TWI276626B - Process for preparing of 3,4-dehydroprolines or 3,4-dehydropiperidines - Google Patents
Process for preparing of 3,4-dehydroprolines or 3,4-dehydropiperidines Download PDFInfo
- Publication number
- TWI276626B TWI276626B TW089104251A TW89104251A TWI276626B TW I276626 B TWI276626 B TW I276626B TW 089104251 A TW089104251 A TW 089104251A TW 89104251 A TW89104251 A TW 89104251A TW I276626 B TWI276626 B TW I276626B
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- Taiwan
- Prior art keywords
- formula
- reaction
- alkyl
- group
- hydrogen
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 11
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 claims 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 abstract description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000006823 (C1-C6) acyl group Chemical group 0.000 abstract 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 abstract 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 abstract 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- -1 trifluoroethylidene Chemical group 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 150000002431 hydrogen Chemical group 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- DVVNPYAVFWSKAB-LURJTMIESA-N (2s)-2-(butylazaniumyl)propanoate Chemical compound CCCCN[C@@H](C)C(O)=O DVVNPYAVFWSKAB-LURJTMIESA-N 0.000 description 1
- VQDMQFJXWAHHJA-QMMMGPOBSA-N (2s)-2-(cycloheptylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1CCCCCC1 VQDMQFJXWAHHJA-QMMMGPOBSA-N 0.000 description 1
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
- LDUWTIUXPVCEQF-LURJTMIESA-N (2s)-2-(cyclopentylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1CCCC1 LDUWTIUXPVCEQF-LURJTMIESA-N 0.000 description 1
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 1
- LPBSHGLDBQBSPI-YFKPBYRVSA-N (2s)-2-amino-4,4-dimethylpentanoic acid Chemical compound CC(C)(C)C[C@H](N)C(O)=O LPBSHGLDBQBSPI-YFKPBYRVSA-N 0.000 description 1
- XGUXJMWPVJQIHI-YFKPBYRVSA-N (2s)-2-azaniumyl-3-cyclopropylpropanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])CC1CC1 XGUXJMWPVJQIHI-YFKPBYRVSA-N 0.000 description 1
- MIZLGWKEZAPEFJ-UHFFFAOYSA-N 1,1,2-trifluoroethene Chemical group FC=C(F)F MIZLGWKEZAPEFJ-UHFFFAOYSA-N 0.000 description 1
- AEFBNJXWRHSZGO-UHFFFAOYSA-N 1,2,3,3a,4,5-hexahydropyrene Chemical class C1=C2CCCC(CC3)C2=C2C3=CC=CC2=C1 AEFBNJXWRHSZGO-UHFFFAOYSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LTHGZYQCFFPTAJ-UHFFFAOYSA-N 2-(1-adamantylamino)acetic acid Chemical compound C1C(C2)CC3CC2CC1(NCC(=O)O)C3 LTHGZYQCFFPTAJ-UHFFFAOYSA-N 0.000 description 1
- KQLGGQARRCMYGD-UHFFFAOYSA-N 2-(cyclobutylamino)acetic acid Chemical compound OC(=O)CNC1CCC1 KQLGGQARRCMYGD-UHFFFAOYSA-N 0.000 description 1
- NPLBBQAAYSJEMO-UHFFFAOYSA-N 2-(cycloheptylazaniumyl)acetate Chemical compound OC(=O)CNC1CCCCCC1 NPLBBQAAYSJEMO-UHFFFAOYSA-N 0.000 description 1
- LRHRHAWNXCGABU-UHFFFAOYSA-N 2-(cyclopentylazaniumyl)acetate Chemical compound OC(=O)CNC1CCCC1 LRHRHAWNXCGABU-UHFFFAOYSA-N 0.000 description 1
- DXQCCQKRNWMECV-UHFFFAOYSA-N 2-(cyclopropylazaniumyl)acetate Chemical compound OC(=O)CNC1CC1 DXQCCQKRNWMECV-UHFFFAOYSA-N 0.000 description 1
- APGLXBINXHAITK-UHFFFAOYSA-N 2-anilinoethanethioic s-acid Chemical compound OC(=S)CNC1=CC=CC=C1 APGLXBINXHAITK-UHFFFAOYSA-N 0.000 description 1
- ZAQXSMCYFQJRCQ-UHFFFAOYSA-N 3-(1-adamantyl)-2-azaniumylpropanoate Chemical compound C1C(C2)CC3CC2CC1(CC(N)C(O)=O)C3 ZAQXSMCYFQJRCQ-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- QRDZSRWEULKVNW-UHFFFAOYSA-N 6-hydroxy-2-oxo-1h-quinoline-4-carboxylic acid Chemical compound C1=C(O)C=C2C(C(=O)O)=CC(=O)NC2=C1 QRDZSRWEULKVNW-UHFFFAOYSA-N 0.000 description 1
- BQKVVWQPYDKCQO-UHFFFAOYSA-N C(C)(C)N(CCCCCCCCCC)C(C)C.[Li] Chemical compound C(C)(C)N(CCCCCCCCCC)C(C)C.[Li] BQKVVWQPYDKCQO-UHFFFAOYSA-N 0.000 description 1
- QYUNTSZVJSFXNN-UHFFFAOYSA-N C(CCCCCCCCC)N.[Li] Chemical group C(CCCCCCCCC)N.[Li] QYUNTSZVJSFXNN-UHFFFAOYSA-N 0.000 description 1
- YXQHWLOTFDERBQ-UHFFFAOYSA-N C1=CC=C2C=C=NC2=C1 Chemical compound C1=CC=C2C=C=NC2=C1 YXQHWLOTFDERBQ-UHFFFAOYSA-N 0.000 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- BYHQZKJXCMXMFX-UHFFFAOYSA-N [Na].NN Chemical compound [Na].NN BYHQZKJXCMXMFX-UHFFFAOYSA-N 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 244000309464 bull Species 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
- 238000001354 calcination Methods 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- MYWGVEGHKGKUMM-UHFFFAOYSA-N carbonic acid;ethene Chemical compound C=C.C=C.OC(O)=O MYWGVEGHKGKUMM-UHFFFAOYSA-N 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- MXZMFOJEOGTLJD-UHFFFAOYSA-N decane hydroiodide Chemical compound I.CCCCCCCCCC MXZMFOJEOGTLJD-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 235000021185 dessert Nutrition 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- YXXQTQYRRHHWFL-UHFFFAOYSA-N diiodophosphanyl(diiodo)phosphane Chemical compound IP(I)P(I)I YXXQTQYRRHHWFL-UHFFFAOYSA-N 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical group COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 1
- 150000004005 nitrosamines Chemical class 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000004033 porphyrin derivatives Chemical class 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical class OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
1276626 五、發明說明（1) 本發明係關於一種製備3, 4-去氩脯胺酸與3, 4 -去氫六氫 吡啶的方法。特定言之，本發明係關於一種製備下式I化 合物的方法 (，n>^C〇r (I) R2 其中 R為氳，Ci-Cr烷氧基、-NHCrQ-烷基、-N(CrC6-烷基）2、 OH，NH2 R1 為氫、CrC6 -烷基、Me3Si、Ci-Q-烷基-S R2為Boc、（^-(^-醯基、甲磺醯基、苯磺醯基、甲苯磺醯 基、三氟乙醯基、A1-A3 -胜肽 η 為 1、2 R4為氫、C6 -烷基。 3，4~去氫脯胺酸是由4 -經基脯胺酸起始經邱加耶夫 (Tschugaeff)反應（P.Grogg，Angew，Chem· 92 ( 1 980 ) 761 )製備而成。此種方法除產量相當低（64%)以外，亦需 處理高毒性化合物如二硫化碳，碘化曱烷與甲硫醇等。而 在180 °C至19 0 °C與12道耳（Torr)之熱解分解反應則需要更 複雜的技術。 替代增原酸鹽，對應之破化物、亞楓或二氧化砸亦可以 熱解反應（J.-R· Dormoy，Synthesis ( 1 982 ) 7 52 )。然 而’該法仍無法解決有關毒性與技術花費等基本問題。
1276626 五、發明說明（2) 非對常性（a c h i r a 1 )合成反應通常使用D比洛羧酸作為起 使物質，其使用碘化磷/碘化氫還原（J. W. Scott,
Synth· Commun. 10 (1980) 529)。然後由使用對掌 (chiral)胺結晶（S.S. Kerwar， J· Bio· Chem· 251 (1976) 503 ; US 4066658)或使用酒石酸結晶（A. Corbella，Chem· Ind· ( 1 9 69 ) 583 )分離消旋物。此合成 之缺點在於必須處理高毒性雄院（p h o s p h a n e )，且消旋物 解析之最大產量為50%。 W0 98/04523中述及去除經基脯胺酸醋之續酸醋，然後^ 進行消旋物之酵素解析反應。
直至最近，吡咯衍生物之倍啟（B i r ch )還原反應才為人 所知。T.J· Donohoe 在 J· Org. Chem· 61 (1996)中第— 次述及吡咯-2-羧酸衍生物之非對掌性倍啟還原反應。如 上所述，迄今彼等只可能以消旋物之古典或酵素解析反應 分離成鏡像物。 W0 9 8/554 56中述及對掌性吡咯-2 -羧酸酯及吡咯-2-羰 醯胺之非鏡像選擇性倍啟還原反應。 3，4-去氫六氫吼咬-2-叛酸衍生物之合成述於D’ Ambra，
B e 1 1，J · 〇 r g · C h e m · 5 4 ( 1 9 8 9 ) 5 6 3 2，及 Krogsgaard-Larsen, J· Labeled Compd. 19 (1982) 6 8 9。這兩種合成反應皆需處理極高毒性化合物（異氰酸 鹽，亞硝胺），且期望產物之產量亦極低。 本發明之一個標的係使用一種簡單的反應序列製備式I 之3, 4-去氫脯胺酸與3, 4 -去氫六氫吡啶。
第7頁 1276626 五、發明說明（3) 3 -吡咯啉的製備，例如經由複分解，在最近文獻中有相 當豐富的記載Grubbs， J· Org· Chem· 62 (1997) 7310 ; Pandit， Tetrahedron Lett· 37 (1996) 547 ; Grubbs， J. Am. Chem. Soc. 1 1 5 ( 1 9 9 3 ) 98 5 6 ; Moreno-Manas, Tetrahedron 54 (1998) 14869) o 已知3 -哦哈啉在2位之烧基化反應，例如，J. A m. C h e m. Soc· 107 (1985) 7974 ; Macdonald, J· Org· Chem· 45 ( 1 980 ) 1 93 ; Francke，Liebigs Ann· ( 1 99 5 ) 1 93，及提 供脯胺酸衍生物之氫甲醯化作用Izawa，Bull. Chem.
Soc· Jpn. 64(1991)620。 吡咯啶之羧化作用已廣為所知，例如Beak，J. Am.
Chem· Soc· 116 (1994) 3231 。然而，Colegate，
Austral· J. Chem· 37 ( 1 9 84) 1 50 3 教導，在曱氧基碳基 - 3 -吡咯琳之類似去質子化反應中，此化合物進行不卻之 分子間反應，產生產量為65%之N -甲氧基碳基-3 -吡咯啉 -2-叛酸1-(3 - D 比哈啉化物（pyrrolinide))。 令人驚奇的是，已發現下式I I中之吡咯啉及3, 4-去氫六 氫吡咯. R4
(〇Η2)η 、N R2 (II) % 其中 R2為Boc-酿基、曱確酿基、苯石黃酿基、曱苯續酿
第8頁 1276626 五、發明說明（4) 基、三氟乙酿基、A1-A3 -胜月太 R4 為Η ’ C!-C6 -烧基 η 為1或2 能夠在下式I I I中之羧化劑或羰化劑存在下進行反應
(III) 其中 R為氫，（：广(：6 -烷氧基、-NHq-Q -烷基、-Ν((^-C6_烷基）2 、OH，NH2 Y 為 Cl、Ci-C6-烷氧基、-NHCi-Q-烷基、-NCCi-C6-烷基）2 、N(C「C6-烷基WCi-Q，其中R並非OH， 或者，對於式I中R = 0H，與C02以及一種一強鹼（以鹼金 屬醯胺為佳）反應，及若適當，進行水解，或與下式IV之 作用物反應 R3 -X ( IV) 其中. X 為Cl 、Br 、I 、MesO 、丁osO 、三氟甲磺酸基（triflate) R3 為氫、CrQ -烷基、Me3Si、（^-(：6 -烷基-S 或NH4 或 R3X 為（q-C6-烷基-S)2。 得到所欲去氫脯胺酸與去氫六氫吡啶產量佳。 較佳之鹼金屬醯胺為下式V之鋰醯胺及鈉醯 MNR5 R6 (V) 1276626 •-— 五、發明說明（5) 其中 Μ 為納、鐘 R5為氫、C广c6_烷基 R6為氫、1~(：6-烷基。 式I I I之較佳意義為二_Ci _Ce -烷基碳酸酯，特別是碳酸 一曱酯及碳酸二乙I旨。
Al-j 3 -胜肚可以理解為一個包含至多三個胺基酸之基 團’胺β基酸為天然（蛋白質源生性）與非天然（非蛋白質源 生性）胺基酸。胜肽可以慣用保護基衍生或保護。 Al-A3 -胜肽包括部份或完全擬肽（pept id〇mimet ic)構造。 A1 ’ A2及A3應特別理解為下列胺基酸； 第二丁基甘胺酸、第三丁基丙胺酸、金剛烷基甘胺酸、 金剛烧基丙胺酸、天然胺基酸及其D -鏡像物、環丙基甘胺 酸、環庚基甘胺酸、環庚基丙胺酸、環丁基甘胺酸、環戊 基甘胺酸、環己基甘胺酸、環丙基丙胺酸、環丁基丙胺 酸、環戊基丙胺酸、環己基丙胺酸、呋喃甘胺酸之所有異 構物、咲喃丙胺酸、萘基甘胺酸、萘基丙胺酸、苯硫基甘 胺酸、苯硫基丙胺酸、異吟琳甘胺酸、異I走琳丙胺酸、邊 啉甘胺酸、电啉丙胺酸、D比洛基甘胺酸、D比洛基丙胺酸、 咪唑基甘胺酸、咪唑基丙胺酸、3, 4 -去氫脯胺酸。 該反應是在反應條件下惰性之溶劑中進行。較佳之溶劑 為(：2-(：8烴，特別是己烷、THF及匕-匕-醚、CrQ-醚/DMPU 混合物、二氧陸圜，與上述溶劑之混合物。 此反應一般是在-100 °C至+ 100 °C及壓力範圍1-200巴下
第10頁 1276626 五、發明說明（6) 進行。較佳之溫度範圍介-2 0。(：至+ 2 0 °C之間。 通常，當反應混和物中不再能偵測到（例如以GC， HPLC ’ TLC) D比洛啉衍生物或去氫六氫π比咬衍生物時，反應 以慣用方式停止。 通$以慣用方法，如蒸館法，過遽法，離心法或萃取 法’再進行處理，此獲得此方法之產物。 本發明方法係以分批方式進行，例如於攪拌反應器中。 然而’這種可以簡單方式進行之方法事實上提供可以轉變 為連續操作之優點，例如利用一個反應試管或一個攪拌 應器階式槽。 右需要，所產生之粗產物可以例如結晶法，萃取法或 層分析再進一步純化。 +可根據本發明方法以簡單方式製備之式I之3, 4_去氫脯 f酸與3，4 -去氫六氫吡啶為合成染劑、農作物保護劑、或 藥物（特別是凝血酶抑制劑）之有用中間物，如上述，例如 於W0 94/29336， W0 95/35309， W0 96/17860， W0 96/246 09， w〇 96/25426， WO 98 /06 741 公開案中。 實例 實例1 % N一第二丁氧基羰基-Δ3-去氫脯胺酸、曱酯 將4·1毫升（48 ·7毫莫耳）碳酸二甲酯及8 ·2克（48.5毫莫 耳）Ν—第三丁氧基羰基-Δ3 -吡咯啉溶於40毫升THF中，將 此此6物冷卻至大約-5 °C。接著將5 4毫升LDA溶液（2Μ於庚 炫’ THF，乙基苯中）逐滴加入，使得内在溫度不超過4
1276626 五、發明說明（7) °C。大約2 0分鐘後’加入完成。反應混合物的顏色轉變成 紅褐色。反應混合物在〇 °C再攪拌10分鐘，然後用150毫升 正戊烷稀釋，將混合物倒入20 0毫升IN HC1中。各相分 離，水相似以每次50毫升正戊烷萃取三次，合併之有機相 連續以0.01N HC1 ’飽和NaHC03溶液及飽和NaCl溶液各洗 二次。接下來有機相以MgS04乾燥，揮發性成份使用旋轉 蒸發器移除。 黃褐色粗產物在120 °C至1 50 °C/0· 4道耳（Torr)下蒸餾產 生一種淡黃色油，其在晶種加入時結晶。此結晶由正戊烷 中結晶進行最後純化。產量：9· 〇6克；理論值之82% ;無色 透明結晶體。 實例2 N—第二丁氧基羰基-2-甲基-Λ3-去氫脯胺酸甲酯 N 一第二丁氧基羰基-A3-去氫脯胺酸曱酯如上述實例1製 備（一批量1· 60毫莫耳等於2 71毫克之N—第三丁氧基羰基一 -吼洛啉）。在所有鋰二異丙基醯胺加入後，混合物於〇 C擾拌5分鐘。此時，〇·；[毫升（丨61毫莫耳）甲基碘加入。 然後混合物在〇 攪拌1 〇分鐘，然後如實例1處理。獲得 3 20宅克（理論值之83%)褐色油，根據氣相層析之分析，其 中含有75%期望產物及24%N-第三丁氧基羰基-Λ3 —去氫脯 胺酸曱酯。 實例3 N一乙氧基羧基-Λ3 -六氫D比唆-2 -致酸甲酯 228毫克（1· 47毫莫耳）N—乙氧基羰基-A3 —六氫吡啶與 1276626 五、發明說明（8) 〇·14毫升（1.66毫莫耳）碳酸二甲酯於3毫升THF中之溶液冷 卻至0 °C，繼之以滴入方式與1 · 5毫升LDA溶液（2M於庚烷， THF，乙基苯中）混合。此反應混合物於〇 攪拌丨〇分鐘， 然後倒入5毫升1 N H C 1與1 0毫升第三丁基甲基醚之混合物 中。各相分離，水相以每次1 0毫升正戊烷萃取三次，合併 之有機相連續以0· 01Ν HC1，飽和NaHC03溶液及飽和NaCl 溶液各洗二次。繼之有機相以MgS04乾燥，其中之揮發性 成份以旋轉蒸發器移除。粗產物以矽膠色層分析（流動相 石油醚：醋酸乙酸8:2)。產量：201毫克無色油（理論值之 64〇/0)。 實例4 氣 甲基N-第三丁氧基羰基-（R)~環己基甘胺醯基—（r，s) —去 脯胺酸曱酯 ^ LDA溶液（2M，2. 6毫莫耳-Fluka)以滴入方式加入N-第= 丁氧基羰基-（R) -環己基甘胺醯基吡咯啉（524毫克，丨·？〜 耄莫耳）及碳酸二甲酯（〇·3毫升，357毫莫耳）於5毫升無 THF中冷至0°C之溶液内。反應混合物於〇。〇攪拌15分鐘“、，7 然後倒入IN HC1 /正戊烷中，NaHC〇3溶液及鹽水洗，然 以MgS〇4乾燥。溶劑使用疑轉蒸發器移除，獲得〇 w克次 色油。最後的純化是以PE:EA 7:3作為流動相之矽膠色1 分析法處理。白色黏狀固體。產量：307毫克（理办 均 49〇/〇)。 。 中文 發明名稱 英文 名S 姓(t 發明人 姓名 (英文） 發明專利說明書
製備3, 4-去氫脯胺酸或3, 4-去氫六氫卩比咬之方法
PROCESS FOR PREPARING OF 3, 4-DEHYDR0PR0LINES OR 3,4-DEHYDROPIPERIDINES 佛成爾奇 沙麥麥l 海十史 德 恩特利蒙 柏蓋優賽 1· 2· 3· 4· 三 申請人
1. BERND SCHAFER 2. GUNTER HELMCHEN 3. ULI KAZMAIER 4. SIMONE SCHLEICH 國籍 1,德國2.德國3.德國4.德國 _ 住、居所 1. 德國迪貝每市奥佩特街22號 2. 德國海德堡市蓋斯堡街21號 3. 德國威斯拉奇市史拉貝街52號 4. 德國海德堡希龠卡號 姓名 (名稱） (中文） 1.德商亞培公司 姓名 (名稱） (英文） 1.ABBOTT GMBH & CO., KG 國籍 1.德國 住、居所 (事務所) 1.德國威斯貝登市烏克斯-佩蘭克-林街2號 代表人 姓名 (中文） 1.L丹克斯 丄基摩曼 代表人 姓名 (英文） l.DANCKERS ZIMMERMANN
O:\63\63007-95l017.ptc 第1頁 11276626 案號89104251 v 年 月 日 修正
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Claims (1)
1276626 案號89104251 碍<年Θ月 Hΐί修正i T 7^% ~y^. 六、申請專利範圍 1 . 一種製備式（I )之3，4 -去氫脯胺酸或3，4 -去氫六氫吡 σ定之方法， R4
(CH^nN/^COR (I) 其中 R為Ci-Ce-烧氧基， R1為氮或Ci-C6_烧基’ R2為第三丁氧基羰基（Boc)，乙氧基羰基或選自C3-C7 環烷基甘胺酸之A1-胜肽，其可經Boc保護， η為1或2 ， R4 為Η， 包含使式（II )之吡咯啉或去氫六氫吡啶衍生物 r4t^\ (CH,)n R2 (Η) 與一種強鹼及式（I I I )之化合物反應 Λ m 其中 γ為^-^-烷氧基，及
O:\63\63007-951017.ptc 第15頁 1276626 案號 89104251 曰 修正 六、申請專利範圍 使式（I I )與式（I I I )的反應產物進行水解，或使該反應產 物與式（I V )之化合物反應， R3_X ( IV) 其中 X 為 Ci，Br 或 I ， R3為烧基， 其中該反應係於介於1至200巴間之壓力範圍内及於介於 -1 0 0至+ 1 0 0 °C間之反應溫度下進行。 2.根據申請專利範圍第1項之方法，其中該式（I I I )之化 合物係二_ C丨-C 6 -烧基碳酸酯。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19913699A DE19913699A1 (de) | 1999-03-26 | 1999-03-26 | Verfahren zur Herstellung von 3,4-Dihydroprolinen und 3,4-Dehydropiperidinen |
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| EP (1) | EP1165509B1 (zh) |
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| CZ (1) | CZ20013456A3 (zh) |
| DE (2) | DE19913699A1 (zh) |
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| HK (1) | HK1045156A1 (zh) |
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| US4291040A (en) * | 1979-10-22 | 1981-09-22 | E. R. Squibb & Sons, Inc. | Mercaptoacyl derivatives of 4-disubstituted prolines and 4-substituted dehydroprolines |
| US5580575A (en) | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
| DE59409568D1 (de) | 1993-09-09 | 2000-11-30 | Schering Ag | Wirkstoffe und gas enthaltende mikropartikel |
| DE19630082A1 (de) * | 1996-07-26 | 1998-01-29 | Basf Ag | Verfahren zur Herstellung von 3-Pyrrolin-2-carbonsäure-Derivaten |
| US6090800A (en) | 1997-05-06 | 2000-07-18 | Imarx Pharmaceutical Corp. | Lipid soluble steroid prodrugs |
| DE19723473A1 (de) * | 1997-06-04 | 1998-12-10 | Basf Ag | Verfahren zur Herstellung von chiralen 3,4-Didehydroprolinen |
| AU753196B2 (en) | 1998-02-09 | 2002-10-10 | Bracco Research S.A. | Targeted delivery of biologically active media |
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- 2000-03-17 MX MXPA01009679A patent/MXPA01009679A/es unknown
- 2000-03-17 IL IL14552599A patent/IL145525A0/xx unknown
- 2000-03-17 RU RU2001129097/04A patent/RU2001129097A/ru unknown
- 2000-03-17 HU HU0200420A patent/HUP0200420A2/hu unknown
- 2000-03-17 TR TR2001/02747T patent/TR200102747T2/xx unknown
- 2000-03-17 HK HK02106153.8A patent/HK1045156A1/zh unknown
- 2000-03-17 EP EP00918809A patent/EP1165509B1/de not_active Expired - Lifetime
- 2000-03-17 KR KR1020017012187A patent/KR20010104730A/ko not_active Abandoned
- 2000-03-17 AT AT00918809T patent/ATE278665T1/de not_active IP Right Cessation
- 2000-03-17 CA CA002368479A patent/CA2368479C/en not_active Expired - Fee Related
- 2000-03-17 CZ CZ20013456A patent/CZ20013456A3/cs unknown
- 2000-03-17 DE DE50008117T patent/DE50008117D1/de not_active Expired - Fee Related
- 2000-03-17 AU AU39625/00A patent/AU3962500A/en not_active Abandoned
- 2000-03-17 US US09/937,312 patent/US6579971B1/en not_active Expired - Lifetime
- 2000-03-17 JP JP2000607987A patent/JP3868210B2/ja not_active Expired - Fee Related
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2001
- 2001-09-17 ZA ZA200107629A patent/ZA200107629B/en unknown
- 2001-09-25 NO NO20014645A patent/NO20014645L/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1165509B1 (de) | 2004-10-06 |
| BR0009330A (pt) | 2002-01-08 |
| RU2001129097A (ru) | 2004-03-20 |
| NO20014645D0 (no) | 2001-09-25 |
| US6579971B1 (en) | 2003-06-17 |
| KR20010104730A (ko) | 2001-11-26 |
| JP2002540190A (ja) | 2002-11-26 |
| DE50008117D1 (de) | 2004-11-11 |
| TR200102747T2 (tr) | 2002-02-21 |
| CA2368479C (en) | 2005-03-01 |
| NO20014645L (no) | 2001-09-25 |
| JP3868210B2 (ja) | 2007-01-17 |
| IL145525A0 (en) | 2002-06-30 |
| CN1345310A (zh) | 2002-04-17 |
| AU3962500A (en) | 2000-10-16 |
| CA2368479A1 (en) | 2000-10-05 |
| ATE278665T1 (de) | 2004-10-15 |
| DE19913699A1 (de) | 2000-09-28 |
| ES2230088T3 (es) | 2005-05-01 |
| MXPA01009679A (es) | 2002-03-14 |
| WO2000058284A1 (de) | 2000-10-05 |
| CZ20013456A3 (cs) | 2002-05-15 |
| HK1045156A1 (zh) | 2002-11-15 |
| ZA200107629B (en) | 2002-09-17 |
| HUP0200420A2 (hu) | 2002-05-29 |
| EP1165509A1 (de) | 2002-01-02 |
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