SI9200332A - Method for making of prolinboronate ester - Google Patents
Method for making of prolinboronate ester Download PDFInfo
- Publication number
- SI9200332A SI9200332A SI19929200332A SI9200332A SI9200332A SI 9200332 A SI9200332 A SI 9200332A SI 19929200332 A SI19929200332 A SI 19929200332A SI 9200332 A SI9200332 A SI 9200332A SI 9200332 A SI9200332 A SI 9200332A
- Authority
- SI
- Slovenia
- Prior art keywords
- formula
- group
- ester
- pinandiol
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 75
- 150000002148 esters Chemical class 0.000 title claims abstract description 28
- -1 N-protected pyrrole Chemical class 0.000 claims abstract description 40
- 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 29
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000002009 diols Chemical class 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 14
- 150000001413 amino acids Chemical class 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 125000004185 ester group Chemical group 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 68
- 230000008569 process Effects 0.000 claims description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- 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
- 125000004747 1,1-dimethylethoxycarbonyl group Chemical group CC(C)(OC(=O)*)C 0.000 claims description 19
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 18
- 239000000463 material Substances 0.000 claims description 16
- 125000005647 linker group Chemical group 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 13
- 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 11
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-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
- 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 9
- 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
- 239000003729 cation exchange resin Substances 0.000 claims description 7
- 238000006138 lithiation reaction Methods 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 7
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical group COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 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 claims description 5
- 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
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- IHPDTPWNFBQHEB-UHFFFAOYSA-N hydrobenzoin Chemical compound C=1C=CC=CC=1C(O)C(O)C1=CC=CC=C1 IHPDTPWNFBQHEB-UHFFFAOYSA-N 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000004649 carbonic acid derivatives Chemical class 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 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 11
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 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 8
- 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 5
- 102000035195 Peptidases Human genes 0.000 abstract description 4
- 108091005804 Peptidases Proteins 0.000 abstract description 4
- 239000004365 Protease Substances 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 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 abstract description 2
- WADSQZHEAXPENM-UHFFFAOYSA-N 1h-pyrrol-2-ylboronic acid Chemical compound OB(O)C1=CC=CN1 WADSQZHEAXPENM-UHFFFAOYSA-N 0.000 abstract description 2
- 125000005620 boronic acid group Chemical group 0.000 abstract description 2
- 150000001735 carboxylic acids Chemical class 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 35
- 239000007787 solid Substances 0.000 description 28
- 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
- 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
- 239000002904 solvent Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- IBFLWIOFZGYDFZ-WCCKRBBISA-N OBO.OC(=O)[C@@H]1CCCN1 Chemical class OBO.OC(=O)[C@@H]1CCCN1 IBFLWIOFZGYDFZ-WCCKRBBISA-N 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 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
- 239000000284 extract Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- MOILFCKRQFQVFS-OORONAJNSA-N (1s,3r,4s,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-OORONAJNSA-N 0.000 description 4
- 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
- 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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 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 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
- 150000001642 boronic acid derivatives Chemical class 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 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
- 239000000725 suspension Substances 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 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
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 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
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 229910052744 lithium Inorganic materials 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
- 239000011259 mixed solution Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 230000037361 pathway Effects 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
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 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
- 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
- 229960004295 valine Drugs 0.000 description 2
- 238000005406 washing 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
- 238000005160 1H NMR spectroscopy Methods 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
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-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
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000295146 Gallionellaceae Species 0.000 description 1
- 239000004471 Glycine Substances 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000006219 Matteson homologation reaction Methods 0.000 description 1
- KTHDTJVBEPMMGL-VKHMYHEASA-N N-acetyl-L-alanine Chemical compound OC(=O)[C@H](C)NC(C)=O KTHDTJVBEPMMGL-VKHMYHEASA-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
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- 239000007868 Raney catalyst Substances 0.000 description 1
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- 239000012491 analyte Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
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- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
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- 229910000085 borane Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 125000005621 boronate group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006251 butylcarbonyl group Chemical group 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-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
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- 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
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- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
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- 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
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- 150000003840 hydrochlorides Chemical class 0.000 description 1
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- 238000002955 isolation Methods 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
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 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 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
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 238000005191 phase separation Methods 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
- 239000001120 potassium sulphate Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N serine Chemical compound OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography 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
- 238000003860 storage Methods 0.000 description 1
- 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 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
- 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
- 230000001052 transient effect Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000001018 virulence Effects 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
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
Postopek za izdelavo prolinboronatnega estraA process for the manufacture of a prolinboronate ester
Izum se nanaša na postopek za izdelavo optično aktivnih prolinboronatnih estrov. Le-ti so koristni kot intermediati pri izdelavi peptidov, ki vključujejo prolinboronsko kislino namesto prolina. Ti peptidi so koristni za inhibiranje raznih biološko pomembnih proteaz.The invention relates to a process for the manufacture of optically active prolinboronate esters. They are useful as intermediates in the production of peptides that include prolineboronic acid instead of proline. These peptides are useful for inhibiting a variety of biologically important proteases.
Zanimanje za analoge boronske kisline α-amino kislin kot tudi za peptide, ki imajo vključen analog boronske kisline «-amino kisline namesto C-terminalnega ostanka, je nastalo z objavami, da so te spojine učinkoviti inhibitorji mnogih serenskih proteaz. Glej npr. Matteson et al. [J. Am. Chem. Soc. 103, 5241 (1981)]; Kettner et al. [J. Biol. Chem. 259,15106 (1984)]; in Kinder et al. [J. Med. Chem. 27,1919 (1985)].The interest in α-amino acid boronic acid analogues, as well as peptides that have a boronic acid analog-amino acid in place of the C-terminal residue, has been reported with the publication that these compounds are effective inhibitors of many serene proteases. See, e.g. Matteson et al. [J. Am. Chem. Soc. 103, 5241 (1981)]; Kettner et al. [J. Biol. Chem. 259,15106 (1984)]; and Kinder et al. [J. Med. Chem. 27, 1919 (1985)].
Razni izvajalci vključno Koehler et al. [Biochemistry, 10, 2477 (1971)] in Rawn et al. [Biochemistry, 13, 3124 (1974)] so domnevali, da prosta p-orbitala centrirana na boru v teh spojinah vzajemno deluje z aktivnim mestom hidroksilne skupine encima, da tvori tetraedrični adukt, ki oponaša prehodno stanje encimatske hidrolize. Mislili so, da se analog boronske kisline veže bolj tesno na encim kot substrat sam in s tem inhibira encimatsko delovanje na substrat. Analogi boronske kisline «-amino kislin in peptidi, ki jih vključujejo so splošno uporabni pri raziskavi, kjer so sposobni, da osvetljujejo biološke funkcije encimov, ki jih inhibirajo. Nadalje kot je razloženo spodaj so tudi terapevtsko koristni.Various contractors including Koehler et al. [Biochemistry, 10, 2477 (1971)] and Rawn et al. [Biochemistry, 13, 3124 (1974)] have hypothesized that the free p-orbitals centered on boron in these compounds interact with the active site of the hydroxyl group of the enzyme to form a tetrahedral adduct mimicking the transient state of enzymatic hydrolysis. The boronic acid analogue was thought to bind more closely to the enzyme than the substrate itself, thereby inhibiting enzymatic action on the substrate. Boronic acid analogues of amino acids and the peptides they include are of general use in research where they are able to illuminate the biological functions of the enzymes that inhibit them. Further as discussed below, they are also therapeutically useful.
Peptidi, ki vključujejo analog «-amino boronske kisline prolina (BoroPro) naPeptides that include the boronic acid proline analog (BoroPro) at the
C-terminusu, so posebno zanimivi, ker so se izkazali, da so potentni inhibitorji določenih post-prolinskih cepitev encimov. Npr. Bachovchin et al. [J. Biol. Chem.C-terminus are of particular interest because they have been shown to be potent inhibitors of certain post-proline cleavage enzymes. E.g. Bachovchin et al. [J. Biol. Chem.
265, 3738 (1990)] navajajo, da so taki peptidi inhibitorji IgA proteinaz določenih bakterij. Ti encimi so močno implicirani v bakterijski virulenci. Flentke et al. [Proč. Natl. Acad. Sci. USA 88, 1556 (1991)] navajajo, da taki peptidi inhibirajo dipeptidil peptidaze IV (DP-IV), ki povzročajo inhibiranje antigenske inducirane proliferacije in IL-2 produkcijo v T-celicah. Zadnji učinki so znani, da povzročajo zatiranje imunskega odziva. Zatiranje imunskega odziva je koristno pri zdravljenju npr. zavračanja transplantacije organa, bolezni transplantant proti gostitelju in raznih autoimunskih bolezni.265, 3738 (1990)] state that such peptides are inhibitors of IgA proteinases of certain bacteria. These enzymes are strongly implicated in bacterial virulence. Flentke et al. [Off. Natl. Acad. Sci. USA 88, 1556 (1991)] state that such peptides inhibit dipeptidyl peptidase IV (DP-IV), which cause inhibition of antigen-induced proliferation and IL-2 production in T cells. The latter effects are known to cause suppression of the immune response. Suppression of the immune response is useful in treating e.g. organ transplant rejection, host transplant disease, and various autoimmune diseases.
Prejšnje sintetične poti za α-amino boronske kisline se opirajo na postopke objavljene leta 1981 od Matteson et al., zgoraj, ki poteka po zaporedju: hidroboriranje (asimetrično) homologiranje s klorometillitijem in aminoliza. Matteson et al. [Organoometallics 3,1284 (1984)] opisujejo uporabo te tehnike za sintezo analogov boronske kisline N-acetilalanina, N-acetilvalina, N-acetilleucina in N-acetilfenilalanina; nekatere od teh so dobili z dobrimi (9:1) diastereomemimi razmerji.Previous synthetic routes for α-amino boronic acids rely on the procedures published in 1981 by Matteson et al., Above, in the following sequence: hydroboration (asymmetric) homologation with chloromethyllithium and aminolysis. Matteson et al. [Organoometallics 3,1284 (1984)] describe the use of this technique for the synthesis of the boronic acid analogues N-acetylalanine, N-acetylvaline, N-acetilleucine and N-acetylphenylalanine; some of these were obtained with good (9: 1) diastereomic ratios.
Uporaba Mattesonovega postopka za sintezo BoroPro je prikazana od Bachovachina, zgoraj in Flentkea zgoraj, toda obsežne modifikacije potrebne za izgradnjo pirolidinskega obroča napravijo le-tega neprivlačnega. Nadalje, pogoje za pripravo posameznega enantiomera BoroPro bodisi z asimetrično sintezo ali z ločitvijo niso navedeni.The use of the Matteson process for BoroPro synthesis is shown from Bachovachin, above, and Flentke above, but the extensive modifications required to construct the pyrrolidine ring make it unattractive. Further, the conditions for the preparation of a single BoroPro enantiomer either by asymmetric synthesis or separation are not specified.
Napori za nadaljnjo raziskavo biokemije postprolinskih cepitvenih encimov, zlasti DP-IV in možne terapevtske uporabe encimskih inhibitorjev, ki temeljijo na BoroPro so ovirani zaradi pomanjkanja učinkovite poti za prolinboronsko kislino.Efforts to further investigate the biochemistry of postprolin cleavage enzymes, in particular DP-IV and the potential therapeutic use of BoroPro-based enzyme inhibitors have been hampered by the lack of an effective pathway for prolineboronic acid.
Potreba za boljši vir BoroProna nas vodi do raziskovanja alternativnih poti za to spojino, posebno spojino v njeni optično aktivni obliki, posledica tega pa je predloženi izum.The need for a better source of BoroPron leads us to explore alternative pathways for this compound, a particular compound in its optically active form, resulting in the present invention.
Prvi obseženi vidik predloženega izuma obsega tri tesno povezane postopke za sintezo estrov prolin boronske kisline. Dve od teh sintez izhajata iz pirola. Tretja izhaja iz pirolidina. V obsegu prvega vidika predloženega izuma so vključeni določeni novi intermediati. Prolin boronska kislina ima kiralni center a glede na atom bora. Drugi obsežen vidik predloženega izuma obsega postopek za ločitev enantiomerov prolin boronske kisline, če želimo. Po tem postopku prolin boronski ester tvorimo z reakcijo s kiralnim alkoholom, pri čemer je uporaba pinandiola zlasti prednostna. Ločitev enantiomerov olajšamo z ločevanjem diasterfeomerne zmesi, ki nastane z uvedbo dodatnih kiralnih centrov. Nastale estre prolin boronske kisline z lahkoto združimo, da aktiviramo skupine karboksilne kisline, kot so značilno uporabljene v peptidni sintezi, da dobimo peptide z estrom prolin boronske kisline namesto amino kisline, na C-terminusu. Estrsko zaščitno skupino lahko odstranimo, da dobimo peptid proste boronske kisline. Če je estrska zaščitna skupina pinandiol, le-ta ni lahko odstranljiva z znanimi tehnikami. Tretji vidik predloženega izuma obsega več postopkov za odstranitev pinandiolne zaščitne skupine.The first comprehensive aspect of the present invention comprises three closely related processes for the synthesis of proline boronic acid esters. Two of these syntheses are derived from pyrrole. The third is derived from pyrrolidine. Certain novel intermediates are included within the scope of the first aspect of the present invention. Proline boronic acid has a chiral center a with respect to the boron atom. Another extensive aspect of the present invention is a process for separating the enantiomers of proline boronic acid, if desired. Following this process, the proline boronic ester is formed by reaction with chiral alcohol, with the use of pinandiol being particularly preferred. Separation of enantiomers is facilitated by the separation of the diastereomeric mixture resulting from the introduction of additional chiral centers. The resulting boronic acid proline esters can be easily combined to activate carboxylic acid groups, as typically used in peptide synthesis, to produce peptides with boronic acid proline ester instead of amino acid, at the C terminus. The ester protecting group can be removed to obtain the free boronic acid peptide. If the ester protecting group is pinandiol, it is not easily removable by known techniques. A third aspect of the present invention comprises several processes for removing a pinandiol protecting group.
Slika 1 prikazuje reakcijsko shemo, ki je prednostna izvedba predloženega izuma.Figure 1 shows the reaction scheme which is a preferred embodiment of the present invention.
Prva sinteza v skladu s predloženim izumom izhaja iz pirola, ki reagira z aktiviranim derivatom ogljikove kisline, zato da zaščitimo dušikov atom s skupino s formulo -COOR, kjer je R C^alkil, C3^cikloalkil, benzil, fenil, fenil substituiran z eno ali več C1 ^alkilnih skupin ali trimetilsililetil, zato da dobimo spojino s formulo I.The first synthesis in accordance with the present 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, where R c is alkyl, C 3 ^ cycloalkyl, benzyl, phenyl, phenyl substituted with one or more C1 ^ alkyl groups, or trimethylsilylethyl, in order to obtain a compound of formula I.
RCK (I)RCK (I)
V prednostnih zaščitnih skupinah je R terc.-butil, benzil, trimetilsililetil, fenil, metil ali etil. Najbolj prednostna zaščitna skupina je terc.butiloksikarbonil ali Boc. Zaščitno skupino vnesemo z uporabo dobro znanih tehnik. Specifična sinteza za 1-Boc-pirol je opisana od Grehn et al. [Angew. Chem. Int. Ed. Engl. 23,296 (1984)].In preferred protecting groups, R is tert-butyl, benzyl, trimethylsilylethyl, phenyl, methyl or ethyl. The most preferred protecting group is tert-butyloxycarbonyl or Boc. The protecting group is introduced using well known techniques. The specific synthesis for 1-Boc-pyrrole has been described by Grehn et al. [Angew. Chem. Int. Ed. Engl. 23, 296 (1984)].
Spojino s formulo I zatem obdelamo z litiiranim sredstvom, da dobimo spojino s formulo II 'LiThe compound of formula I is then treated with a lithiated agent to give the compound of formula II 'Li
RO (II) \RO (II) \
kjer je R definiran kot pred tem.where R is defined as before.
KK
Litiiranje spojine s formulo I lahko izvršimo z obdelavo z litijevim tetrametilpiperididom na znan način, kot npr. tisti opisan od Hasan et al. [J. Org. Chem. 46, 157 (1981)] ali z drugimi oviranimi litijevimi amidi, kot npr. litijevim diizopropilamidom ali litijevim dicikloheksilamidom ali z n-butil litijem v prisotnosti tetrametiletilendiamina. To reakcijo ugodno izvedemo v inertnem topilu, prednostno etru, kot npr. THF, dietiletru, dimetoksietanu ali metil t-butil etru pri temperaturi med -78 °C in -40 °C. Alternativno lahko pirol bromiramo v legi 2 na znan način, kot npr. tisti opisan od Chen et al., [Org. Syn., 70, 151 (1991)], in nastali produkt lahko zaščitimo in nato litiiramo, z uporabo drugih manj dragih litiirnih sredstev, kot npr. n-butil litija z uporabo znanih tehnik.Lithiation of a compound of formula I can be accomplished by treatment with lithium tetramethylpiperidide in a known manner, such as e.g. the one described by Hasan et al. [J. Org. Chem. 46, 157 (1981)] or with other impeded lithium amides, such as e.g. lithium diisopropylamide or lithium dicyclohexylamide or with n-butyl lithium in the presence of tetramethylethylenediamine. This reaction is advantageously carried out in an inert solvent, preferably an ether, such as e.g. THF, diethyl ether, dimethoxyethane or methyl t-butyl ether at a temperature between -78 ° C and -40 ° C. Alternatively, the pyrrole can be brominated in position 2 in a known manner, such as e.g. the one described by Chen et al., [Org. Syn., 70, 151 (1991)], and the resulting product can be protected and then lithified using other less expensive lithiating agents, such as e.g. n-butyl lithium using known techniques.
Intermediat s formulo II, ki ni izoliran, zatem reagira s trialkilboratom, kjer je vsaka alkilna skupina lahko ravna, razvejena ali ciklična in vsebuje 1 do 6 atomov ogljika, prednostno trimetil ali trietil boratom, čemur sledi hidroliza katalizirana s kislino z uporabo šibke kisline, kot npr. citronove ali ocetne kisline ah kalijevega hidrogensulfata, zato da dobimo zaščiteno pirol-2-boronsko kislino s formulo IIIThe intermediate of formula II, which is not isolated, is then reacted with trialkylborate, wherein each alkyl group may be straight, branched or cyclic and contains 1 to 6 carbon atoms, preferably trimethyl or triethyl borate, followed by acid catalyzed hydrolysis using weak acid, such as citric acid or acetic acid ah potassium hydrogen sulphate to give the protected pyrrole-2-boronic acid of formula III
kjer je R definiran kot pred tem.where R is defined as before.
Intermediat s formulo III zatem reduciramo z uporabo katalitičnega hidrogeniranja, da tvorimo zaščiteno prolin boronsko kislino s formulo IVThe intermediate of formula III is subsequently reduced using catalytic hydrogenation to form the protected proline boronic acid of formula IV
(IV) kjer je R definiran kot pred tem.(IV) where R is defined as before.
Katalitično hidrogeniranje intermediata s formulo III lahko izvedemo v organskem topilu, kot npr. etilacetatu ali tetrahidrofurand, z uporabo katalizatorja kot npr. 5 % platine na aktivnem oglju, platinovega oksida, rodija na aktivnem oglju, rodija na aluminijevem oksidu, paladija na aktivnem oglju ali Raneyevega niklja, bodisi pri atmosferskem tlaku ali pri približno 3,45 χ 105 Pa.The catalytic hydrogenation of an intermediate of formula III can be carried out in an organic solvent, such as e.g. ethyl acetate or tetrahydrofurand, using a catalyst such as e.g. 5% platinum on activated carbon, platinum oxide, rhodium on activated carbon, rhodium on aluminum oxide, palladium on activated carbon or Raney nickel, either at atmospheric pressure or at about 3,45 χ 10 5 Pa.
Za alternativno sintezo boronske kisline s formulo IV uporabimo pirolidin, ki ga obdelamo s primernim acilirnim sredstvom, da dobimo zaščiteno spojino s formulo VIII 'NFor the alternative synthesis of boronic acid of formula IV, pyrrolidine is used, which is treated with a suitable acylating agent to give the protected compound of formula VIII 'N
RO (VIII) kjer je R definiran kot pred tem.RO (VIII) where R is defined as before.
Zaščitno skupino izberemo tako, da dopustimo aktiviranje pirolidina za litiiranje v legi sosednji dušiku in le-ta naj vsebuje obsežen delež, ki zavira napad na karbonil z litiimim sredstvom. Prednostno je, da uporabimo karbamoilno zaščitno skupino s formulo -COOR, npr. skupine, kjer je R terc.butoksi ali 2,4,6-tri-terc.butilfenoksi. Vendar lahko uporabimo tudi določene acilne ali aroilne skupine, kot npr. terc.butilkarbonil ali trifenilmetilkarbonil. Druge primerne aktivacijske skupine so prikazane v Beak et al., [Chem. Rev., 84, 471-523, (1984)]. Najbolj prednostna zaščitna skupina je terc.butiloksikarbonil ali Boc. Zaščitno skupino lahko vnesemo v pirolidin z dobro znanimi tehnikami.The protecting group is selected by allowing the activation of the pyrrolidine for lithiation in the position adjacent to the nitrogen, and it should contain a large proportion that inhibits the attack on carbonyl by the lithium agent. It is preferable to use a carbamoyl protecting group of the formula -COOR, e.g. groups where R is tert-butoxy or 2,4,6-tri-tert-butylphenoxy. However, certain acyl or aroyl groups may also be used, such as e.g. tert.butylcarbonyl or triphenylmethylcarbonyl. Other suitable activation groups are shown in Beak et al., [Chem. Rev., 84, 471-523, (1984)]. The most preferred protecting group is tert-butyloxycarbonyl or Boc. The protecting group can be introduced into pyrrolidine by well-known techniques.
Spojine s formulo VIII zatem obdelamo z litiirnim sredstvom, da dobimo spojino s formulo IXThe compounds of formula VIII are then treated with a lithiation agent to give the compound of formula IX
N (IX)N (IX)
RO kjer je R kot je definiran pred tem.RO where R is as previously defined.
Litiiranje spojine s formulo VIII lahko izpopolnimo z obdelavo s sek.butillitijem in tetrametiletilendiaminom na znan način, kot tišti opisan od Beak et al. [Tet. Lett. 30, 1197 (1989)]. To reakcijo ugodno izvedemo v inertnem organskem topilu prednostno etru, kot npr. dietiletru, metil terc.butil etru ali THF pri temperaturi med približno -78 °C in 0 °C, prednostno -78 °C do -40 °C. Litiiranje lahko dosežemo z reaktivnim ali alkil litijem kot npr. sek.butil litijem ali terc.butil litijem prednostno v prisotnosti ustreznega aditiva, kot npr. tetrametil etilendiamina, heksametil fosforamida ali Ν,Ν’-dimetilpropilensečnine (DMPU).The lithiation of a compound of formula VIII can be perfected by treatment with sec.butillithium and tetramethylethylenediamine in a known manner, as described quietly by Beak et al. [Tet. Lett. 30, 1197 (1989)]. This reaction is advantageously carried out in an inert organic solvent, preferably ether, such as e.g. 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 can be achieved by reactive or alkyl lithium such as e.g. sec.Butyl lithium or tert.butyl lithium preferably in the presence of a suitable additive such as e.g. tetramethyl ethylenediamine, hexamethyl phosphoramide or Ν, dim′-dimethylpropylurea (DMPU).
Intermediat s formulo IX, ki ni izoliran, zatem reagira s trialkil boratom, pri čemer je vsaka alkilna skupina lahko ravna, razvejena ali ciklična in vsebuje 1 do 6 atomov ogljika, prednostno trimetil ali trietil boratom, čemur sledi hidroliza z vodo in ekstrakcija v vodni alkaliji, kot npr. natrijevem hidroksidu ali kalijevem hidroksidu, da pospešimo čiščenje. Nakisanje alkalijske raztopine na pH 3 in ekstrakcija, da zaščiteno prolin boronsko kislino s formulo IV.The intermediate of formula IX, which is not isolated, is then reacted with trialkyl borate, each alkyl group being straight, branched or cyclic and containing 1 to 6 carbon atoms, preferably trimethyl or triethyl borate, followed by hydrolysis with water and extraction in aqueous alkalis, such as e.g. sodium hydroxide or potassium hydroxide to speed up cleaning. Acidification of the alkali solution to pH 3 and extraction to give protected proline boronic acid of formula IV.
Zato, da tvorimo ester boronske kisline, intermediat proste boronske kisline s formulo IV zatem esterificiramo z reakcijo z diolom s formulo VIn order to form the boronic acid ester, the free boronic acid intermediate of formula IV is subsequently esterified by reaction with a diol of formula V
ΗΟ-Χ-ΟΗ (V) kjer je X vezna skupina, da dobimo spojino s formulo VIΗΟ-Χ-ΟΗ (V) where X is a bonding group to give the compound of formula VI
kjer je X enaka vezna skupina kot je omenjena zgoraj in je R definiran kot pred tem. Estrska skupina, ki se tako tvori, je namenjena, da deluje samo kot zaščitna skupina, ki jo lahko odstranimo. Strukture, sinteze in postopki za vezavo in odstranitev takih estrskih zaščitnih skupin so na splošno znani v kemijski tehniki. Strokovnjaki v kemijski tehniki morajo upoštevati, da struktura vezne skupine X ni kritična. Vezna skupina X je lahko, ne da bi omejevali primere, nenasičena 2- do 3-členska ogljikovodikova veriga; nasičena 2- do 3-členska ogljikovodikova veriga, ki sestavlja del C512karbocikličnega sistema, ki lahko v danem primeru vsebuje nenasičenja ali obročne spojitve; 2- do 3-členska ogljikovodikova veriga, ki sestavlja del aromatskega obročnega sistema; ali skupina s formulo -(CH2)n-NH-(CH2)m-, kjer sta n in m vsak 2 ali 3; pri čemer so take skupine lahko nesubstituirane ali substituirane z eno ali več Cj 3alkilnih ali fenilnih skupin.wherein X is the same bonding group as mentioned above and R is defined as before. The ester group thus formed is intended to act only as a removable protecting group. The structures, syntheses, and processes for the binding and removal of such ester protecting groups are generally known in the chemical art. Experts in chemical engineering should note that the structure of the bonding group X is not critical. The linking group X may, without limitation, be an unsaturated 2- to 3-membered hydrocarbon chain; a saturated 2- to 3-membered hydrocarbon chain that forms part of a C 512 carbocyclic system which may optionally contain unsaturation or ring couplings; A 2- to 3-membered hydrocarbon chain that forms part of the aromatic ring system; or a group of formula - (CH 2 ) n -NH- (CH 2 ) m - wherein n and m are each 2 or 3; wherein such groups may be unsubstituted or substituted by one or more Cl 3 alkyl or phenyl groups.
Primerni dioli s formulo V so npr. etilen glikol, pinakol, katehol, pinandiol, butan2,3-diol, 2,2-dimetil propan 1,3-diol, dietanolamin in l,2-difeniletan-l,2-diol.Suitable diols of formula V are e.g. ethylene glycol, pinacol, catechol, pinandiol, butane 2,3-diol, 2,2-dimethyl propane 1,3-diol, diethanolamine and 1,2-diphenylethan-1,2-diol.
Z deležem boronske kisline zaščitene z estrsko skupino zatem odstranimo zaščitno skupino na dušiku z uporabo znanih tehnik, kot npr. tistih opisanih od Greene in Protective Groups in Organic Synthesis (J. Wiley & Sons, 1981), da dobimo hidroklorid želenega estra prolin boronske kisline s formulo VIIThe boronic acid content protected by the ester group is subsequently removed from the nitrogen protecting group using known techniques, such as e.g. those described by Greene and Protective Groups and Organic Synthesis (J. Wiley & Sons, 1981) to obtain the hydrochloride of the desired proline boronic acid ester of formula VII
Npr., če je zaščitna skupina Boc, le-to z lahkoto odstranimo s suhim vodikovim kloridom v etil acetatu.For example, if the protecting group is Boc, it is easily removed with dry hydrogen chloride in ethyl acetate.
Prednostno izvedemo esterifikacijo spojine s formulo IV s kiralnim, neracemnim diolom, kot npr. (lS,2S,3R,5S)-(+)-pinandiolom, l,2-difeniletan-l,2-diolom ali butan-2,3-diolom, ker na ta način uvedemo dodatne kiralne centre v molekulo. To dopušča ločitev kiralnega centra a glede na atom bora z uporabo znanih postopkov za ločevanje diastereomerov, kot npr. PHLC ali frakcionirne kristalizacije. To je prikazano z reakcijsko shemo na sl. 1, kjer izomere spojine s formulo VI v kateri je boronska kislina zaščitena s (lS,2S,3R,5S)-(+)-pinandiolom lahko ločimo s HPLC, da dobimo spojine Via in Vib. Alternativno lahko izomere hidroklorida spojine s formulo VII z enako borovo zaščitno skupino ločimo s frakcionirno kristalizacijo v topilu, kot npr. etil acetatu ali zmesi diklormetana/etil acetata, izopropanolu ali etanolu, da dobimo spojino Vllb kot posamezen izomer z R konfiguracijo na ogljiku vezanem na bor.Preferably the esterification of the compound of formula IV with a chiral, non-racemic diol, such as e.g. (1S, 2S, 3R, 5S) - (+) - pinanediol, 1,2-diphenylethane-1,2-diol or butane-2,3-diol, because in this way additional chiral centers are introduced into the molecule. This permits separation of the chiral center a with respect to the boron atom using known methods for separating diastereomers, e.g. PHLC or fractionation crystallization. This is illustrated by the reaction scheme in FIG. 1, where the isomers of the compounds of formula VI in which the boronic acid is protected by (1S, 2S, 3R, 5S) - (+) - pinanediol can be separated by HPLC to give the compounds Via and Vib. Alternatively, the hydrochloride isomers of a compound of formula VII with the same boron protecting group may be separated by fractionation crystallization in a solvent, such as e.g. ethyl acetate or a mixture of dichloromethane / ethyl acetate, isopropanol or ethanol to give compound Vllb as an individual isomer with the R configuration on carbon bound to boron.
Nadaljnja prednost uporabe pinandiola je, da so boranatni estri, ki tako nastanejo bolj stabilni kot tisti izpeljani iz drugih diolov, npr. pinakola s katerimi pogosto opazimo znatno izgubo zaščitne skupine med kromatografijo. To je koristno tako pri čiščenju kot tudi ločenju izomera s kromatografijo na silikagelu, ker dosežemo boljši ponovni dobitek želenega materiala.A further advantage of using pinandiol is that the boranate esters thus formed are more stable than those derived from other diols, e.g. pinacols, which often show a significant loss of the protecting group during chromatography. This is useful for both purification and separation of the isomer by chromatography on silica gel, since a better recovery of the desired material is achieved.
KK
Z rahlo modifikacijo sinteze opisane zgoraj lahko derivatiziran pirol s formulo III direktno esterificiramo z diolom s formulo V. Nastali ester s formulo IIIABy slightly modifying the synthesis described above, the derivatized pyrrole of formula III can be directly esterified with a diol of formula V. The resulting ester of formula IIIA
(IIIA) lahko reduciramo na enak način kot spojino s formulo III, pri čemer dobimo zaščiten ester prolin boronske kisline s formulo VI. Z drugimi besedami vrstni red stopenj v katerih reduciramo pirolni obroč in esterificiramo skupino boronske kisline je lahko obraten.(IIIA) can be reduced in the same manner as a compound of formula III to give the protected boronic acid proline ester of formula VI. In other words, the order of stages in which the pyrrole ring is reduced and the boronic acid group esterified can be reversed.
Estre prolin boronske kisline, ki jih tako izdelamo, z lahkoto spojimo z aktiviranimi karboksilnimi kislinami, kot npr. tistimi, ki jih značilno uporabljamo v peptidni sintezi, npr. amino kislina z zaščitenim dušikom, da dobimo spojino s formulo XThe boronic acid proline esters thus produced can be readily coupled to activated carboxylic acids such as e.g. to those typically used in peptide synthesis, e.g. a protected nitrogen amino acid to give the compound of formula X
(X) kjer je -COOR2 amino zaščitna skupina take vrste, ki jo navadno uporabljamo v peptidni sintezi, tako da je R2 npr. terc.butil, benzil ali fluorenilmetil in je R3 stranska veriga naravne amino kisline, v danem primeru z ustreznimi zaščitnimi skupinami, take vrste, ki jih navadno uporabljamo v peptidni sintezi.(X) where -COOR 2 is an amino protecting group of the kind commonly used in peptide synthesis, such that R 2 is e.g. tert.butyl, benzyl or fluorenylmethyl and R 3 is a side chain of the natural amino acid, optionally with suitable protecting groups, of the kind commonly used in peptide synthesis.
Spojine s formulo X vsebujejo zaščitne skupine tako na boronatnem kot tudi na amino kislinskem dušiku. Morda je potrebno, da odstranimo eno ali obe zaščitni skupini za biološko aktivnost ali za nadaljnjo kemijsko obdelovanje. Zaščitne skupine lahko odstranimo na oba načina. Razni postopki za odstranitev teh zaščitnih skupin so opisani spodaj.The compounds of formula X contain protecting groups on both boronate and amino acid nitrogen. It may be necessary to remove one or both of the protecting groups for biological activity or for further chemical treatment. There are two ways to remove protecting groups. The various procedures for removing these protecting groups are described below.
Odstranitev dušikove zaščitne skupine lahkP dosežemno z znami postopki, da dobimo spojino s formulo XIRemoval of the nitrogen protecting group of lkPP is achievable by known methods to give the compound of formula XI
(xi)(xi)
Esterska skupina, ki ščiti delež boronske kisline je stabilna za nevtralne in kisle organske medije toda mnogi boronatni estri se hitro cepijo pri rahlo bazičnih (pH = 7,5) vodnih pogojih, da dobimo boronsko kislino. V primeru boronatnih estrov pinan diola pa je znano, da je hidroliza težavna in so potrebni posebni pogoji za odstranitev pinandiola. Glej npr. Matteson et al. [J. Am. Chem. Soc., 102, 7590 (1980)] in Brown et al. [J. Organometallic Chem., 385, 15 (1988)]. Ti postopki niso primerni za odstranitev pinandiola iz spojine s formulo VI, X ali XI. Ugotovili smo več postopkov za odstranitev pinandiola iz boranata, kot npr. spojino VI, X ali XI. Torej odstranitev pinandiola lahko dosežemo pri blagih pogojih z uporabo oksidacijskega sredstva sposobnega cepljenja 1,2-diolov, da odstranimo pinandiol iz ravnotežja in na ta način vodimo le-to v smeri proste boronske kisline. Npr. obdelava spojin s formulama VI in X, v katerih je zaščitna skupina pinandiol, z natrijevem metaperjodatom v vodnem amonijevem acetatu in acetonu pri sobni temperaturi, da spojino s formulo IV oz. XII,The boronic acid protecting ester moiety is stable for neutral and acidic organic media, but many boronate esters are rapidly cleaved under slightly basic (pH = 7.5) aqueous conditions to give boronic acid. In the case of the boronate esters of pinane diol, however, hydrolysis is known to be difficult and special conditions are required for the removal of pinandiol. See, e.g. Matteson et al. [J. Am. Chem. Soc., 102, 7590 (1980)] and Brown et al. [J. Organometallic Chem., 385, 15 (1988)]. These procedures are not suitable for the removal of pinandiol from a compound of formula VI, X or XI. Several procedures have been identified for the removal of pinandiol from borane, such as e.g. compound VI, X or XI. Thus, removal of pinandiol can be achieved under mild conditions by using an oxidizing agent capable of grafting 1,2-diols to remove pinandiol from equilibrium and thereby guide it in the direction of free boronic acid. E.g. treating compounds of formulas VI and X in which the protecting group is pinandiol with sodium metaperiodate in aqueous ammonium acetate and acetone at room temperature to give the compound of formula IV or XII,
To reakcijo ugodno izvedemo v vodi, v danem primeru z dodanim pufrom, kot npr.This reaction is advantageously carried out in water, optionally with added buffer, such as e.g.
amonijevim acetatom ali dinatrijevim hidrogenfosfatom pri pH med 3 in 10 prednostno 6 do 8 in temperaturi od 0 do 80 °C, prednostno 20 do 40 °C v prisotnosti or10 ganskega sotopila, ki se meša z vodo, kot npr. acetona, metanola, etanola, THF ali acetonitrila. Primerno oksidacijsko sredstvo jč nenukleofilni oksidant, ki je sposoben cepljenja 1,2-diolov, kot npr. perjodova kislina ali njene soli ali permanganatne soli. Pri teh pogojih ne opazimo oksidativne cepitve vezi ogljik-bor. Upoštevati je treba, da je ta postopek uporaben za katerokoli boronsko kislino zaščiteno s pinandiolom. Nadalje je le-ta uporaben za katerokoli boronatno zaščitno skupino, ki je 1,2-diol, čeprav je posebno koristen za zaščitne skupine, kjer je enostavna vodna hidroliza počasna ali nepopolna.ammonium acetate or disodium hydrogen phosphate at a pH between 3 and 10, preferably 6 to 8, and a temperature of from 0 to 80 ° C, preferably 20 to 40 ° C, in the presence of an or 10 water miscible solubilizer, such as e.g. acetone, methanol, ethanol, THF or acetonitrile. A suitable oxidizing agent is a non-nucleophilic oxidant capable of grafting 1,2-diols, such as e.g. periodic acid or its salts or permanganate salts. Under these conditions, no oxidative cleavage of the carbon-boron bond is observed. It should be borne in mind that this process is applicable to any boronic acid protected by pinandiol. Furthermore, it is useful for any boronate protecting group that is 1,2-diol, although it is particularly useful for protecting groups where simple aqueous hydrolysis is slow or incomplete.
V primeru pinandiolnega boronatnega estra spojine, ki vsebuje nezaščiten amin, kot npr. spojino s formulo XI tudi lahko uporabimo postopek opisan zgoraj toda drug nov postopek je prednosten za spojine tega tipa. Ta postopek sestoji iz nanašanja vodne raztopine spojine s formulo XI pri pH 4 ali nižjem v kolono s kationsko izmenjalno smolo in eluiranja kolone z vodo ali razredčeno ocetno kislino, da odstranimo pinandiol. Na ta način odstranimo pinandiol iz ravnotežja in tako vodimo reakcijo v smeri hidrolize. Kolono nato eluiramo z razredčenim vodnim amonijevim hidroksidom, da odstranimo produkt, ki ga po uparjenju in nakisanju dobimo kot sol spojine s formulo XIII.In the case of the pinandiol boronate ester of a compound containing an unprotected amine, such as e.g. The compound of formula XI can also be used as described above, but another new process is preferred for compounds of this type. This process consists of applying an aqueous solution of a compound of formula XI at pH 4 or lower to a cation exchange resin column and eluting the column with water or dilute acetic acid to remove pinandiol. In this way, the pinandiol is removed from equilibrium to guide the reaction in the direction of hydrolysis. The column was then eluted with dilute aqueous ammonium hydroxide to remove the product obtained after evaporation and acidification as a salt of the compound of formula XIII.
(XIII)(XIII)
Ugodno uporabimo močno kislo kationsko izmenjalno smolo, npr. smolo tipa sulfonske kisline, kot npr. Dowex 50. Pinandiol, ki ga eluiramo iz smole lahko ponovno dobimo iz vodne raztopine in ponovno uporabimo. To najbolj ugodno dosežemo s spuščanjem vodne raztopine skozi kolono neionskega polimernega adsorbenta, kot je npr. Amberlite® XAD-200, ki adsorbira pinandiol skoraj kvantitativno. Pinandiol odstranimo iz kolone z eluiranjem z metanolom ali etanolom. Dve operaciji ionske izmenjave in pinandiolno adsorpcijo združimo v enojnem postopku, v katerem voda reciklira iz ene kolone v drugo z uporabo črpalke. To ima prednost, ker potrebujemo mnogo manjše količine vode in dopušča, da postopek nadaljujejo dovolj dolgo, da dosežemo visoko konverzije v produkt.A strongly acidic cation exchange resin, e.g. a sulfonic acid type resin such as e.g. Dowex 50. Resin-eluting pinandiol can be recovered from aqueous solution and reused. This is most advantageously achieved by lowering the aqueous solution through a column of non-ionic polymer adsorbent, such as e.g. Amberlite® XAD-200, which adsorbs pinandiol almost quantitatively. Pinandiol is removed from the column by elution with methanol or ethanol. The two ion exchange operations and pinandiol adsorption are combined in a single process in which water is recycled from one column to another using a pump. This has the advantage of requiring much smaller amounts of water and allows the process to continue for long enough to achieve high product conversions.
Strokovnjaki naj upoštevajo, da je zgoraj opisan postopek za odstranjevanje pinandiola z uporabo kationske izmenjalne smole tistrezen samo za spojine, ki vsebujejo bazično funkcionalno skupino, kot npr. nezaščiten amin.It should be appreciated by those skilled in the art that the procedure described above for the removal of pinandiol using a cation exchange resin is only appropriate for compounds containing a basic functional group, such as e.g. an unprotected amine.
Tretji postopek je tudi uporaben za pinandiolne estre spojin, ki vsebujejo nezaščiten amin, kot npr. spojino s formulo XI. Ta postopek sestoji iz transesterifikacije pinandiolnega boronata z drugo boronsko kislino s formulo R4-B(OH)2 v dvofaznem sistemu. R4 predstavlja C112ogljiko vodikovo skupino, ki je lahko sestavljena iz ravnih, razvejenih ali cikličnih alkilnih verig in fenilnih obročev. R4 je prednostno fenil. Ena od faz je voda, ki ima naravnan pH pod 7, prednostno pH 1-4 in druga je ogljikovodikovo organsko topilo kot npr. heksan, petroleter ali toluen. Torej obdelava spojine s formulo XI s fenilboronsko kislino v zmesi vode pri pH 1 in heksana, čemur sledi ločitev faz, proizvede pinandiolni ester fenilboronske kisline v organski fazi, ki ga lahko ponovno dobimo enostavno z uparjenjem in raztopino proste boronske kisline s formulo XIII v vodni fazi, ki jo lahko izoliramo z uporabo ionske izmenjalne smole na podoben način, kot je tisti opisan zgoraj. V tem sistemu je edina komponenta, ki je topna v organski fazi pinandiolni fenilboronat in na ta način odstranimo pinandiol iz ravnotežja. Spojino s formulo XI in nastalo spojino s formulo XIII obe ostaneta v vodnem sloju, ker nobena od njih ni topna v ogljikovodikovih topilih. Reakcijo lahko izvedemo s katerokoli boronsko kislino z ogljikovodikovo stransko verigo, pri čemer zagotovimo, njen pinandiolni ester topen v ogljikovodikovih topilih.The third process is also useful for pinandiol esters of compounds containing an unprotected amine, such as e.g. a compound of formula XI. This process consists of transesterification of pinandiol boronate with another boronic acid of formula R 4 -B (OH) 2 in a two-phase system. R 4 represents a C 1-12 carbon hydrogen group which may be composed of straight, branched or cyclic alkyl chains and phenyl rings. R 4 is preferably phenyl. One phase is water having a pH below 7, preferably pH 1-4, and the other is a hydrocarbon organic solvent such as e.g. hexane, petroleum ether or toluene. Thus, treatment of the compound of formula XI with phenylboronic acid in a mixture of water at pH 1 and hexane, followed by phase separation, produces an organic phase pinandiol ester which can be readily obtained by evaporation and a free boronic acid solution of formula XIII in aqueous phase, which can be isolated using an ion exchange resin in a similar manner to that described above. In this system, the only component that is soluble in the organic phase is pinandiol phenylboronate, thus removing pinandiol from equilibrium. The compound of formula XI and the resultant compound of formula XIII both remain in the aqueous layer because neither of them is soluble in hydrocarbon solvents. The reaction can be carried out with any boronic acid with a hydrocarbon side chain, ensuring that its pinandiol ester is soluble in hydrocarbon solvents.
Spojino s formulo XIII, ki je popolnoma nezaščitena, tudi lahko pripravimo z odstranitvijo dušikove zaščitne skupine iz spojine s formulo XII z uporabo znanih postopkov. Upoštevati moramo, da imajo spojine s formulami X, XI, XII in XIII na splošno dva kiralna centra. Eden je soseden borovemu atomu in drugi je prisoten v aminokislinskem deležu, razen če je ta delež glicin. Nadalje moramo upoštevati, da so čisti posamezni diastereoizomeri teh spojin bolj želeni za biološko uporabo kot zmesi diastereoizomerov. Torej je pomembno, da smo sposobni izdelati te spojine kot čiste posamezne izomere. V principu zato, ker so amino kisline na splošno dosegljive kot posamezni enantiomeri to lahko dosežemo z ločenjem zmesi diastereomerov tvorjenih s spajanjem optično čiste amino kisline z racemno prolinboronsko kislino z uporabo znanih tehnik. Vendar smo ugotovili, da so razen v posebnem primeru valina, take ločitve pogosto težavne in časovno zapravljive. Torej je prednostno, da uporabimo obliko prolin boronske kisline, ki je posamezen izomer pri kiralnem centru, ki je soseden boru, ker potem ni potrebna izomerna ločitev po spajanju z optično čisto amino kislino. Priloženi izum zagotavlja enostaven način za ločevanje enantiomerov prolin boronske kislinfe.A compound of formula XIII, which is completely unprotected, can also be prepared by removing a nitrogen protecting group from a compound of formula XII using known methods. It should be appreciated that compounds of formulas X, XI, XII and XIII generally have two chiral centers. One is adjacent to the boron atom and the other is present in the amino acid portion unless that portion is glycine. Furthermore, it should be borne in mind that pure single diastereoisomers of these compounds are more desirable for biological use than mixtures of diastereoisomers. So it is important that we are able to produce these compounds as pure single isomers. In principle, because amino acids are generally available as single enantiomers, this can be achieved by separating mixtures of diastereomers formed by coupling optically pure amino acids with racemic prolineboronic acid using known techniques. However, we have found that, except in the particular case of valine, such separations are often difficult and time-consuming. Thus, it is preferable to use the form of proline boronic acid, which is an individual isomer at the chiral center adjacent to boron, since then isomeric separation is not required after coupling with an optically pure amino acid. The present invention provides an easy way to separate the enantiomers of proline boronic acid.
Naslednji primeri nadalje ponazorjujejo izum.The following examples further illustrate the invention.
PRIMER 1 l-(l,l-dimetiletoksikarbonil)-pirol-2-boronska kislinaEXAMPLE 1 1- (1,1-Dimethylethoxycarbonyl) -pyrrol-2-boronic acid
K raztopini tetrametilpiperidina (8,8 ml, 52 mmol) v THF (275 ml) pri -78 °C ob atmosferi argona dodamo 2M raztopino butillitija v heksanih (26 ml, 52 mmol). Po 15 min dodamo l-(l,l-dimetiletoksikarbonil)-pirol (8,35 g, 50 mmol) v THF (10 ml) in raztopino mešamo 4 h pri -78 °C. Dodamo trietilborat (30 ml, 176 mmol) in zmes pustimo, da se segreje na sobno temperaturo v 3 h. Po dodatnih 12 h reakcijsko zmes razredčimo z etrom (500 ml) in izperemo z IM vodnim KHSO4 (3 x 100 ml) čemur sledi izpiranje z IM vodnim NaHCO3 (1 x 100 ml). S sušenjem preko MgSO4 in rotacijskim uparjenjem izdelamo rjavo trdno snov, ki jo očistimo s flash kromatografijo preko silikagela (EtOAc:heksan 1:9), da dobimo 8,7 g (82 %) bele kristalne trdne snovi (tal. 101,0 -101,5 °C).To a solution of tetramethylpiperidine (8.8 ml, 52 mmol) in THF (275 ml) at -78 ° C under an argon atmosphere was added a 2M solution of butyllithium in hexanes (26 ml, 52 mmol). After 15 min, 1- (1,1-dimethylethoxycarbonyl) -pyrrole (8.35 g, 50 mmol) in THF (10 ml) was added and the solution stirred at -78 ° C for 4 h. Triethylborate (30 ml, 176 mmol) was added and the mixture was allowed to warm to room temperature for 3 h. After a further 12 h, the reaction mixture was diluted with ether (500 mL) and washed with 1 N aqueous KHSO 4 (3 x 100 mL) followed by washing with 1 N aqueous NaHCO 3 (1 x 100 mL). MgSO 4 drying and rotary evaporation produced a brown solid which was purified by flash chromatography over silica gel (EtOAc: hexane 1: 9) to give 8.7 g (82%) of a white crystalline solid (m.p. 101.0 -101.5 ° C).
^-NMR (CDC13) δ 1,65 (s, 9H), 6,26 (t, J = 3,3 Hz, IH), 7,10 (dd, J = 1,6, 3,2 Hz, IH), 7,15 (s, 2H), 7,44 (dd, J = 1,6, 3,2 Hz, IH); 13C NMR (CDC13) 27,9, 85,5,112,0, 127,0,128,7,152,0; CIMS m/z (% rel. int) 212 (MH+, 11), 156 (100), 138 (68); Anal. izrač. za C9H14BNO4: C 51,23, H 6,69, N 6,64. Ugot.: C 51,22, H 6,51, N 6,67.1 H-NMR (CDCl 3 ) δ 1.65 (s, 9H), 6.26 (t, J = 3.3 Hz, 1H), 7.10 (dd, J = 1.6, 3.2 Hz, 1H), 7.15 (s, 2H), 7.44 (dd, J = 1.6, 3.2 Hz, 1H); 13 C NMR (CDCl 3 ) 27.9, 85.5,112.0, 127.0,128.7,152.0; CIMS m / z (% rel. Int) 212 (MH +, 11), 156 (100), 138 (68); Anal. calcd. for C 9 H 14 BNO 4 : C 51.23, H 6.69, N 6.64. Found: C 51.22, H 6.51, N 6.67.
PRIMER 2 l-(l,l-dimetiletoksikarbonil)-pirolidin-2-boronska kislinaEXAMPLE 2 1- (1,1-Dimethylethoxycarbonyl) -pyrrolidine-2-boronic acid
Raztopino 6,15 g (24 mmol) l-(l,l-dimetiletoksikarbonil)-pirol-2-boronske kisline izdelane kot v primeru 1 v EtOAc (100 ml) hidrogeniramo preko 5 % Pt/C (pribl. 500 mg) pri 3,45 χ 105 Pa 24 do 48 h. Nastalo suspenzijo filtriramo skozi blazino celita in koncentriramo. Ta material kromatografiramo na silikagelu z uporabo zaporedja eluiranj z heksani:EtOAc 9:1 in nato z acetonom. Acetonske frakcije koncentriramo, da proizvedemo 6,05 g (97 %) želene spojine kot čisto steklo, ki kristalizira po odstranitvi sledov topil (tal. 100-101 °C).A solution of 6.15 g (24 mmol) of 1- (1,1-dimethylethoxycarbonyl) -pyrrol-2-boronic acid prepared as in Example 1 in EtOAc (100 ml) was hydrogenated over 5% Pt / C (ca. 500 mg) at 3.45 χ 10 5 Well 24 to 48 h. The resulting suspension was filtered through a pad of celite and concentrated. This material is chromatographed on silica gel using elution with hexanes: EtOAc 9: 1 and then with acetone. The acetone fractions were concentrated to produce 6.05 g (97%) of the desired compound as a clear glass which crystallized after removal of the traces of solvents (mp 100-101 ° C).
Ή NMR (CDClg): δ 1,42 (s, 9H), 1,6-2,15 (m, 5H), 3,1 - 3,6 (m, 2H); 13C NMR (CDC13) δ 25,1, 25,7,28,4,45,6, 46,2, 78,6,154,5; CIMS m/z (% Rel. int) 116 (100), 70 (46); Anal. izrač. za C9HlgBNO4: C 50,27, H 8,44, N 6,51.Ή NMR (CDCl3): δ 1.42 (s, 9H), 1.6-2.15 (m, 5H), 3.1-3.6 (m, 2H); 13 C NMR (CDCl 3 ) δ 25.1, 25.7,28,4,45,6, 46,2, 78,6,154,5; CIMS m / z (% Rel. Int) 116 (100), 70 (46); Anal. calcd. for C 9 H lg BNO 4: C 50.27, H 8.44, N 6.51.
Ugot.: C 50,52, H 8,22, N 6,58.Found: C 50.52, H 8.22, N 6.58.
PRIMER 3 (lS,2S,3R,5S)-pinandiol l-(Ll-dimetiletoksikarbonil)-pirolidin-2S-boronat in (lS,2S,3R,5S)-pinandiol l-(l,l-dimetiletoksikarboniI)-pirolidin-2R-boronatEXAMPLE 3 (1S, 2S, 3R, 5S) -pinanediol 1- (L1-dimethylethoxycarbonyl) -pyrrolidine-2S-boronate and (1S, 2S, 3R, 5S) -pinanediol 1- (1,1-dimethylethoxycarbonyl) -pyrrolidine- 2R-Boronate
Raztopino l-(l,l-dimetiletoksikarbonil)-pirolidin-2-boronske kisline izdelane kot v primeru 2 (1,52 g, 7,1 mmol) in (lS,2S,3R,5S)-(+)-pinandiola (1,36 g, 8,0 mmol) mešamo pri sobni temperaturi v etru (25 ml) 2 h. S koncentracijo in flash kromatografijo preko silikagela (heksani:EtOAc 85:15) proizvedemo 2,1 g (85 %) zmesi 1:1 dveh diastereomerov. Le-te ločimo s HPLC preko kolone mikroparasila A300 x 3,9 mm, pri čemer eluiramo z metil terc.butiletrom:heksani (1:9) in z uporaboA solution of 1- (1,1-dimethylethoxycarbonyl) -pyrrolidine-2-boronic acid prepared as in Example 2 (1.52 g, 7.1 mmol) and (1S, 2S, 3R, 5S) - (+) - pinanediol ( 1.36 g, 8.0 mmol) was stirred at room temperature in ether (25 ml) for 2 h. Concentration and flash chromatography over silica gel (hexanes: EtOAc 85:15) produced 2.1 g (85%) of a 1: 1 mixture of two diastereomers. They were separated by HPLC via a A300 x 3.9 mm microparasite column, eluting with methyl tert-butylether: hexanes (1: 9) and using
u.v. detekcije pri 220 nm. Izomer (lS,2S,3R,5S)-pinandiol l-(l,l-dimetiletoksikarbonil)-pirolidin-2S-boronat se prvi eluira pri teh pogojih.u.v. detection at 220 nm. The isomer (1S, 2S, 3R, 5S) -pinanediol 1- (1,1-dimethylethoxycarbonyl) -pyrrolidine-2S-boronate is first eluted under these conditions.
S-izomer: Ή NMR (C6D6); δ 0,55 (s, 3H), 1,09 (s, 3H), 1,52 (s, 9H), 1,60 (s, 3H), 1,2-2,2 (m, 8H), 3,1-3,5 (m, 3H), 4,11 (m, 0,3H), 4,33 (m, 0,7H); 13C NMR (C6D6): δ 23,9, 26,6, 27,1, 27,3, 28,4,28,6, 28,8, 36,0, 38,2, 39,9,46,1, 51,9, 78,3, 78,5, 85,7,154,9.S-isomer: Ή NMR (C 6 D 6 ); δ 0.55 (s, 3H), 1.09 (s, 3H), 1.52 (s, 9H), 1.60 (s, 3H), 1.2-2.2 (m, 8H), 3.1-3.5 (m, 3H), 4.11 (m, 0.3H), 4.33 (m, 0.7H); 13 C NMR (C 6 D 6 ): δ 23.9, 26.6, 27.1, 27.3, 28.4.28.6, 28.8, 36.0, 38.2, 39.9 , 46.1, 51.9, 78.3, 78.5, 85.7,154.9.
R-izomer: JH NMR (C6D6); δ 0,52 (s, 3H), 1,08 (s, 3H), 1,52 (s, 9H), 1,61 (s, 3H), 1,2-2,2 (m, 8H), 3,1-3,6 (m, 3H), 4,01 (m, 0,3H), 4,25 (m, 0,7H); 13C NMR (C6D6)R-isomer: 1 H NMR (C 6 D 6); δ 0.52 (s, 3H), 1.08 (s, 3H), 1.52 (s, 9H), 1.61 (s, 3H), 1.2-2.2 (m, 8H), 3.1-3.6 (m, 3H), 4.01 (m, 0.3H), 4.25 (m, 0.7H); 13 C NMR (C6D 6 )
23,9, 26,6, 27,1, 27,3, 28,4, 28,7, 28,9, 35,8, 38,2, 39,6, 46,2, 51,8, 78,1, 78,5, 85,7,154,5.23.9, 26.6, 27.1, 27.3, 28.4, 28.7, 28.9, 35.8, 38.2, 39.6, 46.2, 51.8, 78, 1, 78.5, 85.7,154.5.
Upoštevati moramo, da (lR,2R,3S,5R)-pinandiol-l-(l,l-dimetiletoksikarbonil)pirolidin-2S-boronat in (lR,2R,3S,5R)-pinandiol-l-(l,l-dimetiletoksikarbonil)pirolidin-2R-boronat lahko proizvedemo na podoben način, pri čemer izhajamo iz (lR,2R,3S,5R)-(-)-pinandiola.It should be appreciated that (1R, 2R, 3S, 5R) -pinanediol-1- (1,1-dimethylethoxycarbonyl) pyrrolidine-2S-boronate and (1R, 2R, 3S, 5R) -pinanediol-1- (1, 1- dimethylethoxycarbonyl) pyrrolidine-2R-boronate can be produced in a similar manner, starting from (1R, 2R, 3S, 5R) - (-) - pinandiol.
PRIMER 4EXAMPLE 4
Hidroklorid (lS,2S,3R,5S)-pinandiol pirolidin-2S-boronataHydrochloride (1S, 2S, 3R, 5S) -pinanediol pyrrolidine-2S-boronate
Raztopino (lS,2S,3R,5S)-pinandiol-l-(l,l-dimetiletoksikarbonil)-pirolidin14Solution of (1S, 2S, 3R, 5S) -pinanediol-1- (1,1-dimethylethoxycarbonyl) -pyrrolidine14
2S-boronata, proizvedeno kot v primeru 3 (28,5 mg, 0,08 mmol) mešamo v raztopini suhega HC1 v EtOAc (približno 3M). Po 2 h raztopino koncentriramo 2-krat iz EtOAc, da proizvedemo 21,2 mg (91 %) želenega hidroklorida kot belo trdno snov (tal. 204 °C (razp.)).The 2S-boronate produced as in Example 3 (28.5 mg, 0.08 mmol) was stirred in a solution of dry HCl in EtOAc (about 3M). After 2 h, the solution was concentrated twice from EtOAc to produce 21.2 mg (91%) of the desired hydrochloride as a white solid (mp 204 ° C (dec.)).
Ή NMR (CDC13): δ 0,83 (s, 3H), 1,14 (d, J = 11Hz, IH), 1,29 (s, 3H), 1,45 (s, 3H),Ή NMR (CDCl 3 ): δ 0.83 (s, 3H), 1.14 (d, J = 11Hz, 1H), 1.29 (s, 3H), 1.45 (s, 3H).
1,85 - 2,15 (m, 6H), 2,17 - 2,50 (m, 3H), 3,18 - 3,25 (m, IH), 3,45 (bs, 2H), 4,42 (dd, J = 1,8, 8,6 Hz, IH), 8,80 (bs, IH), 10,56 (bs, IH); 13C NMR (CDC13); δ 23,9, 24,5, 26,5, 27,0, 27,2, 28,4, 34,9, 38,2, 39,4, 45,8, 51,2, 79,0, 87,6; CIMS m/z (% rel int) 250 (MH+, 100); HRMS (El) za C14H24BNO2 izrač. 249,1900, ugot. 249,1899.1.85 - 2.15 (m, 6H), 2.17 - 2.50 (m, 3H), 3.18 - 3.25 (m, 1H), 3.45 (bs, 2H), 4. 42 (dd, J = 1.8, 8.6 Hz, 1H), 8.80 (bs, 1H), 10.56 (bs, 1H); 13 C NMR (CDCl 3 ); δ 23.9, 24.5, 26.5, 27.0, 27.2, 28.4, 34.9, 38.2, 39.4, 45.8, 51.2, 79.0, 87 , 6; CIMS m / z (% rel int) 250 (MH +, 100); HRMS (El) for C 14 H 24 BNO 2 calc. 249,1900, found. 249,1899.
Upoštevati moramo, da hidroklorid (lR,2R,3S,5R)-pinandiol-pirolidin-2S-boronata lahko proizvedemo na podoben način.It should be appreciated that the hydrochloride of (1R, 2R, 3S, 5R) -pinanediol-pyrrolidine-2S-boronate can be produced in a similar manner.
PRIMER 5EXAMPLE 5
Hidroklorid (lS,2S,3R.5S)-pinandiol-pirolidin-2R-boronataHydrochloride (1S, 2S, 3R.5S) -pinanediol-pyrrolidine-2R-boronate
Raztopino (lS,2S,3R,5S)-pinandiol-l-(l,l-dimetiletoksikarbonil)-pirolidin-2Rboronata, proizvedeno kot v primeru 3 (18,3 mg, 0,05 mmol) obdelamo s suhim HC1 v EtOAc kot zgoraj. Z obdelavo proizvedemo 14,3 mg (96 %) želenega hidroklorida kot belo trdno snov (tal. 248 °C (razp.)).A solution of (1S, 2S, 3R, 5S) -pinanediol-1- (1,1-dimethylethoxycarbonyl) -pyrrolidine-2Rboronate produced as in Example 3 (18.3 mg, 0.05 mmol) was treated with dry HCl in EtOAc as above. Treatment produces 14.3 mg (96%) of the desired hydrochloride as a white solid (mp 248 ° C (dec.)).
Ή NMR (CDC13): δ 0,83 (s, 3H), 1,14 (d, J = 11Hz, IH), 1,29 (s, 3H), 1,45 (s, 3H),Ή NMR (CDCl 3 ): δ 0.83 (s, 3H), 1.14 (d, J = 11Hz, 1H), 1.29 (s, 3H), 1.45 (s, 3H).
1,85 - 2,15 (m, 6H), 2,17 - 2,50 (m, 3H), 3,18 - 3,25 (m, IH), 3,45 (bs, 2H), 4,42 (dd, J = 1,8,8,6 Hz, IH), 8,80 (bs, IH), 10,56 (bs, IH); 13C NMR (CDC13) δ 23,9,24,5, 26,5, 27,0, 27,2, 28,5, 34,9, 38,1, 39,4, 45,8, 51,2, 79,0, 87,8; CIMS m/z (% rel int) 250 (MH+, 100); HRMS (El) za C14H24BNO2 izrač. 249,1900, ugot. 249,1903.1.85 - 2.15 (m, 6H), 2.17 - 2.50 (m, 3H), 3.18 - 3.25 (m, 1H), 3.45 (bs, 2H), 4. 42 (dd, J = 1.8,8.6 Hz, 1H), 8.80 (bs, 1H), 10.56 (bs, 1H); 13 C NMR (CDCl 3 ) δ 23,9,24,5, 26,5, 27,0, 27,2, 28,5, 34,9, 38,1, 39,4, 45,8, 51, 2, 79.0, 87.8; CIMS m / z (% rel int) 250 (MH +, 100); HRMS (El) for C 14 H 24 BNO 2 calc. 249,1900, found. 249,1903.
Upoštevati moramo, da hidroklorid (lR,2R,3S,5R)-pinandiol-pirolidin-2R-boronata lahko proizvedemo na podoben način.It should be appreciated that the hydrochloride of (1R, 2R, 3S, 5R) -pinanediol-pyrrolidine-2R-boronate can be produced in a similar manner.
PRIMER 6 (lS,2S.3R,5S)-pinandiol-l-(l,l-dimetiletoksikarbonil)-pirol-2-boronatEXAMPLE 6 (1S, 2S.3R, 5S) -pinanediol-1- (1,1-dimethylethoxycarbonyl) -pyrrol-2-boronate
Raztopino l-(l,l-dimetiletoksikarbonil)-pirol-2-boronske kisline, proizvedene kot v primeru 1 (1,36 g, 6,45 mmol) in (lS,2S,3R,5S)-(+)-pinandiola (1,10 g, 6,45 mmol) mešamo v 20 ml etra 4 h. Z rotacijskih! uparjenjem, čemur sledi flash kromatografija preko silikagela (heksan:EtOAc 95:5) proizvedemo 1,83 g (82 %) želenega produkta kot čisto olje.A solution of 1- (1,1-dimethylethoxycarbonyl) -pyrrol-2-boronic acid produced as in Example 1 (1.36 g, 6.45 mmol) and (1S, 2S, 3R, 5S) - (+) - pinanediol (1.10 g, 6.45 mmol) was stirred in 20 ml of ether for 4 h. With rotary! evaporation followed by flash chromatography over silica gel (hexane: EtOAc 95: 5) yielded 1.83 g (82%) of the desired product as a pure oil.
Ή NMR (CDC13) S 0,90 (s, 3H), 1,30 (s, 3H), 1,41 (d, J = 11Hz, IH), 1,50 (s, 3H), 1,50 (s, 3H), 1,59 (s, 9H), 1,96 (m, 2H), 2,21 (t, J = 6Hz, IH), 2,16 - 2,40 (m, 2H), 4,45 (dd, J = 2,8 Hz, IH), 6,20 (t, J = 3Hz, IH), 6,65 (d, J= 3Hz, IH), 7,40 (d, J = 3Hz, IH); 13C NMR (CDC13): δ 24,0, 26,4, 27,2, 28,1, 28,6, 35,5, 38,3, 39,8, 51,8, 79,8, 83,6, 83,9, 111,6, 123,2, 124,7, 150,0; CIMS m/z (% rel int) 346 (MH+, 4), 246 (81), 153 (100), 135 (56).Ή NMR (CDCl 3 ) S 0.90 (s, 3H), 1.30 (s, 3H), 1.41 (d, J = 11Hz, 1H), 1.50 (s, 3H), 1.50 (s, 3H), 1.59 (s, 9H), 1.96 (m, 2H), 2.21 (t, J = 6Hz, 1H), 2.16 - 2.40 (m, 2H), 4.45 (dd, J = 2.8 Hz, 1H), 6.20 (t, J = 3Hz, 1H), 6.65 (d, J = 3Hz, 1H), 7.40 (d, J = 3Hz, 1H); 13 C NMR (CDCl 3 ): δ 24.0, 26.4, 27.2, 28.1, 28.6, 35.5, 38.3, 39.8, 51.8, 79.8, 83 , 6, 83.9, 111.6, 123.2, 124.7, 150.0; CIMS m / z (% rel int) 346 (MH +, 4), 246 (81), 153 (100), 135 (56).
Upoštevati moramo, da (lR,2R,3S,5R)-pinandiol-l-(l,l-dimetiletoksikarbonil)-pirol2-boronat lahko proizvedemo na podoben način.It should be appreciated that (1R, 2R, 3S, 5R) -pinanediol-1- (1,1-dimethylethoxycarbonyl) -pyrrol 2-boronate can be produced in a similar manner.
PRIMER 7 l-(l,l-dimetiletoksikarbonil)-pirolidin-2-boronska kislina iz l-(l,l-dimetiletoksikarbonill-pirolidinaEXAMPLE 7 1- (1,1-Dimethylethoxycarbonyl) -pyrrolidine-2-boronic acid from 1- (1,1-dimethylethoxycarbonyl-pyrrolidine)
K raztopini l-(l,l-dimetiletoksikarbonil)-pirolidina (17,1 g, 100 mmol) v dietiletru (200 ml) pri -78 °C ob atmosferi dušika dodamo 1,3M sek.butillitija v cikloheksanu (92,3 ml, 120 mmol) medtem ko vzdržujemo temperaturo pod -60 °C. Po celotnem dodatku reakcijsko zmes mešamo pri -78 °C 4 h. Dodamo trimetilborat (31,1 g, 300 mmol) in zmes pustimo, da se segreje na sobno temperaturo v 3 h. Po dodatnih 12 h, dodamo vodo (150 ml) čemur sledi dodatek 2M NaOH (200 ml). Vodno fazo izoliramo in organsko fazo ponovno ekstrahiramo z 2M NaOH (150 ml). Združene bazične ekstrakte nakisamo na pH 3 z uporabo 2M HC1 in ekstrahiramo z uporabo EtOAc (5 x 200 ml). Združene organske ekstrakte posušimo (Na2SO4) in koncentriramo, da dobimo želen produkt kot belo kristalno trdno snov (15,49 g, 72 %) identično z materialom proizvedenim v primeru 2.To a solution of 1- (1,1-dimethylethoxycarbonyl) -pyrrolidine (17.1 g, 100 mmol) in diethyl ether (200 ml) at -78 ° C under nitrogen atmosphere was added 1.3M sec of butyllithium in cyclohexane (92.3 ml , 120 mmol) while maintaining the temperature below -60 ° C. After complete addition, the reaction mixture was stirred at -78 ° C for 4 h. Trimethylborate (31.1 g, 300 mmol) was added and the mixture was allowed to warm to room temperature for 3 h. After an additional 12 h, water (150 ml) was added followed by the addition of 2M NaOH (200 ml). The aqueous phase was isolated and the organic phase was re-extracted with 2M NaOH (150 ml). The combined basic extracts were acidified to pH 3 using 2M HCl and extracted using EtOAc (5 x 200 ml). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated to give the desired product as a white crystalline solid (15.49 g, 72%) identical to the material produced in Example 2.
PRIMER 8 (lS,2S,3R,5S)-pinandiol-l-(l,l-dimetiletoksikarbonil)-pirolidin-2RS-boronatEXAMPLE 8 (1S, 2S, 3R, 5S) -pinanediol-1- (1,1-dimethylethoxycarbonyl) -pyrrolidine-2RS-boronate
K mešani raztopini materiala dobljenega v primeru 7 (15,49 g, 72,0 mmol) v kloroformu (250 ml) dodamo (lS,2S,3R,5S)-(+)-pinandiol (12,77 g, 75 mmol). Po mešanju pri sobni temperaturi ob atmosferi ddšika 16 h topilo odstranimo in ostanek očistimo s flash kromatografijo preko silikagela (heksan/EtOAc 9:1, 4:1), da dobimo želen produkt kot zmes 1:1 diastereomerov kot olje (23,62 g, 67,7 % temelječ na l-(l,l-dimetiletoksikarbonil)-pirolidinu). Taje identičen z zmesjo izomerov proizvedenih v primeru 3.To a stirred solution of the material obtained in Example 7 (15.49 g, 72.0 mmol) in chloroform (250 ml) was added (lS, 2S, 3R, 5S) - (+) - pinandiol (12.77 g, 75 mmol) . After stirring at ambient temperature at ambient atmosphere for 16 h, the solvent was removed and the residue purified by flash chromatography over silica gel (hexane / EtOAc 9: 1, 4: 1) to give the desired product as a mixture of 1: 1 diastereomers as an oil (23.62 g , 67.7% based on 1- (1,1-dimethylethoxycarbonyl) -pyrrolidine). It is identical to the mixture of isomers produced in Example 3.
±H NMR (CDC13): δ 0,85 (s, 3H), 1,12-1,21 (m, IH), 1,29 (s, 3H), 1,41 (s, 3H), 1,45 (s, 9H), 1,81-2,20 (m, 8H), 2,28-2,39 (m, IH), 3,04-3,18 (m, IH), 3,34-3,45 (m, 2H), 4,28-4,38 (m, IH); 13C NMR (CDC13): δ 23,7, 26,2, 27,1, 28,5, 35,5, 38,2, 39,6, 46,1, 78,0, 78,8, 85,7, 85,8, 154,7; CIMS m/z (% rel int) 350 (MH+, 100), 294 (72), 250 (30)·± H NMR (CDC1 3): δ 0.85 (s, 3H), 1.12-1.21 (m, IH), 1.29 (s, 3H), 1.41 (s, 3H), 1 , 45 (s, 9H), 1.81-2.20 (m, 8H), 2.28-2.39 (m, 1H), 3.04-3.18 (m, 1H), 3.34 -3.45 (m, 2H), 4.28-4.38 (m, 1H); 13 C NMR (CDCl 3 ): δ 23.7, 26.2, 27.1, 28.5, 35.5, 38.2, 39.6, 46.1, 78.0, 78.8, 85 , 7, 85.8, 154.7; CIMS m / z (% rel int) 350 (MH +, 100), 294 (72), 250 (30) ·
PRIMER 9EXAMPLE 9
Analitični postopek za diastereoizomere hidroklorida (lS,2S,3R,5S)-pinandiolpirolidin-2-boronataAnalytical procedure for diastereoisomers of hydrochloride (1S, 2S, 3R, 5S) -pinanediolpyrrolidine-2-boronate
Pripravimo raztopino reagenta 0,2M fenilizotiocianata v diklorometanu :trietilaminu (9:1). Vzorec, ki ga analiziramo (1-5 mg) obdelamo z 10 μΐ raztopine reagenta na μιηοΐ analita in čisto raztopino pustimo, da stoji pri sobni temperaturi 15 min. 1 μΐ vzorec raztopine nato razredčimo v 1,00 ml acetonitrila stopnje HPLC in 10 μΐ te raztopine analiziramo s HPLC (kolona: YMC AQ-303 S-5 120A, 4,6 x 250 mm; mobilna faza: 65 % MeCN - 35 % mM amonijev fosfat, pH 7,5; pretočna hitrost 1 ml/min; detekcija z UV pri 254 nm). Feniltiosečninski derivat R izomera prolin boronske kisline eluiramo pri približno 6,4 min, njen epimer eluiramo pri približno 7,8 min in nezreagiran fenilizotiocianat, ki služi kot interni standard eluiramo pri 12,2 min.A solution of 0.2M phenylisothiocyanate reagent in dichloromethane: triethylamine (9: 1) is prepared. The sample to be analyzed (1-5 mg) was treated with 10 μΐ of reagent solution per μιηοΐ analyte and allowed to stand at room temperature for 15 min. The 1 μΐ sample of the solution is then diluted into 1.00 ml acetonitrile of HPLC grade and 10 μΐ of this solution is analyzed by HPLC (column: YMC AQ-303 S-5 120A, 4.6 x 250 mm; mobile phase: 65% MeCN - 35% mM ammonium phosphate, pH 7.5; flow rate 1 ml / min; detection with UV at 254 nm). The phenylthiourea derivative of the R isomer of proline boronic acid is eluted at about 6.4 min, its epimer is eluted at about 7.8 min, and unreacted phenylisothiocyanate, which serves as the internal standard, is eluted at 12.2 min.
PRIMER 10EXAMPLE 10
Hidroklorid (lS,2S,3R,5S)-pinandiol-pirolidin-2RS-boronataHydrochloride (1S, 2S, 3R, 5S) -pinanediol-pyrrolidine-2RS-boronate
Mešano raztopino (lS,2S,3R,5S)-pinandiol-l-(l,l-dimetiletoksikarbonil)-pirolidin2RS-boronata (224 g, 0,64 mol) v dietiletru (900 ml) ohladimo na ledu in suhi HCl plin spuščamo v raztopino 35 min pri 10-18 °C. Raztopino mešamo pri sobni temperaturi preko noči, ponovno ohladimo v ledu in odfiltriramo oborino. Trdno snov izperemo s hladnim etrom (400 ml) čemur sledi izpiranje s petroletrom/dietiletromA stirred solution of (1S, 2S, 3R, 5S) -pinanediol-1- (1,1-dimethylethoxycarbonyl) -pyrrolidine2RS-boronate (224 g, 0.64 mol) in diethyl ether (900 ml) was cooled on ice and the HCl gas was lowered into the solution for 35 min at 10-18 ° C. The solution was stirred at room temperature overnight, cooled again in ice and the precipitate filtered off. The solid was washed with cold ether (400 ml) followed by washing with petroleum ether / diethyl ether
9:1 (200 ml) in posušimo v vakuumu, da dobimo želen hidroklorid kot belo trdno snov (113 g, 62 %) (tal. 228-234 °C). Analize tčga materiala s HPLC kot je opisano v primeru 9, prikazuje, daje zmes R:S izomerov boronske kisline v razmerju 60:40.9: 1 (200 ml) and dried in vacuo to give the desired hydrochloride as a white solid (113 g, 62%) (mp 228-234 ° C). HPLC analysis of the material as described in Example 9 shows that the R: S mixture of boronic acid isomers is 60:40.
XH NMR (CDC13): δ 0,83 (s, 3H), 1,14 (d, J = 11Hz, IH), 1,29 (s, 3H), 1,45 (s, 3H), X H NMR (CDCl 3 ): δ 0.83 (s, 3H), 1.14 (d, J = 11Hz, 1H), 1.29 (s, 3H), 1.45 (s, 3H).
1,85 - 2,15 (m, 6H), 2,17 - 2,50 (m, 3H), 3,18 - 3,25 (m, IH), 3,45 (bs, 2H), 4,42 (dd, J = 1,8, 8,6 Hz, IH), 8,80 (bs, IH), 10,56 (bs, IH); 13C NMR (CDC13): δ 23,9, 24,5, 26,5, 27,0, 27,2, 28,4, 34,9, 38,2, 39,4, 45,8, 51,2, 79,0, 87,6; CIMS m/z (% rel int) 250 (MH+, 100); Anal. izrač za C14H24BNO2 . HC1: C 58,87, H 8,82, N 4,90, CI 12,41. Ugot. C 58,40, H 8,86, N 4,81, CI 12,39.1.85 - 2.15 (m, 6H), 2.17 - 2.50 (m, 3H), 3.18 - 3.25 (m, 1H), 3.45 (bs, 2H), 4. 42 (dd, J = 1.8, 8.6 Hz, 1H), 8.80 (bs, 1H), 10.56 (bs, 1H); 13 C NMR (CDCl 3 ): δ 23.9, 24.5, 26.5, 27.0, 27.2, 28.4, 34.9, 38.2, 39.4, 45.8, 51 , 2, 79.0, 87.6; CIMS m / z (% rel int) 250 (MH +, 100); Anal. calcd for C 14 H 24 BNO 2 . HCl: C 58.87, H 8.82, N 4.90, CI 12.41. Found. C 58.40, H 8.86, N 4.81, CI 12.39.
Podobne reakcije v količini 29 g, 101 mmol, pri čemer uporabimo etrni HC1 (pribl. 4,5M, 200 ml) in EtOAc (150 ml) kot topilo, da hidroklorid (11,1 g, 47 %) kot zmes R:S izomerov 81:19.Similar reactions in an amount of 29 g, 101 mmol, using ether HCl (ca. 4.5M, 200 ml) and EtOAc (150 ml) as solvent to give the hydrochloride (11.1 g, 47%) as a mixture of R: S isomers 81:19.
PRIMER 11EXAMPLE 11
Frakcionirna kristalizacija hidroklorida (lS,2S,3R,5S)-pinandiol-pirolidin-2RboronataFractional crystallization of hydrochloride (1S, 2S, 3R, 5S) -pinanediol-pyrrolidine-2Rboronate
Postopek A:Procedure A:
Izomerno zmes 60:40 dobljeno v primeru 10 (1,18 g, 4,13 mmol) raztopimo v CH2C12 (65 ml) z rahlim segrevanjem in raztopino filtriramo. Filtrat razredčimo z EtOAc (65 ml) in kristalizacija prične v teku minute. Suspenzijo mešamo 1-2 h pri sobni temperaturi in prvi dobitek trdne snovi zberemo in določimo diastereomerno razmerje kot je opisano v primeru 9 (540 mg, 46 %, R:S razmerje 97,1:2,9). Topilo destiliramo od filtrata dokler ne odstranimo večino CH2C12 nato preostalo raztopino EtOAc mešamo pri sobni temperaturi preko noči, da dobimo drugi dobitek sivo bele trdne snovi (346 mg, 29 %, R:S razmerje 39,2:60,8). Prvi dobitek prekristaliziramo iz izopropilalkohola (10 ml), da dobimo 430 mg (80 %) ponovni dobitek materiala >99 % 2-R izomer (tal. 269-272 °C (razp.) [a]°25 + 0,70° (c=l,15 MeOH).The isomeric mixture 60:40 obtained in Example 10 (1.18 g, 4.13 mmol) was dissolved in CH 2 Cl 2 (65 ml) by gentle heating and the solution filtered. The filtrate was diluted with EtOAc (65 ml) and crystallization commenced within a minute. The suspension was stirred for 1-2 h at room temperature and the first solid was collected and the diastereomeric ratio was determined as described in Example 9 (540 mg, 46%, R: S ratio 97.1: 2.9). The solvent was distilled off from the filtrate until most of the CH 2 C1 2 was removed and the remaining EtOAc solution was stirred at room temperature overnight to give a second yield of a gray-white solid (346 mg, 29%, R: S ratio 39.2: 60.8) . The first yield was recrystallized from isopropyl alcohol (10 ml) to give 430 mg (80%) of a material recovery of > 99% 2-R isomer (m.p. 269-272 ° C (dec.) [A] ° 25 + 0.70 ° (c = 1.15 MeOH).
Ή NMR (CDClj): δ 0,83 (s, 3H), 1,14 (d, J = 11Hz, IH), 1,29 (s, 3H), 1,45 (s, 3H), 1,85-2,15 (m, 6H), 2,17-2,50 (m, 3H), 3,18-3,25 (m, IH), 3,45 (bs, 2H), 4,42 (dd, J = 1,8, 8,6 Hz, IH), 8,80 (bs, IH), 10,56 (bs, IH); 13C NMR (CDC13) δ 23,9, 24,5, 26,5, 27,0, 27,2, 28,5, 34,9, 38,1, 39,4, 45,8, 51,2, 79,0, 87,8; CIMS m/z (% rel int) 250 (ΜΗ+, 100); Anal. izrač. za C^BNC^ . HC1: C 58,87, H 8,82, N 4,90, CI 12,41. Ugot.: C 58,64, H 8,79, N 4,90, CI 12,66.Ή NMR (CDCl3): δ 0.83 (s, 3H), 1.14 (d, J = 11Hz, 1H), 1.29 (s, 3H), 1.45 (s, 3H), 1.85 -2.15 (m, 6H), 2.17-2.50 (m, 3H), 3.18-3.25 (m, 1H), 3.45 (bs, 2H), 4.42 (dd , J = 1.8, 8.6 Hz, 1H), 8.80 (bs, 1H), 10.56 (bs, 1H); 13 C NMR (CDCl 3 ) δ 23.9, 24.5, 26.5, 27.0, 27.2, 28.5, 34.9, 38.1, 39.4, 45.8, 51, 2, 79.0, 87.8; CIMS m / z (% rel int) 250 (ΜΗ +, 100); Anal. calcd. for C ^ BNC ^. HCl: C 58.87, H 8.82, N 4.90, CI 12.41. Found: C 58.64, H 8.79, N 4.90, CI 12.66.
POSTOPEK B:PROCEDURE B:
Suspenzijo hidroklorida (lS,2S,3R,5S)-pinandiol-pirolidin-2RS-boronata kot zmes izomera 1:1 (850 mg, 2,98 mmol) v EtOAc (60 ml) segrevamo ob refluksu z mešanjem 4 h. Zmes vročo filtriramo in zbrano trdno snov posušimo, da dobimo material obogaten z R-izomerom (541 mg, 64 %), R:S 2:1. Uparjenje filtrata da material obogaten z S-izomerom (217 mg), R:S razmerje je 1:4. Filtrirano trdno snov (500 mg) obdelamo na enak način z EtOAc (45 ml) v 1,5 h in ponovno vročo filtriramo, da dobimo trdno snov (366 mg, 73 %), R:S = 7:1. Ta material ponovno obdelujemo z EtOAc (38 ml, 1,5 h). Izolirana trdna snov (287 mg, 78 %) ima sedaj R:S razmerje 97:3. Spektralne lastnosti so enake kot tiste od materiala dobljenega s postopkom A.A suspension of hydrochloride (1S, 2S, 3R, 5S) -pinanediol-pyrrolidine-2RS-boronate as a mixture of isomer 1: 1 (850 mg, 2.98 mmol) in EtOAc (60 ml) was heated at reflux with stirring for 4 h. The mixture was filtered hot and the collected solid was dried to give an R-isomer-enriched material (541 mg, 64%), R: S 2: 1. Evaporation of the filtrate gave the material enriched with the S-isomer (217 mg), R: S ratio being 1: 4. The filtered solid (500 mg) was treated in the same way with EtOAc (45 ml) in 1.5 h and filtered again hot to give a solid (366 mg, 73%), R: S = 7: 1. This material was re-treated with EtOAc (38 ml, 1.5 h). The isolated solid (287 mg, 78%) now has an R: S ratio of 97: 3. The spectral properties are the same as those of the process A material.
PRIMER 12 l-(l,l-dimetiletoksikarbonil)-pirolidin-2-boronska kislina iz (lS,2S,3R,5S)-pinandioll-(l,l-dimetiletoksikarbonil)-pirolidin-2-boronataEXAMPLE 12 1- (1,1-Dimethylethoxycarbonyl) -pyrrolidine-2-boronic acid from (1S, 2S, 3R, 5S) -pinanediol- (1,1-dimethylethoxycarbonyl) -pyrrolidine-2-boronate
K raztopini (lS,2S,3R,5S)-pinandiol-l-(l,l-dimetiletoksikarbonil)-pirolidin-2RSboronata iz primera 8 (1,9 g, 5,44 mmol) v acetonu (80 ml) dodamo 0,lM raztopine amonijevega acetata (80 ml) in natrijevega metaperjodata (3,49 g, 16,33 mmol). Reakcijsko zmes mešamo pri sobni temperaturi 40 h, nato aceton uparimo in preostanek obdelamo z 2M raztopino NaOH. Vodno fazo izperemo s CH2C12 (2 x 80 ml), nakisamo z 2M HC1 na pH 3 in ekstrahiramo s CH2C12 (4 x 80 ml). Združene organske ekstrakte posušimo (Na2SO4) in koncentriramo, da dobimo želen produkt kot belo penasto trdno snov (890 mg, 76 %), ki ima identičen NMR kot material pripravljen v primeru 2. Boronsko kislino derivatiziramo s pinakolom za namene analize.To a solution of (1S, 2S, 3R, 5S) -pinanediol-1- (1,1-dimethylethoxycarbonyl) -pyrrolidine-2RSboronate of Example 8 (1.9 g, 5.44 mmol) in acetone (80 ml) was added 0. 1M solution of ammonium acetate (80 ml) and sodium metaperiodate (3.49 g, 16.33 mmol). The reaction mixture was stirred at room temperature for 40 h, then the acetone was evaporated and the residue was treated with a 2M NaOH solution. The aqueous phase was washed with CH 2 Cl 2 (2 x 80 ml), acidified with 2M HCl to pH 3 and extracted with CH 2 Cl 2 (4 x 80 ml). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated to give the desired product as a white foamy solid (890 mg, 76%) having the same NMR as the material prepared in Example 2. The boronic acid was derivatized with pinacol for analysis purposes.
PRIMER 13EXAMPLE 13
LL
Pinakol l-( 1, l-dimetiletoksikarbonil)-pirolidin-2RS-boronatPinacol 1- (1,1-dimethylethoxycarbonyl) -pyrrolidine-2RS-boronate
K mešani raztopini boronske kisline iz primera 12 (890 mg, 4,14 mmol) v kloroformu dodamo pinakol (489 mg, 4,14 mmol). Po mešanju 16 h pri sobni temperaturi topilo odstranimo in preostanek očistimo s kromatografijo preko silikagela (heksan/EtOAc, 4:1), da dobimo želen produkt kot belo trdno snov (1,04 g, 85 %) (tal. 73-75 °C).To the mixed boronic acid solution of Example 12 (890 mg, 4.14 mmol) in chloroform was added pinacol (489 mg, 4.14 mmol). After stirring for 16 h at room temperature, the solvent was removed and the residue was purified by silica gel chromatography (hexane / EtOAc, 4: 1) to give the desired product as a white solid (1.04 g, 85%) (mp 73-75 ° C).
Ή NMR (CDC13): S 1,18 (s, 6H), 1,21 (s, 6H), 1,38 (s, 9H), 1,57-2,00 (m, 4H), 2,98 (br s, IH), 3,27 (m, 2H); 13C NMR (CDC13): δ 24,3, 24,5, 24,7, 24,9, 25,3, 27,0, 27,6, 28,4, 28,6, 43,6, 45,8, 46,3, 78,8, 83,2,154,4,154,8; CIMS m/z (% rel int) 298 (18), 242 (100 MH+ - tBu), 198 (30, MH+ - Boc); Anal. izrač. za C15H2gBNO4: C 60,62, H 9,50, N 4,71. Ugot.: C 60,94, H 9,65, N 4,88.Ή NMR (CDCl 3 ): S 1.18 (s, 6H), 1.21 (s, 6H), 1.38 (s, 9H), 1.57-2.00 (m, 4H), 2. 98 (br s, 1H), 3.27 (m, 2H); 13 C NMR (CDCl 3 ): δ 24.3, 24.5, 24.7, 24.9, 25.3, 27.0, 27.6, 28.4, 28.6, 43.6, 45 , 8, 46,3, 78,8, 83,2,154,4,154,8; CIMS m / z (% rel int) 298 (18), 242 (100 MH + - tBu), 198 (30, MH + - Boc); Anal. calcd. for C 15 H 2g BNO 4 : C 60.62, H 9.50, N 4.71. Found: C 60.94, H 9.65, N 4.88.
PRIMER 14 (lS,2S,3R,5S)-pinandiol ester N-(l,l-dimetiletoksikarbonil)-L-valilpirolidin2R-boronataEXAMPLE 14 (1S, 2S, 3R, 5S) -N- (1,1-Dimethylethoxycarbonyl) -L-valylpyrrolidine2R-boronate ester
Raztopino t-BOC-L-valina (351,7 g, 1,62 mol) v CH2C12 (1,6 1) ohladimo v ledeni kopeli in dodamo raztopino dicikloheksilkarbodiimida (161,8 g, 0,784 mol) v CH2C12 (0,75 1) v teku 40 min pri 0-2 °C. Po dodatku raztopino mešamo 3,5 h pri 0-5 °C. Beli precipitat odfiltriramo in izperemo s CH2C12 (0,21). Nastalo čisto raztopino dodamo pri 18-20 °C (hlajenje z vodno kopeljo) k raztopini hidroklorida (1S,2S,3R,5S)pinandiol pirolidin-2RS-boronata (210 g, 0,735 mol), ki je pripravljena kot v primeru 10 v CH2C12 (2,0 1), ki vsebuje N-metilmorfolin (164 g, 1,62 mol). Zmes pustimo mešati pri sobni temperaturi preko noči. Motno raztopino filtriramo skozi blazino silikagela premera 16 cm višine 2 cm (200-425 mesh) in izperemo s CH2C12 (1,5 1). Topilo uparimo, da dobimo visoko viskozno olje (542 g). To olje raztopimo v etilacetatu (0,7 1) in zmes ohladimo v ledeni kopeli. Tvorijo se kristali, ki jih odfiltriramo pri nizki temperaturi in izperemo s hladnim etilacetatom (0,1 1). Moker filtrni kolač prenesemo v petroleter (0,65 1) in mešamo pri sobni temperaturi 1 h. Belo trdno snov filtriramo, izperemo s hladnim petroletrom (0,1 1) in posušimo do konstantne mase, da dobimo naslovno spojino kot belo trdno snov (113,4 g) (tal. 128-130 °C). Vse matične lužnice združimo in koncentriramo do volumna približno 0,8 1. Po shranjevanju dva dni v zmrzovalniku se tvori trdna snov, ki jo odfiltriramo in obdelamo s petroletrom kot zgoraj, da dobimo trdno bež snov (50,4 g). To je zmes nečistot in neželenega diastereoizomera. Matično lužnico od zgoraj koncentriramo in ostanek očistimo v koloni s silikagelom (premer 14 cm x 60 cm) z uporabo heksana/etilacetata (85:15) (14 1). Ustrezne frakcije zberemo, obdelamo s petroletrom, trdno snov zberemo s filtracijo in posušimo, da dobimo več želenega produkta (18,5 g). Dobimo tudi drugi diastereoizomer (7,5 g) (tal. 82-83 °C). V drugi koloni izvedemo čiščenje združenih mešanih frakcij in matičnih lužnic, da dobimo dodatno čisto spojino (13,5 g), celoten združen dobitek želenega diastereomera je 145,4 g (44,3 %) (tal. 128-130 °C).A solution of t-BOC-L-valine (351.7 g, 1.62 mol) in CH 2 C1 2 (1.6 1) was cooled in an ice bath and a solution of dicyclohexylcarbodiimide (161.8 g, 0.784 mol) in CH 2 was added. C1 2 (0.75 1) for 40 min at 0-2 ° C. After the addition, the solution was stirred for 3.5 h at 0-5 ° C. The white precipitate was filtered off and washed with CH 2 Cl 2 (0.21). The resulting pure solution was added at 18-20 ° C (water bath cooling) to a solution of the hydrochloride (1S, 2S, 3R, 5S) pinandiol pyrrolidine-2RS-boronate (210 g, 0.735 mol) prepared as in Example 10 in CH 2 C1 2 (2.0 L) containing N-methylmorpholine (164 g, 1.62 mol). The mixture was allowed to stir at room temperature overnight. The cloudy solution was filtered through a 2 cm diameter 2 cm (200-425 mesh) silica gel pad and washed with CH 2 Cl 2 (1.5 L). The solvent was evaporated to give a high viscous oil (542 g). Dissolve this oil in ethyl acetate (0.7 L) and cool the mixture in an ice bath. Crystals are formed, which are filtered off at low temperature and washed with cold ethyl acetate (0.1 L). Transfer the wet filter cake to petroleum ether (0.65 l) and stir at room temperature for 1 h. The white solid was filtered, washed with cold petroleum ether (0.1 L) and dried to constant weight to give the title compound as a white solid (113.4 g) (mp 128-130 ° C). All mother liquors were combined and concentrated to a volume of about 0.8 1. After storage for two days in a freezer, a solid was formed, which was filtered off and treated with petroleum ether as above to give a solid beige solid (50.4 g). It is a mixture of impurities and unwanted diastereoisomer. The mother liquor from above was concentrated and the residue was purified in a silica gel column (14 cm x 60 cm diameter) using hexane / ethyl acetate (85:15) (14 L). The appropriate fractions were collected, treated with light petroleum, the solid collected by filtration and dried to give the desired product (18.5 g). A second diastereoisomer (7.5 g) (mp 82-83 ° C) was also obtained. In the second column, the combined mixed fractions and mother liquors were purified to give an additional pure compound (13.5 g), the total combined yield of the desired diastereomer being 145.4 g (44.3%) (mp 128-130 ° C).
Ή NMR (CDC13): δ 0,83 (s, 3H), 0,91 d, J = 6,7 Hz, 3H), 0,97 (d, J = 6,7 Hz, 3H),Ή NMR (CDCl 3 ): δ 0.83 (s, 3H), 0.91 d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H).
1.27 (s, 3H), 1,35-1,45 (m, IH), 1,39 (s, 3H), 1,41 (s, 9H), 1,72-2,14 (m, 9H), 2,26-2,36 (m, IH), 3,15 (dd, J = 6,7, 10,1Hz, IH), 3,43-3,51 (m, IH), 3,70-3,81 (m, IH), 4,194.28 (m, 2H), 5,29 (d, J = 9,2 Hz, IH); 13C NMR (CDC13): δ 17,3, 19,2, 24,0, 26,3,1.27 (s, 3H), 1.35-1.45 (m, 1H), 1.39 (s, 3H), 1.41 (s, 9H), 1.72-2.14 (m, 9H) , 2.26-2.36 (m, 1H), 3.15 (dd, J = 6.7, 10.1Hz, 1H), 3.43-3.51 (m, 1H), 3.70- 3.81 (m, 1H), 4,194.28 (m, 2H), 5.29 (d, J = 9.2 Hz, 1H); 13 C NMR (CDCl 3 ): δ 17.3, 19.2, 24.0, 26.3,
27,1, 27,2, 27,4, 28,4, 28,6, 31,4, 33,9, 35,5, 38,2, 39,6, 46,7, 51,2, 56,6, 77,8, 79,2, 85,8,27.1, 27.2, 27.4, 28.4, 28.6, 31.4, 33.9, 35.5, 38.2, 39.6, 46.7, 51.2, 56, 6, 77.8, 79.2, 85.8,
155,9, 170,2; CIMS m/z (% rel int) 449 (MH+, 100), 393 (50); Anal. izrač. za C^BN^: C 64,28, H 9,22, N 6,25. Ugot.: C 64,58, H 9,33, N 6,52.155.9, 170.2; CIMS m / z (% rel int) 449 (MH +, 100), 393 (50); Anal. calcd. for C22BN4: C, 64.28; H, 9.22; N, 6.25. Found: C 64.58, H 9.33, N 6.52.
PRIMER 15EXAMPLE 15
Hidrogen maleat (lS,2S,3R,5S)-pinandiol estra L-valilpirolidin-2R-boronata (lS,2S,3R,5S)-pinandiol ester N-(l,l-dimetiletoksikarbonil)-L-valilpirolidin-2Rboronata (248 mg, 0,553 mmol) dodamo k mešani raztopini suhega vodikovega klorida v etilacetatu. Po 1,5 h topilo uparimo, da ostane nezaščiten hidroklorid. Ostanek razdelimo med CH2C12 in raztopino natrijevega karbonata in organsko plast posušimo preko magnezijevega sulfata. Organska plast vsebuje prosto bazo naslovne spojine, ki obstaja kot ciklična oblika, ki vsebuje vez dušik-bor vendar jo vrnemo v odprto obliko z dodajanjem kisline. Organsko raztopino filtriramo v raztopino maleinske kisline (64 mg, 0,553 mmol) v metanolu (5 ml) in topilo uparimo, da ostane kristalni preostanek (258 mg), ki ga prekristaliziramo iz etilacetata, da dobimo naslovno spojino (193 mg, 75 %), (tal. 145-146 °C).Hydrogen Maleate (1S, 2S, 3R, 5S) -N-(1,1-Dimethylethoxycarbonyl) -L-valylpyrrolidine-2R-boronate (1S, 2S, 3R, 5S) -pinanediol ester (248 mg, 0.553 mmol) was added to a mixed solution of dry hydrogen chloride in ethyl acetate. After 1.5 h, the solvent was evaporated to leave unprotected hydrochloride. The residue was partitioned between CH 2 Cl 2 and sodium carbonate solution and the organic layer was 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 returned to the open form by the addition of acid. The organic solution was filtered into a solution of maleic acid (64 mg, 0.553 mmol) in methanol (5 ml) and the solvent was evaporated to leave a crystalline residue (258 mg) recrystallized from ethyl acetate to give the title compound (193 mg, 75%) , (mp 145-146 ° C).
Ή NMR (CDC13); δ 0,84 (s, 3H), 1,08 (d, J = 6,9Hz, 3H), 1,13 (d, J = 6,9Hz, 3H), 1,26-1,31 (m, 2h), 1,29 (s, 3H), 1,38 (s, 3H), 1,72-2,15 (m, 7H), 2,24-2,38 (m, 2H), 3,28 (dd, J = 6,9, 9,4 Hz, IH), 3,38-3,47 (m, IH), 3,73-3,78 (m, IH), 4,14 (d, J = 5,1Hz, IH), 4,26 (d, J = 7,1Hz, IH), 6,25 (s, 2H), 7,5-9,0 (v. br, 4H); 13C NMR (CDC13): δΉ NMR (CDC1 3); δ 0.84 (s, 3H), 1.08 (d, J = 6.9Hz, 3H), 1.13 (d, J = 6.9Hz, 3H), 1.26-1.31 (m, 2h), 1.29 (s, 3H), 1.38 (s, 3H), 1.72-2.15 (m, 7H), 2.24-2.38 (m, 2H), 3.28 (dd, J = 6.9, 9.4 Hz, 1H), 3.38-3.47 (m, 1H), 3.73-3.78 (m, 1H), 4.14 (d, J = 5.1Hz, 1H), 4.26 (d, J = 7.1Hz, 1H), 6.25 (s, 2H), 7.5-9.0 (v br, 4H); 13 C NMR (CDCl 3 ): δ
17,0,18,4, 24,0, 26,3, 27,0, 27,1, 28,7, 30,0, 35,4, 38,2, 39,5, 47,3, 51,2, 56,6, 78,1, 86,2,17,0,18,4, 24,0, 26,3, 27,0, 27,1, 28,7, 30,0, 35,4, 38,2, 39,5, 47,3, 51, 2, 56.6, 78.1, 86.2,
135,6, 166,3, 169,5; CIMS m/z (% rel int) 349 (MH+, 100), 197 (18); Anal. izrač. za C^H^N^: C 59,49, H 8,03, N 6,03. Ugot.: C 59,50, H 8,13, N 6,03.135.6, 166.3, 169.5; CIMS m / z (% rel int) 349 (MH +, 100), 197 (18); Anal. calcd. Calcd for C25H25N3O: C 59.49, H 8.03, N 6.03. Found: C 59.50, H 8.13, N 6.03.
PRIMER 16EXAMPLE 16
Metansulfonat L-valilpirolidin-2R-boronske kislineL-valylpyrrolidine-2R-boronic acid methanesulfonate
a) ciklo-L-valilpirolidin-2R-boronska kislinaa) Cyclo-L-valylpyrrolidine-2R-boronic acid
Raztopino maleatne soli, ki jo dobimo v primeru 15 (5,0 g, 10,8 mmol) v razredčeni ocetni kislini (1,0 %, 60 ml) damo v kolono (višina 3,5 cm, premer 4 cm) z ionsko izmenjalno smolo v H+ obliki Dowex 50X2-200. Kolono nato eluiramo z ocetno kislino (1,0 %, 141), vodo (421) in raztopino amonijevega hidroksida (razredčenje 1:100 tržne 0,880 raztopine). Pinandiol lahko ponovno dobimo iz nevtralnih in kislih frakcij. Produkt ugotovimo v prvih bazičnih frakcijah, ki jih zberemo in izperemo s CH2C12 (2 x 100 ml). Organske ekstrakte posušimo in koncentriramo, da ponovno dobimo prosto bazo izhodnega materiala (741 mg, 20 %) skupaj z nekaj pinandiola. Vodno fazo liofiliziramo, da dobimo naslovno spojino, ki obstaja v ciklični obliki z vezjo dušik-bor kot belo trdno snov (1,52 g, 66 %) (tal. 120-130 °C).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 added to a column (height 3.5 cm, diameter 4 cm) with ionic H + exchange resin Dowex 50X2-200. The column was then eluted with acetic acid (1.0%, 141), water (421) and ammonium hydroxide solution (1: 100 dilution of a marketable 0,880 solution). Pinandiol can be recovered from neutral and acidic fractions. The product was found in the first basic fractions, which were collected and washed with CH 2 Cl 2 (2 x 100 ml). The organic extracts were dried and concentrated to give a free base of starting material (741 mg, 20%) together with some pinandiol. The aqueous phase was lyophilized to give the title compound which existed in a cyclic form with a nitrogen-boron bond as a white solid (1.52 g, 66%) (mp 120-130 ° C).
Ή NMR (D2O). δ 0,97 (d, J = 7,0 Hz, 3H), 1,06 (d, J = 7,0Hz, 3H), 1,59-1,80 (m, 2H), 1,95-2,03 (m, 2H), 2,41-2,51 (m, IH), 2,62-2,69 (m, IH), 3,23-3,32 (m, IH), 3,51-3,58 (m s prekrivajočim dubletom, J = 4,2 Hz, 2H); 13C NMR (D2O): δ 19,0, 21,7, 27,3, 30,7, 29,9, 49,6, 61,0, 170,3; IR (cm1) 3400-3314, 3221-3108, 2961-2872, 1637, 1452-1369; CIMS m/z (% rel int) 375 (90, M2H+-3H2O), 197 (100, MH+H2O); Anal. izrač. za C9H19BN2O3: C 50,50, H 8,95, N 13,09. Ugot.: C 50,43, H 8,76, N 12,93.Ή NMR (D 2 O). δ 0.97 (d, J = 7.0 Hz, 3H), 1.06 (d, J = 7.0Hz, 3H), 1.59-1.80 (m, 2H), 1.95-2 , 03 (m, 2H), 2.41-2.51 (m, 1H), 2.62-2.69 (m, 1H), 3.23-3.32 (m, 1H), 3.51 -3.58 (ms overlapping doublet, J = 4.2 Hz, 2H); 13 C NMR (D 2 O): δ 19.0, 21.7, 27.3, 30.7, 29.9, 49.6, 61.0, 170.3; IR (cm 1 ) 3400-3314, 3221-3108, 2961-2872, 1637, 1452-1369; CIMS m / z (% rel int) 375 (90, M2H + -3H 2 O), 197 (100, MH + H 2 O); Anal. calcd. for C 9 H 19 BN 2 O 3 : C 50.50, H 8.95, N 13.09. Found: C 50.43, H 8.76, N 12.93.
b) Metansulfonat L-valilpirolidin-2R-boronske kislineb) L-valylpyrrolidine-2R-boronic acid methanesulfonate
K mešani suspenziji ciklizirane boronske kisline, ki jo dobimo zgoraj (5,17 g, 24,16 mmol) v acetonitrilu (190 ml) ob dušiku dodamo raztopino metansulfonske kisline (2,32 g, 24,16 mmol) v acetonitrilu (10 ml) po kapljicah v teku 5 minut in zmes mešamo pri sobni temperaturi 2 h. Trdno snov zberemo s filtracijo, izperemo dobro z acetonitrilom in diietiletrom in posušimo, da dobimo naslovno spojino kot belo trdno snov (6,14 g, 82 %), (tal. 179-180 °C). Kristalizacija tega materiala iz dimetilformamida/acetonitrila da 70 %-ni portovni dobitek materiala v posemeznem dobitku (tal. 181-182 °C).To a stirred suspension of cyclized boronic acid, obtained above (5.17 g, 24.16 mmol) in acetonitrile (190 ml), nitrogen was added with a solution of methanesulfonic acid (2.32 g, 24.16 mmol) in acetonitrile (10 ml ) dropwise over 5 minutes and the mixture was stirred at room temperature for 2 h. The solid was collected by filtration, washed well with acetonitrile and diethyl ether and dried to give the title compound as a white solid (6.14 g, 82%), (mp 179-180 ° C). Crystallization of this material from dimethylformamide / acetonitrile yields a 70% port yield of the material in a single yield (mp 181-182 ° C).
XH NMR (D2O, fosfat, pH 2): 5 0,99 (d, J = 6,8 Hz, 3H), 1,09 (d, J = 6,9Hz, 3H), 1,69-1,75 (m, IH), 1,90-1,99 (m, IH), 2,10-2,14 (m, 2H), 2,28-2,35 (m, IH), 2,80 (s, 3H), 3,07 (dd, J = 7,0 in 11,2 Hz, IH), 3,46-3,51 (m, IH), 3,75 (t, J = 9,0 Hz, IH), 4,14 (d, J = 5,1 Hz, IH); cis amidni rotamer (pribl. 3 %) tudi opazimo pri 3,53-3,55 (m) in 3,83 (d, J = 6,2 Hz); 13C NMR: δ 16,2, 18,4, 26,9, 27,1, 29,0, 38,8, 47,9, 49,0, 57,2, 167,2; pike zaradi cis amidnega rotamera opazimo pri 16,8, 24,3, 29,9, 57,8, 167,5; IR (cm4) 3387, 3000 (br), 2972, 2655, 1646, 1370, 1197; CIMS m/z (% rel int, etilen glikolni adukt) 241 (MH+ 100); Anal. izrač. za C1QH23BN2O6S: C 38,72, H 7,47, N 9,03. Ugot.: C 38,65, H 7,45, N 8,44. X H NMR (D 2 O, phosphate, pH 2): δ 0.99 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.9Hz, 3H), 1.69-1. 75 (m, 1H), 1.90-1.99 (m, 1H), 2.10-2.14 (m, 2H), 2.28-2.35 (m, 1H), 2.80 ( s, 3H), 3.07 (dd, J = 7.0 and 11.2 Hz, 1H), 3.46-3.51 (m, 1H), 3.75 (t, J = 9.0 Hz) , 1H), 4.14 (d, J = 5.1 Hz, 1H); The cis amide rotamer (approx. 3%) was also observed at 3.53-3.55 (m) and 3.83 (d, J = 6.2 Hz); 13 C NMR: δ 16.2, 18.4, 26.9, 27.1, 29.0, 38.8, 47.9, 49.0, 57.2, 167.2; spots due to the cis amide rotamer are observed at 16.8, 24.3, 29.9, 57.8, 167.5; IR (cm 4 ) 3387, 3000 (br), 2972, 2655, 1646, 1370, 1197; CIMS m / z (% rel int, ethylene glycol adduct) 241 (MH + 100); Anal. calcd. for C1QH 23 BN 2 O 6 S: C 38.72, H 7.47, N 9.03. Found: C 38.65, H 7.45, N 8.44.
PRIMER 17EXAMPLE 17
N-(l,l-dimetiletoksikarbonil)-L-valilpirolidin-2R-boronska kislinaN- (1,1-dimethylethoxycarbonyl) -L-valylpyrrolidine-2R-boronic acid
K mešani raztopini (lS,2S,3R,5S)-pinandiol estra N-(l,l-dimetiletoksikarbonil)-Lvalilpiro!idin-2R-boronata pripravljenega kot v primeru 14 (1,0 g, 2,3 mmol) v acetonu (75 ml) dodamo raztopino amonijevega acetata (60 ml, 0,lM) in natrijevega metaperjodata (1,48 g, 6,91 mmol). Reakcijsko zmes mešamo pri sobni temperaturi 48 h nato aceton uparimo. Preostanek obdelamo z 2M raztopino natrijevega hidroksida (100 ml) in izperemo s CH2C12 (2 x 50 ml). Vodno plast previdno nakisamo z 2N klorovodikovo kislino na pH 3 in ekstrahiramo s CH2C12 (4 x 70 ml). Združene organske ekstrakte kislinske raztopine posušimo preko natrijevega sulfata in koncentriramo, da dobimo želen produkt kot belo penasto trdno snov (700 mg, 97 %). Nadaljnje čiščenje s kromatografijo preko silikagela (CF^CL^metanol, 9:1), da boronsko kislino spet kot belo trdno snov (449 mg, 62 %) (tal. 82-92 °C).To a mixed solution of (1S, 2S, 3R, 5S) -N- (1,1-dimethylethoxycarbonyl) -valonylpyrrolidine-2R-boronate ester prepared as in Example 14 (1.0 g, 2.3 mmol) in acetone (75 ml) was added a solution of ammonium acetate (60 ml, 0, 1M) and sodium metaperiodate (1.48 g, 6.91 mmol). The reaction mixture was stirred at room temperature for 48 h then the acetone was evaporated. The residue was treated with 2M sodium hydroxide solution (100 ml) and washed with CH 2 Cl 2 (2 x 50 ml). The aqueous layer was carefully acidified with 2N hydrochloric acid to pH 3 and extracted with CH 2 C1 2 (4 x 70 ml). The combined organic extracts of the acid solution were dried over sodium sulfate and concentrated to give the desired product as a white foamy solid (700 mg, 97%). Further purification by chromatography over silica gel (CF2Cl2 / methanol, 9: 1) to give boric acid again as a white solid (449 mg, 62%) (mp 82-92 ° C).
Ή NMR (CDC13): δ 0,95 (d, J = 5,7 Hz, 6H), 1,42 (s, 9H), 1,55-1,80 (m, IH), 1,802,20 (m, 4H), 2,89-3,07 (m, IH), 3,30-3,55 (m, IH), 3,55-3,65 (m, IH), 4,10-4,30 (m, IH), 5,34 (d, J = 9,2 Hz, lh); 13C NMR (CDC13): δ 18,0, 19,1, 26,3, 27,7, 28,3, 31,2, 46,1, 52,0, 55,7, 79,5, 155,6, 170,8; IR (cm4) 3395-3319, 2971-2875, 1711, 1619, 1400, 1174; CIMS m/z (% rel int, etilen glikolni adukt) 341 (MH+, 100), 285 (MH+-tBu, 67), 241 (MH+-BOC, 21).Ή NMR (CDCl 3 ): δ 0.95 (d, J = 5.7 Hz, 6H), 1.42 (s, 9H), 1.55-1.80 (m, 1H), 1.802.20 ( m, 4H), 2.89-3.07 (m, 1H), 3.30-3.55 (m, 1H), 3.55-3.65 (m, 1H), 4.10-4, 30 (m, 1H), 5.34 (d, J = 9.2 Hz, 1h); 13 C NMR (CDCl 3 ): δ 18.0, 19.1, 26.3, 27.7, 28.3, 31.2, 46.1, 52.0, 55.7, 79.5, 155 , 6, 170.8; IR (cm 4 ) 3395-3319, 2971-2875, 1711, 1619, 1400, 1174; CIMS m / z (% rel int, ethylene glycol adduct) 341 (MH +, 100), 285 (MH + -tBu, 67), 241 (MH + -BOC, 21).
PRIMER 18 iEXAMPLE 18 i
Hidroklorid L-valilpirolidin-2R-boronske kislineL-valylpyrrolidine-2R-boronic acid hydrochloride
N-(l,l-dimetiletoksikarbonil)-L-valilpirolidin-2R-boronsko kislino, ki jo dobimo v primeru 17 (250 mg, 0,796 mmol) mešamo s HCl/etrom (4,5 M, 20 ml) pri sobni temperaturi ob dušiku 1,5 h. Topilo nato uparimo in preostanek trituriramo z dietiletrom (3 x 10 ml) in vsakič eter dekantiramo. Ostanek posušimo, da dobimo naslovno spojino kot belo praškasto trdno snov (172 mg, 86 %) (tal. 211-213 °C).N- (1,1-dimethylethoxycarbonyl) -L-valylpyrrolidine-2R-boronic acid, obtained in Example 17 (250 mg, 0.796 mmol) was stirred with HCl / ether (4.5 M, 20 ml) at room temperature at nitrogen 1.5 h. The solvent was then evaporated and the residue triturated with diethyl ether (3 x 10 ml) and the ether decanted. The residue was dried to give the title compound as a white powdery solid (172 mg, 86%) (mp 211-213 ° C).
Ή NMR (D2O, fosfat pH 2): δ 0,99 (d, J = 6,9 Hz, 3H), 1,09 (d, J = 7,0 Hz, 3H), 1,67-1,76 (m, IH), 1,87-2,01 (m, IH), 2,09-2,15 (m, 2H), 2,28-2,35 (m, IH), 3,07 (dd, J - 7,0 in 11,4 Hz, IH), 3,48 (dt, J = 6,7 in 10,3 Hz, IH), 3,73 (dt, J = 1,7 in 10,2 Hz, IH), 4,14 (d, J = 5,2 Hz, IH); 13C NMR: δ 16,0,18,3, 26,9, 27,1, 28,9, 47,9, 48,9, 57,2, 167,3; IR (cm1) 3400-2800, 3368, 2970/2880, 1635, 1475-1378, 1400; CIMS m/z (% rel int, etilen glikolni adukt) 241 (MH+, 100).Ή NMR (D 2 O, phosphate pH 2): δ 0.99 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 7.0 Hz, 3H), 1.67-1 , 76 (m, 1H), 1.87-2.01 (m, 1H), 2.09-2.15 (m, 2H), 2.28-2.35 (m, 1H), 3.07 (dd, J - 7.0 and 11.4 Hz, 1H), 3.48 (dt, J = 6.7 and 10.3 Hz, 1H), 3.73 (dt, J = 1.7 and 10 , 2 Hz, 1H), 4.14 (d, J = 5.2 Hz, 1H); 13 C NMR: δ 16,0,18,3, 26,9, 27,1, 28,9, 47,9, 48,9, 57,2, 167,3; IR (cm 1 ) 3400-2800, 3368, 2970/2880, 1635, 1475-1378, 1400; CIMS m / z (% rel int, ethylene glycol adduct) 241 (MH +, 100).
PRIMER 19EXAMPLE 19
Transesterifiikaciia ciklo-L-valilpirolidin-2R-boronske kisline s fenilboronsko kislinoTransesterification of cyclo-L-valylpyrrolidine-2R-boronic acid with phenylboronic acid
Raztopino hidroklorida (lS,2S,3R,5S)-pinandiol estra L-valilpirolidin-2R-boronata pripravljeno kot v primeru 15 (501 mg, 1,3 mmol) v IM klorovodikove kisline (10 ml), ki vsebuje heksan (20 ml) in fenilboronsko kislino (500 mg, 2,6 mmol) mešamo intenzivno 1 h pri sobni temperaturi. Heksan odstranimo z dekantiranjem nato dodamo več heksana (20 ml) in zmes mešamo nadaljnjih 30 min. Plasti ločimo in združene heksanske plasti posušimo preko natrijevega sulfata in koncentriramo, da dobimo pinandiolni fenilboronat (331 mg, 99 %) kot belo kristalno trdno snov.A solution of hydrochloride (1S, 2S, 3R, 5S) -pinanediol ester of L-valylpyrrolidine-2R-boronate prepared as in Example 15 (501 mg, 1.3 mmol) in 1M hydrochloric acid (10 ml) containing hexane (20 ml ) and phenylboronic acid (500 mg, 2.6 mmol) were stirred vigorously for 1 h at room temperature. The hexane was removed by decantation, then more hexane (20 ml) was added and the mixture was stirred for a further 30 min. The layers were separated and the combined hexane layers were dried over sodium sulfate and concentrated to give pinandiol phenylboronate (331 mg, 99%) as a white crystalline solid.
Vodno plast nato spustimo skozi kolono ionske izmenjalne smole Dowex 50. Kolono najprej eluiramo z vodo (200 ml) in nato' z raztopino amonijevega hidroksida (razredčenje 1:100 tržne 0,880 raztopine, 50 ml). Izolacija bazičnih frakcij, kateri sledi liofilizacija, da prosto boronsko kislino (230 mg, 83 %) kot bel prašek, ki ima NMR identičen z materialom dobljenim v primeru 16a.The aqueous layer was then passed through a column of Dowex 50 ion exchange resin. The column was eluted first with water (200 ml) and then with ammonium hydroxide solution (dilution 1: 100 of a marketable 0,880 solution, 50 ml). Isolation of the base fractions followed by lyophilization gave free boronic acid (230 mg, 83%) as a white powder having an NMR identical to the material obtained in Example 16a.
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