998 A AU 6051998A AU 6051998 A AU6051998 A AU 6051998A
- Authority
- AU
- Australia
- Prior art keywords
- phase
- solid
- cleaving
- solution
- supported intermediate
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims description 90
- 150000001875 compounds Chemical class 0.000 title claims description 17
- 238000010532 solid phase synthesis reaction Methods 0.000 title description 4
- 239000007790 solid phase Substances 0.000 claims description 104
- 239000003153 chemical reaction reagent Substances 0.000 claims description 64
- 239000012071 phase Substances 0.000 claims description 62
- 239000007859 condensation product Substances 0.000 claims description 59
- 239000007787 solid Substances 0.000 claims description 48
- -1 4-hydroxy-2-nitrophenyl Chemical group 0.000 claims description 44
- 125000005647 linker group Chemical group 0.000 claims description 39
- 239000004793 Polystyrene Substances 0.000 claims description 23
- 229920002223 polystyrene Polymers 0.000 claims description 23
- 150000001412 amines Chemical group 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- 150000001298 alcohols Chemical group 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 7
- 150000001448 anilines Chemical class 0.000 claims description 7
- 238000006482 condensation reaction Methods 0.000 claims description 7
- 239000012038 nucleophile Substances 0.000 claims description 7
- 125000002524 organometallic group Chemical group 0.000 claims description 7
- 229920000642 polymer Polymers 0.000 claims description 7
- 150000003573 thiols Chemical class 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000003776 cleavage reaction Methods 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000000543 intermediate Substances 0.000 description 53
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 31
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- MSTNXYPEXBMXNS-UHFFFAOYSA-N n-(3-amino-3-oxopropyl)-2-[[4-(dimethylamino)phenyl]diazenyl]benzamide Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=CC=C1C(=O)NCCC(N)=O MSTNXYPEXBMXNS-UHFFFAOYSA-N 0.000 description 3
- NZJYQBNQROPUML-UHFFFAOYSA-N n-[3-(butylamino)-3-oxopropyl]-2-[[4-(dimethylamino)phenyl]diazenyl]benzamide Chemical compound CCCCNC(=O)CCNC(=O)C1=CC=CC=C1N=NC1=CC=C(N(C)C)C=C1 NZJYQBNQROPUML-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- ZKADLOGPYJUFCB-UHFFFAOYSA-N n-(2-amino-2-oxoethyl)-4-methoxybenzamide Chemical compound COC1=CC=C(C(=O)NCC(N)=O)C=C1 ZKADLOGPYJUFCB-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- BYQQQHLNNCWLGU-UHFFFAOYSA-N 1-n,1-n'-dimethylethane-1,1,2-triamine Chemical compound CNC(CN)NC BYQQQHLNNCWLGU-UHFFFAOYSA-N 0.000 description 1
- RXMTUVIKZRXSSM-UHFFFAOYSA-N 2,2-diphenylethanamine Chemical compound C=1C=CC=CC=1C(CN)C1=CC=CC=C1 RXMTUVIKZRXSSM-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- SIEIOUWSTGWJGE-UHFFFAOYSA-N 2-[(4-methoxyphenyl)formamido]acetic acid Chemical group COC1=CC=C(C(=O)NCC(O)=O)C=C1 SIEIOUWSTGWJGE-UHFFFAOYSA-N 0.000 description 1
- TUQMQTLZTAIKQD-UHFFFAOYSA-N 2-[[4-(dimethylamino)phenyl]diazenyl]-n-[3-(2,2-diphenylethylamino)-3-oxopropyl]benzamide Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=CC=C1C(=O)NCCC(=O)NCC(C=1C=CC=CC=1)C1=CC=CC=C1 TUQMQTLZTAIKQD-UHFFFAOYSA-N 0.000 description 1
- SMUYGGGTEZPMJG-UHFFFAOYSA-N 2-[[4-(dimethylamino)phenyl]diazenyl]-n-[3-(3-methoxypropylamino)-3-oxopropyl]benzamide Chemical compound COCCCNC(=O)CCNC(=O)C1=CC=CC=C1N=NC1=CC=C(N(C)C)C=C1 SMUYGGGTEZPMJG-UHFFFAOYSA-N 0.000 description 1
- CEQFOVLGLXCDCX-UHFFFAOYSA-N 2-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=CC=C1C(O)=O CEQFOVLGLXCDCX-UHFFFAOYSA-N 0.000 description 1
- WCFJUSRQHZPVKY-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NCCC(O)=O WCFJUSRQHZPVKY-UHFFFAOYSA-N 0.000 description 1
- FJHRSRTZVNKFSX-UHFFFAOYSA-N 3-[[2-[[4-(dimethylamino)phenyl]diazenyl]benzoyl]amino]propanoic acid Chemical group C1=CC(N(C)C)=CC=C1N=NC1=CC=CC=C1C(=O)NCCC(O)=O FJHRSRTZVNKFSX-UHFFFAOYSA-N 0.000 description 1
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000005289 controlled pore glass Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001916 cyano esters Chemical class 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- GOSYNCLIYPUWGK-UHFFFAOYSA-N n-[2-(benzylamino)-2-oxoethyl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NCC(=O)NCC1=CC=CC=C1 GOSYNCLIYPUWGK-UHFFFAOYSA-N 0.000 description 1
- SUIXDYTZNLNJSZ-UHFFFAOYSA-N n-[2-[2-(3,4-dimethoxyphenyl)ethylamino]-2-oxoethyl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NCC(=O)NCCC1=CC=C(OC)C(OC)=C1 SUIXDYTZNLNJSZ-UHFFFAOYSA-N 0.000 description 1
- PPKNPKGNGBISKS-UHFFFAOYSA-N n-[2-[2-(dimethylamino)ethylamino]-2-oxoethyl]-4-methoxybenzamide Chemical compound COC1=CC=C(C(=O)NCC(=O)NCCN(C)C)C=C1 PPKNPKGNGBISKS-UHFFFAOYSA-N 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
- C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
- C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Structural Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
NOVEL SOLID-PHASE SYNTHESIS TECHNIQUES FOR PREPARING MULTIPLE
ANALOGOUS COMPOUNDS
FIELD OF THE INVENTION This invention relates to chemical synthesis using solid-phase techniques.
BACKGROUND OF THE INVENTION
Solid-phase synthesis techniques are used in preparing peptides (Merrifield, J. Am. Chem. Soc. 85:2149-2154 (1963)), oligonucleotides {Oligonucleotide Synthesis: A Practical Approach, Gait, ed. IRL Press, Oxford (1964)) and small organic molecules (Leznoff, Ace. Chem. Res., If, 327 (1978); Hermkins, Tetrahedron, 52, 4527-4554 (1996)). Solid-phase synthesis techniques are powerful methods for the combinatorial synthesis of large libraries (Bunin et al., J. Am. Chem. Soc. 114, 10997-10998 (1992)), which libraries are in themselves powerful tools in pharmaceutical research (U.S. Patent No. 5,506,337; Terrett et al, Tetrahedron, 51, 8135-8173 (1995)).
One of the advantages of solid-phase techniques is that reactions can be driven to completion by using reagents in large excess, whereupon the excess reagent is removed simply by filtration. The solid-phase supported product is then released from the solid support by a cleaving reagent, whereupon the solution-phase product is separated from the solid-phase by filtration. Alternatively, the final step reaction in the solid-phase synthetic scheme is coupled with the cleavage reaction resulting in the formation of final product and a concomitant release of the product into the solution-phase (Dewitt and Czarnik, Ace. Chem. Res., 29, 114 (1996)). Thus, as traditionally applied, solid-phase synthetic methods afford a single solution-phase product from each aliquot of solid-phase supported starting material or intermediate. Techniques are needed that will allow for the preparation of multiple compounds from one aliquot of solid-phase supported intermediate.
The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.
SUMMARY OF THE INVENTION This application relates to a process for synthesizing multiple analogous compounds, which process comprises:
(a) reacting a solid-phase supported intermediate with a cleaving/condensing reagent by a means which results in the formation of a solution-phase condensation product and affords remainder solid-phase supported intermediate;
(b) separating the solution-phase condensation product formed by step (a) from the solid-phase;
(c) reacting remainder solid-phase supported intermediate with a cleaving/condensing reagent distinct from the cleaving/condensing reagent applied in step (a) to give a solution-phase condensation product analogous to the solution-phase condensation product formed by step (a);
(d) separating the solution-phase condensation product formed by step (c) from the solid-phase; and
(e) optionally repeating process steps (c) and (d) one or more additional times, if remainder solid-phase supported intermediate is present, using a further distinct cleaving/condensing reagent for each repetition to give additional analogous solution-phase condensation products.
A second aspect of this invention relates to a process for synthesizing multiple analogous compounds, which process comprises:
(a) reacting a solid-phase supported intermediate with a cleaving/condensing reagent by a means which results in the formation of a solution-phase condensation product and affords remainder solid-phase supported intermediate;
(b) separating the solution-phase condensation product formed by step (a) from the solid-phase;
(c) optionally repeating process steps (a) and (b) one or more additional times using a distinct cleaving/condensing reagent for each repetition to give analogous solution-phase condensation products;
(d) modifying remainder solid-phase supported intermediate to give a solid-phase supported intermediate analogous to the solid phase-support intermediate used in steps (a) through (c);
(e) reacting the analogous solid-phase supported intermediate with a cleaving/condensing reagent to give a solution-phase condensation product analogous to the solution-phase condensation product(s) formed by steps (a) or (c);
(f) separating the solution-phase condensation product formed by step (e) from the solid-phase;
(g) optionally repeating process steps (e) and (f) one or more additional times, if remainder solid-phase supported intermediate is present, using a further distinct cleaving/condensing reagent for each repetition to give additional analogous solution-phase condensation products; and
(h) optionally repeating process steps (d) through (g) one or more additional times to give additional analogous solution-phase condensation products.
A third aspect of this invention relates to a combinatorial library comprising multiple analogous compounds prepared by the processes of this invention.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms used in this specification and claims have the meanings given below.
"Alkyl", as in 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfmylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-aminosulfonylbenzoylaminoalkyl, and 3-aminosulfonylpropionylaminoalkyl, means a straight branched, saturated, aliphatic hydrocarbon radical having from 1 to 6 carbon atoms.
"Analogous compounds" or "analogous solution-phase condensation products" means that the compounds or products described are chemically similar to one another in that they are derived from similar starting materials or intermediates, but they are chemically distinct.
"Linking group" means a divalent radical which links an intermediate compound to the solid support. For the purposes of this application linking groups are referred to in the specification and the claims as the monovalent precursor radical is attached to the solid support. Thus, for example, a linking group of the following formula:
wherein SS is the solid support, is referred to as 4-hydroxyphenylthioalkyl, which includes, for example, 4-hydroxyphenylthiomethyl.
"Optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "optionally repeating process steps (c) and (d)" means that the process steps referred to may or may not occur in order to fall within the scope of the invention.
"Remainder solid-phase supported intermediate" means solid-phase supported intermediate that remains unreacted and attached to the solid-phase support after a portion of the solid-phase supported intermediate has been subjected to a cleaving/condensation reaction and the resulting solution-phase condensation product has been separated from the solid-phase.
"Substoichiometric amount" means a molar amount which is less than one molar equivalent. Thus, when referring to substoichiometric amounts of cleaving/condensing reagents in describing or claiming the process of this invention, it is intended that the molar amount of reagent present in the reaction medium is a fraction of the molar amount of solid-phase supported intermediate present.
The process of this invention relates to the synthesis of multiple analogous compounds by the sequential treatment of a solid-phase supported intermediate by a means that results in the formation of a solution-phase condensation product and affords an amount of the solid-phase supported intermediate in remainder sufficient to perform subsequent
cleavage/condensation reactions with other cleaving/condensing reagents. For example, the process of this invention can be depicted by the following reaction scheme:
Scheme 1
,ss
,ss
1 (a)
Rπv .ss
1 (b)
RnY optional
,ss
1 (n)
wherein SS is a solid support, X is a the linking group between the solid support and the solid-phase supported intermediate, Y is any moiety capable of causing a cleavage/condensation reaction, R1, Ra, Rb and R" are each any non-reactive moiety and Z is a connecting moiety formed by the condensation reaction.
The process of this invention comprises reacting a solid-phase supported intermediate (Formula 1) with an appropriate cleaving/condensing reagent (RΥ) by any means whereby the solid-phase supported intermediate is cleaved from the solid support and concomitantly condensed with the cleaving/condensing agent to form a first solution-phase condensation product (Formula 2(a)) and some fraction of the solid-phase supported intermediate remains unreacted, separating the first solution-phase condensation product from the solid-phase, reacting
the remainder solid-phase supported intermediate (Formula 1(a)) with a second distinct cleaving/condensing reagent (RbY) to give a second solution-phase condensation product (Formula 2(b)); and then separating the second solution-phase condensation product from the solid-phase. Remainder solid-phase supported intermediate present after separation of the second solution-phase condensation product (Formula 1(b)) or after any subsequent condensation/cleavage reaction and separation steps (Formula \{nj) is optionally further reacted with an appropriate cleaving/condensing reagent (R"Y) to give additional analogous solution-phase condensation products (Formula 2(«)).
Remainder solid-phase supported intermediate can be afforded by any means which results in an incomplete reaction relative to the amount of solid-phase supported intermediate used. For example, an incomplete reaction can be effected by varying the reaction conditions (e.g., reaction temperatures or pressures, solvents, etc.) to slow the rate of reaction or by limiting the reaction times. A convenient means for providing that an incomplete reaction occurs is by using a substoichiometric amount of the cleaving/condensing reagent relative to the amount of solid-phase supported intermediate used.
Suitable solid supports include polymers (e.g., polystyrene, poly(ethylene glycol) grafted polystyrene, poly(ethylene glycol) grafted polyacrylamide, etc.), cellulose, derivatized silica gel supports, derivatized controlled-pore glass, and the like. Suitable linking groups can comprise any chemical functionality or bond that is capable of reacting with the cleaving/condensing reagent. For example, suitable linking groups for carboxylic acid intermediates include 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, and the like, wherein an ester linkage is formed between the intermediate and linking group, or 4-aminosulfonylbenzoylaminoalkyl, 3-aminosulfonylpropionylaminoalkyl, and the like, wherein an amide linkage is formed. Other suitable linkers for various intermediate compounds are known to those of ordinary skill in the art.
Suitable cleaving/condensing reagents include nucleophilic amines, organometallic reagents (e.g., Grignard reagents, organolithium reagents, etc.), alcohols, anilines, phenols, thiols, activated carbon nucleophiles (e.g., beta keto esters, beta diesters, beta cyanoesters, nitroalkanes, etc.), and the like.
While the broadest definition of this invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. For example, generally preferred is a
process in which remainder solid-phase supported intermediate is afforded by reacting the solid-phase supported intermediate with a substoichiometric amount of the cleaving/condensing reagent. More preferred is a process in which the solid support is a polymer and the solid-phase supported intermediate is a carboxylic acid derivative which together with the linking group to which it is attached forms an ester or amide linkage. More preferred is a process in which the linking group is selected from 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfmylalkyl, 4-hydroxyphenylsulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl and 3-aminosulfonylpropionylalkyl. Particularly preferred is a process in which the cleaving/condensing reagent is selected from amines and organometallic reagents or in which the linking group is 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl and the cleaving/condensing reagent is selected from alcohols, anilines, thiols and carbon nucleophiles. More particularly preferred is a process in which the solid support is selected from polystyrene and poly(ethylene glycol) grafted polystyrene. Most preferred is a process in which the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the cleaving/condensing reagent is an amine.
By further example, a process of this invention in which the solid-phase supported intermediate forms an ester linkage with the linking group and Y is amino is depicted by the
following reaction scheme:
Scheme 2
wherein SS is a solid support and R2, Ra, Rb and R" are each any non-reactive moiety.
The process of this invention in which the solid-phase supported intermediate forms an ester linkage with the linking group and the cleaving/condensing reagent is an amine can be carried out under standard acylation reaction conditions and using typical separation techniques. For example, the cleavage/condensation reaction can be carried out in the presence of a suitable base (e.g., triethylamine, diisopropylethylamine, l,4-diazabicyclo[2.2.2]octane, N-methylmorpholine, etc., preferably triethylamine) in a suitable solvent (e.g., 2,6-lutidine, pyridine, toluene, tetrahydrofuran, etc., preferably 2,6-lutidine or pyridine) at 0 to 70°C, preferably at approximately ambient temperature, and requires 1 to 100 hours. The solution-phase condensation product can separated from the solid-phase by filtering and washing
the solid support with suitable solvents (e.g., dichloromethane, methanol, tert-butyl methyl ether, toluene, tetrahydrofuran, diethylether, etc.). Certain solid supports (e.g., polystyrene) swell in the presence of organic solvents and in such cases separation can be facilitated by washing the solid support alternately with a solvent that produces a large amount of swelling (e.g., dichloromethane, toluene or tetrahydrofuran) and a solvent that produces a small amount of swelling (e.g., tert-butyl methyl ether, diethyl ether or methanol). Further details of the procedures set forth above are provided in Examples 3 and 4, infra.
The solid-phase supported intermediates used in the process of this invention can be prepared by methods known in the art. For example, solid-phase supported intermediates which form an ester linkage with the linking group, wherein the linking group is
4-hydroxyphenylthioalkyl can be prepared by reacting an appropriate carboxylic acid or activated ester (e.g., carboxylic acid halide), or protected derivative thereof, with an appropriate 4-hydroxyphenylthioalkylpolystyrene. The reaction can be effected in the presence of a suitable coupling agent (e.g., diisopropylcarbodumide, benzotriazole-1-yloxytrispynolidinophosphonium hexafluorophosphate (PyBOP ), bromotrispyrrolidinophosphonim hexafluorophosphate, 0-benzotriazole-N,N,N 'N -tetramethyluronium hexafluorophosphate, NTVN'N-tetramethylfluoroformamidinium hexafluorophosphate, etc.) a suitable base (e.g., triethylamine, N-methylmorpholine, diisopropylethylamine, etc.) and a suitable catalyst (e.g., 4-dimethylaminopyridine, 1-hydroxybenzotriazole, l-hydroxy-7-azabenzotriazole, etc.) at 20 to 60 °C, preferably at approximately ambient temperature, and requires 10 to 100 minutes. Further details of the procedures set forth above are provided in Examples 1 and 2, infra.
Proceeding in a fashion similar to that described above, the process of this invention can be performed and solid-phase supported intermediates can be prepared using the other solid supports and linking groups described herein or known to those of ordinary skill in the art.
An alternative process of this invention can be depicted by the following reaction scheme:
Scheme 3
,ss
R'\ ^,SS
1 (a)
„ss
\ „ss
3(a)
An alternative process of this invention comprises reacting a solid-phase supported intermediate by any means whereby a first solution-phase condensation product and some fraction of the solid-phase supported intermediate remains unreacted, separating the first solution-phase condensation product from remainder solid-phase supported intermediate, modifying the remainder solid-phase supported intermediate to give a second solid-phase supported intermediate (Formula 3) and then reacting the second solid-phase supported intermediate with a cleaving/condensing reagent to give an analogous solution-phase condensation product Formula (4(a)).
Examples:
EXAMPLE 1 4-(4-Methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene
The following describes the preparation of a solid-phase supported intermediate in which the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the intermediate is 4-methoxybenzoylaminoacetic acid.
A mixture of tert-butoxycarbonylaminoacetic acid (160 mg, 0.91 mmol) and diisopropylcarbodumide (145 μL, 0.93 mmol) in dichloromethane (2 mL) was swirled to give a slurry. The slurry was combined with 4-hydroxyphenylthiomethylpolystyrene (236 mg, 1.23 meq/g), triethylamine (290 μL, 2.09 mmol) and 4-dimethylaminopyridine (a few crystals). The mixture was vortexed and then allowed to stand at ambient temperature for 1 hour. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x) to give 4-tert-butoxycarbonylaminoacetoxyphenylthiomethylpolystyrene.
The 4-tert-butoxycarbonylaminoacetoxyphenylthiomethylpolystyrene was treated with dichloromethane/trifiuoroacetic acid/anisole (50:48:2 by volume) for 0.5 hours at ambient temperature. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x) to give 4-aminoacetoxyphenylthiomethylpolystyrene.
A mixture of 4-methoxybenzoic acid (135 mg, 0.91 mmol) and excess thionyl chloride was heated at reflux for 5 minutes. The excess thionyl chloride was removed under vacuum to give crude 4-methoxybenzoyl chloride. The crude 4-methoxybenzoyl chloride was dissolved in dichloromethane (2 mL) and the solution was added to a mixture of 4-aminoacetoxyphenyl- thiomethylpolystyrene and excess triethylamine. The mixture was vortexed and allowed to stand at ambient temperature for 0.5 hours. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x) to give 4-(4-methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene.
EXAMPLE 2 4-{3-[2-(4-Dimethylaminophenylazo)benzoylamino]propionyloxy}phenylthiomethylpolystyrene
The following describes the preparation of solid-phase supported intermediate in which
the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the intermediate is 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionic acid.
A mixture of 3-tert-butoxycarbonylaminopropionic acid (409 mg, 2.15 mmol) and diisopropylcarbodumide (360 μL, 2.3 mmol) in dichloromethane (10 mL) was swirled to give a slurry. The slurry was combined with 4-hydroxyphenylthiomethylpolystyrene (1.02 g, 0.75 meq/g), 4-dimethylaminopyridine (70 mg, 0.64 mmol) and TV-methylmorpholine (0.6 mL, 5.5 mmol). The mixture was bubbled with nitrogen gas at ambient temperature for 2 hours. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x) to give 4-(3-tert-butoxycarbonylaminopropionyloxy)phenylthiomethylpolystyrene.
The 4-(3-tert-butoxycarbonylaminopropionyloxy)phenylthiomethylpolystyrene was treated with dichloromethane/trifluoroacetic acid/anisole (50:48:2 by volume) for 0.5 hours at ambient temperature. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x) to give 4-aminopropionyloxyphenylthiomethylpolystyrene.
A mixture of the 4-aminopropionyloxyphenylthiomethylpolystyrene, 2-(4-dimethylamino-phenylazo)benzoic acid (0.67 g, 2.5 mmol), PyBOP* (1.35 g, 2.6 mmol) and ΛXnethylmoφholine (0.67 mL, 6.1 mmol) in N,Λ-dimethylformamide (DMF) (25 mL) was allowed to stand for 3 hours. The mixture was filtered and the solid residue was washed with DMF (2x) and alternately with dichloromethane and then methanol until the washes were colorless. The mixture was filtered and the solid residue was dried under vacuum to give 4-{3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxy}phenylthiomethylpolystyrene.
EXAMPLE 3
N-Benzyl-2-(4-methoxybenzoylamino)acetamide, N-[2-(3,4-dimethoxyphenyl)ethyl]-
2-(4-methoxybenzoylamino)acetamide and N-(2-dimethylaminoethyl)-
2-(4-methoxybenzoylamino)acetamide
The following describes the process of this invention in which three batches of solution-phase condensation products are prepared from a single batch of solid-phase supported intermediate. Step l
A mixture of 4-(4-methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene, prepared as in Example 1, benzylamine (5 μL, 45.8 μmol) and triethylamine (15 μL, 0.11 mmol) in 2,6-lutidine (2 mL) was allowed to stand for 4 hours. The mixture was filtered and the solid-phase was washed with dichloromethane (lx) and then methanol (3x). The combined filtrate and washes were concentrated by evaporation to give ,V-benzyl- 2-(4-methoxybenzoylamino)acetamide. Step 2
A mixture of remainder 4- (4-methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene, obtained from Step 1, 2-(3,4-dimethoxyphenyl)ethylamine (5 μL, 29.6 μmol) and triethylamine (20 μL, 0.14 mmol) in 2,6-lutidine (2 mL) for approximately 12 hours. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x). The combined filtrate and washes were concentrated by evaporation to give N-[2-(3,4-dimethoxyphenyl)ethyl]- 2-(4-methoxybenzoylamino)acetamide (8.8 mg, 24.4 μmol). Step 3
A mixture of remainder 4-(4-methoxybenzoylaminoacetoxy)phenylthiomethylpolystyrene, obtained from Step 2, 2-dimethylaminoethylamine (4 μL, 36.4 μmol) and triethylamine (35 μL, 0.25 mmol) in 2,6-lutidine (2 mL) for approximately 12 hours. The mixture was then filtered and the solid residue was washed alternately with dichloromethane and then methanol (3x). The combined filtrate and washes were concentrated by evaporation to give crude N-(2-dimethylaminoethyl)- 2-(4-methoxybenzoylamino)acetamide (16.8 mg, 60.1 mmol).
EXAMPLE 4
N-Butyl-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide, Λ^-allyl-
3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide, N-(3-methoxypropyl)-
3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide and N-(2,2-diphenylethyl)-
3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide
The following describes the process of this invention in which five batches of solution-phase condensation products were prepared from a single batch of solid-phase supported intermediate. Step l
A mixture of 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxyphenylthio- methylpolystyrene (111 mg), prepared as in Example 2, triethylamine (0.05 mL, 0.36 mmol) and butylamine (5 μL, 50.6 μmol) in pyridine (0.95 mL) was allowed to stand for 1.5 hours at ambient temperature. The mixture was filtered and the solid residue was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until the washes were colorless. The combined filtrate and washes were concentrated and the residue was purified by flash column chromotography eluting with chloroform/methanol (95:5) to give N-butyl- 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide (7.6 mg, 19.2 μmol).
Η ΝMR: 9.54 (t, 1H, ΝH); 8.32 (d, 1H, ArH); 7.82 (d, 2H, ArH); 7.80 (d, 1H, ArH); 7.46 (m, 2H, ArH); 6.79 (d, 1H, ArH); 6.18 (t, 1H, ΝH); 3.80 (q, 2H, CH2); 3.12 (q, 2H, CH2); 3.12 (s, 3H, CH3); 2.56 (t, 2H, CH2); 1.33 (m, 2H, CH2); 1.18 (m, 2H, CH2); 0.75 (t, 3H, CH3).
ESMS: (M+H) calc'd. 396.2, obs'd. 396.1.
Step 2
A mixture of remainder 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxy- phenylthiomethylpolystyrene, obtained in Step 1, triethylamine (0.05 mL, 0.36 mmol) and allylamine (5 μL, 66.6 μmol) in pyridine (0.95 mL) was allowed to stand for 1.5 hours at ambient temperature. The mixture was filtered and the solid residue was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until the washes
were colorless. The combined filtrate and washes were concentrated and the residue was purified by flash column chromotography eluting with chloroform/methanol (95:5) to give N-allyl- 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide (5.2 mg, 13.7 μmol).
Η ΝMR: 9.57 (t, 1H ΝH); 8.32 (d, 1H, ArH); 7.82 (d, 2H, ArH); 7.80 (d, 1H, ArH); 7.46 (m, 2H, ArH); 6.79 (d, 1H, ArH); 6.02 (t, 1H, ΝH); 5.70 (m, 1H, =CH); 5.03 (m, 2H, =CH2); 3.80 (m, 4H, CH2); 3.13 (s, 3H, CH3); 2.60 (t, 2H, CH2).
ESMS (M+H) calc'd. 380.2, obs'd. 380.1.
Step 3
A mixture of remainder 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxy- phenylthiomethylpolystyrene, obtained in Step 2, triethylamine (0.05 mL, 0.36 mmol) and 3-methoxypropylamine (5 μL, 49 μmol) in pyridine (0.95 mL) was allowed to stand for 1.5 hours at ambient temperature. The mixture was filtered and the solid residue was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until the washes were colorless. The combined filtrate and washes were concentrated and the residue was purified by flash column chromotography eluting with chloroform/methanol (95:5) to give N-(3-methoxypropyl)-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide (7.9 mg, 19.2 μmol).
'H ΝMR: 9.55 (t, 1H, ΝH); 8.32 (d, 1H, ArH); 7.82 (d, 2H, ArH); 7.80 (d, 1H, ArH); 7.46 (m, 2H, ArH); 6.79 (d, 1H, ArH); 6.31 (t, 1H, ΝH); 3.80 (q, 2H, CH2); 3.27 (m, 4H, CH2); 3.17 (s, 3H, CH3); 3.12 (s, 3H, CH3); 2.55 (t, 2H, CH2); 1.62 (5°, 2H, CH2).
ESMS (M+H) calc'd. 412.2, obs'd. 412.1.
Step 4
A mixture of remainder 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxy- phenylthiomethylpolystyrene, obtained in Step 3, triethylamine (0.05 mL, 0.36 mmol) and 2,2-diphenylethylamine (5.5 mg, 25.3 μmol) in pyridine (0.95 mL) was allowed to stand for
1.5 hours at ambient temperature. The mixture was filtered and the solid residue was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until the washes were colorless. The combined filtrate and washes were concentrated and the residue was purified by flash column chromotography eluting with chloroform/methanol (95:5) to give N-(2,2-diphenylethyl)-3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide (4.1 mg, 7.9 μmol).
■H ΝMR: 9.43 (t, IH, ΝH); 8.32 (d, IH, ArH); 7.82 (d, 2H, ArH); 7.80 (d, IH, ArH); 7.46 (m, 2H, ArH); 6.79 (d, IH, ArH); 5.77 (t, IH, ΝH); 5.33 (t, IH, CH); 3.99 (t, 2H, CH2); 3.76 (q, 2H, CH2); 3.07 (s, 3H, CH3); 2.20 (t, 2H, CH2).
ESMS (M+H) calc'd. 520.3, obs'd. 520.3.
Step 5
A mixture of remainder 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionyloxy- phenylthiomethylpolystyrene, obtained in Step 4, triethylamine (0.05 mL, 0.36 mmol) and butylamine (50 μL, 0.51 mmol) in pyridine (0.95 mL) was allowed to stand for 1.5 hours at ambient temperature. The mixture was filtered and the solid residue was washed alternately with dichloromethane and methanol or dichloromethane and tert-butyl methyl ether until the washes were colorless. The combined filtrate and washes were concentrated and the residue was purified by flash column chromotography eluting with chloroform/methanol (95:5) to give N-butyl- 3-[2-(4-dimethylaminophenylazo)benzoylamino]propionamide (66.2 mg, 170 μmol).
Η NMR: 9.54 (t, IH, NH); 8.32 (d, IH, ArH); 7.82 (d, 2H, ArH); 7.80 (d, IH, ArH); 7.46 (m, 2H, ArH); 6.79 (d, IH, ArH); 6.18 (t, IH, NH); 3.80 (q, 2H, CH2); 3.12 (q, 2H, CH2); 3.12 (s, 3H, CH3); 2.56 (t, 2H, CH2); 1.33 (m, 2H, CH2); 1.18 (m, 2H, CH2); 0.75 (t, 3H, CH3).
ESMS: (M+H) calc'd. 396.2, obs'd. 396.1.
Claims (37)
1. A process for synthesizing compounds, which process comprises:
(a) reacting a solid-phase supported intermediate with a cleaving/condensing reagent by a means which results in the formation of a solution-phase condensation product and affords remainder solid-phase supported intermediate; and
(b) separating the solution-phase condensation product formed by step (a) from the solid-phase.
2. The process of Claim 1 in which the condensation/cleavage reaction of step (a) is effected by reacting the solid-phase supported intermediate with a substoichiometric amount of the cleaving/condensing reagent.
3. The process of Claim 2 in which the solid support is a polymer and the solid-phase supported intermediate forms an ester or amide linkage with the linking group.
4. The process of Claim 3 in which the linking group is selected from 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfmylalkyl, 4-hydroxyphenysulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl and 3-aminosulfonylpropionylaminoalkyl.
5. The process of Claim 4 in which the cleaving/condensing reagent is selected from amines and organometallic reagents.
6. The process of Claim 5 in which the linking group is 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl and the cleaving/condensing reagent is selected from alcohols, anilines, thiols and carbon nucleophiles.
7. The process of Claim 6 in which the solid support is selected from polystyrene and poly(ethylene glycol) grafted polystyrene.
8. The process of Claim 7 in which the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the cleaving/condensing moiety is an amine.
9. A process for synthesizing multiple analogous compounds, which process comprises:
(a) reacting a solid-phase supported intermediate with a cleaving/condensing reagent by a means which results in the formation of a solution-phase condensation product and affords remainder solid-phase supported intermediate;
(b) separating the solution-phase condensation product formed by step (a) from the solid-phase;
(c) reacting remainder solid-phase supported intermediate with a cleaving/condensing reagent distinct from the cleaving/condensing reagent applied in step (a) to give a solution-phase condensation product analogous to the solution-phase condensation product formed by step (a);
(d) separating the solution-phase condensation product formed by step (c) from the solid-phase; and
(e) optionally repeating process steps (c) and (d) one or more additional times, if remainder solid-phase supported intermediate is present, using a further distinct cleaving/condensing reagent for each repetition to give additional analogous solution-phase condensation products.
10. The process of Claim 9 in which remainder solid-phase supported intermediate is afforded by reacting the solid-phase supported intermediate with a substoichiometric amount of the cleaving/condensing reagent.
11. The process of Claim 10 in which the solid support is a polymer and the solid-phase supported intermediate forms an ester or amide linkage with the linking group.
12. The process of Claim 10 in which the linking group is selected from 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenysulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl and 3-aminosulfonylpropionylaminoalkyl.
13. The process of Claim 12 in which the cleaving/condensing reagent is selected from amines and organometallic reagents.
14. The process of Claim 13 in which the linking group is 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl and the cleaving/condensing reagent is selected from alcohols, anilines, thiols and carbon nucleophiles.
15. The process of Claim 14 in which the solid support is selected from polystyrene and poly(ethylene glycol) grafted polystyrene.
16. The process of Claim 15 in which the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the cleaving/condensing moiety is an amine.
17. A process for synthesizing multiple analogous compounds, which process comprises:
(a) reacting a solid-phase supported intermediate with a cleaving/condensing reagent by a means which results in the formation of a solution-phase condensation product and affords remainder solid-phase supported intermediate;
(b) separating the solution-phase condensation product formed by step (a) from the solid-phase;
(c) optionally repeating process steps (a) and (b) one or more additional times using a distinct cleaving/condensing reagent for each repetition to give analogous solution-phase condensation products;
(d) modifying remainder solid-phase supported intermediate to give a solid-phase supported intermediate analogous to the solid-phase support intermediate used in steps (a) through (c);
(e) reacting the analogous solid-phase supported intermediate with a cleaving/condensing reagent to give a solution-phase condensation product analogous to the solution-phase condensation product(s) formed by steps (a) or (c);
(f) separating the solution-phase condensation product formed by step (e) from the solid-phase;
(g) optionally repeating process steps (e) and (f) one or more additional times, if remainder solid-phase supported intermediate is present, using a further distinct cleaving/condensing reagent for each repetition to give additional analogous solution-phase condensation products; and
(h) optionally repeating process steps (d) through (g) one or more additional times to give additional analogous solution-phase condensation products.
17. The process of Claim 16 in which remainder solid-phase supported intermediate is afforded by reacting the solid-phase supported intermediate with a substoichiometric amount of the cleaving/condensing reagent.
18. The process of Claim 17 in which the solid support is a polymer and the solid-phase supported intermediate forms an ester or amide linkage with the linking group.
19. The process of Claim 18 in which the linking group is selected from 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenysulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl and 3-aminosulfonylpropionylaminoalkyl.
20. The process of Claim 19 in which the cleaving/condensing reagent is selected from amines and organometallic reagents.
21. The process of Claim 19 in which the linking group is 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl and the cleaving/condensing reagent is selected from alcohols, anilines, thiols and carbon nucleophiles.
22. The process of Claim 20 in which the solid support is selected from polystyrene and poly(ethylene glycol) grafted polystyrene.
23. The process of Claim 22 in which the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the cleaving/condensing moiety is an amine.
24. A combinatorial library of multiple analogous compounds prepared by a process which comprises:
(a) reacting a solid-phase supported intermediate with a cleaving/condensing reagent by a means which results in the formation of a solution-phase condensation product and affords remainder solid-phase supported intermediate;
(b) separating the solution-phase condensation product formed by step (a) from the solid-phase;
(c) reacting remainder solid-phase supported intermediate with a cleaving/condensing reagent distinct from the cleaving/condensing reagent applied in step (a) to give a solution-phase condensation product analogous to the solution-phase condensation product formed by step (a);
(d) separating the solution-phase condensation product formed by step (c) from the solid-phase; and
(e) optionally repeating process steps (c) and (d) one or more additional times, if remainder solid-phase supported intermediate is present, using a further distinct cleaving/condensing reagent for each repetition to give additional analogous solution-phase condensation products.
25. The combinatorial library of Claim 24 prepared by the process in which the solid support is a polymer and the solid-phase supported intermediate forms an ester or amide linkage with the linking group.
26. The combinatorial library of Claim 25 prepared by the process in which the linking group is selected from 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenysulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl and 3-aminosulfonylpropionylaminoalkyl.
27. The combinatorial library of Claim 26 prepared by the process in which the cleaving/condensing reagent is selected from amines and organometallic reagents.
28. The combinatorial library of Claim 27 prepared by the process in which the linking group is 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl and the cleaving/condensing reagent is selected from alcohols, anilines, thiols and carbon nucleophiles.
29. The combinatorial library of Claim 28 prepared by the process in which the solid support is selected from polystyrene and poly( ethylene glycol) grafted polystyrene.
30. The combinatorial library of Claim 29 prepared by the process in which the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the cleaving/condensing moiety is an amine.
31. A combinatorial library of multiple analogous compounds prepared by a process for synthesizing multiple analogous compounds, which process comprises:
(a) reacting a solid-phase supported intermediate with a cleaving/condensing reagent by a means which results in the formation of a solution-phase condensation product and affords remainder solid-phase supported intermediate;
(b) separating the solution-phase condensation product formed by step (a) from the solid-phase;
(c) optionally repeating process steps (a) and (b) one or more additional times using a distinct cleaving/condensing reagent for each repetition to give analogous solution-phase condensation products;
(d) modifying remainder solid-phase supported intermediate to give a solid-phase supported intermediate analogous to the solid-phase support intermediate used in steps (a) through (c);
(e) reacting the analogous solid-phase supported intermediate with a cleaving/condensing reagent to give a solution-phase condensation product analogous to the solution-phase condensation product(s) formed by steps (a) or (c);
(f) separating the solution-phase condensation product formed by step (e) from the solid-phase;
(g) optionally repeating process steps (e) and (f) one or more additional times, if remainder solid-phase supported intermediate is present, using a further distinct cleaving/condensing reagent for each repetition to give additional analogous solution-phase condensation products; and
(h) optionally repeating process steps (d) through (g) one or more additional times to give additional analogous solution-phase condensation products.
32. The combinatorial library of Claim 31 prepared by the process in which the solid support is a polymer and the solid-phase supported intermediate forms an ester or amide linkage with the linking group.
33. The combinatorial library of Claim 32 prepared by the process in which the linking group is selected from 4-hydroxyphenylthioalkyl, 4-hydroxyphenylsulfinylalkyl, 4-hydroxyphenysulfonylalkyl, 4-hydroxy-2-nitrophenyl, 4-hydroxy-3-nitrophenyl, 4-aminosulfonylbenzoylaminoalkyl and 3-aminosulfonylpropionylaminoalkyl.
34. The combinatorial library of Claim 33 prepared by the process in which the cleaving/condensing reagent is selected from amines and organometallic reagents.
35. The combinatorial library of Claim 34 prepared by the process in which the linking group is 4-aminosulfonylbenzoylaminoalkyl or 3-aminosulfonylpropionylaminoalkyl and the cleaving/condensing reagent is selected from alcohols, anilines, thiols and carbon nucleophiles.
36. The combinatorial library of Claim 35 prepared by the process in which the solid support is selected from polystyrene and poly(ethylene glycol) grafted polystyrene.
37. The combinatorial library of Claim 36 prepared by the process in which the solid support is polystyrene, the linking group is 4-hydroxyphenylthiomethyl and the cleaving/condensing moiety is an amine.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3489297P | 1997-01-31 | 1997-01-31 | |
US60034892 | 1997-01-31 | ||
PCT/US1998/001854 WO1998033751A1 (en) | 1997-01-31 | 1998-01-29 | Novel solid-phase synthesis techniques for preparing multiple analogous compounds |
Publications (1)
Publication Number | Publication Date |
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AU6051998A true AU6051998A (en) | 1998-08-25 |
Family
ID=21879267
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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AU60519/98A Abandoned AU6051998A (en) | 1997-01-31 | 1998-01-29 | Novel solid-phase synthesis techniques for preparing multiple analogous compounds |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0960084A1 (en) |
JP (1) | JP2001509809A (en) |
AU (1) | AU6051998A (en) |
CA (1) | CA2279208A1 (en) |
HU (1) | HUP0003125A3 (en) |
WO (1) | WO1998033751A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000053545A1 (en) * | 1999-03-10 | 2000-09-14 | Axys Pharmaceuticals, Inc. | Process for the synthesis of dihydropyridones |
WO2001010890A2 (en) * | 1999-08-10 | 2001-02-15 | Chemrx Advanced Technologies, Inc. | Process of synthesis of fluorescent protease substrates |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US6180718B1 (en) * | 1996-03-01 | 2001-01-30 | Warner-Lambert Company | Process for preparation of aromatic and heteroaromatic molecules |
-
1998
- 1998-01-29 HU HU0003125A patent/HUP0003125A3/en unknown
- 1998-01-29 CA CA002279208A patent/CA2279208A1/en not_active Abandoned
- 1998-01-29 EP EP98903865A patent/EP0960084A1/en not_active Withdrawn
- 1998-01-29 AU AU60519/98A patent/AU6051998A/en not_active Abandoned
- 1998-01-29 JP JP53312798A patent/JP2001509809A/en active Pending
- 1998-01-29 WO PCT/US1998/001854 patent/WO1998033751A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
HUP0003125A3 (en) | 2001-07-30 |
JP2001509809A (en) | 2001-07-24 |
CA2279208A1 (en) | 1998-08-06 |
HUP0003125A2 (en) | 2001-01-29 |
WO1998033751A1 (en) | 1998-08-06 |
EP0960084A1 (en) | 1999-12-01 |
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