CN111868030A - 1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法及1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶 - Google Patents
1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法及1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶 Download PDFInfo
- Publication number
- CN111868030A CN111868030A CN201980019702.5A CN201980019702A CN111868030A CN 111868030 A CN111868030 A CN 111868030A CN 201980019702 A CN201980019702 A CN 201980019702A CN 111868030 A CN111868030 A CN 111868030A
- Authority
- CN
- China
- Prior art keywords
- benzyl
- piperidinylacetyl
- ethyl
- tert
- following formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- HCPHGCCJTBULLI-UHFFFAOYSA-N tert-butyl 4-[2-(4-methylsulfonyloxypiperidin-1-yl)-2-oxoethyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CC(=O)N1CCC(OS(C)(=O)=O)CC1 HCPHGCCJTBULLI-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 61
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 60
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 30
- OZHPKNRLWYTYHD-UHFFFAOYSA-N ethyl 2-(1-benzylpiperidin-4-yl)acetate Chemical compound C1CC(CC(=O)OCC)CCN1CC1=CC=CC=C1 OZHPKNRLWYTYHD-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000012044 organic layer Substances 0.000 claims abstract description 25
- XBUDOKOIMBMWTD-UHFFFAOYSA-N 2-(1-benzylpiperidin-4-yl)-1-(4-hydroxypiperidin-1-yl)ethanone Chemical compound C1CC(O)CCN1C(=O)CC1CCN(CC=2C=CC=CC=2)CC1 XBUDOKOIMBMWTD-UHFFFAOYSA-N 0.000 claims abstract description 21
- ZKKOLEGJTTYPDH-UHFFFAOYSA-N ethyl 2-(1-benzylpiperidin-4-ylidene)acetate Chemical compound C1CC(=CC(=O)OCC)CCN1CC1=CC=CC=C1 ZKKOLEGJTTYPDH-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000010410 layer Substances 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 11
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 1-tert-butoxycarbonyl-4-piperidinylacetyl Chemical group 0.000 claims description 29
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- 239000011541 reaction mixture Substances 0.000 claims description 11
- PKNDOZDZQPOYBO-UHFFFAOYSA-N [1-[2-(1-benzylpiperidin-4-yl)acetyl]piperidin-4-yl] methanesulfonate Chemical compound C1CC(OS(=O)(=O)C)CCN1C(=O)CC1CCN(CC=2C=CC=CC=2)CC1 PKNDOZDZQPOYBO-UHFFFAOYSA-N 0.000 claims description 10
- 229930195733 hydrocarbon Natural products 0.000 claims description 10
- 239000004215 Carbon black (E152) Substances 0.000 claims description 9
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 150000002430 hydrocarbons Chemical class 0.000 claims description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- IHSUFLCKRIHFGY-UHFFFAOYSA-N ethyl 2-piperidin-4-ylacetate Chemical compound CCOC(=O)CC1CCNCC1 IHSUFLCKRIHFGY-UHFFFAOYSA-N 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 238000006722 reduction reaction Methods 0.000 abstract description 9
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 31
- 238000000605 extraction Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 239000006227 byproduct Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 3
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N 1,2-diethylbenzene Chemical compound CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- GXDHCNNESPLIKD-UHFFFAOYSA-N 2-methylhexane Natural products CCCCC(C)C GXDHCNNESPLIKD-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- IFTRQJLVEBNKJK-UHFFFAOYSA-N Ethylcyclopentane Chemical compound CCC1CCCC1 IFTRQJLVEBNKJK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethylcyclohexane Chemical compound CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 2
- ZUBZATZOEPUUQF-UHFFFAOYSA-N isononane Chemical compound CCCCCCC(C)C ZUBZATZOEPUUQF-UHFFFAOYSA-N 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methylcyclopentane Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- CRSOQBOWXPBRES-UHFFFAOYSA-N neopentane Chemical compound CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- CFJYNSNXFXLKNS-UHFFFAOYSA-N p-menthane Chemical compound CC(C)C1CCC(C)CC1 CFJYNSNXFXLKNS-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KRCHGUHLZHESPJ-UHFFFAOYSA-N 1-(4-hydroxypiperidin-1-yl)-2-piperidin-4-ylethanone Chemical compound C1CC(O)CCN1C(=O)CC1CCNCC1 KRCHGUHLZHESPJ-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- UMWPTXOKSJXVDS-UHFFFAOYSA-N 1-methyl-2-propan-2-ylcyclohexane Chemical compound CC(C)C1CCCCC1C UMWPTXOKSJXVDS-UHFFFAOYSA-N 0.000 description 1
- QRDCBPPMQOPHOU-UHFFFAOYSA-N 1-methyl-3-propan-2-ylcyclohexane Chemical compound CC(C)C1CCCC(C)C1 QRDCBPPMQOPHOU-UHFFFAOYSA-N 0.000 description 1
- ZXFLMSIMHISJFV-UHFFFAOYSA-N 2-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]acetic acid Chemical compound CC(C)(C)OC(=O)N1CCC(CC(O)=O)CC1 ZXFLMSIMHISJFV-UHFFFAOYSA-N 0.000 description 1
- YBDQLHBVNXARAU-UHFFFAOYSA-N 2-methyloxane Chemical compound CC1CCCCO1 YBDQLHBVNXARAU-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LMGZGXSXHCMSAA-UHFFFAOYSA-N cyclodecane Chemical compound C1CCCCCCCCC1 LMGZGXSXHCMSAA-UHFFFAOYSA-N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VCRYGHPVKURQMM-UHFFFAOYSA-N methane;platinum Chemical compound C.[Pt] VCRYGHPVKURQMM-UHFFFAOYSA-N 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 229930004008 p-menthane Natural products 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- XTVMZZBLCLWBPM-UHFFFAOYSA-N tert-butylcyclohexane Chemical compound CC(C)(C)C1CCCCC1 XTVMZZBLCLWBPM-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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- C07D211/34—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明的目的在于提供一种杂质含量少的1‑(1‑叔丁氧羰基‑4‑哌啶基乙酰基)‑4‑甲磺酰氧基哌啶。所述技术问题能够通过本发明的1‑(1‑苄基‑4‑哌啶基乙酰基)‑4‑羟基哌啶的制备方法而解决,所述制备方法包含:(1)使下述式[1]所表示的1‑苄基‑4‑亚哌啶基乙酸乙酯进行还原反应,从而得到下述式[2]所表示的1‑苄基‑4‑哌啶基乙酸乙酯的工序;(2)向包含所述1‑苄基‑4‑哌啶基乙酸乙酯的溶液中添加氯化铵水溶液及有机溶剂,进行混合,并分离成有机层及水层的工序;(3)从所述有机层中回收1‑苄基‑4‑哌啶基乙酸乙酯的工序;及(4)通过在碱的存在下使所得到的1‑苄基‑4‑哌啶基乙酸乙酯与下述式[3]所表示的4‑羟基哌啶进行反应,从而得到下述式[4]所表示的1‑(1‑苄基‑4‑哌啶基乙酰基)‑4‑羟基哌啶的工序。
Description
技术领域
本发明涉及一种1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法。根据本发明,能够制备一种作为副产物的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-甲磺酰氧基哌啶-1-基)-2-氧基乙基)哌啶的混入量少的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶。
背景技术
已经公开了1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶例如作为法尼基蛋白转移酶抑制剂的合成中间体是有用的(专利文献1)。
作为所述1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法,公开了在碱的存在下,使N-芳烷基哌啶衍生物(例如,1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶)与甲磺酰卤化物(甲磺酰氯)进行反应,并使所得到的甲磺酰衍生物(1-(1-苄基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶)与二碳酸二叔丁酯在氢气与含有钯的催化剂的存在下进行反应,从而得到1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(专利文献2)。
现有技术文献
专利文献
专利文献1:日本特表2006-511481号公报
专利文献2:日本特开2004-131486号公报
发明内容
本发明要解决的技术问题
本申请的发明人通过引用文献2中记载的方法制备了1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(以下,有时称作PAA-MPN),其结果得知,其中含有微量作为杂质的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-甲磺酰氧基哌啶-1-基)-2-氧基乙基)哌啶(以下,有时称作WPA-MPN)。
如上所述,可将1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶用作药物的合成中间体。因此,优选1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶所含有的杂质尽可能少。
因此,本发明的目的为提供一种杂质含量少的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶。
解决技术问题的技术手段
本申请的发明人对杂质含量少的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(PAA-MPN)进行了认真研究。
具体而言,所述专利文献2中记载的PAA-MPN的制备方法通过以下工序而合成PAA-MPN:在碱的存在下,使1-苄基-4-哌啶酮(以下,有时称作1-BPD)与二乙基膦酰基乙酸乙酯(以下,有时称作EDEPA)进行反应的工序(I);使所得到的1-苄基-4-亚哌啶基乙酸乙酯(以下,有时称作1-BPDE)进行还原反应的工序(II);在碱的存在下,使所得到的1-苄基-4-哌啶基乙酸乙酯(以下,有时称作1-BPAE)与4-羟基哌啶(以下,有时称作4-HPPN)进行反应的工序(III);使所得到的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶(以下,有时称作BnPA-H)与甲磺酰氯进行反应的工序(IV);使所得到的1-(1-苄基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(以下,有时称作BnPA-M)与二碳酸二叔丁酯进行反应的工序(V)。
本申请的发明人惊讶地发现,通过利用氯化铵水溶液及有机溶剂对所述工序(II)中得到的1-BPAE进行分液萃取,并将萃取的1-BPAE用于工序(III)中,PAA-MPN所含有的副产物的WPA-MPN急剧减少。
本发明以上述见解为基础。
因此,本发明涉及:
[1]一种1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的制备方法,其包含:(1)使下述式[1]所表示的1-苄基-4-亚哌啶基乙酸乙酯进行还原反应,从而得到下述式[2]所表示的1-苄基-4-哌啶基乙酸乙酯的工序;(2)向包含所述1-苄基-4-哌啶基乙酸乙酯的溶液中添加氯化铵水溶液及有机溶剂,进行混合,并分离成有机层及水层的工序;(3)从所述有机层中回收1-苄基-4-哌啶基乙酸乙酯的工序;及(4)在碱的存在下,使所得到的1-苄基-4-哌啶基乙酸乙酯与下述式[3]所表示的4-羟基哌啶进行反应,从而得到下述式[4]所表示的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的工序。
[化学式1]
[化学式2]
[化学式3]
[化学式4]
[2]根据[1]所述的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的制备方法,其中,所述有机溶剂为选自由烃类有机溶剂、酯类有机溶剂、醚类有机溶剂及卤素类有机溶剂组成的组中的有机溶剂。
[3]一种1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法,其包含:[1]所述的工序(1)~(4);以及(5)在碱的存在下,使工序(4)中得到的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶与甲磺酰氯进行反应,从而得到下述式[5]所表示的1-(1-苄基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的工序;及(6)在氢气与含有钯的催化剂的存在下,使所述1-(1-苄基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶与二碳酸二叔丁酯进行反应,从而得到下述式[6]所表示的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的工序。
[化学式5]
[化学式6]
[4]根据[3]所述的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法,其中,所述有机溶剂为选自由烃类有机溶剂、酯类有机溶剂、醚类有机溶剂及卤素类有机溶剂组成的组中的有机溶剂。
[5]一种1-苄基-4-哌啶基乙酸乙酯的回收方法,其包含:(1)使下述式[1]所表示的1-苄基-4-亚哌啶基乙酸乙酯进行还原反应,从而得到下述式[2]所表示的1-苄基-4-哌啶基乙酸乙酯的工序;(2)向1-苄基-4-哌啶基乙酸乙酯的反应混合物中添加氯化铵水溶液及有机溶剂,进行混合,并分离成有机层及水层的工序;以及(3)从所述有机层中回收1-苄基-4-哌啶基乙酸乙酯的工序。
[化学式7]
[化学式8]
[6]根据[5]所述的4-哌啶基乙酸乙酯的回收方法,其中,所述有机溶剂为选自由烃类有机溶剂、酯类有机溶剂、醚类有机溶剂及卤素类有机溶剂组成的组中的有机溶剂。
[7]一种下述式[6]所表示的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶,其中,下述式[7]所表示的(1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-甲磺酰氧基哌啶-1-基)-2-氧基乙基)哌啶的含量为1.0%以下。
[化学式9]
[化学式10]
发明效果
根据本发明的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法,能够制备作为副产物的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-甲磺酰氧基哌啶-1-基)-2-氧基乙基)哌啶的混入量非常少的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶。
具体实施方式
[1]1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法
本发明的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法包含:
(1)使1-苄基-4-亚哌啶基乙酸乙酯进行还原反应,从而得到1-苄基-4-哌啶基乙酸乙酯的工序;
(2)向包含所述1-苄基-4-哌啶基乙酸乙酯的溶液中添加氯化铵水溶液及有机溶剂,进行混合,并分离成有机层及水层的工序;
(3)从所述有机层中回收1-苄基-4-哌啶基乙酸乙酯的工序;
(4)通过在碱的存在下,使所得到的1-苄基-4-哌啶基乙酸乙酯与4-羟基哌啶进行反应,从而得到1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的工序;
(5)在碱的存在下,使所得到的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶与甲磺酰氯进行反应,从而得到1-(1-苄基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的工序;及
(6)在氢气与含有钯的催化剂的存在下,使所述1-(1-苄基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶与二碳酸二叔丁酯进行反应,从而得到1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的工序。
另外,所述工序(1)中使用的1-苄基-4-亚哌啶基乙酸乙酯可通过在碱的存在下使1-苄基-4-哌啶酮与二乙基膦酰基乙酸乙酯进行反应,从而得到1-苄基-4-亚哌啶基乙酸乙酯的工序而得到。
PAA-MPN可通过本发明的PAA-MPN的制备方法中的工序(1)及工序(4)~(6)而制备(专利文献2)。通过该制备方法而得到的PAA-MPN中含有1.2%左右的作为副产物的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-甲磺酰氧基哌啶-1-基)-2-氧基乙基)哌啶(WPA-MPN)(比较例1)。通过本发明的PAA-MPN的制备方法中的工序(2)及(3),能够将PAA-MPN所含有的WPA-MPN的含量降低至1.0%以下。
只要能够得到本发明的效果,则工序(2)中的氯化铵水溶液的浓度没有特别限定,例如氯化铵水溶液的浓度的下限为0.5重量%以上,更优选为1重量%以上,进一步优选为2重量%以上。氯化铵水溶液的浓度的上限也没有限定,为氯化铵的溶解度27重量%(20℃)以下,优选为20重量%以下,更优选为15重量%以下。所述氯化铵水溶液的浓度的上限值与下限值可以独立地进行组合。即,能够将上限值与下限值的各个组合作为氯化铵水溶液的浓度范围。
通过使用0.5重量%以上的氯化铵水溶液,能够充分降低PAA-MPN所含有的WPA-MPN的浓度。例如,认为通过使用1重量%的氯化铵水溶液,能够将PAA-MPN所含有的WPA-MPN的浓度降低至小于0.1%。
只要能够得到本发明的效果,则氯化铵水溶液的pH没有特别限定,例如,pH的下限为pH1以上,更优选为pH1.5以上。pH的上限为pH12以下,更优选为pH11以下,进一步优选为pH10以下,最优选为pH9以下。
本发明的制备方法中使用的有机溶剂只要为能够与氯化铵水溶液分离的有机溶剂,则没有特别限定,例如可列举出烃类有机溶剂、酯类有机溶剂、醚类有机溶剂、卤素类有机溶剂或酮类有机溶剂。
作为所述烃类有机溶剂,只要能够溶解1-BPAE,则没有特别限定,可列举出脂肪族烃、脂环式烃、芳香族烃。作为脂肪族烃,可列举出戊烷、异戊烷、新戊烷、己烷、庚烷、异庚烷、辛烷、异辛烷、壬烷、异壬烷、癸烷、十一烷、十二烷等;作为脂环式烃,可列举出环戊烷、甲基环戊烷、乙基环戊烷、环己烷、甲基环己烷、乙基环己烷、叔丁基环己烷、邻薄荷烷、间薄荷烷、对薄荷烷、环庚烷、环辛烷、环癸烷、萘烷等;作为芳香族烃,可列举出苯、甲苯、乙苯、异丙苯、邻二甲苯、间二甲苯、对二甲苯、二乙基苯、均三甲苯、四氢化萘等。
作为所述酯类有机溶剂,只要能够溶解1-BPAE,则没有特别限定,例如可列举出乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、乙酸异丙酯或丙酸乙酯。
作为所述醚类有机溶剂,只要能够溶解1-BPAE,则没有特别限定,例如可列举出叔丁基甲基醚(MTBE)、二乙醚、二甲氧基乙烷、四氢呋喃(THF)、二噁烷、二异丙基醚、二丁醚、环戊基甲基醚、或甲基四氢呋喃、甲基四氢吡喃。
作为所述卤素类有机溶剂,只要能够溶解1-BPAE,则没有特别限定,例如可列举出氯仿、二氯甲烷、二氯乙烷、四氯化碳或氯苯。
只要能够使1-BPAE溶解于有机溶剂并使杂质溶解于氯化铵水溶液,则氯化铵水溶液与有机溶剂的比例没有特别限定。其中,例如相对于1容量份的有机溶剂,氯化铵水溶液为0.05~10容量份,优选为0.1~5容量份,进一步优选为0.2~2容量份。
此外,只要能够得到本发明的效果,则氯化铵水溶液及有机溶剂的总量相对于包含1-BPAE的溶液的比例也没有特别限定,例如相对于1容量份的包含1-BPAE的溶液,氯化铵水溶液及有机溶剂的总量为0.5~50容量份,优选为1~20容量份,最优选为2~10容量份。
(1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的制备方法)
通过本发明的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法中的工序(1)~(4),能够制备1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶。
即,本发明的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的制备方法包含:(1)使1-苄基-4-亚哌啶基乙酸乙酯进行还原反应,从而得到1-苄基-4-哌啶基乙酸乙酯的工序;(2)向包含所述1-苄基-4-哌啶基乙酸乙酯的溶液中添加氯化铵水溶液与有机溶剂,进行混合,并分离成有机层及水层的工序;(3)从所述有机层中回收1-苄基-4-哌啶基乙酸乙酯的工序;及(4)通过在碱的存在下使所得到的1-苄基-4-哌啶基乙酸乙酯与4-羟基哌啶进行反应,从而得到1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的工序。
能够将通过本发明的制备方法而得到的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶有用地用作PAA-MPN的原料。
(1-苄基-4-哌啶基乙酸乙酯的回收方法)
通过本发明的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法中的工序(1)~(3),能够从混入了4-哌啶基乙酸乙酯(以下,有时称作EPNA)的反应混合物中回收1-苄基-4-哌啶基乙酸乙酯。即,本发明的1-苄基-4-哌啶基乙酸乙酯的回收方法包含:(1)使1-苄基-4-亚哌啶基乙酸乙酯进行还原反应,从而得到1-苄基-4-哌啶基乙酸乙酯的工序;(2)向1-苄基-4-哌啶基乙酸乙酯的反应混合物中添加氯化铵水溶液及有机溶剂,进行混合,并分离成有机层及水层的工序;以及(3)从所述有机层中回收1-苄基-4-哌啶基乙酸乙酯的工序。
[2]1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶
本发明的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(PAA-MPN)中,1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-甲磺酰氧基哌啶-1-基)-2-氧基乙基)哌啶(WPA-MPN)的含量为1.0%以下。
WPA-MPN的含量优选为0.8%,更优选为0.5%,最优选为0.1%。此处,WPA-MPN的含量根据利用液相色谱的分析的面积比而计算。具体而言,所述WPA-MPN的含量能够通过利用液相色谱对所获得的PAA-MPN进行测定,并以其面积百分比来表示。
《作用》
在通过本发明的制备方法而得到的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(PAA-MPN)中,作为副产物的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-甲磺酰氧基哌啶-1-基)-2-氧基乙基)哌啶(WPA-MPN)的含量少的机理推测如下。然而,本发明并不受以下推测的限定。
根据专利文献2中记载的方法,通过以下工序而合成PAA-MPN:在碱的存在下使1-BPD与EDEPA进行反应的工序;使所得到的1-BPDE进行还原反应的工序;在碱的存在下,使所得到的1-BPAE与4-HPPN进行反应的工序;使所得到的BnPA-H与甲磺酰氯进行反应的工序;在氢气与含有钯的催化剂的存在下,使所得到的BnPA-M与二碳酸二叔丁酯进行反应的工序。关于副产物的WPA-MPN,本申请的发明人推测:如以下的反应式[8]所示,在使1-BPDE进行还原反应的工序中,1-BPDE的苄基被过度还原,由此,副产的4-哌啶基乙酸乙酯(EPNA)与4-HPPN进行反应而成为1-(1-苄基-4-哌啶基乙酰基)-4-(2-(4-羟基哌啶-1-基)-2-氧基乙基)哌啶,并由其生成WPA-MPN。
[化学式11]
如实施例所示,本申请的发明人确认到在1-BPDE的还原反应工序后得到的1-BPAE中包含少量的EPNA。因此推测,通过在1-BPDE的还原反应工序后去除EPNA,能够抑制副产物的WPA-MPN的生成,并且可抑制WPA-MPN在PAA-MPN中的混入量。
认为在以往的制备方法中,由于未进行EPNA的去除,因此通过所述的反应工序而最终得到的PAA-MPN中混入了作为副产物的WPA-MPN。进一步,认为即使在通过专利文献2以外的合成方法来制备PAA-MPN的情况下,若在该制备工序中混入了相同的前驱体,就会混入作为副产物的WPA-MPN。
实施例
以下,通过实施例对本发明进行具体说明,但本发明的范围并不限定于此。
《实施例1》
1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(PAA-MPN)的合成
[1-苄基-4-亚哌啶基乙酸乙酯的合成工序]
在5~15℃下,向235.4g(1.05mol)的二乙基膦酰基乙酸乙酯、618g的甲苯、374.3g的20%乙醇钠的乙醇溶液(换算成乙醇钠为1.10mol)的混合物中滴加189.3g(1.00mol)的1-苄基-4-哌啶酮与190g的甲苯的混合溶液。在相同温度下反应1小时后,在室温下用水洗涤反应混合物3次。用无水硫酸镁对有机层进行干燥后,在减压下进行浓缩。得到247.2g作为残渣的橙色油状的标题化合物(收率为95.3%)。
[工序1]
1-苄基-4-哌啶基乙酸乙酯(1-BPAE)的合成
向5L的四口反应瓶中加入310g(1.195mol)的1-苄基-4-亚哌啶基乙酸乙酯、1623g的2-丙醇、31g的含水50%的3%铂炭并进行搅拌。一边鼓泡一边在常压下加入氢,在55℃下反应5小时。将所得到的反应混合物冷却至室温,滤出催化剂,在减压下进行浓缩。得到286g作为残渣的浅黄色油状的标题化合物(收率为91%)。
[工序2及3]
向24.6g(0.094mol)的实施例1的工序1中得到的1-苄基-4-哌啶基乙酸乙酯(1-BPAE)中添加98g的甲苯及48g的5%氯化铵水溶液,并进行混合。分离甲苯层与水层,并回收甲苯层。
[工序4]
1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的合成
向300mL的四口反应瓶中加入122g的上述1-苄基-4-哌啶基乙酸乙酯的甲苯溶液(含有24.6g(0.094mol)的1-苄基-4-哌啶基乙酸乙酯)、10.0g(0.099mol)的4-羟基哌啶及9.1g的28%甲醇钠的甲醇溶液(换算成甲醇钠为0.047mol)。在常压下蒸馏去除78g的溶剂,切换至回流并在内部温度107℃下反应3小时。反应结束后,将反应混合物冷却至50℃,使用食盐水及10%HCl水进行水洗,得到标题化合物的甲苯溶液。
[工序5]
1-(1-苄基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的合成
向300mL的四口反应瓶中加入214g的甲苯、84g的工序4中得到的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶甲苯溶液(含有29.8g(0.094mol)的BnPA-H)、12.4g(0.122mol)的三乙胺。冷却至10℃以下后,在0~10℃下滴加10.8g(0.094mol)的甲磺酰氯,在相同温度下反应1小时。反应结束后,用碳酸氢钠水溶液及食盐水进行水洗,得到有机层。在减压下对所得到的有机层进行浓缩,使其从2-丙醇中析出并进行固液分离,从而得到30.2g白色粉末状的标题化合物(收率为81.8%)。
[工序6]
1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(PAA-MPN)的合成
向200mL的高压釜中加入9g的2-丙醇、0.56g(0.003mol)的二碳酸二叔丁酯、0.2g的含水50%的5%钯炭、及1.0g(0.003mol)的工序5中得到的1-(1-苄基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶,在0.5MPa氢气的加压下,于45℃反应4小时。将所得到的反应混合物冷却至室温,滤出催化剂。减压浓缩而去除2-丙醇,加入甲苯及食盐水并进行分液萃取。在减压下对所得到的有机层进行浓缩,向浓缩残渣中加入4g的甲苯并用冰冷却,滤取析出的晶体。在减压下干燥湿结晶,得到0.77g的白色结晶性粉末的标题化合物(收率为74.6%)。使用液相色谱进行分析,其结果,目标化合物为98.4%、WPA-MPN为0.03%。
《比较例1》
1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶(PAA-MPN)的合成
除了未实施工序[2]及[3]以外,重复实施例1的操作。所得到的PAA-MPN中的WPA-MPN为1.2%。
使用气相色谱对实施例1及比较例1的工序[1]中得到的1-BPAE进行分析,其结果,1-BPAE为98.1%,含有0.8%的作为副产物的EPNA。此外,使用气相色谱对利用实施例1的工序[2]及[3]而得到的甲苯层进行分析,其结果未检测到EPNA。
认为1-BPAE与其所含有的少量的EPNA进行反应,通过所述反应式[8]所示的反应工序而生成WPA-MPN。
《实施例2~6》
本实施例中研究从含有EPNA的1-BPAE中去除EPNA的方法。
向容量为20mL的两口烧瓶中加入4g的萃取溶剂与1.0g的含有气相色谱的面积百分比为0.9%的EPNA的1-BPAE。向其中加入2g的10%氯化铵水溶液并实施分液及萃取操作,确认所得到的有机层中的EPNA含量。实施例2中,使用甲苯作为萃取溶剂,实施例3中,使用己烷作为萃取溶剂,实施例4中,使用AcOEt(乙酸乙酯)作为萃取溶剂,实施例5中,使用MTBE(甲基叔丁基醚)作为萃取溶剂,实施例6中,使用CHCl3(氯仿)作为萃取溶剂。将结果示于表1。即使在使用任意萃取溶剂的情况下,也能够有效地去除EPNA。
[表1]
《实施例7~13》
向容量为20mL的两口烧瓶中加入4g的作为萃取溶剂的甲苯、1.0g的含有气相色谱的面积百分比为0.9%的EPNA的1-BPAE。向其中加入2g的10%氯化铵水溶液并实施分液及萃取操作,确认所得到的有机层中的EPNA含量。向实施例7中使用的10%氯化铵水溶液中加入HCl水溶液,将pH调节至2后,进行分液及萃取操作。以同样的方式,在实施例8~13中,使用HCl水溶液或NH3水溶液将pH调节至2~8。将结果示于表2。使用氯化铵水溶液时,即使在任意pH下,均可有效地去除EPNA。
[表2]
《比较例2~7》
向容量为20mL的两口烧瓶中加入4g的作为萃取溶剂的甲苯、1.0g的含有气相色谱的面积百分比为0.9%的EPNA的1-BPAE。比较例2中,向其中添加预先使用HCl水溶液将pH调节至3.00的水,进行分液及萃取操作。以同样的方式,在比较例3~7中,添加使用HCl水溶液或氢氧化钠水溶液将pH调节至4~8的水,并实施分液及萃取操作,确认所得到的有机层中的EPNA含量。将结果示于表3。使用氯化铵水溶液时,难以有效地去除EPNA。
[表3]
《参考例2》
本参考例中合成WPA-MPN。
[工序1]
(1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-羟基哌啶-1-基)-2-氧基乙基)哌啶的合成
向容量为300mL的反应烧瓶中加入22.5g(0.093mol)的1-叔丁氧羰基-4-哌啶乙酸及113g的二氯甲烷,在10℃以下,加入18.1g(0.095mol)的1-乙基-3-(3-二甲基氨基丙基)-碳二亚胺盐酸盐。在20℃下加入21.0g(0.093mol)的参考专利4207201而合成的1-(4-哌啶基乙酰基)-4-羟基哌啶,在相同温度下反应5小时。使所得到的反应混合物成为室温并用1%盐酸进行水洗,在减压下对所得到的有机层进行浓缩,其结果,得到38.2g无色油状的标题化合物(收率为91.0%)。
1HNMR(CDCl3)δ(ppm):1.12(m,4H),1.45(s,9H),1.48(m,1H),1.72(d,J=12.5Hz,2H),1.78(d,J=12.9Hz,1H),1.86(d,J=11.3Hz,3H),1.97(m,1H),2.10(m,1H),2.24(d,J=6.7Hz,4H),2.27(m,1H),2.58(t,J=12.5Hz,1H),2.72(t,J=11.0Hz,2H),2.90(s,1H),3.04(t,J=11.9Hz,1H),3.22(m,2H),3.73(m,1H),3.85(d,J=13.7Hz,1H),3.93(s,1H),4.06(m,3H),4.61(d,J=13.3Hz,1H)
13CNMR(CDCl3)δ(ppm):28.33,31.99,32.07,32.83,33.13,33.15,33.78,34.45,34.48,38.88,38.91,39.16,39.43,41.83,42.84,42.87,45.89,66.58,66.63,79.24,154.75,169.57,169.82
[工序5]
(1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-甲磺酰氧基哌啶-1-基)-2-氧基乙基)哌啶的合成
向容量为500mL的反应烧瓶中加入30.0g(0.066mol)的参考例2的工序1中得到的(1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-(2-(4-羟基哌啶-1-基)-2-氧基乙基)哌啶、8.74g(0.086mol)的三乙胺及254g的甲苯,在10℃以下加入7.61g(0.066mol)的甲磺酰氯。在相同温度下反应5小时。使所得到的反应混合物成为室温并用食盐水进行水洗,在减压下对所得到的有机层进行浓缩,其结果,得到无色油状的标题化合物。用凝胶色谱提纯后,滤取使用甲苯而析出的晶体。在减压下干燥湿结晶,得到20.5g白色结晶性粉末的标题化合物(收率为58.3%)。所得到的化合物的利用液相色谱而得到的分液结果与实施例1及比较例1的PAA-MPN中混入的副产物WPA-MPN相同。
1HNMR(CDCl3)δ(ppm):1.12(m,4H),1.45(s,9H),1.72(d,J=12.5Hz,2H),1.78(d,J=14.9Hz,1H),1.86(m,3H),1.98(m,3H),2.10(m,1H),2.24(d,J=7.0Hz,2H),2.27(m,2H),2.58(t,J=12.9Hz,1H),2.72(t,J=12.3Hz,2H),3.03(m,1H),3.06(s,3H),3.41(m,1H),3.57(m,1H),3.68(m,1H),3.85(d,J=12.5Hz,2H),4.08(br,2H),4.64(d,J=13.3Hz,1H),4.95(m,1H)
13CNMR(CDCl3)δ(ppm):28.34,31.26,32.00,32.11,32.25,32.84,33.03,33.16,38.07,38.70,39.10,39.42,41.75,41.99,43.77,45.82,76.58,79.15,154.72,169.60,169.73
质谱分析(EI):530(M+H)
工业实用性
通过本发明的制备方法而得到的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶作为用于合成药物的中间体是有用的。
Claims (7)
1.一种1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的制备方法,其包含:
(1)使下述式[1]所表示的1-苄基-4-亚哌啶基乙酸乙酯进行还原反应,从而得到下述式[2]所表示的1-苄基-4-哌啶基乙酸乙酯的工序;
(2)向包含所述1-苄基-4-哌啶基乙酸乙酯的溶液中添加氯化铵水溶液及有机溶剂,进行混合,并分离成有机层及水层的工序;
(3)从所述有机层中回收1-苄基-4-哌啶基乙酸乙酯的工序;及
(4)通过在碱的存在下,使所得到的1-苄基-4-哌啶基乙酸乙酯与下述式[3]所表示的4-羟基哌啶进行反应,从而得到下述式[4]所表示的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的工序,
[化学式1]
[化学式2]
[化学式3]
[化学式4]
2.根据权利要求1所述的1-(1-苄基-4-哌啶基乙酰基)-4-羟基哌啶的制备方法,其中,所述有机溶剂为选自由烃类有机溶剂、酯类有机溶剂、醚类有机溶剂及卤素类有机溶剂组成的组中的有机溶剂。
4.根据权利要求3所述的1-(1-叔丁氧羰基-4-哌啶基乙酰基)-4-甲磺酰氧基哌啶的制备方法,其中,所述有机溶剂为选自由烃类有机溶剂、酯类有机溶剂、醚类有机溶剂及卤素类有机溶剂组成的组中的有机溶剂。
6.根据权利要求5所述的4-哌啶基乙酸乙酯的回收方法,其中,所述有机溶剂为选自由烃类有机溶剂、酯类有机溶剂、醚类有机溶剂及卤素类有机溶剂组成的组中的有机溶剂。
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2019
- 2019-01-18 WO PCT/JP2019/001427 patent/WO2019142901A1/ja unknown
- 2019-01-18 CN CN201980019702.5A patent/CN111868030B/zh active Active
- 2019-01-18 JP JP2019566520A patent/JP7457940B2/ja active Active
- 2019-01-18 EP EP19741616.7A patent/EP3741743A4/en active Pending
- 2019-01-18 US US16/962,397 patent/US11827603B2/en active Active
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2023
- 2023-12-19 JP JP2023213608A patent/JP2024037958A/ja active Pending
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US20040235865A1 (en) * | 2001-09-04 | 2004-11-25 | Hiroshi Ikegami | Imidazo[1,2-a]pyrimidine and fungicidal compositions containing thereof |
EP1400511A1 (en) * | 2002-09-18 | 2004-03-24 | Yuki Gosei Kogyo Co., Ltd. | Methods of producing n-alkoxycarbonylpiperidine derivatives and intermediates therefor |
CN1717392A (zh) * | 2002-10-03 | 2006-01-04 | 先灵公司 | 三环化合物的对映选择性烷基化 |
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JP2005179351A (ja) * | 2003-11-28 | 2005-07-07 | Tanabe Seiyaku Co Ltd | 医薬組成物 |
JP2006104130A (ja) * | 2004-10-06 | 2006-04-20 | Koei Chem Co Ltd | 混合酸無水物類およびその製造方法 |
CN101454299A (zh) * | 2006-03-27 | 2009-06-10 | 东丽株式会社 | 酰脲衍生物及其医药用途 |
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JPWO2019142901A1 (ja) | 2021-01-07 |
US11827603B2 (en) | 2023-11-28 |
EP3741743A1 (en) | 2020-11-25 |
EP3741743A4 (en) | 2021-10-20 |
WO2019142901A1 (ja) | 2019-07-25 |
US20220388959A1 (en) | 2022-12-08 |
CN111868030B (zh) | 2024-07-19 |
JP7457940B2 (ja) | 2024-03-29 |
JP2024037958A (ja) | 2024-03-19 |
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