WO1993010127A1 - Method for making a prolineboronate ester - Google Patents
Method for making a prolineboronate ester Download PDFInfo
- Publication number
- WO1993010127A1 WO1993010127A1 PCT/US1992/009845 US9209845W WO9310127A1 WO 1993010127 A1 WO1993010127 A1 WO 1993010127A1 US 9209845 W US9209845 W US 9209845W WO 9310127 A1 WO9310127 A1 WO 9310127A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- pinanediol
- yield
- group
- ester
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 82
- 150000002148 esters Chemical class 0.000 title claims abstract description 23
- -1 N-protected pyrrole Chemical class 0.000 claims abstract description 43
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 claims abstract description 42
- 125000006239 protecting group Chemical group 0.000 claims abstract description 31
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000002253 acid Substances 0.000 claims abstract description 26
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000002009 diols Chemical class 0.000 claims abstract description 15
- 150000001413 amino acids Chemical class 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- 125000004185 ester group Chemical group 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 69
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000000463 material Substances 0.000 claims description 16
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 16
- 125000005647 linker group Chemical group 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 14
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 10
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical group [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000003729 cation exchange resin Substances 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical group COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 6
- 150000000180 1,2-diols Chemical class 0.000 claims description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 5
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- OVVMNBVQOPZMPY-NTEAFONJSA-N 149716-73-4 Chemical compound Cl.O([C@]1(C)[C@@H]2C[C@H](C[C@@H]1O1)C2(C)C)B1[C@H]1CCCN1 OVVMNBVQOPZMPY-NTEAFONJSA-N 0.000 claims description 4
- ZWGMJLNXIVRFRJ-UHFFFAOYSA-N [1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrol-2-yl]boronic acid Chemical compound CC(C)(C)OC(=O)N1C=CC=C1B(O)O ZWGMJLNXIVRFRJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000004927 fusion Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims 4
- 230000001681 protective effect Effects 0.000 claims 4
- MOILFCKRQFQVFS-AZQAYCESSA-N (1s,3s,4r,5s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@H]2C(C)(C)[C@@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-AZQAYCESSA-N 0.000 claims 3
- 150000004653 carbonic acids Chemical class 0.000 claims 3
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- 239000011260 aqueous acid Substances 0.000 claims 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 14
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 229910052796 boron Inorganic materials 0.000 abstract description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 4
- 125000005620 boronic acid group Chemical group 0.000 abstract description 4
- 230000002829 reductive effect Effects 0.000 abstract description 4
- 102000035195 Peptidases Human genes 0.000 abstract description 3
- 108091005804 Peptidases Proteins 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- WADSQZHEAXPENM-UHFFFAOYSA-N 1h-pyrrol-2-ylboronic acid Chemical compound OB(O)C1=CC=CN1 WADSQZHEAXPENM-UHFFFAOYSA-N 0.000 abstract description 2
- 239000004365 Protease Substances 0.000 abstract description 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- HISWWEXBLOFKSH-UHFFFAOYSA-N [Li]C1CCCN1 Chemical compound [Li]C1CCCN1 HISWWEXBLOFKSH-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 61
- 239000000243 solution Substances 0.000 description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
- 239000007787 solid Substances 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 150000001642 boronic acid derivatives Chemical class 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 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
- 229940043376 ammonium acetate Drugs 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000006138 lithiation reaction Methods 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- MOILFCKRQFQVFS-VUMZSGCYSA-N (3r,4s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1C2C(C)(C)C1C[C@@H](O)[C@]2(O)C MOILFCKRQFQVFS-VUMZSGCYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 3
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000008206 alpha-amino acids Nutrition 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001640 fractional crystallisation Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 0 *OC(N1CCCC1)=O Chemical compound *OC(N1CCCC1)=O 0.000 description 2
- 125000004747 1,1-dimethylethoxycarbonyl group Chemical group CC(C)(OC(=O)*)C 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIUYLRUCQCTST-UHFFFAOYSA-N [1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)(C)OC(=O)N1CCCC1B(O)O UIIUYLRUCQCTST-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001371 alpha-amino acids Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 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
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- CQMHKCYAPOVFMJ-UHFFFAOYSA-N phenylboronic acid 2,6,6-trimethylbicyclo[3.1.1]heptane-1,2-diol Chemical compound OB(O)C1=CC=CC=C1.C1C2(O)C(C)(C)C1CCC2(O)C CQMHKCYAPOVFMJ-UHFFFAOYSA-N 0.000 description 2
- 229940117953 phenylisothiocyanate Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- IZPYBIJFRFWRPR-UHFFFAOYSA-N tert-butyl pyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC=C1 IZPYBIJFRFWRPR-UHFFFAOYSA-N 0.000 description 2
- LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- AWNXKZVIZARMME-UHFFFAOYSA-N 1-[[5-[2-[(2-chloropyridin-4-yl)amino]pyrimidin-4-yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol Chemical compound N=1C(NCC(C)(O)C)=NC=C(C=2N=C(NC=3C=C(Cl)N=CC=3)N=CC=2)C=1CC1CC1 AWNXKZVIZARMME-UHFFFAOYSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 238000006219 Matteson homologation reaction Methods 0.000 description 1
- WXNXCEHXYPACJF-ZETCQYMHSA-N N-acetyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-ZETCQYMHSA-N 0.000 description 1
- CBQJSKKFNMDLON-JTQLQIEISA-N N-acetyl-L-phenylalanine Chemical compound CC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-JTQLQIEISA-N 0.000 description 1
- IHYJTAOFMMMOPX-LURJTMIESA-N N-acetyl-L-valine Chemical compound CC(C)[C@@H](C(O)=O)NC(C)=O IHYJTAOFMMMOPX-LURJTMIESA-N 0.000 description 1
- FULZLIGZKMKICU-UHFFFAOYSA-N N-phenylthiourea Chemical class NC(=S)NC1=CC=CC=C1 FULZLIGZKMKICU-UHFFFAOYSA-N 0.000 description 1
- IBFLWIOFZGYDFZ-WCCKRBBISA-N OBO.OC(=O)[C@@H]1CCCN1 Chemical compound OBO.OC(=O)[C@@H]1CCCN1 IBFLWIOFZGYDFZ-WCCKRBBISA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 229960000669 acetylleucine Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 125000005621 boronate group Chemical group 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- PMPYSSMGWFNAAQ-UHFFFAOYSA-N dichloromethane;n,n-diethylethanamine Chemical compound ClCCl.CCN(CC)CC PMPYSSMGWFNAAQ-UHFFFAOYSA-N 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000011905 homologation Methods 0.000 description 1
- IHPDTPWNFBQHEB-UHFFFAOYSA-N hydrobenzoin Chemical compound C=1C=CC=CC=1C(O)C(O)C1=CC=CC=C1 IHPDTPWNFBQHEB-UHFFFAOYSA-N 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000004073 interleukin-2 production Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical class [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- VQEVKEKJZVEGPH-UHFFFAOYSA-N lithium;chloromethane Chemical compound [Li+].Cl[CH2-] VQEVKEKJZVEGPH-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- DIHKMUNUGQVFES-UHFFFAOYSA-N n,n,n',n'-tetraethylethane-1,2-diamine Chemical compound CCN(CC)CCN(CC)CC DIHKMUNUGQVFES-UHFFFAOYSA-N 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- AGVMWTWBONEXNA-UHFFFAOYSA-N pyrrolidin-2-ylboronic acid;hydrochloride Chemical compound Cl.OB(O)C1CCCN1 AGVMWTWBONEXNA-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to a method for making optically active prolineboronate esters. These are useful as intermediates in the production of peptides which incorporate prolineboronic acid instead of proline. These peptides, in turn, are useful for inhibiting various biologically important proteases.
- Peptides which incorporate the ⁇ -aminoboronic acid analog of proline (BoroPro) at the C-terminus are of special interest because they have been shown to be potent inhibitors of certain post-proline cleaving enzymes.
- Bachovchin et al. J. Biol. Chem. 265, 3738 (1990)] have reported that such peptides are inhibitors of IgA proteinases from certain bacteria. These enzymes are strongly implicated in bacterial virulence.
- Flentke et al. Proc. Natl. Acad. Sci.
- a first broad aspect of the present invention comprises three closely related methods for the synthesis of prolineboronic acid esters. Two of these syntheses commence from pyrrole. The third commences from pyrrolidine. Included within the scope of this first aspect of the invention are certain novel intermediates. Prolineboronic acid has a chiral center a to the boron atom. A second broad aspect of the invention comprises a method for resolving the enantiomers of prolineboronic acid, if desired. According to this method, the prolineboronic ester is formed through reaction with a chiral alcohol, with the use of pinanediol being particularly preferred.
- prolineboronic acid esters can be easily coupled to activated carboxylic acid groups, such as are typically used in peptide synthesis, to yield peptides having a prolineboronic acid ester, instead of an amino acid, at the C-terminus.
- the ester protecting group can be removed to yield the free boronic acid peptide.
- the ester protecting group is pinanediol, it is not easily removed by known per se techniques.
- a third aspect of the invention comprises several methods for removing the pinanediol protecting group.
- Figure 1 illustrates a reaction scheme which is a preferred embodiment of the invention.
- a first synthesis according to the invention commences with pyrrole, which is reacted with an activated derivative of carbonic acid, in order to protect the nitrogen atom with a group of the formula -COOR, wherein R is C- .alkyl, C_ --cycloalkyl, benzyl, phenyl, phenyl substituted with one or more C 1.—D-- alkyl groups, or trimethylsilylethyl, in order to yield a compound of the formula I.
- R is tert-butyl, benzyl, trimethylsilylethyl, phenyl, methyl or ethyl.
- the most preferred protecting group is tert-butyloxycarbonyl, or Boc.
- the protecting group is applied using well known techniques. A specific synthesis for 1-Boc-pyrrole has been described by Grehn et al. [Angew. Chem. Int. Ed. Engl. 23, 296 (1984)].
- R is defined as before.
- Lithiation of the compound of formula I can be accomplished by treatment with lithium tetramethylpiperidide in a known per se manner, such as that described by Hasan et al. [J. Org. Chem. 46, 157 (1981)], or with other hindered lithium amides such as lithium diisopropyl amide or lithium dicyclohexylamide, or with n-butyl lithium in the presence of tetra ethyl ethylenediamine.
- This reaction is conveniently carried out in an inert solvent, preferably an ether such as THF, diethyl ether, dimethoxyethane, or methyl t-butyl ether at a temperature between -78°C and -40°C.
- pyrrole can be brominated at the 2-position, in a known per se manner, such as that described by Chen et al. r [Org. Syn. , 70, 151 (1991)], and the resulting product can be protected and then lithiated, using other less expensive lithiating agents, such as n-butyl lithium, using known per se techniques.
- each alkyl group may be straight, branched or cyclic and contains 1 to 6 carbon atoms, preferably tri ethyl or triethyl borate, followed by acid-catalyzed hydrolysis, using a weak acid such as citric or acetic acid, or potassium hydrogen sulfate, in order to yield a protected pyrrole-2-boronic acid of formula III
- R is defined as before.
- R is defined as before.
- the catalytic hydrogenation of the intermediate of formula III may be carried out in an organic solvent, such as ethyl acetate or tetrahydrofuran, using a catalyst such as 5% platinum on carbon, platinum oxide, rhodium on carbon, rhodium on alumina, palladium on carbon, or Raney nickel, either at atmospheric pressure, or at about 50 psi.
- organic solvent such as ethyl acetate or tetrahydrofuran
- a catalyst such as 5% platinum on carbon, platinum oxide, rhodium on carbon, rhodium on alumina, palladium on carbon, or Raney nickel, either at atmospheric pressure, or at about 50 psi.
- R is defined as before.
- the protecting group is chosen to allow activation of the pyrrolidine to lithiation adjacent to the nitrogen, and it should contain a bulky moiety which hinders attack on the carbonyl by the lithiating agent. It is preferred to use a carbamoyl protecting group of the formula -COOR, for example, groups wherein R is tert-butoxy or 2,4,6-tri-tert- butylphenoxy. However, certain acyl or aroyl groups can also be used, for example tert-butylcarbonyl or triphenylmethylcarbonyl. Other suitable activating groups are outlined in Beak et al. , [Chem. Rev., 84, 471-523, (1984)]. The most preferred protecting group is tert-butyloxycarbonyl, or Boc. The protecting group may be applied to pyrrolidine by well known techniques.
- R is defined as before.
- Lithiation of the compound of formula VIII can be accomplished by treatment with sec-butyl lithium and tetramethyl ethylenediamine in a known per se manner, such as that described by Beak et al. [Tet. Lett. 30, 1197 (1989)].
- This reaction is conveniently carried out in an inert organic solvent, preferably an ether such as diethyl ether, methyl tert-butyl ether or THF at a temperature between about -78°C and 0°C, preferably -78°C to -40°C.
- Lithiation may be achieved with a reactive alkyl lithium such as sec-butyl lithium or tert-butyl lithium, preferably in the presence of a coordinating additive such as tetramethyl ethylenediamine, hexamethyl phosphoramide or N,N'-dimethylpropyleneurea (DMPU) .
- a reactive alkyl lithium such as sec-butyl lithium or tert-butyl lithium
- a coordinating additive such as tetramethyl ethylenediamine, hexamethyl phosphoramide or N,N'-dimethylpropyleneurea (DMPU) .
- the intermediate of formula IX which is not isolated, is next reacted with a trialkyl borate wherein each alkyl group may be straight, branched or cyclic and contains 1 to 6 carbon atoms, preferably trimethyl or triethyl borate, followed by hydrolysis with water and extraction into aqueous alkali such as sodium hydroxide or potassium hydroxide to aid puri ication. Acidification of the alkali solution to about pH 3 and extraction yields the protected prolineboronic acid of formula IV. In order to form a boronic acid ester, the free boronic acid intermediate of formula IV, is next esterified by reaction with a diol of the formula V,
- the ester group thus formed is intended to function only as a removable protecting group.
- the structures, syntheses, and methods for attachment and removal of such ester protecting groups are generally known in the chemical art. Accordingly, those skilled in the chemical art will appreciate that the structure of the linking group X is not critical.
- the linking group X can be, by way of non-limiting examples, a saturated 2- to 3-membered hydrocarbon chain; a saturated 2- to 3-membered hydrocarbon chain which constitutes part of a C j .
- carbocyclic system which may optionally contain unsaturations or ring fusions; a 2- to 3-membered hydrocarbon chain which constitutes part of an aromatic ring system; or, a group of the formula -(CH2,,)'n-NH-(CH2_,) ; m-,' wherein n and m are each 2 or 3; wherein such groups may be unsubstituted or substituted by one or more C alkyl or phenyl groups.
- suitable diols of formula V are, for example, ethylene glycol, pinacol, catechol, pinanediol, butan-2, 3-diol, 2,2-dimethyl propan 1,3-diol, diethanolamine and 1, 2-diphenylethan- 1,2-diol.
- the protecting group on the nitrogen is next removed using known per se techniques, such as those described by Greene in “Protective Groups in Organic Synthesis” (J. Wiley & Sons, 1981) , to yield the hydrochloride of the desired prolineboronic acid ester of the formula VII.
- the protecting group is Boc
- it may be easily removed with dry hydrogen chloride in ethyl acetate.
- the isomers of the hydrochloride of the compound of formula VII, with the same boron protecting group may be separated by fractional crystallization in a solvent such as ethyl acetate, or a dichloromethane/ethyl acetate mixture, isopropanol, or ethanol to give compound Vllb as a single isomer with the R configuration at the carbon attached to boron.
- a solvent such as ethyl acetate, or a dichloromethane/ethyl acetate mixture, isopropanol, or ethanol
- pinanediol A further advantage of using pinanediol is that the boronate esters so formed are more stable than those derived from other diols, for example, pinacol, with which significant loss of the protecting group is often observed during chromatography. This is useful in both purification and isomer separation by chromatography on silica gel, since better recovery of the desired material is achieved.
- a derivatized pyrrole of formula III can be directly esterified with a diol of the formula V.
- prolineboronic acid esters thus produced are easily coupled to activated carboxylic acids such as those typically used in peptide synthesis, for example a nitrogen-protected amino acid to yield a compound of the formula X
- -COOR 2 i.s an ammo protecting group of the sort commonly used in peptide synthesis, so that R 2 is, for example, tert-butyl, benzyl, or fluorenylmethyl
- R 3 i.s the side chain of a naturally occurring amino acid, optionally with appropriate protecting groups of the sort commonly used in peptide synthesis.
- Compounds of formula X contain protecting groups both on the boronate and on the amino acid nitrogen. It may be necessary to remove either or both protecting groups for biological activity or for further chemical manipulation. The protecting groups may be removed in either order. Various methods for removing these protecting groups are described below.
- Removal of the nitrogen protecting group may be achieved by known methods to yield a compound of the formula XI.
- hydrolysis is known to be difficult, and special conditions are required for removal of the pinanediol. See for example Matteson et al. [J. Am. Chem. Soc, 102, 7590 (1980)] and Brown et al. [J. Organometallic Chem., 385, 15 (1988)].
- pinanediol is not suitable for the removal of pinanediol from a compound of formula VI, X, or XI.
- a boronate such as compound VI, X or XI.
- removal of the pinanediol may be achieved under mild conditions using an oxidizing agent capable of cleaving 1,2 diols to remove the pinanediol from the equilibrium and hence drive it in the direction of the free boronic acid.
- This reaction is conveniently carried out in water, optionally with an added buffer such as ammonium acetate or disodium hydrogen phosphate, at a pH between 3 and 10, preferably 6 to 8, and a temperature of 0 to 80 °C, preferably 20 to 40 ° C , in the presence of a water miscible organic cosolvent such as acetone, methanol, ethanol, THF, or acetonitrile.
- a water miscible organic cosolvent such as acetone, methanol, ethanol, THF, or acetonitrile.
- the oxidizing agent is a non-nucleophilic oxidant capable of cleaving 1,2-diols such as periodic acid or its salts or permanganate salts. Under these conditions oxidative cleavage of the carbon-boron bond is not observed.
- this method is applicable to any boronic acid protected with pinanediol. Furthermore, it is applicable to any boronate protecting group which is a 1,2-diol, although it is particularly useful for protecting groups where simple aqueous hydrolysis is slow or incomplete.
- a pinanediol boronate ester of a compound containing an unprotected amine such as a compound of formula XI
- the method described above may also be employed, but a second new method is preferable for compounds of this type.
- This method consists of applying an aqueous solution of a compound of formula XI, at pH 4 or lower, to a column of a cation exchange resin, and eluting the column with water or dilute acetic acid to remove the pinanediol. This removes the pinanediol from the equilibrium, and thus drives the reaction in the direction of hydrolysis.
- the column is then eluted with dilute aqueous ammonium hydroxide to remove the product, which after evaporation and acidification is obtained as a salt of the compound of formula XIII.
- a strongly acidic cation exchange resin for example a sulfonic acid type of resin is used, such as, for example, Dowex 50.
- the pinanediol eluted from the resin may be recovered from the water solution and reused. This is most conveniently achieved by passing the water solution through a column of a nonionic polymeric adsorbent, such as Amberlite XAD-200, which adsorbs pinanediol almost quantitatively.
- the pinanediol is removed from the column by elution with methanol or ethanol.
- the two operations of ion exchange and pinanediol adsorption may be combined in a single process in which water is recycled from one column to the other using a pump. This has the advantage of requiring much smaller amounts of water, and allows the process to be continued long enough to achieve a high conversion to the product.
- a third method is also applicable to pinanediol esters of compounds containing an unprotected amine, such as a compound of the formula XI.
- This method consists of transesterification of the pinanediol boronate with
- R represents a C hydrocarbon group, which may be composed of straight, branched or cyclic alkyl chains and phenyl rings.
- R is preferably phenyl.
- One of the phases is water adjusted to a pH below 7, preferably pH 1-4, and the other is a hydrocarbon organic solvent such as hexane, petroleum ether, or toluene.
- a compound of formula XI with phenylboronic acid in a mixture of water at pH 1 and hexane, followed by separation of the phases, produces the pinanediol ester of phenylboronic acid in the organic phase, which may be recovered simply by evaporation, and a solution of the free boronic acid of formula XIII in the aqueous phase, which may be isolated using an ion exchange resin in a similar manner to that described above.
- the only component which is soluble in the organic phase is the pinanediol phenylboronate, thus removing the pinanediol from the equilibrium.
- the reaction may be carried out with any boronic acid with a hydrocarbon sidechain, providing its pinanediol ester is soluble in hydrocarbon solvents.
- the fully deprotected compound of formula XIII may also be prepared by removal of the nitrogen protecting group from a compound of the formula XII using known methods. It will be appreciated that compounds of formula X, XI, XII, and XIII generally posess two chiral centers. One is adjacent to the boron atom, and the other is present in the amino acid moiety, except when that moiety is glycine. It will be further appreciated that the pure single diastereoisomers of these compounds are more desirable for biological use than mixtures of diastereoisomers. Accordingly it is important to be able to produce these compounds as pure single isomers.
- reaction mixture was diluted with ether (500 mL) and washed with 1M aqueous KHSO (3 x 100 mL) followed by 1M aqueous NaHCO (1 x 100 L) . Drying over MgSO and rotary evaporation produced a brown solid which was purified by flash chromatography over silica gel (1:9 EtOAc:Hexane) to yield 8.7 g (82%) of a white crystalline solid (mp 101.0 - 101.5 °C) .
- 1-(1,1-dimethylethoxycarbonyl)-pyrrolidine-2R-boronate could be produced in an analogous manner, starting with (1R,2R,3S,5R)-(-)-pinanediol.
- the aqueous phase was isolated and the organic phase was reextracted with 2M NaOH (150 mL) .
- the combined basic extracts were acidified to pH 3 using 2M HC1 and extracted using EtOAc (5 x 200 mL) .
- the combined organic extracts were dried (Na_SO ) and concentrated to afford the desired product as a white crystalline solid (I5.49g, 72%) , identical with the material produced in Example 2.
- Example 7 To a stirred solution of the material obtained in Example 7 (15.49 g, 72.0 mmol) in chloroform (250 mL) was added (IS, 2S, 3R, 5S) -(+) -pinanediol (12.77 g, 75 mmol) . After stirring at room temperature under a nitrogen atmosphere for 16 h, the solvent was removed and the residue purified via flash chromatography over silica gel (hexane/EtOAc 9:1, 4:1) to give the desired product as a 1:1 mixture of diastereomers as an oil (23.62 g, 67.7% based on 1-(1,1-dimethyl ⁇ ethoxycarbonyl)-pyrrolidine) . This was identical with the mixture of isomers produced in Example 3.
- a reagent solution of 0.2 M phenyl isothiocyanate in dichloromethane-triethylamine (9:1) was prepared.
- the sample to be analyzed (1-5 mg) was treated with 10 ⁇ L of the reagent solution per / xmole of analyte and the clear solution was allowed to stand at room temperature for 15 min.
- the phenylthiourea derivative of the R isomer of proline boronic acid elutes at about 6.4 min, its epi er elutes at about 7.8 min, and unreacted phenyl isothiocyanate, which serves as an internal standard, elutes at 12.2 min.
- Example 10 The 60:40 isomeric mixture obtained in Example 10 (1.18 g 4.13 mmol) was dissolved in CH Cl (65 mL) with slight warming, and the solution filtered. The filtrate was diluted with EtOAc (65 mL) and crystallization began within a minute. The suspension was stirred for 1-2 h at room temperature and the first crop of solid was collected and the diastereomeric ratio determined as described in Example 9 (540 mg, 46%, R:S ratio 97.1:2.9) . Solvent was distilled from the filtrate until most of the CH2C12 was removed, then the residual EtOAc solution was stirred at room temperature overnight to afford a second crop of off-white solid (346 mg, 29%, R:S ratio 39.2:60.8) .
- Pinacol 1- (1, 1-dimethylethoxycarbonyl) - pyrrolidine-2RS-boronate
- N-(1, 1-Dimethylethoxycarbonyl) -L-valylpyrrolidine-2R- boronate (IS, 2S, 3R, 5S) -pinanediol ester (248 mg, 0.553 mmol) was added to a stirred solution of dry hydrogen chloride in ethyl acetate. After 1.5 h the solvent was evaporated to leave the deprotected hydrochloride. The residue was partitioned between CH-.C1 and sodium carbonate solution, and the organic layer dried over magnesium sulfate. The organic layer contains the free base of the title compound, which exists as a cyclic form containing a nitrogen-boron bond, but reverts to the open form on adding acid.
- a solution of the maleate salt obtained in Example 15 (5.0 g, 10.8 mmol) in dilute acetic acid (1.0%, 60 mL) was loaded on to a column (3.5 cm deep x 4 cm dia.) of Dowex 50X2-200 ion exchange resin in the H+ form. The column was then eluted with acetic acid (1.0%, 14 L) , water (42 L) and ammonium hydroxide solution (1:100 dilution of commercial 0.880 solution) . Pinanediol could be recovered from the neutral and acidic fractions. The product was found in early basic fractions, which were collected and washed with CH Cl (2 x 100 mL) .
- N-(l,1-Dimethylethoxycarbonyl)-L-valylpyrrolidine-2R- boronic acid, obtained in Example 17 was stirred with HCl/ether (4.5M, 20 mL) at room temperature under nitrogen for 1.5 h. The solvent was then evaporated and the residue triturated with diethyl ether (3 x 10 L) and each time the ether was decanted. The residue was dried to yield the title compound as a white powdery solid (172 mg, 86%) (mp 211-213°C) .
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SK592-94A SK59294A3 (en) | 1991-11-22 | 1992-11-19 | Method of making a prolineboronate ester |
EP92925238A EP0641347A1 (en) | 1991-11-22 | 1992-11-19 | Method for making a prolineboronate ester |
AU31368/93A AU661362B2 (en) | 1991-11-22 | 1992-11-19 | Method for making a prolineboronate ester |
JP5509442A JPH07501078A (en) | 1991-11-22 | 1992-11-19 | Production method of proline boronate ester |
FI942345A FI942345A0 (en) | 1991-11-22 | 1994-05-20 | Process for the preparation of proline boronate ester |
NO941905A NO941905L (en) | 1991-11-22 | 1994-05-20 | Process for Preparation of a Proline Boronate Ester |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US79614891A | 1991-11-22 | 1991-11-22 | |
US07/796,148 | 1991-11-22 | ||
US93619892A | 1992-08-26 | 1992-08-26 | |
US07/936,198 | 1992-08-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993010127A1 true WO1993010127A1 (en) | 1993-05-27 |
Family
ID=27121696
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/009845 WO1993010127A1 (en) | 1991-11-22 | 1992-11-19 | Method for making a prolineboronate ester |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP0641347A1 (en) |
JP (1) | JPH07501078A (en) |
CN (1) | CN1073946A (en) |
AU (1) | AU661362B2 (en) |
CA (1) | CA2123128A1 (en) |
CZ (1) | CZ124494A3 (en) |
FI (1) | FI942345A0 (en) |
HU (1) | HUT67937A (en) |
IL (1) | IL103817A0 (en) |
MX (1) | MX9206628A (en) |
NO (1) | NO941905L (en) |
NZ (1) | NZ245207A (en) |
PT (1) | PT101079A (en) |
SI (1) | SI9200332A (en) |
SK (1) | SK59294A3 (en) |
TW (1) | TW232697B (en) |
WO (1) | WO1993010127A1 (en) |
Cited By (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5965532A (en) * | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
WO1999062914A1 (en) * | 1998-06-05 | 1999-12-09 | Point Therapeutics, Inc. | Cyclic boroproline compounds |
US6100234A (en) * | 1997-05-07 | 2000-08-08 | Tufts University | Treatment of HIV |
US6258597B1 (en) | 1997-09-29 | 2001-07-10 | Point Therapeutics, Inc. | Stimulation of hematopoietic cells in vitro |
WO2001062266A2 (en) * | 2000-02-25 | 2001-08-30 | Novo Nordisk A/S | Use of dpp-iv inhibitors for the treatment of diabetes |
US6300314B1 (en) | 1998-05-04 | 2001-10-09 | Point Therapeutics, Inc. | Hematopoietic stimulation |
WO2003063903A2 (en) * | 2002-02-01 | 2003-08-07 | Probiodrug Ag | Modulation of t lymphocytes using dp iv inhibitors |
US6692753B2 (en) | 1997-05-07 | 2004-02-17 | Trustees Of Tufts College | Potentiation of the immune response |
US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
WO2005105817A2 (en) * | 2004-04-27 | 2005-11-10 | Wyeth | Coupling process for generating reactive boron containing derivatives of n-substituted pyrrole-2 carbonitriles to produce biaryls |
US6979697B1 (en) | 1998-08-21 | 2005-12-27 | Point Therapeutics, Inc. | Regulation of substrate activity |
EP1743676A1 (en) * | 2003-11-12 | 2007-01-17 | Phenomix Corporation | Heterocyclic boronic acid derivatives, dipeptidyl peptidase IV inhibitors |
WO2007100374A2 (en) * | 2005-12-19 | 2007-09-07 | Trustees Of Tufts College | Soft protease inhibitors and pro-soft forms thereof |
US7317109B2 (en) | 2003-11-12 | 2008-01-08 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US7399869B2 (en) | 2005-05-19 | 2008-07-15 | Genentech, Inc. | Fibroblast activation protein inhibitor compounds and methods |
US7576121B2 (en) | 2003-11-12 | 2009-08-18 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
EP2116235A1 (en) | 2005-01-10 | 2009-11-11 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
EP2165703A2 (en) | 2004-01-20 | 2010-03-24 | Novartis Pharma AG. | Direct compression formulation and process |
US7767828B2 (en) | 2003-11-12 | 2010-08-03 | Phenomix Corporation | Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US7825139B2 (en) | 2005-05-25 | 2010-11-02 | Forest Laboratories Holdings Limited (BM) | Compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
EP2253311A2 (en) | 2006-04-11 | 2010-11-24 | Arena Pharmaceuticals, Inc. | Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto |
WO2011005929A1 (en) | 2009-07-09 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Piperidine derivative and its use for the treatment of diabets and obesity |
WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012040279A1 (en) | 2010-09-22 | 2012-03-29 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
US8883714B2 (en) | 2008-04-07 | 2014-11-11 | Arena Pharmaceuticals, Inc. | Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues |
EP2839832A2 (en) | 2003-11-17 | 2015-02-25 | Novartis AG | Use of dipeptidyl peptidase IV inhibitors |
US9523687B2 (en) | 2014-02-28 | 2016-12-20 | Institut Pasteur | Levels of CXCL 10/IP-10 forms and soluble CD26/DPPIV activity as early predictive biomarkers for HIV/SIV associated mucosal inflammation and progression towards AIDS |
WO2018162722A1 (en) | 2017-03-09 | 2018-09-13 | Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke | Dpp-4 inhibitors for use in treating bone fractures |
US10526351B2 (en) | 2008-06-17 | 2020-01-07 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US11241448B2 (en) | 2014-05-20 | 2022-02-08 | Millennium Pharmaceuticals, Inc. | Methods for cancer therapy |
US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1331835C (en) * | 2005-10-18 | 2007-08-15 | 武汉大学 | Preparation method of optically active beta-hydroxy ketone |
DK1971862T3 (en) | 2006-04-11 | 2011-02-14 | Arena Pharm Inc | Methods of Using GPR119 Receptor to Identify Compounds Useful for Increasing Bone Mass in a Person |
CN108047257B (en) * | 2017-12-17 | 2020-03-13 | 沧州普瑞东方科技有限公司 | Preparation process of chiral N-BOC-pyrrolidine-2-boric acid |
CN110452258B (en) * | 2019-09-03 | 2021-01-01 | 上海馨远医药科技有限公司 | Preparation method of dipeptide valine boron proline salt |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989003223A1 (en) * | 1987-10-06 | 1989-04-20 | Bachovchin William W | Protease inhibitors |
WO1991016339A1 (en) * | 1990-04-14 | 1991-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
EP0471651A2 (en) * | 1990-08-13 | 1992-02-19 | Sandoz Ltd. | Peptide boronic acid derivatives having protease inhibiting activity |
-
1992
- 1992-11-18 MX MX9206628A patent/MX9206628A/en unknown
- 1992-11-19 JP JP5509442A patent/JPH07501078A/en active Pending
- 1992-11-19 CA CA002123128A patent/CA2123128A1/en not_active Abandoned
- 1992-11-19 HU HU9401350A patent/HUT67937A/en unknown
- 1992-11-19 PT PT101079A patent/PT101079A/en not_active Application Discontinuation
- 1992-11-19 SK SK592-94A patent/SK59294A3/en unknown
- 1992-11-19 SI SI19929200332A patent/SI9200332A/en unknown
- 1992-11-19 WO PCT/US1992/009845 patent/WO1993010127A1/en not_active Application Discontinuation
- 1992-11-19 AU AU31368/93A patent/AU661362B2/en not_active Expired - Fee Related
- 1992-11-19 CZ CZ941244A patent/CZ124494A3/en unknown
- 1992-11-19 EP EP92925238A patent/EP0641347A1/en not_active Withdrawn
- 1992-11-20 TW TW081109304A patent/TW232697B/zh active
- 1992-11-20 NZ NZ24520792A patent/NZ245207A/en unknown
- 1992-11-20 IL IL103817A patent/IL103817A0/en unknown
- 1992-11-23 CN CN92113215A patent/CN1073946A/en active Pending
-
1994
- 1994-05-20 NO NO941905A patent/NO941905L/en unknown
- 1994-05-20 FI FI942345A patent/FI942345A0/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989003223A1 (en) * | 1987-10-06 | 1989-04-20 | Bachovchin William W | Protease inhibitors |
WO1991016339A1 (en) * | 1990-04-14 | 1991-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
EP0471651A2 (en) * | 1990-08-13 | 1992-02-19 | Sandoz Ltd. | Peptide boronic acid derivatives having protease inhibiting activity |
Cited By (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7230074B2 (en) | 1991-10-22 | 2007-06-12 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
US5965532A (en) * | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
US6875737B1 (en) | 1996-06-28 | 2005-04-05 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
US6692753B2 (en) | 1997-05-07 | 2004-02-17 | Trustees Of Tufts College | Potentiation of the immune response |
US6100234A (en) * | 1997-05-07 | 2000-08-08 | Tufts University | Treatment of HIV |
US6503882B2 (en) | 1997-05-07 | 2003-01-07 | Trustees Of Tufts College | Treatment of HIV |
US6258597B1 (en) | 1997-09-29 | 2001-07-10 | Point Therapeutics, Inc. | Stimulation of hematopoietic cells in vitro |
US6703238B2 (en) | 1997-09-29 | 2004-03-09 | Point Therapeutics, Inc. | Methods for expanding antigen-specific T cells |
US7067489B2 (en) | 1998-05-04 | 2006-06-27 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US6770628B2 (en) | 1998-05-04 | 2004-08-03 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US6300314B1 (en) | 1998-05-04 | 2001-10-09 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US6355614B1 (en) | 1998-06-05 | 2002-03-12 | Point Therapeutics | Cyclic boroproline compounds |
WO1999062914A1 (en) * | 1998-06-05 | 1999-12-09 | Point Therapeutics, Inc. | Cyclic boroproline compounds |
US6979697B1 (en) | 1998-08-21 | 2005-12-27 | Point Therapeutics, Inc. | Regulation of substrate activity |
US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
US6949514B2 (en) | 1999-05-25 | 2005-09-27 | Point Therapeutics, Inc. | Anti-tumor agents |
WO2001062266A2 (en) * | 2000-02-25 | 2001-08-30 | Novo Nordisk A/S | Use of dpp-iv inhibitors for the treatment of diabetes |
WO2001062266A3 (en) * | 2000-02-25 | 2002-05-02 | Novo Nordisk As | Use of dpp-iv inhibitors for the treatment of diabetes |
WO2003063903A2 (en) * | 2002-02-01 | 2003-08-07 | Probiodrug Ag | Modulation of t lymphocytes using dp iv inhibitors |
WO2003063903A3 (en) * | 2002-02-01 | 2007-12-21 | Probiodrug Ag | Modulation of t lymphocytes using dp iv inhibitors |
US7674913B2 (en) | 2003-11-12 | 2010-03-09 | Phenomix Corporation | Heterocyclic boronic acid compounds |
US8415295B2 (en) | 2003-11-12 | 2013-04-09 | Phenomix Corporation | Heterocyclic boronic acid compounds |
US7317109B2 (en) | 2003-11-12 | 2008-01-08 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
EP1743676A1 (en) * | 2003-11-12 | 2007-01-17 | Phenomix Corporation | Heterocyclic boronic acid derivatives, dipeptidyl peptidase IV inhibitors |
US7906658B2 (en) | 2003-11-12 | 2011-03-15 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US7576121B2 (en) | 2003-11-12 | 2009-08-18 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US7884217B2 (en) | 2003-11-12 | 2011-02-08 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US7767828B2 (en) | 2003-11-12 | 2010-08-03 | Phenomix Corporation | Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
EP2839832A2 (en) | 2003-11-17 | 2015-02-25 | Novartis AG | Use of dipeptidyl peptidase IV inhibitors |
EP3023095A1 (en) | 2004-01-20 | 2016-05-25 | Novartis AG | Direct compression formulation and process |
EP3738585A1 (en) | 2004-01-20 | 2020-11-18 | Novartis Ag | Direct compression formulation and process |
EP3366283A1 (en) | 2004-01-20 | 2018-08-29 | Novartis AG | Direct compression formulation and process |
EP2165703A2 (en) | 2004-01-20 | 2010-03-24 | Novartis Pharma AG. | Direct compression formulation and process |
US8129523B2 (en) | 2004-04-27 | 2012-03-06 | Wyeth Llc | Coupling process for generating reactive boron-containing derivatives of N-substituted pyrrole-2-carbonitriles to produce biaryls |
WO2005105817A2 (en) * | 2004-04-27 | 2005-11-10 | Wyeth | Coupling process for generating reactive boron containing derivatives of n-substituted pyrrole-2 carbonitriles to produce biaryls |
WO2005105817A3 (en) * | 2004-04-27 | 2006-01-12 | Wyeth Corp | Coupling process for generating reactive boron containing derivatives of n-substituted pyrrole-2 carbonitriles to produce biaryls |
US7446211B2 (en) | 2004-04-27 | 2008-11-04 | Wyeth | Coupling process for generating reactive boron-containing derivatives of N-substituted pyrrole-2-carbonitriles to produce biaryls |
EP2116235A1 (en) | 2005-01-10 | 2009-11-11 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US7399869B2 (en) | 2005-05-19 | 2008-07-15 | Genentech, Inc. | Fibroblast activation protein inhibitor compounds and methods |
US7825139B2 (en) | 2005-05-25 | 2010-11-02 | Forest Laboratories Holdings Limited (BM) | Compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US8933056B2 (en) | 2005-12-19 | 2015-01-13 | Trustees Of Tufts College | Soft protease inhibitors and pro-soft forms thereof |
US8563533B2 (en) | 2005-12-19 | 2013-10-22 | Trustees Of Tufts College | Soft protease inhibitors and pro-soft forms thereof |
WO2007100374A2 (en) * | 2005-12-19 | 2007-09-07 | Trustees Of Tufts College | Soft protease inhibitors and pro-soft forms thereof |
US8268880B2 (en) | 2005-12-19 | 2012-09-18 | Trustees Of Tufts College | Soft protease inhibitors and pro-soft forms thereof |
WO2007100374A3 (en) * | 2005-12-19 | 2008-11-13 | Tufts College | Soft protease inhibitors and pro-soft forms thereof |
US9192646B2 (en) | 2005-12-19 | 2015-11-24 | Trustees Of Tufts College | Soft protease inhibitors and pro-soft forms thereof |
AU2006339348B2 (en) * | 2005-12-19 | 2013-01-17 | Trustees Of Tufts College | Soft protease inhibitors and pro-soft forms thereof |
EP2253311A2 (en) | 2006-04-11 | 2010-11-24 | Arena Pharmaceuticals, Inc. | Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto |
US8883714B2 (en) | 2008-04-07 | 2014-11-11 | Arena Pharmaceuticals, Inc. | Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues |
US10526351B2 (en) | 2008-06-17 | 2020-01-07 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
US10604538B2 (en) | 2008-06-17 | 2020-03-31 | Millenium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
US11485746B2 (en) | 2008-06-17 | 2022-11-01 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
WO2011005929A1 (en) | 2009-07-09 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Piperidine derivative and its use for the treatment of diabets and obesity |
WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
EP3323818A1 (en) | 2010-09-22 | 2018-05-23 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012040279A1 (en) | 2010-09-22 | 2012-03-29 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
US9523687B2 (en) | 2014-02-28 | 2016-12-20 | Institut Pasteur | Levels of CXCL 10/IP-10 forms and soluble CD26/DPPIV activity as early predictive biomarkers for HIV/SIV associated mucosal inflammation and progression towards AIDS |
US10254282B2 (en) | 2014-02-28 | 2019-04-09 | Institut Pasteur | Levels of CXCL10/IP-10 forms and soluble CD26/DPPIV activity as early predictive biomarkers for HIV/SIV associated mucosal inflammation and progression towards AIDS |
US11241448B2 (en) | 2014-05-20 | 2022-02-08 | Millennium Pharmaceuticals, Inc. | Methods for cancer therapy |
US10772865B2 (en) | 2015-03-09 | 2020-09-15 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US11400072B2 (en) | 2015-03-09 | 2022-08-02 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
WO2018162722A1 (en) | 2017-03-09 | 2018-09-13 | Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke | Dpp-4 inhibitors for use in treating bone fractures |
US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
Also Published As
Publication number | Publication date |
---|---|
JPH07501078A (en) | 1995-02-02 |
CZ124494A3 (en) | 1995-07-12 |
NZ245207A (en) | 1994-07-26 |
AU661362B2 (en) | 1995-07-20 |
FI942345A (en) | 1994-05-20 |
HUT67937A (en) | 1995-05-29 |
SI9200332A (en) | 1993-06-30 |
FI942345A0 (en) | 1994-05-20 |
MX9206628A (en) | 1993-05-01 |
TW232697B (en) | 1994-10-21 |
HU9401350D0 (en) | 1994-08-29 |
CA2123128A1 (en) | 1993-05-27 |
PT101079A (en) | 1994-02-28 |
IL103817A0 (en) | 1993-04-04 |
EP0641347A1 (en) | 1995-03-08 |
SK59294A3 (en) | 1995-02-08 |
NO941905D0 (en) | 1994-05-20 |
CN1073946A (en) | 1993-07-07 |
NO941905L (en) | 1994-07-14 |
AU3136893A (en) | 1993-06-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU661362B2 (en) | Method for making a prolineboronate ester | |
US5384410A (en) | Removal of boronic acid protecting groups by transesterification | |
CA2121369C (en) | Inhibitors of dipeptidyl-aminopeptidase type iv | |
US5462928A (en) | Inhibitors of dipeptidyl-aminopeptidase type IV | |
EP0528858B1 (en) | Inhibitors of dipeptidyl-aminopeptidase type iv | |
US6825169B1 (en) | Inhibitors of dipeptidyl-aminopeptidase type IV | |
Katz et al. | Episelection: novel Ki. apprx. nanomolar inhibitors of serine proteases selected by binding or chemistry on an enzyme surface | |
KR100939598B1 (en) | Synthesis of boronic ester and acid compounds | |
EP1846424B1 (en) | Proteasome inhibitors and methods of using the same | |
EP0724446A1 (en) | Electrophilic peptide analogs as inhibitors of trypsin-like enzymes | |
EP1743676A1 (en) | Heterocyclic boronic acid derivatives, dipeptidyl peptidase IV inhibitors | |
WO1995011689A1 (en) | Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells | |
CA2852685A1 (en) | Inhibitors of arginase and their therapeutic application | |
Kelly et al. | The efficient synthesis and simple resolution of a prolineboronate ester suitable for enzyme-inhibition studies | |
CA2174311A1 (en) | Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring | |
EP0599633B1 (en) | Boronic ester synthesis | |
US5543526A (en) | 1-amino-4-(1H-imidazole)- aminobutaneboronic acid derivatives, their preparation and use as synthetic intermediates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA CS FI HU JP KR NO PL RU UA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2123128 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 59294 Country of ref document: SK |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV1994-1244 Country of ref document: CZ Ref document number: 942345 Country of ref document: FI |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1992925238 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1992925238 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: PV1994-1244 Country of ref document: CZ |
|
WWR | Wipo information: refused in national office |
Ref document number: PV1994-1244 Country of ref document: CZ |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1992925238 Country of ref document: EP |