US20040014984A1 - Process for the preparation of derivatives of 4-amino-3-hydroxypyrrole-2-carboxylic acid - Google Patents
Process for the preparation of derivatives of 4-amino-3-hydroxypyrrole-2-carboxylic acid Download PDFInfo
- Publication number
- US20040014984A1 US20040014984A1 US10/332,181 US33218103A US2004014984A1 US 20040014984 A1 US20040014984 A1 US 20040014984A1 US 33218103 A US33218103 A US 33218103A US 2004014984 A1 US2004014984 A1 US 2004014984A1
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- 238000000034 method Methods 0.000 title claims abstract description 155
- 230000008569 process Effects 0.000 title claims abstract description 146
- 238000002360 preparation method Methods 0.000 title claims description 75
- CRXHOQAMRKIBOA-UHFFFAOYSA-N 4-amino-3-hydroxy-1h-pyrrole-2-carboxylic acid Chemical class NC1=CNC(C(O)=O)=C1O CRXHOQAMRKIBOA-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 344
- 238000006243 chemical reaction Methods 0.000 claims abstract description 109
- -1 nitroacetate ester Chemical class 0.000 claims abstract description 79
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 66
- 230000000903 blocking effect Effects 0.000 claims abstract description 53
- 238000006798 ring closing metathesis reaction Methods 0.000 claims abstract description 23
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 16
- 108010049175 N-substituted Glycines Proteins 0.000 claims abstract description 12
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims abstract description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 62
- 125000000304 alkynyl group Chemical group 0.000 claims description 62
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
- 239000003153 chemical reaction reagent Substances 0.000 claims description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 37
- 239000002585 base Substances 0.000 claims description 33
- 229930194542 Keto Natural products 0.000 claims description 32
- 125000000468 ketone group Chemical group 0.000 claims description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 28
- 238000006722 reduction reaction Methods 0.000 claims description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 25
- 150000005691 triesters Chemical class 0.000 claims description 24
- 230000009467 reduction Effects 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 239000011541 reaction mixture Substances 0.000 claims description 16
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 15
- ZPOROQKDAPEMOL-UHFFFAOYSA-N 1h-pyrrol-3-ol Chemical class OC=1C=CNC=1 ZPOROQKDAPEMOL-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- 238000012546 transfer Methods 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 11
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 11
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 11
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 11
- 125000004692 haloalkylcarbonyl group Chemical group 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 230000001737 promoting effect Effects 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- KOOADCGQJDGAGA-UHFFFAOYSA-N [amino(dimethyl)silyl]methane Chemical compound C[Si](C)(C)N KOOADCGQJDGAGA-UHFFFAOYSA-N 0.000 claims description 7
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 5
- 229920002866 paraformaldehyde Polymers 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- 150000001266 acyl halides Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 3
- FHRRJZZGSJXPRQ-UHFFFAOYSA-N benzyl phenylmethoxycarbonyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OC(=O)OCC1=CC=CC=C1 FHRRJZZGSJXPRQ-UHFFFAOYSA-N 0.000 claims 2
- 239000002981 blocking agent Substances 0.000 claims 2
- 125000005353 silylalkyl group Chemical group 0.000 claims 2
- HOGBYTMDQJBMCL-UHFFFAOYSA-N 9h-fluoren-1-ylmethoxycarbonyl 9h-fluoren-1-ylmethyl carbonate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)OC(OCC=1C3=C(C4=CC=CC=C4C3)C=CC=1)=O)=CC=C2 HOGBYTMDQJBMCL-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 53
- 230000015572 biosynthetic process Effects 0.000 abstract description 51
- 239000004952 Polyamide Substances 0.000 abstract description 45
- 229920002647 polyamide Polymers 0.000 abstract description 45
- 239000000178 monomer Substances 0.000 abstract description 39
- 239000000543 intermediate Substances 0.000 abstract description 18
- 108020004414 DNA Proteins 0.000 abstract description 15
- 238000007127 saponification reaction Methods 0.000 abstract description 6
- 102000053602 DNA Human genes 0.000 abstract description 3
- 229920002554 vinyl polymer Polymers 0.000 abstract description 3
- HVLZOHAPFUYHLT-UHFFFAOYSA-N 3-hydroxy-4-nitro-1H-pyrrole-2-carboxylic acid Chemical compound OC(=O)C=1NC=C([N+]([O-])=O)C=1O HVLZOHAPFUYHLT-UHFFFAOYSA-N 0.000 abstract 1
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 abstract 1
- 0 [1*]N1C=C(N)C(O[Rb])=C1C(=O)O Chemical compound [1*]N1C=C(N)C(O[Rb])=C1C(=O)O 0.000 description 137
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 29
- 125000001424 substituent group Chemical group 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000758 substrate Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 7
- 238000006116 polymerization reaction Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DEYCERCIKGEAOL-UHFFFAOYSA-N ethyl 3-hydroxy-1-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(O)C(NC(=O)OC(C)(C)C)=CN1C DEYCERCIKGEAOL-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000012948 isocyanate Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 125000005241 heteroarylamino group Chemical group 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DICIKNLRECQYQM-UHFFFAOYSA-N ethyl 1-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[(2-methylpropan-2-yl)oxycarbonyloxy]pyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(OC(=O)OC(C)(C)C)C(NC(=O)OC(C)(C)C)=CN1C DICIKNLRECQYQM-UHFFFAOYSA-N 0.000 description 4
- BTKSUULMJNNXHG-UHFFFAOYSA-N ethyl 2-(methylamino)acetate Chemical compound CCOC(=O)CNC BTKSUULMJNNXHG-UHFFFAOYSA-N 0.000 description 4
- JETJNVMYQIEZTL-UHFFFAOYSA-N ethyl 3-hydroxy-1-methyl-4-nitropyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(O)C([N+]([O-])=O)=CN1C JETJNVMYQIEZTL-UHFFFAOYSA-N 0.000 description 4
- GYYMJXYRMTYQML-UHFFFAOYSA-N ethyl 4-amino-3-hydroxy-1-methylpyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(O)C(N)=CN1C GYYMJXYRMTYQML-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- YZHUMGUJCQRKBT-UHFFFAOYSA-M sodium chlorate Chemical compound [Na+].[O-]Cl(=O)=O YZHUMGUJCQRKBT-UHFFFAOYSA-M 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tertiry butyl alcohol Natural products CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- JPOMZFNBINJENV-UHFFFAOYSA-N 3-methoxy-1-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrole-2-carboxylic acid Chemical compound COC=1C(NC(=O)OC(C)(C)C)=CN(C)C=1C(O)=O JPOMZFNBINJENV-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 239000003849 aromatic solvent Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000000451 chemical ionisation Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- OZCWOWBECSSCNZ-UHFFFAOYSA-N ethyl 3-methoxy-1-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(OC)C(NC(=O)OC(C)(C)C)=CN1C OZCWOWBECSSCNZ-UHFFFAOYSA-N 0.000 description 3
- BFTHXZKRUYELAD-UHFFFAOYSA-N ethyl 3-methoxy-1-methyl-4-nitropyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(OC)C([N+]([O-])=O)=CN1C BFTHXZKRUYELAD-UHFFFAOYSA-N 0.000 description 3
- CFBBYMAWJFSGLL-UHFFFAOYSA-N ethyl 4-amino-3-methoxy-1-methylpyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(OC)C(N)=CN1C CFBBYMAWJFSGLL-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- NIDZUMSLERGAON-UHFFFAOYSA-N ethyl 2-(methylamino)acetate;hydron;chloride Chemical compound Cl.CCOC(=O)CNC NIDZUMSLERGAON-UHFFFAOYSA-N 0.000 description 2
- FTKASJMIPSSXBP-UHFFFAOYSA-N ethyl 2-nitroacetate Chemical compound CCOC(=O)C[N+]([O-])=O FTKASJMIPSSXBP-UHFFFAOYSA-N 0.000 description 2
- NCRBAZRGVXAEOT-UHFFFAOYSA-N ethyl 3-ethoxy-2-nitroprop-2-enoate Chemical compound CCOC=C([N+]([O-])=O)C(=O)OCC NCRBAZRGVXAEOT-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229940071089 sarcosinate Drugs 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 238000006276 transfer reaction Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- YMGBDORZBGLLER-UHFFFAOYSA-N 1-methylpyrrol-3-ol Chemical compound CN1C=CC(O)=C1 YMGBDORZBGLLER-UHFFFAOYSA-N 0.000 description 1
- WLODWTPNUWYZKN-UHFFFAOYSA-N 1h-pyrrol-2-ol Chemical compound OC1=CC=CN1 WLODWTPNUWYZKN-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- MEAPYKBCOZWIAP-UHFFFAOYSA-N 4-amino-3-methoxy-1H-pyrrole-2-carboxylic acid Chemical compound COC1=C(NC=C1N)C(=O)O MEAPYKBCOZWIAP-UHFFFAOYSA-N 0.000 description 1
- JZPGZQCCALKOBO-UHFFFAOYSA-N 5-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-3-carboxylic acid Chemical compound CCOC(=O)C1=C(O)C(C(O)=O)=CN1C JZPGZQCCALKOBO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XPNPWRJZWMQKIQ-UHFFFAOYSA-N C(C)OC(CN(C)C=CC(=O)OC(C)[N+](=O)[O-])=O Chemical compound C(C)OC(CN(C)C=CC(=O)OC(C)[N+](=O)[O-])=O XPNPWRJZWMQKIQ-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- MTEQPMGMWBGSSL-SOFGYWHQSA-N [H]/C(=C(/C(=O)OCC)[N+](=O)[O-])N(C)CC(=O)OCC Chemical compound [H]/C(=C(/C(=O)OCC)[N+](=O)[O-])N(C)CC(=O)OCC MTEQPMGMWBGSSL-SOFGYWHQSA-N 0.000 description 1
- NCRBAZRGVXAEOT-AATRIKPKSA-N [H]/C(OCC)=C(/C(=O)OCC)[N+](=O)[O-] Chemical compound [H]/C(OCC)=C(/C(=O)OCC)[N+](=O)[O-] NCRBAZRGVXAEOT-AATRIKPKSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000012644 addition polymerization Methods 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- RCTFHBWTYQOVGJ-UHFFFAOYSA-N chloroform;dichloromethane Chemical compound ClCCl.ClC(Cl)Cl RCTFHBWTYQOVGJ-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- JFHAMNVZHGKQDQ-UHFFFAOYSA-N ethyl 4,6-dimethyl-2-oxo-3,4-dihydro-1h-pyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=C(C)NC(=O)NC1C JFHAMNVZHGKQDQ-UHFFFAOYSA-N 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000012452 mother liquor Substances 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011027 product recovery Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Chemical class OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- ZUFONQSOSYEWCN-UHFFFAOYSA-M sodium;2-(methylamino)acetate Chemical compound [Na+].CNCC([O-])=O ZUFONQSOSYEWCN-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/42—Nitro radicals
Definitions
- This invention relates the preparation of compounds useful as monomers in the preparation of polyamides, and more particularly to novel methods and novel intermediates for the preparation of 3-hydroxypyrrole monomers for polyamides that are useful in nucleotide sequence recognition.
- Certain polyamides derived from heteroaryl amino acid monomers are capable of binding to dsDNA and have been found useful in the recognition of nucleotide sequences as well as other applications. See, for example, Dervan U.S. Pat. No. 5,998,140 and Urbach et al., “Sequence Selectivity of 3-Hyroxypyrrole/Pyrrole Ring Pairings in the DNA Minor Groove,” J. Am. Chem. Soc., 1999, 121, 11621-11629. Polyamides containing various combinations of amino acid units respectively comprising pyrrole, hydroxypyrrole and imidazole moieties have been found particularly suitable for this purpose.
- G/C base pairs have been found to be complemented by the juxtaposed combination of N-methylimidazole/N-methylpyrrole, C/G pairs by N-methylpyrrole/N-methylimdazole, and T/A pairs by N-methylpyrrole/N-methylpyrrole or N-methyl-3-hydroxypyrrole/N-methylpyrrole.
- Polyamides containing these combinations can form intracellular complexes by complementation with sequences in dsDNA, the complementation being advantageously facilitated by providing a hairpin turn in the polyamide, or may be accomplished by using two amide oligomers.
- a particularly preferred monomer for the preparation of heteroaryl polyamides is the 3-hydroxypyrrole derivative corresponding to the formula
- R 1 is typically methyl
- R b a protective group to block side reactions during the course of the polyamide synthesis.
- Urbach describes a method for producing such monomer in which ethyl 4-carboxyl-3-hydroxy-1-methylpyrrole-2-carboxylate is reacted with diphenylphosphoryl azide in the presence of triethylamine in acetonitrile to form the isocyanate which is thereafter reacted with benzyl alcohol to produce ethyl 4-[(benzyloxycarbonyl)amino]-3-hydroxy-1-methyl-2-carboxylate.
- the latter compound is reacted with methyl iodide in the presence of 4-dimethylaminopyridine and potassium carbonate in acetone to produce the 3-methoxy derivative, after which di(t-butyl)carbonate and 10% Pd/C are added to the mixture, and the mixture stirred under a hydrogen atmosphere to produce ethyl 4-[(t-butoxycarbonyl)amino]-3-methoxy-2-carboxylate.
- the latter compound is saponified to the 2-carboxylic acid, which is useful as a monomer in the synthesis of polyamides of the type effective in the sequence identification procedures described in Dervan U.S. Pat. No. 5,998,140 and the Urbach article.
- the invention is directed to a process for the preparation of a compound of Formula II
- R 1 and R 3 substituted or unsubstituted alkyl (preferably C 1 to C 6 ), alkenyl (preferably C 2 to C 6 ), alkynyl (preferably C 2 to C 6 ), aralkyl, or aryl;
- R2 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, arylkoxycarbonyl, aryloxycarbonyl or substituted silyl;
- R 4 is hydrogen or methyl; and
- R 5 is a carbamate-forming blocking group.
- the process comprises reducing the nitro group of a compound of Formula IV
- R 1 , R 2 , R 3 and R 4 are as defined above.
- the compound of Formula III is contacted with a blocking group reagent thereby substituting a blocking group on the 4-amino group.
- the invention is further directed to a process for the preparation of the compound of Formula III.
- the process comprises reducing the nitro compound of a group of Formula IV.
- the invention is further directed to a process for the preparation of the compound of Formula IV.
- a 3-hydroxypyrrole derivative corresponding to Formula V is further directed to a process for the preparation of the compound of Formula IV.
- R 1 , R 3 and R 4 are as set forth above, with a blocking reagent effective to form an —OR 2 group at the 3-position of the compound of Formula V.
- the invention is further directed to a process for the preparation of a 3-hydroxypyrrole derivative corresponding to Formula V or the keto tautomer thereof (as corresponding to Formula Va).
- the process comprises contacting a compound of Formula VII with a reagent effective for promoting ring closure.
- the compound of Formula VII corresponds to the structure
- R 1 , R 3 and R 4 are as defined above and —OR 6 is a leaving group.
- the invention is further directed to a process for the preparation of a compound corresponding to Formula VII.
- a compound of Formula VIII is reacted with an N-substituted glycine ester corresponding to Formula IX.
- the compound of Formula VIII has the structure
- R 3 is as defined above.
- the invention is further directed to a process for the preparation of the compound corresponding to Formula XI
- R 1 , R 3 , R 4 and R 5 are as defined above.
- the process comprises contacting a compound of Formula XII and/or the keto tautomer thereof with a blocking group reagent thereby substituting a blocking group on the 4-amino group.
- the compound of Formula XII has the structure
- R 1 , R 3 and R 4 are as defined above.
- the invention is further directed to a process for the preparation of a compound of Formula XII.
- the process comprises reducing a nitro group of a compound of Formula V or the keto tautomer of Formula V.
- the invention is further directed to a compound corresponding to Formula XIV
- R 10 is selected from among hydrogen, substituted and unsubstituted alkyl (preferably C 1 to C 6 ), alkenyl (preferably C 2 to C 6 ), alkynyl (preferably C 2 to C 6 ), aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl and substituted silyl; and R 1 , R 3 and R 4 are as defined above.
- the invention is further directed to a compound corresponding to Formula XV
- R 1 , R 3 , R 4 and R 10 are as defined above; and the keto tautomer of Formula XV wherein R10 of Formula XV would otherwise be hydrogen.
- the invention is further directed to a compound corresponding to Formula VII
- R 1 , R 3 , R 4 and R 6 are as defined above.
- the invention is further directed to a process for the preparation of a compound corresponding to Formula XVI
- R 15 is selected from among alkyl (preferably C 1 to C 6 ), alkenyl (preferably C 2 to C 6 ), alkynyl (preferably C 2 to C 6 ), aralkyl and aryl; and R 1 , R 2 , R 3 and R 4 are as defined above.
- the process comprises contacting a compound of Formula III with a carbonyl compound under conditions effective for the reaction of the 4-amino group of the compound of Formula III with the carbonyl compound, to produce the compound of Formula XVII
- R 15 is selected from unsubstituted alkyl (preferably C 1 to C 6 ), alkenyl (preferably C 2 to C 6 ), alkynyl (preferably C 2 to C 6 ), aralkyl, and aryl; and R 1 , R 2 , R 3 and R 4 are as defined above.
- the invention is further directed to a process for the preparation of a compound of Formula XIX
- R 1 , R 4 and R 5 are as defined above; or the keto tautomer of such compound of Formula XIX.
- the process comprises hydrolyzing a compound of Formula XX by contacting it with a base.
- the compound of Formula XX has the structure
- R 1 , R 4 and R 5 are as defined above.
- the invention is further directed to the preparation of a compound of Formula XX.
- the process comprises reacting a compound of Formula XXI with a blocking reagent
- R 1 and R 4 are as defined above.
- the invention is further directed to the preparation of a compound of Formula XXI.
- the process comprises reducing the nitro group of a compound of Formula XXII
- R 1 and R 4 are as defined above.
- the invention is further directed to a process for the preparation of a compound corresponding to Formula XXII
- R 1 and R 4 are as defined above.
- the process comprises reacting a compound of Formula V or the keto tautomer thereof with paraformaldehyde in the presence of a nitrogenous base.
- the invention is further directed to a compound corresponding to the Formula XXII wherein R 1 and R 4 are as defined above.
- the invention is further directed to a compound corresponding to Formula XXI
- R 1 and R 4 are as defined above.
- the invention is further directed to a compound corresponding to Formula XX
- R 1 , R 4 and R 5 are as defined above.
- the invention is further directed to a compound corresponding to Formula XXIII
- R 1 , R 4 and R 5 are as defined above; and R 11 is selected from the group consisting of alkyl (preferably C 1 to C 6 ), alkenyl (preferably C 2 to C 6 ), alkynyl (preferably C 2 to C 6 ), aralkyl and aryl.
- R 5 is preferably
- R 8 is selected from among substituted and unsubstituted alkyl (preferably C 1 to C 6 ), alkenyl (preferably C 2 to C 6 ), alkynyl (preferably C 2 to C 6 ), aralkyl and aryl.
- the invention is further directed to a compound corresponding to the formula
- R 1 , R 4 , R 5 and R 11 are as defined above.
- the invention is further directed to a compound corresponding to Formula XXIV
- R 1 , R 4 and R 5 are as defined above; and R 12 , R 13 and R 14 are independently alkyl (preferably C 1 to C 6 ).
- novel and advantageous processes are provided for the synthesis of heteroaryl amino acids.
- Novel intermediates are produced in the course of the various syntheses of the invention.
- the heteroaryl amino acid products of these syntheses are useful in the preparation of polyamides, e.g., hairpin polyamides, which bind to the minor groove of DNA and are effective for the identification of polynucleotide sequences.
- the monomers ultimately used in the synthesis of dsDNA-complementing polyamides are 4-amino-3-hydroxy-2-carboxylic acids derivatives corresponding to the Formula XXV
- the 3-hydroxyl is protected by the R b blocking group to prevent side reactions during polyamide synthesis.
- the monomers are typically unsubstituted in the 5-position, a substituent may optionally be present at this position provided that it creates no problems in polymerization arising from steric hindrance, electronic configuration, or reactivity.
- the monomers are synthesized to also comprise a blocking substituent on the 4-amino group, i.e., the monomers correspond to the structure of Formula I
- R 1 , R 2 , R 4 and R 5 are as defined above.
- the R 5 blocking group is removed at the N-terminus of the oligoamide immediately prior to coupling the next monomer unit, e.g., by treatment with trifluoroacetic acid.
- R 1 may independently be substituted and unsubstituted alkyl, alkenyl or alkynyl, preferably C 1 to C 6 alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, and may also be aralkyl or aryl.
- R 1 may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, amyl and hexyl, vinyl, allyl, 2-butenyl, 3-pentenyl, ethynyl, phenyl, naphthyl and benzyl.
- alkyl groups are preferred, among which ethyl, i-propyl and t-butyl are more preferred.
- R 1 is methyl.
- R 2 in Formula I may be selected from among any of the substituents which may constitute R 1 , and may alternatively be substituted or unsubstituted alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxcarbonyl, aralkoxycarbonyl, aryloxycarbonyl or substituted silyl.
- R 2 is methyl, allyl, or benzyl. Where R 2 is further substituted, it may comprise any of the further substituents that are described above for substitution on R 1 .
- R 4 in Formula I is ordinarily hydrogen, but may alternatively be methyl.
- R 4 is as defined above
- R 7 is a suitable leaving group
- —O—R 6 is a leaving group subject to removal in a subsequent ring closure reaction.
- R 6 and R 7 can be any of the constituents which may constitute R 3 as described above.
- R 6 and R 7 are independently C 1 to C 6 alkyl, more preferably methyl or ethyl, most preferably ethyl.
- a nitroacetate ester compound corresponding to Formula X may be reacted with a trialkyl orthoformate or trialkyl orthoacetate, (e.g., triethyl orthoformate) and a carboxylic anhydride, preferably acetic anhydride.
- the substrate of Formula X has the structure
- R 6 is as defined above.
- R 6 is methyl or ethyl, more preferably ethyl.
- the preferred orthocarboxylate ester reactant comprises a lower alkyl ester, e.g., a trimethyl or triethyl ester.
- an orthoformate triester is typically preferred.
- the reaction between the nitroacetate ester, orthoformate triester and acetic anhydride yields a compound of Formula VIII in which R 4 is hydrogen.
- Use of the orthoacetate triester yields the corresponding compound in which R 4 is methyl.
- the reaction is conducted under temperature and pressure conditions effective to drive off the by-product alcohol.
- the reaction may conveniently be conducted at atmospheric pressure and a temperature of between about 100° and about 175° C.
- both orthoformate ester and acetic anhydride are introduced into the reaction zone in molar excess with respect to the nitroacetate ester substrate.
- excess orthocarboxylate ester and carboxylic anhydride are removed, preferably under reduced pressure to yield the intermediate of Formula VIII.
- the N-substituted glycine reagent of Formula IX is a sarcosinate ester (i.e., R 1 is methyl), more preferably ethyl sarcosinate (R 3 is ethyl).
- Preferred moieties which can constitute R 3 include those described above as groups which can constitute R 1 .
- the reaction is preferably conducted with substantially equimolar proportions of the compound of Formula VIII and the N-substituted glycine ester of Formula IX. The temperature of the reaction is not critical.
- the reaction is conducted at room temperature under agitation and cooling for removal of the exothermic heat of reaction.
- the reactants are co-fed to the reaction zone gradually over time, or one reactant is charged initially to the reaction zone and the other gradually added over time, so that the reaction rate and exotherm proceed at a controlled rate.
- the reaction can be conducted in a solvent medium such as water, dimethylsulfoxide, dimethylformamide, a lower alcohol such as ethanol or isopropanol, an aromatic solvent such as benzene, toluene, or xylene, or an ester such as ethyl acetate.
- maximum reactor payloads are provided where the reactants are introduced neat. Reaction time is typically under 2 hours. After the reaction is complete, by-product alcohol (R 7 OH) is removed by evaporation, yielding an oily liquid product.
- a product of enhanced purity may be obtained by extracting the product from the reaction medium, and then driving off the extraction solvent.
- the product of Formula VII may be extracted in a more volatile solvent, e.g., ethyl acetate or an aromatic solvent.
- DMSO is the reaction medium, the product may be extracted with water. In the latter instance, the product may be recovered either by diluting water and back extracting into a more volatile solvent and recovering the product by driving off the latter solvent. The DMSO remains in the aqueous phase.
- the compound of Formula VII is a novel compound useful in the synthesis of polyamides, and potentially useful as a multi-purpose intermediate and even as a monomer useful in preparation of polymers by addition polymerization.
- the substituents thereof are preferably selected on the basis outlined above. Most preferably R 1 is methyl and R 3 is ethyl.
- the substituent R 6 which is removed in a subsequent reaction step, is preferably C 1 to C 6 alkyl, most preferably methyl, propyl, isopropyl, n-butyl, or t-butyl, most preferably ethyl.
- R 1 , R 3 , and R 4 are as set forth above.
- the compound of Formula V can exist in equilibrium with its keto tautomer
- the compound of Formula VII is preferably contacted with a base effective for promoting the ring closure reaction.
- the compound of Formula V/Va may be contacted with an alkali metal alkoxide in the presence of the alcohol, typically the alcohol corresponding to the alkoxide.
- the reaction may be conducted at ambient or elevated temperature, conveniently at atmospheric reflux in the alcohol medium. Heating may be required to sustain the desired reaction temperature.
- the alcohol medium is removed under reduced pressure to provide a residue comprising the crude alkali metal salt of the product of Formula V.
- the residue is taken up in water and acidified, e.g., with dilute sulfuric acid, to precipitate the 3-hydroxypyrrole derivative of Formula V and/or its keto tautomer of Formula Va.
- the 3-hydroxy compound of Formula V/Va can be precipitated directly by acidification of the reaction solution, after which the precipitate can be taken up in alkaline solution and the product extracted with an organic solvent such as an ether, ester, or halogenated solvent to remove neutral by-products.
- an organic solvent such as an ether, ester, or halogenated solvent to remove neutral by-products.
- the compound of formula IV/IVa can be extracted into an ether, ester or halogenated solvent. Removal of the solvent yields the product of Formula V/Va.
- bases other than an alkoxide can be used in the cyclization reaction. Certain of the other bases can be used if desired in a process in which a carbanion of Formula VIIa is first produced at low temperatures.
- the carbanion may be initially produced by reaction in the cold in a solution comprising an organic solvent, the compound of Formula VII, and a base such as, e.g., Li or Na diisopropylamide or Li bis(trimethylsilylamide).
- a stable carbanion can be formed at temperatures in the range of ⁇ 60° C. to ⁇ 90° C. Warming the solution results in ring closure.
- This reaction may be conducted in any of a variety of solvents including tetrahydrofuran, benzene, toluene, and DMSO.
- the resulting solution containing a Li salt of the compound of Formula V may be treated with acid to precipitate the compound of Formula V and/or the tautomer of Formula Va.
- Formula V/Va product may be refined by taking up the precipitate in aqueous base, and extracting neutral by-products and Z isomer of Formula VII using an organic solvent such as ether, ethyl acetate or other low molecular weight ester, 1,2-dichloroethane or other halogenated solvent.
- the compound of Formula V and its tautomer of Formula Va are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the substituents R 1 and R 3 of the compounds of Formula V/Va are the same as for corresponding substituents of the compounds of Formula VII.
- the reagent effective for introducing the blocking group is preferably an etherifying agent corresponding to the formula
- X is halo and R 2 is defined above.
- the reaction is conducted under basic conditions, e.g., in the presence of an alkali metal carbonate or nitrogenous base.
- the etherifying agent is a halide (R 2 X)
- the substrate of Formula V may be converted to the 3-hydroxy salt, and thereafter reacted with R 2 X in the presence of an amine compound serving as a hydrogen halide scavenger.
- a sulfate etherifying agent is used, the reaction is preferably conducted in an organic solvent medium, e.g., a low molecular weight ketone in the presence of an alkali metal carbonate at a moderately elevated temperature, conveniently the atmospheric reflux temperature of the organic solvent. Acetone is particularly suitable.
- a substantial molar excess of (R 2 O) 2 SO 4 can be used to assure essentially quantitative conversion of the 3-hydroxy substrate of Formula V to the 3-OR 2 intermediate product of Formula IV.
- the product may be recovered by filtering to remove alkali metal carbonate and any other solid alkali metal salts, adding water to the filtered reaction mass and extracting the compound of Formula IV with an organic solvent of limited miscibility with water, e.g., diethyl ether.
- the extract is washed with an alkaline solution before removal of the solvent by evaporation.
- the residue may be partially refined by taking it up in another solvent, preferably a halogenated solvent, and drying and filtering the resulting solution.
- the halogenated solvent is then removed by evaporation. Drying may be accomplished before or during evaporation of solvent by contacting the solution with a dessicant such as CaCl 2 or by sparging with dry air or inert gas.
- the residue may be recrystallized as desired, preferably from a solvent comprising an alkane/ester mixture.
- the compound of Formula IV is a novel compound having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products.
- monomers for polyamides that bind to DNA For use in synthesis of monomers for polyamides that bind to DNA, preferences for the various substituents of the compound of Formula IV are the same as for compounds of Formula V.
- Reduction of the nitro group may be accomplished by contacting the compound of Formula IV with a hydrogen transfer agent in the presence of a catalyst for the reduction reaction.
- a preferred catalyst is palladium, preferably on a carbon support.
- a typically suitable catalyst is 5% Pd/C or 10% Pd/C.
- a typical hydrogen transfer agents useful in the nitro reduction step is ammonium formate.
- the reaction is preferably conducted in an organic solvent, e.g., an ester such as ethyl acetate at moderately elevated temperature, conveniently at the atmospheric reflux temperature of the solvent. Alternatively, the reaction can be conducted in methanol at ambient temperature.
- a substantial excess of hydrogen transfer agent is preferably charged to the reaction to assure essentially quantitative reduction of the nitro group.
- An ester solvent such as ethyl acetate is especially preferred because it does not dissolve a hydrogen transfer agent such as ammonium formate, allowing excess transfer agent to be removed by filtration and recycled to the nitro reduction reactor. Reaction time is typically 20 to 60 minutes. The catalyst and excess undissolved hydrogen transfer agent are removed by filtration and the solvent evaporated, preferably under reduced pressure, for recovery of the product of Formula III.
- Literature describing reduction of a nitro group on a heterocyclic ring with ammonium formate generally calls for a high weight ratio of catalyst to nitroheterocyclic substrate, e.g., a charge of 10% Pd/C catalyst essentially equal in weight to the substrate, or at least about 10% by weight Pd metal based on the substrate.
- a relative low catalyst charge i.e., a charge providing as low as 1% by weight Pd based on the substrate charge, or even lower.
- the amount of catalyst charged to the reaction zone is between about 5% and about 1% by weight based on substrate, achieved for example by charging a 20% Pd/C catalyst in a proportion of between about 5% and about 25% by weight based on the substrate of Formula IV.
- the low catalyst charge provides advantages both in the consumption of catalyst and in facilitating the removal of catalyst by filtration.
- reduction of the nitro group may be conducted by contacting the compound of Formula IV with hydrogen under pressure in the presence of a catalyst for the reaction.
- a catalyst for the reaction The same catalysts useful in the hydrogen transfer reaction can be used for catalytic hydrogenation.
- Substantially elevated hydrogen pressure is required for the reaction, e.g., 100 to 900 psig or higher.
- Formula IV substrate is charged to the reaction zone in an organic solvent solution. Reaction may be conducted at temperatures comparable to those used in the hydrogen transfer reaction.
- the compounds of Formula III are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products.
- the compound of Formula III may be reacted with a blocking group reagent to produce a compound of Formula II
- R 5 represents a carbamate-forming-blocking group and R 1 , R 2 , R 3 , and R 4 are as defined above.
- the blocking group reagent is a dicarbonate ester corresponding to the Formula
- R 5 and R 11 are independently selected from among substituted or unsubstituted alkyl (preferably C 1 to C 6 ), alkenyl (preferably C 2 to C 6 ), alkynyl (preferably C 2 to C 6 ), aralkyl or aryl, or substituted silyl.
- Preferred substituents which may constitute R 8 include t-butyl, fluorenylmethyl, allyl, trialkylsilylmethyl and benzyl.
- Other substituents which may constitute R 8 include those described above with respect to R 2 and R 3 .
- the reaction may be conducted using an oxycarbonyl halide corresponding to the Formula
- R 8 are as defined above and X is halide.
- a solution of the compound of Formula III and dicarbonate ester is prepared, preferably in an aqueous solvent, more preferably in an acetone/water solvent mixture.
- another polar solvent e.g., dioxane
- Substantially quantitative blocking of the 4-amino group is promoted by charging at least a slight excess of the dicarbonate.
- the reaction proceeds satisfactorily at room temperature, preferably under neutral to basic conditions.
- the product may be recovered by extraction with a water-immiscible solvent, preferably a halogenated solvent such as dichloromethane, chloroform or 1,2-dichloroethane.
- the extract may be washed with water for removal of impurities, dried over a dessicant such as calcium chloride, or under vacuum or other convenient method, after which the solvent is removed by evaporation.
- the compound of Formula II is converted to the compound of Formula I in a conventional manner, i.e., by saponification of the 2-carboxylate ester to the 2-carboxylic acid.
- Reaction scheme 2 proceeds in the same manner as reaction scheme 1 through the preparation of the intermediate compound of Formula V.
- the 4-nitro group of the compound of Formula V is then reduced to yield the compound of Formula XII
- reduction of the Formula V compound nitro group can be accomplished by reaction with a hydrogen transfer agent such as ammonium formate in the presence of a catalyst for the reaction such as 5% or 10% Pd/C.
- a hydrogen transfer agent such as ammonium formate
- the nitro reduction can be effected by catalytic hydrogenation under elevated hydrogen pressure.
- the conditions for the reaction are essentially identical to those applicable to the preparation of the compound of Formula III from the compound of Formula IV.
- the compounds of Formula XII are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products.
- a blocking group is then introduced as a substituent on the 4-amino group of the compound of Formula XII, yielding a compound of Formula XI
- R 1 , R 3 , R 4 and R 5 are as defined above.
- the reactions for preparation of the compound of Formula XI from the compound of Formula XII are the same as those described above per reaction scheme 1 for introducing a blocking group on the 4-amino substituent of the compound of Formula III to produce the compound of Formula II.
- Conditions for the reaction are also substantially the same as for the conversion of the Formula III compound to Formula II.
- the compounds of Formula XI are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products.
- preferences for the substituents R 1 , R 3 , R 4 and R 5 of the compounds of Formula XI are the same as for compounds of Formula II.
- the compound of Formula XI may be converted to the compound of Formula XIX by the same saponification reaction used for the conversion of the compound of Formula II to the compound of Formula I
- the 4-amino blocking substituent and N-substituent (R 1 ) of the compound of Formula XIX are the same as those of the compound of Formula I.
- Novel compounds of Formulae III and XII may be generically defined by Formula XIV
- R 10 includes all groups that may constitute R 2 , plus hydrogen.
- the intermediate of Formula XXII is formed by reacting the compound of Formula V with paraformaldehyde in the presence of a base, preferably a nitrogenous base such as N,N′-diisopropylethylamine (DIEA).
- a base preferably a nitrogenous base such as N,N′-diisopropylethylamine (DIEA).
- DIEA N,N′-diisopropylethylamine
- the reaction may be carried out by heating the compound of Formula V with a several fold molar excess of paraformaldehyde in a polar solvent such as dimethylformamide or dimethyl sulfoxide at a temperature high enough to depolymerize the paraformaldehyde.
- Reaction temperature may typically range from about 25° C. to about 150° C.
- the compound of Formula XXII is a novel intermediate useful in the synthesis of polyamides and potentially as an intermediate for other syntheses.
- Preferred substituents which may constitute R 1 are the same as those for the other intermediates as described hereinabove.
- a blocking group is then introduced on the 4-amino group of the compound of Formula XXI to produce the compound of Formula XX
- R 1 , R 4 and R 5 are as described above.
- Introduction of the blocking group is effected by the same reaction used to convert the compound of Formula III to the compound of Formula II.
- the reagents and conditions of the reaction are essentially the same as for the conversion of the compound of Formula III to Formula II, and the preferences in the nature of the blocking group are also the same.
- the compounds of Formulae XX, XXI and XXII are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products.
- preferences for the substituents R 1 and R 5 of the compounds of Formulae XX, XXI and XXII are the same as for compounds of Formula II.
- the 3-hydroxy group may be protected by introducing an O-substituent with a trialkylsilyl chloride, aryl halide, or aryl anhydride and a suitable nitrogenous base in a nonpolar solvent.
- Suitable bases include pyridine, imidazole and trialkamine.
- Suitable solvents include ethers, esters and haloalkanes.
- R 8 and R 11 are as defined above and may be the same or different, to produce a compound of Formula XXIII
- R 4 , R 5 and R 11 are as defined above.
- An acyl halide such as R 11 C(O)Cl or R 11 C(O)Br can also be used.
- a compound of Formula XIX may be reacted with a dicarbonate diester of Formula XIII
- R 1 , R 4 , and R 5 are as defined above.
- R 5 is R 8 —O—C(O)—, where R 8 is as defined above.
- R 12 , R 13 , and R 14 are independently C 1 to C 6 alkyl and R 1 , R 4 and R 5 are as defined above. Again, R 5 is preferably R 8 —O—C(O)—.
- the compounds of Formulae XXIII and XXIV are also novel compounds useful in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products.
- preferences for the substituents R 1 and R 5 of the compounds of Formulae XX, XXI and XXII are the same as for compounds of Formula II.
- each of the above-described reaction schemes avoids the problem of 4-decarboxylation which is encountered when water is present in the synthesis of a blocked 4-amino group according the reaction scheme disclosed by Momose et al., supra.
- R 1 , R 2 , R 3 and R 4 are as defined above;
- R 15 is unsubstituted alkyl (preferably C 1 to C 6 ), alkenyl (preferably C 2 to C 6 ), alkynyl (preferably C 2 to C 6 ), aralkyl or aryl, or substituted silyl; and R 1 , R 2 , R 3 and R 4 are as defined above.
- the isocyanate of Formula XVII is heated with a 1-5 fold molar excess of the alcohol in an aromatic solvent (e.g., toluene or xylene) in the presence of a nitrogenous base catalyst such as trialkylamine.
- an aromatic solvent e.g., toluene or xylene
- the compounds of Formula XVII are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products.
- preferences for the substituents R 1 , R 2 , R 3 , and R 4 are the same as for compounds of Formula II, and the preferences are the same as the preferences for R 2 in Formula II.
Abstract
Novel processes and intermediates are provided for the synthesis of derivatives of 4-amino-3-hydroxypyrrole-2-carboxylic acids that are useful as monomers for polyamides capable of binding dsDNA. According to one preferred reaction scheme, an alkyl alkoxymethylene nitroacetate (Formula VIII) is prepared by reaction of a trialkyl orthoformate or orthoacetate with a nitroacetate ester in the presence of a carboxylic anhydride. The compound of Formula VIII is condensed with an N-substituted glycine to yield an N-substituted (2-nitro-2-alkoxycarbonyl)vinyl glycinate ester (Formula VII). Ring closure in the presence of an alkali metal alkoxide yields a 4-nitro-3-hydroxypyrrole-2-carboxylic ester (Formula V). After blocking of the 3-hydroxy group to produce a further intermediate (Formula IV), the 4-nitro group is reduced to a 4-amino group (Formula III), and the 4-amino group is then blocked by reaction with a dicarbonate diester to produce the fully blocked intermediate (Formula II). Saponification of the 2-carboxylic acid ester yields a monomer having a free 2-carboxylic ester moiety (Formula I).
Description
- This invention relates the preparation of compounds useful as monomers in the preparation of polyamides, and more particularly to novel methods and novel intermediates for the preparation of 3-hydroxypyrrole monomers for polyamides that are useful in nucleotide sequence recognition.
- Certain polyamides derived from heteroaryl amino acid monomers are capable of binding to dsDNA and have been found useful in the recognition of nucleotide sequences as well as other applications. See, for example, Dervan U.S. Pat. No. 5,998,140 and Urbach et al., “Sequence Selectivity of 3-Hyroxypyrrole/Pyrrole Ring Pairings in the DNA Minor Groove,”J. Am. Chem. Soc., 1999, 121, 11621-11629. Polyamides containing various combinations of amino acid units respectively comprising pyrrole, hydroxypyrrole and imidazole moieties have been found particularly suitable for this purpose. G/C base pairs have been found to be complemented by the juxtaposed combination of N-methylimidazole/N-methylpyrrole, C/G pairs by N-methylpyrrole/N-methylimdazole, and T/A pairs by N-methylpyrrole/N-methylpyrrole or N-methyl-3-hydroxypyrrole/N-methylpyrrole. Polyamides containing these combinations can form intracellular complexes by complementation with sequences in dsDNA, the complementation being advantageously facilitated by providing a hairpin turn in the polyamide, or may be accomplished by using two amide oligomers.
- Methods for the preparation of hairpin polyamide polymers and monomers useful in their synthesis are described in the above-cited Dervan patent and Urbach et al. article. An earlier article of Momose et al., “3-Hydroxypyrrole. I. A General Synthetic Route to 4,5-Unsubstituted Alkyl 3-Hydroxypyrrole-2-carboxylates,”Chem. Pharm. Bull., 26(7), 2224-2238 (1979) also describes methods for the preparation of amino acids derivatives of 3-hydroxypyrrole.
-
- wherein R1 is typically methyl, and Rb a protective group to block side reactions during the course of the polyamide synthesis. Urbach describes a method for producing such monomer in which ethyl 4-carboxyl-3-hydroxy-1-methylpyrrole-2-carboxylate is reacted with diphenylphosphoryl azide in the presence of triethylamine in acetonitrile to form the isocyanate which is thereafter reacted with benzyl alcohol to produce ethyl 4-[(benzyloxycarbonyl)amino]-3-hydroxy-1-methyl-2-carboxylate. The latter compound is reacted with methyl iodide in the presence of 4-dimethylaminopyridine and potassium carbonate in acetone to produce the 3-methoxy derivative, after which di(t-butyl)carbonate and 10% Pd/C are added to the mixture, and the mixture stirred under a hydrogen atmosphere to produce ethyl 4-[(t-butoxycarbonyl)amino]-3-methoxy-2-carboxylate. The latter compound is saponified to the 2-carboxylic acid, which is useful as a monomer in the synthesis of polyamides of the type effective in the sequence identification procedures described in Dervan U.S. Pat. No. 5,998,140 and the Urbach article.
- In the synthesis of Urbach, the steps required to introduce a blocked 4-amino group have an adverse tendency to decarboxylate at the 4-position, especially in the presence of water. Thus, for satisfactory monomer synthesis per the Urbach route, it is necessary that measures be taken to substantially exclude moisture from the reaction mixture. Moreover, the synthesis described by Urbach involves release of nitrogen gas from the reaction mixture. Unless the reaction conditions are carefully controlled, the rate of gas release may potentially pose an operational hazard, particularly in large scale synthesis.
- In synthesis of the polyamides, it is also important that the 3-hydroxy group be protected so that it does not participate in side reactions which produce branched or cross-linked polyamides that are less suitable for nucleotide recognition than are the unbranched polyamides described by Dervan and Urbach. After polymerization, the O-methyl group is removed since the free hydroxyl is the desired structure for use in nucleic acid binding. Although O-methylation provides very satisfactory protection of the 3-hydroxy group during the polymerization reaction, and is a preferred protective procedure for many applications, the O-methyl group can be difficult to remove after the polymerization is complete. It would, therefore, be useful to provide other protective groups which are effective to prevent branching or cross-linking during the polymerization but more susceptible to removal from the polyamide product.
- Among the objects of the present invention may be noted the provision of a method for the preparation of heteroaryl amino acid monomers useful in the preparation of polyamides; the provision of such a method which avoids the loss of desired substituents from the heteraryl ring during the course of synthesis reactions; the provision of such a process which can be constantly operated without rapid gas release from any reaction step; the provision of alternative protective groups at the 3-position of a 3-hydroxypyrrole derivative; and the provision of novel intermediates useful in the synthesis of monomers for bioactive polyamides.
-
-
-
- wherein R1, R2, R3 and R4 are as defined above. The compound of Formula III is contacted with a blocking group reagent thereby substituting a blocking group on the 4-amino group. The invention is further directed to a process for the preparation of the compound of Formula III. The process comprises reducing the nitro compound of a group of Formula IV.
-
-
- wherein R1, R3 and R4 are as set forth above, with a blocking reagent effective to form an —OR2 group at the 3-position of the compound of Formula V.
- The invention is further directed to a process for the preparation of a 3-hydroxypyrrole derivative corresponding to Formula V or the keto tautomer thereof (as corresponding to Formula Va). The process comprises contacting a compound of Formula VII with a reagent effective for promoting ring closure. The compound of Formula VII corresponds to the structure
- wherein R1, R3 and R4 are as defined above and —OR6 is a leaving group.
-
- wherein R4 and R6 are as defined above and R7 is a leaving group. The compound of Formula IX has the structure
- R1NHCH2C(O)OR3
- wherein R3 is as defined above.
-
-
-
-
- In both Formula XII and Formula XIIa, R1, R3 and R4 are as defined above.
- The invention is further directed to a process for the preparation of a compound of Formula XII. The process comprises reducing a nitro group of a compound of Formula V or the keto tautomer of Formula V.
-
- wherein R10 is selected from among hydrogen, substituted and unsubstituted alkyl (preferably C1 to C6), alkenyl (preferably C2 to C6), alkynyl (preferably C2 to C6), aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl and substituted silyl; and R1, R3 and R4 are as defined above.
-
- wherein R1, R3, R4 and R10 are as defined above; and the keto tautomer of Formula XV wherein R10 of Formula XV would otherwise be hydrogen.
-
- wherein R1, R3, R4 and R6 are as defined above.
-
-
- and contacting the compound of Formula XVII with an alcohol of Formula XVIII
- R15OH
- wherein R15 is selected from unsubstituted alkyl (preferably C1 to C6), alkenyl (preferably C2 to C6), alkynyl (preferably C2 to C6), aralkyl, and aryl; and R1, R2, R3 and R4 are as defined above.
-
-
- wherein R1, R4 and R5 are as defined above.
-
- wherein R1 and R4 are as defined above.
-
- wherein R1 and R4 are as defined above.
-
- wherein R1 and R4 are as defined above. The process comprises reacting a compound of Formula V or the keto tautomer thereof with paraformaldehyde in the presence of a nitrogenous base.
- The invention is further directed to a compound corresponding to the Formula XXII wherein R1 and R4 are as defined above.
-
- wherein R1 and R4 are as defined above.
-
- wherein R1, R4 and R5 are as defined above.
-
-
- where R8 is selected from among substituted and unsubstituted alkyl (preferably C1 to C6), alkenyl (preferably C2 to C6), alkynyl (preferably C2 to C6), aralkyl and aryl.
-
- where R1, R4, R5 and R11 are as defined above.
-
- wherein R1, R4 and R5 are as defined above; and R12, R13 and R14 are independently alkyl (preferably C1 to C6).
- Other objects and features will be in part apparent and in part pointed out hereinafter.
- In accordance with the present invention, novel and advantageous processes are provided for the synthesis of heteroaryl amino acids. Novel intermediates are produced in the course of the various syntheses of the invention. The heteroaryl amino acid products of these syntheses are useful in the preparation of polyamides, e.g., hairpin polyamides, which bind to the minor groove of DNA and are effective for the identification of polynucleotide sequences.
-
-
- wherein R1, R2, R4 and R5 are as defined above. In the course of solid phase polyamide synthesis, the R5 blocking group is removed at the N-terminus of the oligoamide immediately prior to coupling the next monomer unit, e.g., by treatment with trifluoroacetic acid.
- In accordance with the invention, several alternative process schemes have been discovered for synthesis of 4-nitro-3-hydroxy-2-carboxylate esters and conversion thereof to 4-amino-3-hydroxy-2-carboxyate esters which are protected with blocking substituents at both the 3-position oxygen and and the 4-position nitrogen.
-
- In the structure of Formula I, R1 may independently be substituted and unsubstituted alkyl, alkenyl or alkynyl, preferably C1 to C6 alkyl, C2 to C6 alkenyl, or C2 to C6 alkynyl, and may also be aralkyl or aryl. For example, R1 may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, amyl and hexyl, vinyl, allyl, 2-butenyl, 3-pentenyl, ethynyl, phenyl, naphthyl and benzyl. Generally, alkyl groups are preferred, among which ethyl, i-propyl and t-butyl are more preferred. Most preferably, R1 is methyl.
- R2 in Formula I may be selected from among any of the substituents which may constitute R1, and may alternatively be substituted or unsubstituted alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxcarbonyl, aralkoxycarbonyl, aryloxycarbonyl or substituted silyl. Preferably, R2 is methyl, allyl, or benzyl. Where R2 is further substituted, it may comprise any of the further substituents that are described above for substitution on R1.
- R4 in Formula I is ordinarily hydrogen, but may alternatively be methyl.
- R5 represents a carbamate-forming blocking group.
- Preferred blocking groups include t-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trialkylsilyloxycarbonyl, and benzyloxycarbonyl.
- The several reaction schemes of the invention are described below.
- Reaction Scheme 1
-
- wherein R4 is as defined above, R7 is a suitable leaving group, and —O—R6 is a leaving group subject to removal in a subsequent ring closure reaction. R6 and R7 can be any of the constituents which may constitute R3 as described above. Preferably, R6 and R7 are independently C1 to C6 alkyl, more preferably methyl or ethyl, most preferably ethyl. In the preparation of the compound of Formula VIII, a nitroacetate ester compound corresponding to Formula X may be reacted with a trialkyl orthoformate or trialkyl orthoacetate, (e.g., triethyl orthoformate) and a carboxylic anhydride, preferably acetic anhydride. The substrate of Formula X has the structure
- O2NCH2C(O)OR6 (Formula X)
- where R6 is as defined above. Preferably, R6 is methyl or ethyl, more preferably ethyl. Generally, the preferred orthocarboxylate ester reactant comprises a lower alkyl ester, e.g., a trimethyl or triethyl ester. In the synthesis of heteroaryl amino acid monomers, an orthoformate triester is typically preferred. The reaction between the nitroacetate ester, orthoformate triester and acetic anhydride yields a compound of Formula VIII in which R4 is hydrogen. Use of the orthoacetate triester yields the corresponding compound in which R4 is methyl. The reaction is conducted under temperature and pressure conditions effective to drive off the by-product alcohol. Where a triethyl ester is used, the reaction may conveniently be conducted at atmospheric pressure and a temperature of between about 100° and about 175° C. Preferably, both orthoformate ester and acetic anhydride are introduced into the reaction zone in molar excess with respect to the nitroacetate ester substrate. After the reaction is complete, excess orthocarboxylate ester and carboxylic anhydride are removed, preferably under reduced pressure to yield the intermediate of Formula VIII.
- In the next step of reaction scheme 1, the intermediate of Formula VIII is condensed with an N-substituted glycine reagent of Formula IX
- R1NHCH2C(O)OR3 (Formula IX)
-
- wherein R1, R3, R4 and R6 are as defined above. Preferably, the N-substituted glycine reagent of Formula IX is a sarcosinate ester (i.e., R1 is methyl), more preferably ethyl sarcosinate (R3 is ethyl). Preferred moieties which can constitute R3 include those described above as groups which can constitute R1. The reaction is preferably conducted with substantially equimolar proportions of the compound of Formula VIII and the N-substituted glycine ester of Formula IX. The temperature of the reaction is not critical. Conveniently, it is conducted at room temperature under agitation and cooling for removal of the exothermic heat of reaction. Preferably, the reactants are co-fed to the reaction zone gradually over time, or one reactant is charged initially to the reaction zone and the other gradually added over time, so that the reaction rate and exotherm proceed at a controlled rate. If desired, the reaction can be conducted in a solvent medium such as water, dimethylsulfoxide, dimethylformamide, a lower alcohol such as ethanol or isopropanol, an aromatic solvent such as benzene, toluene, or xylene, or an ester such as ethyl acetate. However, maximum reactor payloads are provided where the reactants are introduced neat. Reaction time is typically under 2 hours. After the reaction is complete, by-product alcohol (R7OH) is removed by evaporation, yielding an oily liquid product.
- Where the reaction of the compound of Formula VIII with the compound of Formula IX is conducted in a solvent, a product of enhanced purity may be obtained by extracting the product from the reaction medium, and then driving off the extraction solvent. For example, where the reaction is conducted in water, the product of Formula VII may be extracted in a more volatile solvent, e.g., ethyl acetate or an aromatic solvent. Where DMSO is the reaction medium, the product may be extracted with water. In the latter instance, the product may be recovered either by diluting water and back extracting into a more volatile solvent and recovering the product by driving off the latter solvent. The DMSO remains in the aqueous phase.
- The compound of Formula VII is a novel compound useful in the synthesis of polyamides, and potentially useful as a multi-purpose intermediate and even as a monomer useful in preparation of polymers by addition polymerization. Where the compound of Formula VII is used in the synthesis of polyamides for binding to DNA, the substituents thereof are preferably selected on the basis outlined above. Most preferably R1 is methyl and R3 is ethyl. For such applications, the substituent R6, which is removed in a subsequent reaction step, is preferably C1 to C6 alkyl, most preferably methyl, propyl, isopropyl, n-butyl, or t-butyl, most preferably ethyl.
-
-
- For utility as an intermediate in preparation of monomers for polyamides that bind to DNA, there is no practical difference between the tautomers. In preparation of the compound of Formula V and/or Va, the compound of Formula VII is preferably contacted with a base effective for promoting the ring closure reaction. For example, the compound of Formula V/Va may be contacted with an alkali metal alkoxide in the presence of the alcohol, typically the alcohol corresponding to the alkoxide. The reaction may be conducted at ambient or elevated temperature, conveniently at atmospheric reflux in the alcohol medium. Heating may be required to sustain the desired reaction temperature. The alcohol medium is removed under reduced pressure to provide a residue comprising the crude alkali metal salt of the product of Formula V. The residue is taken up in water and acidified, e.g., with dilute sulfuric acid, to precipitate the 3-hydroxypyrrole derivative of Formula V and/or its keto tautomer of Formula Va.
- Only the E isomer form of the compound of Formula VII undergoes ring closure to yield the salt of the compound of Formula V. Thus, unreacted Z isomer and reaction by-products are preferably removed from the precipitated compound of Formula V/Va. The precipitate is first separated from the acidified mother liquor by filtration or centrifugation, and washed with water, after which the washed solids are taken up in a solvent; preferably a halogenated solvent such as dichloromethane chloroform or 1,2-dichloroethane. The product may be passed through an adsorbent such as silica gel for further purification. The Formula V/Va product may be further purified, if desired, by recrystallization, e.g., from an ester/alkane solvent mixture.
- In an alternative product recovery scheme, the 3-hydroxy compound of Formula V/Va can be precipitated directly by acidification of the reaction solution, after which the precipitate can be taken up in alkaline solution and the product extracted with an organic solvent such as an ether, ester, or halogenated solvent to remove neutral by-products. After acidification of the aqueous phase, the compound of formula IV/IVa can be extracted into an ether, ester or halogenated solvent. Removal of the solvent yields the product of Formula V/Va.
-
- wherein R1, R3, R4 and R6 are as defined above. For example, the carbanion may be initially produced by reaction in the cold in a solution comprising an organic solvent, the compound of Formula VII, and a base such as, e.g., Li or Na diisopropylamide or Li bis(trimethylsilylamide). Typically, a stable carbanion can be formed at temperatures in the range of −60° C. to −90° C. Warming the solution results in ring closure. This reaction may be conducted in any of a variety of solvents including tetrahydrofuran, benzene, toluene, and DMSO. The resulting solution containing a Li salt of the compound of Formula V may be treated with acid to precipitate the compound of Formula V and/or the tautomer of Formula Va. Formula V/Va product may be refined by taking up the precipitate in aqueous base, and extracting neutral by-products and Z isomer of Formula VII using an organic solvent such as ether, ethyl acetate or other low molecular weight ester, 1,2-dichloroethane or other halogenated solvent. The compound of Formula V and its tautomer of Formula Va are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the substituents R1 and R3 of the compounds of Formula V/Va are the same as for corresponding substituents of the compounds of Formula VII.
-
- where R1, R2, and R3 are defined above. The reagent effective for introducing the blocking group is preferably an etherifying agent corresponding to the formula
- (R2O)2SO4 (Formula VI)
- or Formula VIa
- R2X (Formula VIa)
- where X is halo and R2 is defined above. The reaction is conducted under basic conditions, e.g., in the presence of an alkali metal carbonate or nitrogenous base. Where the etherifying agent is a halide (R2X), the substrate of Formula V may be converted to the 3-hydroxy salt, and thereafter reacted with R2X in the presence of an amine compound serving as a hydrogen halide scavenger. Where a sulfate etherifying agent is used, the reaction is preferably conducted in an organic solvent medium, e.g., a low molecular weight ketone in the presence of an alkali metal carbonate at a moderately elevated temperature, conveniently the atmospheric reflux temperature of the organic solvent. Acetone is particularly suitable. A substantial molar excess of (R2O)2SO4 can be used to assure essentially quantitative conversion of the 3-hydroxy substrate of Formula V to the 3-OR2 intermediate product of Formula IV. However, it may be desirable to avoid a substantial excess in order to minimize consumption of the sulfate diester which can be difficult to recover economically, and may need to be destroyed after the etherification reaction is complete, e.g., by addition of aqueous ammonia. Thereafter, the product may be recovered by filtering to remove alkali metal carbonate and any other solid alkali metal salts, adding water to the filtered reaction mass and extracting the compound of Formula IV with an organic solvent of limited miscibility with water, e.g., diethyl ether. Preferably, the extract is washed with an alkaline solution before removal of the solvent by evaporation. The residue may be partially refined by taking it up in another solvent, preferably a halogenated solvent, and drying and filtering the resulting solution. The halogenated solvent is then removed by evaporation. Drying may be accomplished before or during evaporation of solvent by contacting the solution with a dessicant such as CaCl2 or by sparging with dry air or inert gas. The residue may be recrystallized as desired, preferably from a solvent comprising an alkane/ester mixture.
- The compound of Formula IV is a novel compound having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the various substituents of the compound of Formula IV are the same as for compounds of Formula V.
-
- wherein R1, R2, R3 and R4 are as defined above. Reduction of the nitro group may be accomplished by contacting the compound of Formula IV with a hydrogen transfer agent in the presence of a catalyst for the reduction reaction. A preferred catalyst is palladium, preferably on a carbon support. A typically suitable catalyst is 5% Pd/C or 10% Pd/C. A typical hydrogen transfer agents useful in the nitro reduction step is ammonium formate. The reaction is preferably conducted in an organic solvent, e.g., an ester such as ethyl acetate at moderately elevated temperature, conveniently at the atmospheric reflux temperature of the solvent. Alternatively, the reaction can be conducted in methanol at ambient temperature. A substantial excess of hydrogen transfer agent is preferably charged to the reaction to assure essentially quantitative reduction of the nitro group. An ester solvent such as ethyl acetate is especially preferred because it does not dissolve a hydrogen transfer agent such as ammonium formate, allowing excess transfer agent to be removed by filtration and recycled to the nitro reduction reactor. Reaction time is typically 20 to 60 minutes. The catalyst and excess undissolved hydrogen transfer agent are removed by filtration and the solvent evaporated, preferably under reduced pressure, for recovery of the product of Formula III.
- Literature describing reduction of a nitro group on a heterocyclic ring with ammonium formate generally calls for a high weight ratio of catalyst to nitroheterocyclic substrate, e.g., a charge of 10% Pd/C catalyst essentially equal in weight to the substrate, or at least about 10% by weight Pd metal based on the substrate. In accordance with the invention, it has been discovered that reduction of the nitro group of compound IV can be accomplished using a relative low catalyst charge, i.e., a charge providing as low as 1% by weight Pd based on the substrate charge, or even lower. Preferably, the amount of catalyst charged to the reaction zone is between about 5% and about 1% by weight based on substrate, achieved for example by charging a 20% Pd/C catalyst in a proportion of between about 5% and about 25% by weight based on the substrate of Formula IV. The low catalyst charge provides advantages both in the consumption of catalyst and in facilitating the removal of catalyst by filtration.
- Alternatively, reduction of the nitro group may be conducted by contacting the compound of Formula IV with hydrogen under pressure in the presence of a catalyst for the reaction. The same catalysts useful in the hydrogen transfer reaction can be used for catalytic hydrogenation.
- Substantially elevated hydrogen pressure is required for the reaction, e.g., 100 to 900 psig or higher. Conveniently, Formula IV substrate is charged to the reaction zone in an organic solvent solution. Reaction may be conducted at temperatures comparable to those used in the hydrogen transfer reaction.
- The compounds of Formula III are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the various substituents of the compound of Formula III are the same as for compounds of Formula IV.
-
-
- is R5 and R11 are independently selected from among substituted or unsubstituted alkyl (preferably C1 to C6), alkenyl (preferably C2 to C6), alkynyl (preferably C2 to C6), aralkyl or aryl, or substituted silyl. Preferred substituents which may constitute R8 include t-butyl, fluorenylmethyl, allyl, trialkylsilylmethyl and benzyl. Other substituents which may constitute R8 include those described above with respect to R2 and R3. Alternatively, the reaction may be conducted using an oxycarbonyl halide corresponding to the Formula
- R8OC(O)X
-
- and R8 are as defined above and X is halide.
- In conducting the blocking reaction with a dicarbonate ester of Formula XIII, a solution of the compound of Formula III and dicarbonate ester is prepared, preferably in an aqueous solvent, more preferably in an acetone/water solvent mixture. Alternatively, another polar solvent, e.g., dioxane, can be used. Substantially quantitative blocking of the 4-amino group is promoted by charging at least a slight excess of the dicarbonate. The reaction proceeds satisfactorily at room temperature, preferably under neutral to basic conditions. The product may be recovered by extraction with a water-immiscible solvent, preferably a halogenated solvent such as dichloromethane, chloroform or 1,2-dichloroethane. The extract may be washed with water for removal of impurities, dried over a dessicant such as calcium chloride, or under vacuum or other convenient method, after which the solvent is removed by evaporation.
- The compound of Formula II is converted to the compound of Formula I in a conventional manner, i.e., by saponification of the 2-carboxylate ester to the 2-carboxylic acid.
-
- Reaction Scheme 2
-
- As in the conversion of the compound of Formula IV to the compound of Formula III per reaction scheme 1, reduction of the Formula V compound nitro group can be accomplished by reaction with a hydrogen transfer agent such as ammonium formate in the presence of a catalyst for the reaction such as 5% or 10% Pd/C. Alternatively, the nitro reduction can be effected by catalytic hydrogenation under elevated hydrogen pressure. In either case the conditions for the reaction are essentially identical to those applicable to the preparation of the compound of Formula III from the compound of Formula IV.
- The compounds of Formula XII are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the various substituents of the compounds of Formula XII are the same as for compounds of Formula V.
-
- where R1, R3, R4 and R5 are as defined above. The reactions for preparation of the compound of Formula XI from the compound of Formula XII are the same as those described above per reaction scheme 1 for introducing a blocking group on the 4-amino substituent of the compound of Formula III to produce the compound of Formula II. Conditions for the reaction are also substantially the same as for the conversion of the Formula III compound to Formula II. In conversion of the compound of Formula XII to that of Formula XI, it is especially important to operate under neutral to acidic conditions to avoid reaction of the 3-hydroxyl group.
- The compounds of Formula XI are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the substituents R1, R3, R4 and R5 of the compounds of Formula XI are the same as for compounds of Formula II.
-
- Preferably, the 4-amino blocking substituent and N-substituent (R1) of the compound of Formula XIX are the same as those of the compound of Formula I.
- Although, the compound of Formula XIX may be used in the synthesis of polyamides, the 3-hydroxy group is preferably blocked also to prevent branching and crosslinking in the polymerization reaction. For this purpose, the compound of Formula XI is preferably reacted with a reagent which introduces such a protective group at the 3-position prior to saponification to the 2-carboxylic acid. The reagents and conditions for introduction of the protective group are the same as described above for the conversion of the compound of Formula V to the compound of Formula IV. When this reaction is conducted on the substrate of Formula XI, the O-protected product of the reaction is the compound of Formula II. Saponification of the compound of Formula II to the compound of Formula I is described above.
-
- When polyamides produced from the monomers of Formula I or XXV are used in DNA recognition, the O-protective group R2 must be removed. Although a methyl group functions effectively as the O-protective group R2 in the polymerization reaction, removal of a methyl group requires harsh conditions. Substituents such as acyl, trialkylsilyl, benzyl and allyl may be preferred in some cases.
-
-
- In each of Formulae XIV and XV R10 includes all groups that may constitute R2, plus hydrogen.
- Reaction Scheme 3
-
- where R1 and R4 are defined above. The intermediate of Formula XXII is formed by reacting the compound of Formula V with paraformaldehyde in the presence of a base, preferably a nitrogenous base such as N,N′-diisopropylethylamine (DIEA). The reaction may be carried out by heating the compound of Formula V with a several fold molar excess of paraformaldehyde in a polar solvent such as dimethylformamide or dimethyl sulfoxide at a temperature high enough to depolymerize the paraformaldehyde. Reaction temperature may typically range from about 25° C. to about 150° C.
- The compound of Formula XXII is a novel intermediate useful in the synthesis of polyamides and potentially as an intermediate for other syntheses. Preferred substituents which may constitute R1 are the same as those for the other intermediates as described hereinabove.
- The 4-nitro group of the compound of Formula XXII is reduced by catalytic reaction with a hydrogen transfer agent or by catalytic hydrogenation in the manner and under the conditions described hereinabove for the conversion of the compound of Formula IV to the compound of Formula III, thereby yielding the 4-amino compound of Formula XXI
- wherein R1 is as described above.
-
- wherein R1, R4 and R5 are as described above. Introduction of the blocking group is effected by the same reaction used to convert the compound of Formula III to the compound of Formula II. The reagents and conditions of the reaction are essentially the same as for the conversion of the compound of Formula III to Formula II, and the preferences in the nature of the blocking group are also the same.
- The compounds of Formulae XX, XXI and XXII are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the substituents R1 and R5 of the compounds of Formulae XX, XXI and XXII are the same as for compounds of Formula II.
- The compound of Formula XX may then be saponified to produce the compound of Formula XIX or a salt thereof. Saponification may be conducted by contacting the compound of Formula XX with 1-5 equivalents of an alkali metal hydroxide (e.g., LiOH, NaOH or KOH) in aqueous alcohol or aqueous DMSO. The reaction temperature may range from about 25° C. to about 100° C. and is preferably in the lower end of that range. LiOH is a preferred saponifying reagent.
- The 3-hydroxy group may be protected by introducing an O-substituent with a trialkylsilyl chloride, aryl halide, or aryl anhydride and a suitable nitrogenous base in a nonpolar solvent. Suitable bases include pyridine, imidazole and trialkamine. Suitable solvents include ethers, esters and haloalkanes.
-
-
-
- or the haloformate:
- R8OC(O)X
-
- wherein R1, R4, and R5 are as defined above. Preferably R5 is R8—O—C(O)—, where R8 is as defined above.
-
- wherein R12, R13, and R14 are independently C1 to C6 alkyl and R1, R4 and R5 are as defined above. Again, R5 is preferably R8—O—C(O)—.
- The compounds of Formulae XXIII and XXIV are also novel compounds useful in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the substituents R1 and R5 of the compounds of Formulae XX, XXI and XXII are the same as for compounds of Formula II.
-
- In providing the 4-amino group by reduction of a 4-nitro group, each of the above-described reaction schemes avoids the problem of 4-decarboxylation which is encountered when water is present in the synthesis of a blocked 4-amino group according the reaction scheme disclosed by Momose et al., supra.
- Further in accordance with the present invention, another alternative reaction scheme is provided which can utilize a starting material comprising a 4-carboxyl pyrrole derivative.
- Reaction Scheme 4
-
- wherein:
- R1, R2, R3 and R4 are as defined above;
-
-
- wherein R15 is unsubstituted alkyl (preferably C1 to C6), alkenyl (preferably C2 to C6), alkynyl (preferably C2 to C6), aralkyl or aryl, or substituted silyl; and R1, R2, R3 and R4 are as defined above. In carrying out this reaction, the isocyanate of Formula XVII is heated with a 1-5 fold molar excess of the alcohol in an aromatic solvent (e.g., toluene or xylene) in the presence of a nitrogenous base catalyst such as trialkylamine.
- The compounds of Formula XVII are novel compounds having utility in the synthesis of monomers for polyamides, and potentially for synthesis of other useful products. For use in synthesis of monomers for polyamides that bind to DNA, preferences for the substituents R1, R2, R3, and R4 are the same as for compounds of Formula II, and the preferences are the same as the preferences for R2 in Formula II.
-
- In a more preferred reaction scheme, the isocyanate of Formula XVII may be used directly in the preparation of polyamides. The isocyanate moiety of one monomer molecule reacts with the 2-carboxylate of another to form the amide linkage with extrusion of CO2.
- The following examples illustrate the reactions.
- Instrumentation and General Methods.1H and 13C were recorded on a Varian VXR-300 (1H, 300 MHZ and 13C, 75.4 MHZ) or a Varian INOVA (1H, 400 MHZ and 13C, 100 MHZ) spectrometer in CDCl3 or DMSO-d6 as solvent unless otherwise stated. All NMR data are reported in ppm or d values downfield from tetramethylsilane (TMS, d=0.00, as an internal reference) and coupling constants, J, are reported in Hz. 13C NMR spectra were proton decoupled and recorded in CDCl3. The center peak of the solvent CDCl3 at 77.00 ppm was used as an internal reference. The multiplicities of the 13C NMR signals were determined by the attached proton test (APT) pulse sequence. Electron impact (EI) and chemical ionization (CI) mass spectra were recorded, at 70 eV ionizing voltage, on a Hewlett-Packard 5988A twin EI and CI quadrupole mass spectrometer connected to a Hewlett-Packard 5890A gas chromatograph fitted with a Hewlett-Packard 12 m×0.33 mm Ultra-1 (cross-linked methyl silicone) column.
- Low resolution liquid chromatography-mass spectrometry (LC-MS) experiments were performed utilizing a Hewlett Packard 1100 HPLC system and a Micromass Platform LCZ single quadrupole mass spectrometer with Electrospray as the ion source was operated in positive or negative mode. Exact mass measurements were performed on a Mariner™ Biospectrometry™ Workstation (Perceptive Biosystems, Inc.), time of flight (TOF) mass spectrometer. Molecular weight measurements have mass accuracies +/−100 ppm of the theoretical mass utilizing an external calibrant. The mass spectrometer was operated in positive mode using electrospray as the ion source.
- Solutions were evaporated under reduced pressure with a rotary evaporator, and the residues were flash chromatographed on a silica gel column using an ethyl acetate/hexane mixture as the eluent unless specified otherwise. Chromatographic separations on the Chromatotron were accomplished using 2 mm or 4 mm Kieselgel 60 PF254 gypsum coated plates. Analytical thin-layer chromatography (TLC) analyses were performed on EM silica gel plates, 60PF254. Visualization was accomplished with UV light or iodine. Melting points were determined on a Dynamics Optics AHT 713921 hot-stage apparatus and are uncorrected.
- Microanalyses were performed by Atlantic Microlab, Inc., Norcross, Ga.
- Materials and Reagents. Sarcosine ethyl ester hydrochloride, triethylamine, ethyl nitroacetate, triethyl orthoformate, acetic anhydride, ethyl acetate, hexane, toluene, dimethyl sulfate, ammonium formate, Pd on activated charcoal (10%) and di-tert-butyldicarbonate, were obtained from Aldrich and used as such. Methylene chloride, dioxane, acetone, and tert-butyl alcohol were obtained from EM Science. Absolute ethyl alcohol (AAPER), sodium metal (Fisher), sodium hydroxide (J. T. Baker), ammonia (Matheson), diethyl ether and potassium carbonate (Mallinckrodt) were reagent grade and used as received.
- Ethyl Sarcosinate (CH3NHCH2COOC2H5)
- The liberation of the free ester from its hydrochloride salt was accomplished by passing dry ammonia gas through a suspension of sarcosine ethyl ester hydrochloride (50 g, 325.5 mmol) in diethyl ether (600 mL) at 0° C. (ice-bath) for 3 h. Precipitated ammonium chloride was removed by filtration and washed with ether. The filtrate was concentrated, first by rotary evaporation and then on a vacuum pump for 30 min afforded ethyl sarcosinate as a pale pink liquid (38.55 g, 100%);1H NMR (300 MHZ, CDCl3) d 1.28 (t, J=7.1 Hz, 3H, CH3—CH2—), 1.60 (S, 1H, CH3—NH—), 2.44 (s, 3H, CH3—NH—), 3.36 (S, 2H, —NH—CH2—), 4.20 (q, J=7.1 Hz, 2H, CH3—CH2—); 13C NMR (75.4 MHZ, CDCl3) d 14.19, 36.08, 52.65, 60.62, 172.32.
-
- A mixture of ethyl nitroacetate (30 g, 225.4 mmol), triethyl orthoformate (75 mL, 450 mmol) and acetic anhydride (61 mL, 640 mmol) were heated for 1 h at 120° C. and for a further 1 h at 130° C. in a distillation apparatus. The reaction mixture was finally heated at 140° C. and the distillate (˜100 mL) was collected. The excess of triethyl orthoformate and acetic anhydride was removed under reduced pressure to give a dark orange viscous liquid (41.4 g). Fractional distillation of the crude product under reduced pressure (105-106° C./0.2 mm Hg) afforded a light yellow liquid (33.87 g, 79%). GC and1H NMR analysis of the purified product indicated the presence of Z,E-isomers in a 73:27 ratio.
- (Z)-isomer:1H NMR (400 MHZ, CDCl3) d 1.31 (t, J=7.2 Hz, 3H, CH3—CH2—), 1.43 (t, J=7.2 Hz, 3H, CH3—CH2), 4.30 (q, J=7.2 Hz, 2H, CH3—CH2—), 4.31 (q, J=7.2 Hz, 2H, CH3—CH2—), 7.52 (s, 1H); 13C NMR (100 MHZ, CDCl3) d 14.05, 15.11, 61.88, 73.93, 127.01, 155.94, 159.81; MS (EI, 70 eV) m/z (relative intensity) 190 (M+1, 5), 189 (M+, 49), 172 (36), 161(6), 144 (60), 117 (19), 116 (55), 115 (100), 99 (61), 88 (63), 87 (54), 86 (70), 71 (85), 70 (56), 54 (33), 43 (28), Calcd for C7H11NO5: 189.18. (E)-isomer: 1H NMR (400 MHZ, CDCl3) d 1.34 (t, J=7.2 Hz, 3H, CH3—CH2—), 1.46 (t, J=7.2 Hz, 3H, CH3—CH2), 4.35 (q, J=7.2 Hz, 2H, CH3—CH2—), 4.36 (q, J=7.2 Hz, 2H, CH3—CH2—), 8.22 (s, 1H); 13C NMR (100 MHZ, CDCl3) d 13.92, 15.15, 61.97, 74.60, 129.35, 159.06, 162.86; MS (EI, 70 eV) m/z (relative intensity) 190 (M+1, 5), 189 (M+, 37), 172 (30), 161(7), 144 (96), 117 (19), 116 (65), 115 (100), 99 (56), 88 (62), 87 (51), 86 (77), 71 (93), 54 (35), 43 (23), Calcd for C7H11NO5: 189.18.
-
- Ethyl sarcosinate (3.30 g, 28.17 mmol) was added to ethyl ethoxymethylenenitroacetate (5.26 g, 27.80 mmol) at room temperature, an exothermic reaction occurred and a dark orange red solution was obtained. The reaction mixture was stirred at room temperature for 2 h. Ethanol was removed by rotary evaporation to afford an orange red oily liquid (7.186 g, 99%): MS (EI, 70 eV) m/z (relative intensity) 261 (M+1, 1), 260 (M+, 12), 214 (10), 187 (37), 159 (100), 142 (24), 113 (41), 85 (72), 69 (17), 42(70), Calcd for C10H16N2O6: 260.25.
-
- To a solution of ethyl-N-[(2-nitro-2-ethoxycarbonyl)vinyl]sarcosinate (32.12 g, 123.42 mmol) in abs. ethanol (150 mL) was added a solution of sodium ethoxide prepared from sodium (4.0 g, 174.0 mmol) and abs. ethanol (100 mL). The reaction mixture was refluxed under a nitrogen atmosphere for 2 h to afford a dark orange-brown solution. Ethanol was removed under reduced pressure to give a dark brown residue. The residue was dissolved in water (500 mL) and acidified with 20% H2SO4 to give a brown precipitate, filtered and washed with water. The filtrate was extracted with CH2Cl2 (10×100 mL). The brown solid was dissolved in CH2Cl2 and the solution was mixed with CH2Cl2 extracts. The combined extracts were dried with anhydrous Na2SO4. Filtration and rotary evaporation gave an orange brown solid (11.28 g). The residue was dissolved in CH2Cl2 (250 mL) and passed through a pad of Silica gel (100 g), washed several times with CH2Cl2, evaporation of the solvent gave an orange crystalline solid (5.60 g, 21.2%). Recrystallization from ethyl acetate/hexane afforded very pale yellow needles; mp 126-128° C.; 1H NMR (300 MHZ, CDCl3) d 1.41 (t, J=7.2 Hz, 3H, CH3—CH2—), 3.88 (s, 3H, CH3—N—), 4.41 (q, J=7.2 Hz, 2H, CH3—CH2—), 7.40 (s, 1H, H-5), 8.85 (s, 1H, —OH); 13C NMR (100 MHZ, CDCl3) d 14.35, 38.77, 61.06, 107.45, 123.44, 125.24, 147.42, 161.52; MS (EI, 70 eV) m/z (relative intensity) 215 (M+1, 3), 214 (M+, 30), 169 (19), 168 (100), 152 (26), 140 (14), 94 (8), 53 (19), 42 (11), Calcd for C8H10N2O5: 214.18. HRMS: Calcd for C8H11N2O5 [M+H+]: 215.0668, Found; 215.0666. Anal. Calcd for C8H10N2O5: C, 44.86; H, 4.70; N, 13.07. Found: C, 44.97; H, 4.76; N, 12.97. TLC (ethyl acetate) Rf 0.44.
-
- To a solution of ethyl 1-methyl-4-nitro-3-hydroxypyrrole-2-carboxylate (0.90 g, 4.20 mmol) in ethyl acetate (50 mL) was added ammonium formate (2.64 g, 41.86 mmol) and 10% Pd/C (1.20 g) and the reaction mixture was refluxed under a nitrogen atmosphere for 30 min. The reaction mixture was filtered through a bed of Celite, washed with ethyl acetate (2×50 mL). The solvent was evaporated under reduced pressure to afford the crude product as a dirty yellow solid (0.664 g, 86%);1H NMR (300 MHZ, CDCl3) d 1.37 (t, J=7.2 Hz, 3H, CH3—CH2—), 3.66 (s, 3H, CH3—N—), 4.35 (q, J=7.2 Hz, 2H, CH3—CH2—), 6.26 (s, 1H, H-5); 13C NMR (100 MHZ, CDCl3) d 14.37, 36.38, 59.67, 105.23, 116.49, 118.72, 145.22, 162.46; MS (EI, 70 eV) m/z (relative intensity) 185 (M+1, 3), 184 (M+, 35), 139 (16), 138 (100), 137 (16), 110 (25), 109 (9), 82 (9), 55 (9), 42 (10), Calcd for C8H12N2O3: 184.19. TLC (ethyl acetate) Rf 0.27. Above sample was used for the preparation of ethyl 1-methyl-4-(tert-butoxycarbonyl)amino-3-hydroxypyrrole-2-carboxylate.
-
- A mixture of ethyl 1-methyl-4-nitro-3-hydroxypyrrole-2 carboxylate (0.071 g, 0.3315 mmol), dimethyl sulfate (0.055 g, 0.436 mmol) and anhydrous potassium carbonate (0.5 g, 3.90 mmol) in dry acetone (20 mL) was refluxed under a nitrogen atmosphere for 22 h. Potassium carbonate was removed by filtration and the filtrate was evaporated under reduced pressure to afford an orange crystalline solid. Excess dimethyl sulfate was destroyed by treating the residue with aqueous ammonia (1 mL). Water (2 mL) was added and the residue was extracted with ether (30 mL). The combined ether extracts were washed with aqueous sodium hydroxide solution and water. Removal of ether under reduced pressure afforded a cream residue. The residue was dissolved in CH2Cl2 (25 mL), dried with anhydrous Na2SO4, filtered and evaporated under reduced pressure to yield a cream microcrystalline solid (0.067 g, 89%). Recrystallization from acetone/hexane afforded colorless needles, mp 145-147° C.; 1H NMR (300 MHZ, CDCl3) d 1.40 (t, J=7.2 Hz, 3H, CH3—CH2—), 3.90 (s, 3H, CH3—N—), 3.95 (s, 3H, CH3O—), 4.36 (q, J=7.0 Hz, 2H, CH3—CH2—), 7.47 (s, 1H, H-5); 13C NMR (100 MHZ, CDCl3) d 14.22, 38.92, 60.67, 63.02, 114.73, 125.76, 127.79, 146.18, 160.09; MS (EI, 70 eV) m/z (relative intensity) 229 (M+1, 3), 228 (M+, 30), 211 (12), 183 (12), 167 (20), 153 (25), 152 (100), 141 (7), 109 (12), 84 (8), 67 (6), 53 (31), 42 (17), Calcd for C9H12N2O5: 228.20. HRMS (M+H): Calcd for C9H13N2O5 [M+H+]: 229.0824, Found 229.0834. Anal. Calcd for C9H12N2O5: C, 47.37; H, 5.29; N, 12.27. Found. C, 47.44; H, 5.36; N, 12.28. TLC (ethyl acetate/Hexane, 1:3) Rf 0.23.
-
- To a solution of ethyl 1-methyl-4-nitro-3-methoxypyrrole-2-carboxylate (3.34 g, 14.64 mmol) in ethyl acetate (150 mL) was added ammonium formate (9.23 g, 146.37 mmol) and 10% Pd/C (4.5 g) and the reaction mixture was refluxed under a nitrogen atmosphere for 30 min. The reaction mixture was filtered through a bed of Celite, washed with ethyl acetate (50 mL). The solvent was evaporated under reduced pressure to afford the product as an orange viscous liquid (2.753 g, 95%);1H NMR (300 MHZ, CDCl3) d 1.37 (t, J=7.1 Hz, 3H, CH3—CH2—), 2.87 (br s, 2H, —NH2), 3.74 (s, 3H, CH3—N—), 3.82 (s, 3H, —OCH3), 4.31 (q, J=7.2 Hz, 2H, CH3—CH2—), 6.26 (s, 1H, H-5); MS (EI, 70 eV) m/z (relative intensity) 199 (M+1, 5), 198 (M+, 41), 183 (8), 137 (100), 109 (6), 81 (5), 54 (6), 42 (8), Calcd for C9H14N2O3: 198.22. TLC (ethyl acetate) Rf 0.20.
-
- A solution of ethyl 1-methyl-4-amino-3-methoxypyrrole-2-carboxylate (2.75 g, 13.873 mmol) and di-tert-butyldicarbonate (3.37 g, 15.441 mmol) in dioxane (15 mL) was stirred at room temperature under a nitrogen atmosphere for 22 h. The solvent was removed under reduced pressure and the residue was treated with water (100 mL) and the mixture was extracted with CH2Cl2 (100 mL). The CH2Cl2 layer was washed with water and dried with anhydrous Na2SO4, filtered and the solvent was removed on a rotary evaporator to give an orange viscous liquid (4.888 g). 1H NMR of the crude residue indicated the presence of a sufficiently pure sample of ethyl 1-methyl-4-(tert-butoxycarbonyl)amino-3-methoxypyrrole-2-carboxylate contaminated with a trace of di-tert-butyldicarbonate. 1H NMR of the crude residue was identical with that of an authentic sample.
-
- Crude ethyl 1-methyl-4-(tert-butoxycarbonyl)amino-3-methoxypyrrole-2-carboxylate (4.88 g, 16.38 mmol) was dissolved in ethanol (16 mL) and a solution of sodium hydroxide, prepared from NaOH (1.376 g) in water (15 mL), was added and the reaction mixture was stirred at room temperature for six days. Ethanol was removed under reduced pressure. Water (50 ml) was added and the solution was extracted with ether (2×50 mL) to remove any unreacted starting ester (0.183 g). The aqueous layer was acidified with H2SO4 to pH 2-3 to afford a colorless precipitate. The precipitated product was extracted with ether, dried with anhydrous Na2SO4. Filtration and rotary evaporation gave a dirty cream crystalline solid (2.922 g); 1H NMR (400 MHZ, DMSO-d6) d 1.42 (s, 9H, (CH3)3C—), 3.67 (s, 3H, CH3N—), 3.69 (s, 3H, CH3O—), 6.96 (br s, 1H), 8.32 (br s, 1H), 12.10 (br s, 1H, —COOH). 4-[(tert-Butoxycarbonyl)amino]-1-methyl-3-methoxypyrrole-2-carboxylic acid prepared by the above new method was identical in all aspects with the authentic sample.
-
- A solution of ethyl 1-methyl-4-amino-3-hydroxypyrrole-2-carboxylate (0.650 g, 3.529 mmol), N,N-diisopropylethylamine (1 mL, 5.741 mmol) and di-tert-butyldicarbonate (1.0 g, 4.615 mmol) in dioxane (7 mL) was stirred at room temperature under a nitrogen atmosphere for 19 h. The solvent was removed under reduced pressure and the residue was treated with water (50 mL) and the mixture was extracted with diethyl ether (3×50 mL). The ether layer was washed with water and dried with anhydrous Na2SO41 filtered and the solvent was removed on a rotary evaporator to give an orange brown paste (1.115 g). 1H NMR of the crude residue indicated the presence of two products: ethyl 1-methyl-4-(tert-butoxycarbonyl)amino-3-hydroxypyrrole-2-carboxylate and ethyl 1-methyl-4-(tert-butoxycarbonyl)amino-3-(tert-butoxycarbonyl)oxypyrrole-2-carboxylate (an O,N-bis-BOC protected derivative). Purification of the residue by radial chromatography on the Chromatotron using silica gel plate and elution with ethyl acetate/hexane (10/90) afforded ethyl 1-methyl-4-(tert-butoxycarbonyl)amino-3-hydroxypyrrole-2-carboxylate as a colorless crystalline solid (0.377 g, 38%) which was identical in all aspects (1H, 13C NMR and MS) with the authentic sample of ethyl 1-methyl-4-(tert-butoxycarbonyl) amino-3-hydroxypyrrole-2-carboxylate prepared by the curtius reaction.
- Further elution with the same solvent system afforded ethyl 1-methyl-4-(tert-butoxy carbonyl)amino-3-(tert-butoxycarbonyl)oxypyrrole-2-carboxylate as a colorless waxy solid (0.503 g, 37%).1H NMR (300 MHZ, CDCl3) d 1.33 (t, J=7.0 Hz, 3H, CH3—CH2—), 1.50 (s, 9H, (CH3)3C—), 1.56 (s, 9H, (CH3)3C—), 3.83 (s, 3H, CH3—N—), 4.28 (q, J=7.0 Hz, 2H, CH3—CH2—), 6.14 (br s, 1H), 7.12 (br s, 1H, H-5), 13C NMR (100 MHZ, CDCl3) d 14.42, 27.66, 28.27, 37.54, 59.96, 80.50, 83.87, 111.11, 114.78, 117.66, 141.48, 151.17, 152.73, 160.06; MS (EI, 70 eV) m/z (relative intensity) 285 (M+1-BOC, 0.3), 284 (M+-BOC, 4), 228 (12), 182 (18), 138 (100), 110 (4), 57 (58); Calcd for CO2H28N2O7: 384.43.
- LRMS: Found; 407 [M+Na+]. Calcd for C18H28N2O7Na: 407.
Claims (132)
1. A process for the preparation of a compound of Formula II:
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R2 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, haloalkylcarbonyl, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, and aryloxycarbonyl, and substituted silyl;
R4 is selected from the group consisting of hydrogen and methyl; and
R5 represents a carbamate-forming blocking group
the process comprising:
reducing the nitro group of a compound of Formula IV
wherein R1, R2, R3 and R4 are as defined above, thereby producing a compound of Formula III
wherein R1, R2, R3 and R4 are as defined above; and
contacting said compound of Formula III with a blocking group reagent thereby substituting a blocking group on the 4-amino group.
2. A process as set forth in claim 1 wherein said blocking group is selected from the group consisting of t-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trialkylsilylethoxycarbonyl, and benzyloxycarbonyl.
3. A process as set forth in claim 2 wherein said blocking group is introduced by contacting said compound of Formula III with a blocking reagent selected from the group consisting of di(t-butyl)dicarbonate, t-butoxycarbonyl halide, di(fluorosceinylmethyl)dicarbonate, fluorenylmethoxycarbonyl halide, di(allyl)dicarbonate, allyloxycarbonyl halide, di(benzyl)dicarbonate and benzyloxycarbonyl halide.
5. A process as set forth in claim 1 wherein said nitro reduction comprises contacting said compound of Formula IV with a hydrogen transfer agent in the presence of a catalyst for the reduction reaction.
6. A process as set forth in claim 5 wherein said nitro reduction comprises introducing said compound of Formula IV and a palladium catalyst into a reaction zone, the proportion of palladium introduced into said reaction zone relative to said compound of Formula IV being not greater than about 2% by weight.
7. A process as set forth in claim 1 wherein said nitro reduction comprises contacting said compound of Formula IV with hydrogen under pressure in the presence of a catalyst for the reaction.
8. A process as set forth in claim 1 further comprising preparation of said compound of Formula IV, comprising:
reacting a 3-hydroxypyrrole derivative corresponding to Formula V or the keto tautomer of said compound of Formula V with blocking reagent comprising R2, said compound of Formula V having the structure:
and the keto tautomer of said compound of Formula V having the structure:
wherein R1, R2, R3, and R4 are as set forth above, said blocking reagent being effective to form an —OR2 group at the 3-position of said compound of Formula V.
9. A process as set forth in claim 8 wherein said blocking reagent comprises an etherifying agent corresponding to Formula VI
(R2O)2SO4 (Formula VI)
or Formula VIa
R2X (Formula VIa)
where X is halo and R2 is as defined above, and the reaction is conducted under basic conditions.
10. A process as set forth in claim 9 wherein R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, and benzyl.
11. A process as set forth in claim 8 further comprising preparation of said compound of Formula V and/or Va, comprising contacting a compound of Formula VII with a reagent effective for promoting ring closure, said compound of Formula VII corresponding to the structure:
wherein R1, R3 and R4 are as defined above and —OR6 is a leaving group.
12. A process as set forth in claim 11 wherein R6 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
13. A process as set forth in claim 12 wherein said compound of Formula VII is contacted with an alkali metal alkoxide in the presence of an alcohol.
14. A process a set forth in claim 12 wherein said ring closure reagent comprises a base selected from the group consisting of an alkali metal alkoxide, Li or Na bis(trimethylsilylamide), and Li diisopropylamide.
15. A process as set forth in claim 14 wherein said compound of Formula VII is contacted with said base at a temperature effective to form an intermediate ring closure reaction mixture containing the carbanion of Formula VIIa:
16. A process as set forth in claim 12 further comprising the preparation of said compound of Formula VII, comprising:
reacting a compound of Formula VIII with an N-substituted glycine ester corresponding to Formula IX, said compound of Formula VIII having the structure:
wherein R4 and R6 are as defined above and —OR7 is a leaving group;
said compound of Formula IX having the structure:
R1NHCH2C(O)OR3 (Formula IX)
wherein R3 is as defined above.
17. A process as set forth in claim 16 wherein R7 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
18. A process as set forth in claim 16 further comprising preparation of said compound of Formula VIII, the preparation of said compound of Formula VIII comprising:
reacting a nitroacetate compound of Formula X with a reagent selected from the group consisting of an orthoformate triester, an orthoacetate triester, a formate ester, an acetate ester, and a 1,1,-dihalomethyl ether, said nitroacetate compound of Formula X having the structure:
O2NCH2C(O)OR6 (Formula X)
wherein R6 is as defined above.
19. A process as set forth in claim 18 wherein said compound of Formula VIII is formed by contacting an orthoformate or orthoacetate triester, said compound of Formula X and a carboxylic anhydride.
20. A process as set forth in claim 1 comprising contacting said compound of Formula III with a compound of Formula XIII under acidic or neutral conditions, said compound of Formula XIII having the structure:
wherein R8 and R11 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl, silylalkyl and substituted silyl.
21. A process as set forth in claim 1 wherein said blocking reagent corresponds to the formula:
R8—OC(O)X
wherein X is halo R8 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl, silylalkyl and substituted silyl; and X is halide.
22. A process for the preparation of a compound corresponding to Formula III:
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R2 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, and aryloxycarbonyl, and substituted silyl; and
R4 is selected from the group consisting of hydrogen and methyl;
the process comprising:
reducing the nitro group of a compound of Formula IV:
wherein R1, R2, R3 and R4 are as defined above.
23. A process as set forth in claim 22 wherein said nitro reduction comprises contacting said compound of Formula IV with a hydrogen transfer agent in the presence of a catalyst for the reduction reaction.
24. A process as set forth in claim 23 wherein said nitro reduction comprises introducing said compound of Formula IV and a palladium catalyst into a reaction zone, the proportion of palladium introduced into said reaction zone relative to said compound of Formula I being not greater than about 2% by weight.
25. A process as set forth in claim 22 wherein said nitro reduction comprises contacting said compound of Formula IV with hydrogen under pressure in the presence of a catalyst for the reaction.
26. A process as set forth in claim 22 further comprising preparation of said compound of Formula IV, comprising:
reacting a 3-hydroxypyrrole derivative corresponding to Formula V or the keto tautomer of said compound of Formula V with a blocking reagent comprising R2, said compound of Formula V having the structure:
and the keto tautomer of said compound of Formula V having the structure:
wherein R1, R2, R3, and R4 are as set forth above, said blocking reagent being effective to form an —OR2 group at the 3-position of said compound of Formula II.
27. A process as set forth in claim 26 wherein said blocking agent comprises an etherifying agent corresponding to Formula VI
(R2O)2SO4 (Formula VI)
or Formula VIa
R2X (Formula VIa)
where X is halo and R2 is as defined above, and the reaction is conducted under basic conditions.
28. A process as set forth in claim 27 wherein R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, and benzyl.
29. A process as set forth in claim 26 further comprising preparation of said compound of Formula V and/or Va, comprising contacting a compound of Formula VII with a reagent effective for promoting ring closure, said compound of Formula VII corresponding to the structure:
wherein R1, R3 and R4 are as defined above and —OR6 is a leaving group.
30. A process as set forth in claim 29 wherein R6 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
31. A process as set forth in claim 29 wherein said compound of Formula VII is contacted with an alkali metal alkoxide in the presence of an alcohol.
32. A process a set forth in claim 29 wherein said ring closure reagent comprises a base selected from the group consisting of an alkali metal alkoxide, Li or Na bis(trimethylsilylamide), and Li diisopropylamide.
33. A process as set forth in claim 32 wherein said compound of Formula VII is contacted with said base at a temperature effective for forming an intermediate ring closure reaction mixture containing the carbanion of Formula VIIa:
34. A process as set forth in claim 29 further comprising the preparation of said compound of Formula VII, Formula VII comprising:
reacting a compound of Formula VIII with an N-substituted glycine ester corresponding to Formula IX, said compound of Formula VIII having the structure:
wherein R4 and R6 are as defined above and —OR7 is a leaving group;
said compound of Formula IX having the structure:
R1NHCH2C(O)OR3 (Formula IX)
wherein R3 is as defined above.
35. A process as set forth in claim 34 wherein R7 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
36. A process as set forth in claim 34 further comprising preparation of said compound of Formula VIII, the preparation of said compound of Formula VIII comprising:
reacting a nitroacetate compound of Formula X with a reagent selected from the group consisting of an orthoformate triester, an orthoacetate triester, a formate ester, an acetate ester, and a 1,1,-dihalomethyl ether, said nitroacetate compound of Formula X having the structure:
O2NCH2C(O)OR6 (Formula X)
wherein R6 is as defined above.
37. A process as set forth in claim 36 wherein said compound of Formula VIII is formed by contacting an orthoformate or orthoacetate triester, said compound of Formula X and a carboxylic anhydride.
38. A process for the preparation of a compound corresponding to Formula IV:
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R2 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, and aryloxycarbonyl, and substituted silyl;
R4 is selected from the group consisting of hydrogen and methyl;
the process comprising:
reacting a 3-hydroxypyrrole derivative corresponding to Formula V:
or the keto tautomer of said 3-hydroxypyrrole derivative, said keto tautomer corresponding to the structure:
wherein R1, R3, and R4 are as set forth above, with a blocking reagent effective to form an —OR2 group at the 3-position of said compound of Formula V.
39. A process as set forth in claim 38 wherein said blocking reagent comprises an etherifying agent corresponding to Formula VI
(R2O)2SO4 (Formula VI)
or Formula VIa
R2X (Formula VIa)
where X is halo and R2 is as defined above, and the reaction is conducted under basic conditions.
40. A process as set forth in claim 38 where in R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, and benzyl.
41. A process as set forth in claim 38 further comprising preparation of said compound of Formula V and/or Va, comprising contacting a compound of Formula VII with a reagent effective for promoting ring closure, said compound of Formula VII corresponding to the structure:
wherein R1, R3 and R4 are as defined above and —OR6 is a leaving group.
42. A process as set forth in claim 41 wherein R6 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
43. A process as set forth in claim 41 wherein said compound of Formula VII is contacted with an alkali metal alkoxide in the presence of an alcohol.
44. A process a set forth in claim 41 wherein said ring closure reagent comprises a base selected from the group consisting of an alkali metal alkoxide, Li or Na bis(trimethylsilylamide), and Li diisopropylamide.
45. A process as set forth in claim 44 wherein said compound of Formula VIIa is contacted with said base at a temperature effective for forming an intermediate ring closure reaction mixture containing the carbanion of Formula VIIa:
46. A process as set forth in claim 41 further comprising the preparation of said compound of Formula VII, comprising:
reacting a compound of Formula VIII with an N-substituted glycine ester corresponding to Formula IX, said compound of Formula VIII having the structure:
wherein R4 and R6 are as defined above and —OR7 is a leaving group, said compound of Formula IX having the structure:
R1NHCH2C(O)OR3 (Formula IX)
wherein R3 is as defined above.
47. A process as set forth in claim 46 wherein R7 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
48. A process as set forth in claim 46 further comprising preparation of said compound of Formula VIII, the preparation of said compound of Formula VIII comprising:
reacting a nitroacetate compound of Formula X with a reagent selected from the group consisting of an orthoformate triester, an orthoacetate triester, a formate ester, an acetate ester, and a 1,1,-dihalomethyl ether, said nitroacetate compound of Formula X having the structure:
O2NCH2C(O)OR6 (Formula X)
wherein R6 is as defined above.
49. A process as set forth in claim 48 wherein said compound of Formula VIII is formed by contacting an orthoformate or orthoacetate triester, said nitroacetate compound of Formula X and a carboxylic anhydride.
50. A process for the preparation of a 3-hydroxypyrrole derivative corresponding to Formula V or the keto tautomer thereof, said compound of Formula V having the structure:
and said keto tautomer of said compound of Formula V having the structure:
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl; and
R4 is selected from the group consisting of hydrogen and methyl;
the process comprising:
contacting a compound of Formula VII with a reagent effective for promoting ring closure, said compound of Formula VII corresponding to the structure:
wherein R1, R3 and R4 are as defined above and —OR6 is a leaving group.
51. A process as set forth in claim 50 wherein R6 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
52. A process as set forth in claim 50 wherein said compound of Formula VII is contacted with an alkali metal alkoxide in the presence of an alcohol.
53. A process a set forth in claim 50 wherein said ring closure reagent comprises a base selected from the group consisting of an alkali metal alkoxide, Li or Na bis(trimethylsilylamide), and Li diisopropylamide.
54. A process as set forth in claim 53 wherein said compound of Formula VII is contacted with said base at a temperature effective for forming an intermediate ring closure reaction mixture containing the carbanion of Formula VIIa:
55. A process as set forth in claim 50 further comprising the preparation of said compound of Formula VII, comprising:
reacting a compound of Formula VIII with an N-substituted glycine ester corresponding to Formula IX, said compound of Formula VIII having the structure:
wherein R4 and R6 are as defined above and —OR7 is a leaving group;
said compound of Formula IX having the structure:
R1NHCH2C(O)OR3 (Formula IX)
wherein R3 is as defined above.
56. A process as set forth in claim 55 wherein R7 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
57. A process as set forth in claim 55 further comprising preparation of said compound of Formula VIII, comprising:
reacting a nitroacetate compound of Formula X with a reagent selected from the group consisting of an orthoformate triester, an orthoacetate triester, a formate ester, an acetate ester, and a 1,1,-dihalomethyl ether, said nitroacetate compound of Formula X having the structure:
O2NCH2C(O)OR6 (Formula X)
wherein R6 is as defined above.
58. A process as set forth in claim 57 wherein said compound of Formula VIII is formed by contacting an orthoformate or orthoacetate triester, said compound of Formula X and a carboxylic anhydride.
59. A process for the preparation of a compound corresponding to the Formula:
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R4 is selected from the group consisting of hydrogen and methyl; and
—OR6 is a leaving group;
the process comprising:
reacting a compound of Formula VIII with an N-substituted glycine ester corresponding to Formula IX, said compound of Formula VIII having the structure:
wherein R4 and R6 are as defined above and —OR7 is a leaving group;
said compound of Formula IX having the structure:
R1NHCH2C(O)OR3 (Formula IX)
wherein R3 is as defined above.
60. A process as set forth in claim 59 wherein R6 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
61. A process as set forth in claim 59 wherein R7 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
62. A process as set forth in claim 59 further comprising preparation of said compound of Formula VIII, the preparation of said compound of Formula VIII comprising:
reacting a nitroacetate compound of Formula X with a reagent selected from the group consisting of an orthoformate triester, an orthoacetate triester, a formate ester, an acetate ester, and a 1,1,-dihalomethyl ether, said nitroacetate compound of Formula X having the structure:
O2NCH2C(O)OR6 (Formula X)
wherein R6 is as defined above.
63. A process as set forth in claim 62 wherein said compound of Formula VIII is formed by contacting an orthoformate or orthoacetate triester, said compound of Formula X and a carboxylic anhydride.
64. A process for the preparation of a compound corresponding to Formula XI:
or the keto tautomer thereof:
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R4 is selected from the group consisting of hydrogen and methyl; and
R5 is a carbamate-forming blocking group;
the process comprising:
contacting a compound of Formula XII and/or the keto tautomer thereof with a blocking group reagent thereby substituting a blocking group on the 4-amino group, said compound of Formula XII having the structure:
said keto tautomer of Formula XII corresponding to the formula:
wherein R1, R3, and R4 are as defined above.
65. A process as set forth in claim 64 wherein said compound of Formula XII is contacted with said blocking reagent under neutral or acidic conditions.
66. A process as set forth in claim 64 further comprising the preparation of said compound of Formula XII, comprising:
reduction of the nitro group of a compound of Formula V or the keto tautomer thereof, said compound of Formula V having the structure:
and said keto tautomer of Formula V having the structure:
wherein R1, R3 and R4 are as defined above.
67. A process as set forth in claim 64 further comprising the preparation of said compound of Formula V or Va comprising:
contacting a compound of Formula VII with a reagent effective for promoting ring closure, said compound of Formula VII corresponding to the structure:
wherein R1, R3 and R4 are as defined above and —OR6 is a leaving group.
68. A process as set forth in claim 67 wherein R6 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
69. A process as set forth in claim 67 wherein said compound of Formula VII is contacted with an alkali metal alkoxide in the presence of an alcohol.
70. A process a set forth in claim 67 wherein said ring closure reagent comprises a base selected from the group consisting of an alkali metal alkoxide, Li or Na bis(trimethylsilylamide), and Li diisopropylamide.
71. A process as set forth in claim 70 wherein said compound of Formula VII is contacted with said base at a temperature effective for forming an intermediate ring closure reaction mixture containing the carbanion of Formula VIIa:
72. A process as set forth in claim 67 further comprising the preparation of said compound of Formula VII, comprising:
reacting a compound of Formula VIII with an N-substituted glycine ester corresponding to Formula IX, said compound of Formula VIII having the structure:
wherein R4 and R6 are as defined above and —OR7 is a leaving group;
said compound of Formula IX having the structure:
R1NHCH2C(O)OR3 (Formula IX)
wherein R3 is as defined above.
73. A process as set forth in claim 72 wherein R7 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
74. A process as set forth in claim 72 further comprising preparation of said compound of Formula VIII, the preparation of said compound of Formula VIII comprising:
reacting a nitroacetate compound of Formula X with a reagent selected from the group consisting of an orthoformate triester, an orthoacetate triester, a formate ester, an acetate ester, and a 1,1,-dihalomethyl ether, said nitroacetate compound of Formula X having the structure:
O2NCH2C(O)OR6 (Formula X)
wherein R6 is as defined above.
75. A process as set forth in claim 74 wherein said compound of Formula VIII is formed by contacting an orthoformate or orthoacetate triester, said nitroacetate compound of Formula X and a carboxylic anhydride.
76. A process as set forth in claim 64 further comprising reacting said compound of Formula XI or said tautomer of Formula XIa with blocking agent to produce a compound of Formula II:
wherein R1, R3, R4 and R5 are as set forth above, and R2 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, and aryloxycarbonyl and substituted silyl, said etherifying agent comprising R2 and being effective to form an —OR2 group at the 3-position of said compound of Formula XI.
77. A process as set forth in claim 76 wherein said etherifying agent corresponding to Formula VI:
(R2O)2SO4 (Formula VI)
or Formula VIa:
R2X (Formula VIa)
where X is halo, R2 is as defined above and the reaction is conducted under basic conditions.
78. A process as set forth in claim 77 where in R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, and benzyl.
79. A process as set forth in claim 64 wherein said blocking group reagent is selected from the group consisting of di(t-butyl)dicarbonate, t-butoxycarbonyl halide, di(fluorenylmethyl)dicarbonate, fluorenylmethyoxycarbonyl halide, di(allyl)dicarbonate, allyloxycarbonyl halide, di(benzyl)dicarbonate and benzyloxycarbonyl halide.
81. A process for the preparation of a compound of Formula XII:
or the keto tautomer thereof:
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl; and
R4 is hydrogen or methyl;
the process comprising:
reducing the nitro group of a compound of Formula V:
or the keto tautomer of Formula V thereof:
wherein R1, R3 and R4 are as defined above.
82. A process as set forth in claim 81 wherein said nitro reduction comprises contacting said compound of Formula V and/or Va with a hydrogen transfer agent in the presence of a catalyst for the reduction reaction.
83. A process as set forth in claim 82 wherein said nitro reduction comprises introducing said compound of Formula V and/or Va and a palladium catalyst into a reaction zone, the proportion of palladium introduced into said reaction zone relative to said compound of Formula V or Va being not greater than about 2% by weight.
84. A process as set forth in claim 81 wherein said nitro reduction comprises contacting said compound of Formula V and/or Va with hydrogen under pressure in the presence of a catalyst for the reaction.
85. A process as set forth in claim 81 further comprising preparation of said compound of Formula V and/or Va, comprising contacting a compound of Formula VII with a reagent effective for promoting ring closure, said compound of Formula VII corresponding to the structure:
wherein R1, R3 and R4 are as defined above, and —OR6 is a leaving group.
86. A process as set forth in claim 85 wherein R6 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
87. A process as set forth in claim 85 wherein said compound of Formula VII is contacted with an alkali metal alkoxide in the presence of an alcohol.
88. A process a set forth in claim 85 wherein said ring closure reagent comprises a base selected from the group consisting of an alkali metal alkoxide, Li or Na bis(trimethylsilylamide), and Li diisopropylamide.
89. A process as set forth in claim 88 wherein said compound of Formula VII is contacted with said base at a temperature effective for forming an intermediate ring closure reaction mixture containing the carbanion of Formula VIIa:
90. A process as set forth in claim 85 further comprising the preparation of said compound of Formula VII, comprising:
reacting a compound of Formula VIII with an N-substituted glycine ester corresponding to Formula IX, said compound of Formula VIII having the structure:
wherein R4 and R6 are as defined above and R7 is a leaving group;
said compound of Formula IX having the structure:
R1NHCH2C(O)OR3 (Formula IX)
wherein R3 is as defined above.
91. A process as set forth in claim 90 wherein R7 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
92. A process as set forth in claim 90 further comprising preparation of said compound of Formula VIII, the preparation of said compound of Formula VIII comprising:
reacting a nitroacetate compound of Formula X with a reagent selected from the group consisting of an orthoformate triester, an orthoacetate triester, a formate ester, an acetate ester, and a 1,1,-dihalomethyl ether, said nitroacetate compound of Formula X having the structure:
O2NCH2C(O)OR6 (Formula X)
wherein R6 is as defined above.
93. A process as set forth in claim 92 wherein said of Formula VIII is formed by contacting an orthoformate or orthoacetate triester, said nitroacetate compound of Formula X and a carboxylic anhydride.
94. A compound corresponding to the formula:
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R10 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl and substituted silyl;
R4 is selected from the group consisting of hydrogen and methyl
and the keto tautomer of Formula XIV when R10 of Formula XIV would otherwise be hydrogen.
95. A compound as set forth in claim 94 wherein R1 and R3 are C1 to C6 alkyl, R10 is hydrogen or C1 to C6 alkyl, and R4 is hydrogen.
96. A compound as set forth in claim 95 wherein each of R1 and R3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl and t-butyl, and R10 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and isopropyl.
97. A compound as set forth in claim 96 wherein R1 is methyl and R10 is hydrogen.
98. A compound as set forth in claim 97 wherein R3 is ethyl.
99. A compound as set forth in claim 96 wherein R1 is methyl and R10 is methyl.
100. A compound as set forth in claim 99 wherein R3 is ethyl.
101. A compound corresponding to the formula:
(Formula XV)
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R10 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkkynoxycarbonyl, aralkoxycarbonyl, and aryloxycarbonyl and substituted silyl;
R4 is selected from the group consisting of hydrogen and methyl
and the keto tautomer of Formula XV when R10 of Formula XV would otherwise be hydrogen.
102. A compound as set forth in claim 101 wherein R1 and R3 are C1 to C6 alkyl, R10 is hydrogen or C1 to C6 alkyl, and R4 is hydrogen.
103. A compound as set forth in claim 102 wherein each of R1 and R3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl and t-butyl, and R10 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and isopropyl.
104. A compound as set forth in claim 103 wherein R1 is methyl and R10 is hydrogen.
105. A compound as set forth in claim 104 wherein R3 is ethyl.
106. A compound as set forth in claim 103 wherein R1 is methyl and R10 is methyl.
107. A compound as set forth in claim 106 wherein R3 is ethyl.
109. A compound as set forth in claim 108 wherein R1, R3 and R6 are C1 to C6 alkyl, and R4 is hydrogen.
110. A compound as set forth in claim 109 wherein each of R1, R3, and R6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl and t-butyl.
111. A compound as set forth in claim 110 wherein R1 is methyl.
112. A compound as set forth in claim 111 wherein R3 is ethyl.
113. A process for the preparation of a compound corresponding to the formula:
wherein:
R1 and R3 are selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R4 is selected from the group consisting of hydrogen and methyl;
R15 is selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl and aryl; and
R2 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkkynoxycarbonyl, aralkoxycarbonyl, and aryloxycarbonyl, and substituted silyl; contacting a compound of Formula III with a carbonyl compound under conditions effective for the reaction of the 4-amino group of the compound of Formula III with the carbonyl compound to produce a compound of Formula XVII, said compound of Formula III having the structure:
wherein R1, R3, R4 and R10 are as defined above, said compound of Formula XVII having the structure:
wherein R1, R2, R3 and R4 are as defined above; and
contacting said compound of Formula XVII with an alcohol of Formula XVIII
R15OH (Formula XVIII)
wherein R15 is as defined above.
114. A process for the preparation of a compound of Formula XIX:
wherein:
R1 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R4 is hydrogen or methyl; and
R5 is a carbamate-forming blocking group;
or the keto tautomer of such compound of Formula XIX, the process comprising:
hydrolyzing a compound of Formula XX by contacting it with a base, said compound of Formula XX having the structure:
wherein R1, R4, and R5 are as defined above.
118. A process as set forth in claim 117 wherein said nitro reduction comprises contacting said compound of Formula XXII with a hydrogen transfer agent in the presence of a catalyst for the reduction reaction.
119. A process as set forth in claim 118 wherein said nitro reduction comprises introducing said compound of Formula XXII and a palladium catalyst into a reaction zone, the proportion of palladium introduced into said reaction zone relative to said compound of Formula XXII being not greater than about 2% by weight.
120. A process as set forth in claim 117 further comprising the preparation of said compound of Formula XXII, comprising:
reacting a compound of Formula V with formaldehyde in the presence of a nitrogenous base, said compound of Formula V having the structure:
or the keto tautomer thereof, wherein R1 is as defined above and R3 is selected from the group consisting of of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
121. A process as set forth in claim 115 wherein said nitro reduction comprises contacting said compound of Formula XXII with hydrogen under pressure in the presence of a catalyst for the reaction.
122. A process as set forth in claim 114 further comprising reacting said compound of Formula XIX with a carboxylic anhydride or acyl halide in the presence of a base to produce a compound of Formula XXIII:
124. A process for the preparation of a compound corresponding to the formula:
wherein:
R1 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl; and
R4 is selected from the group consisting of hydrogen and methyl;
the process comprising reacting a compound of Formula XXI with a blocking reagent, the compound of Formula XXI having the structure:
wherein R1 and R4 are as defined above.
125. A process for the preparation of a compound corresponding to the formula:
wherein
R1 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl; and
R4 is selected from the group consisting of hydrogen and methyl;
the process comprising reducing the nitro group of a compound having the structure:
wherein R1 and R4 are as defined above.
126. A process for the preparation of a compound corresponding to the formula
wherein;
R1 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl; and
R4 is hydrogen or methyl
the process comprising:
reacting a compound of Formula V or the keto tautomer thereof with paraformaldehyde in the presence of a nitrogenous base, said compound of Formula V having the structure:
wherein R1 and R4 are as defined above and R3 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
130. A compound corresponding to the formula:
wherein:
R1 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R4 is selected from the group consisting of hydrogen and methyl;
R5 is a carbamate-forming blocking group; and
R11 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl.
131. A compound corresponding to the formula:
wherein:
R1 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R4 is selected from the group consisting of hydrogen and methyl;
R5 is a carbamate-forming blocking group; and
R12, R13, and R14 are independently C1 to C6 alkyl.
132. A compound corresponding to the formula
wherein:
R1 and R3 are independently selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl and aryl;
R2 is selected from the group consisting of substituted and unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, haloalkylcarbonyl, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aralkoxycarbonyl, and aryloxycarbonyl, and substituted silyl; and
R4 is selected from the group consisting of hydrogen and methyl.
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US10/332,181 US20040014984A1 (en) | 2000-07-06 | 2001-07-05 | Process for the preparation of derivatives of 4-amino-3-hydroxypyrrole-2-carboxylic acid |
PCT/US2001/021274 WO2002004417A1 (en) | 2000-07-06 | 2001-07-05 | Process for the preparation of derivatives of 4-amino-3-hydroxypyrrole-2-carboxylic acid |
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US10/332,181 Abandoned US20040014984A1 (en) | 2000-07-06 | 2001-07-05 | Process for the preparation of derivatives of 4-amino-3-hydroxypyrrole-2-carboxylic acid |
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CA2738909A1 (en) | 2008-10-01 | 2010-05-06 | The University Of North Carolina At Chapel Hill | Hematopoietic protection against ionizing radiation using selective cyclin-dependent kinase 4/6 inhibitors |
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US10694739B2 (en) | 2015-10-14 | 2020-06-30 | X-Therma, Inc. | Compositions and methods for reducing ice crystal formation |
US11510407B2 (en) | 2015-10-14 | 2022-11-29 | X-Therma, Inc. | Compositions and methods for reducing ice crystal formation |
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