CN110642726A - 光学纯环氨基醇及其盐的制备 - Google Patents
光学纯环氨基醇及其盐的制备 Download PDFInfo
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- CN110642726A CN110642726A CN201910038209.XA CN201910038209A CN110642726A CN 110642726 A CN110642726 A CN 110642726A CN 201910038209 A CN201910038209 A CN 201910038209A CN 110642726 A CN110642726 A CN 110642726A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- -1 cyclic aminoalcohols Chemical class 0.000 title claims abstract description 37
- 150000003839 salts Chemical class 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 230000007062 hydrolysis Effects 0.000 claims abstract description 20
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 16
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 12
- 229910001507 metal halide Inorganic materials 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 238000006464 oxidative addition reaction Methods 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 4
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000010936 titanium Substances 0.000 claims description 4
- 229910052719 titanium Inorganic materials 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical group 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical class OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 claims description 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000005309 metal halides Chemical class 0.000 claims 3
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical class [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 claims 1
- 229910052720 vanadium Inorganic materials 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000003756 stirring Methods 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
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- 239000000047 product Substances 0.000 description 5
- YHFYRVZIONNYSM-CRCLSJGQSA-N (1r,3s)-3-aminocyclopentan-1-ol Chemical compound N[C@H]1CC[C@@H](O)C1 YHFYRVZIONNYSM-CRCLSJGQSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
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- 238000010992 reflux Methods 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- IKBODWVMBDBFDL-UHFFFAOYSA-K [Ru](Cl)(Cl)(Cl)=O Chemical compound [Ru](Cl)(Cl)(Cl)=O IKBODWVMBDBFDL-UHFFFAOYSA-K 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
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- 238000010511 deprotection reaction Methods 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
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- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
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- YXQDKXIKUNYQLR-UHFFFAOYSA-L Cl[Cu](Cl)=O Chemical compound Cl[Cu](Cl)=O YXQDKXIKUNYQLR-UHFFFAOYSA-L 0.000 description 1
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- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
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- SDKNNSIZBFUBIQ-UHFFFAOYSA-N O1CCCC1.C1(=CC=C(C=C1)C)C Chemical compound O1CCCC1.C1(=CC=C(C=C1)C)C SDKNNSIZBFUBIQ-UHFFFAOYSA-N 0.000 description 1
- NMXXSIWRKRGTPU-UHFFFAOYSA-L OO.[Cu](Cl)Cl Chemical compound OO.[Cu](Cl)Cl NMXXSIWRKRGTPU-UHFFFAOYSA-L 0.000 description 1
- AKVRYYXIBVXPIE-UHFFFAOYSA-L OO.[Ni](Cl)Cl Chemical compound OO.[Ni](Cl)Cl AKVRYYXIBVXPIE-UHFFFAOYSA-L 0.000 description 1
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- SJPDVIOPSKNAJB-VHSXEESVSA-N [(1R,3S)-3-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopentyl] acetate Chemical compound CC(=O)O[C@@H]1CC[C@@H](C1)NC(=O)OC(C)(C)C SJPDVIOPSKNAJB-VHSXEESVSA-N 0.000 description 1
- MXBDKYAOMJHLSZ-UHFFFAOYSA-N [Cl-].OO.C1=CC=[NH+]C=C1 Chemical compound [Cl-].OO.C1=CC=[NH+]C=C1 MXBDKYAOMJHLSZ-UHFFFAOYSA-N 0.000 description 1
- KUJCPBFJWZQWAO-UHFFFAOYSA-L [Ni](Cl)(Cl)=O Chemical compound [Ni](Cl)(Cl)=O KUJCPBFJWZQWAO-UHFFFAOYSA-L 0.000 description 1
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Abstract
本发明涉及化学制药领域,具体涉及光学纯环氨基醇及其盐的制备方法。所述方法包括:1)催化氢化:化合物(12)经催化氢化得到化合物(13);2)水解:将催化氢化步骤得到的化合物(13)进行水解得到化合物(1)。
Description
技术领域
本发明涉及化学制药领域,具体涉及光学纯环氨基醇及其盐的制备方法。
背景技术
光学纯环氨基醇(1),(1R,3S)-3-氨基环戊醇,或其盐(2)是生产治疗艾滋病药物Bictegravir(3)的一个关键中间体。
WO2015195656A2公开了光学纯环氨基醇(1)及其盐(2)的制备方法,该方法是经内酰胺光学拆分、钯碳氢化还原、氨基保护、格氏试剂开环、过氧酸氧化、碱水解、酸去保护、酸成盐八个步骤实现的。理论上该方法的第一步仅有50%的收率;加之后续步骤使用的保护剂(Boc2O)、格式试剂(CH3MgBr)、过氧酸 (mCPBA)价格都比较昂贵;合成路线冗长,总收率低;不易于工业化大生产。
因此,有必要对光学纯环氨基醇((1R,3S)-3-氨基环戊醇)或其盐的制备方法进行改进。
发明内容
为解决上述问题,本发明提供式(1)所示光学纯环氨基醇的制备方法,包括:
1)催化氢化:化合物(12)经催化氢化得到化合物(13);
2)水解:将催化氢化步骤得到的化合物(13)进行水解得到化合物(1)。
根据本发明的制备方法,催化氢化步骤的反应温度为-20℃~150℃,优选为 0℃~100℃,例如为室温或60~70℃;
根据本发明的制备方法,催化氢化步骤使用的溶剂可以是甲苯、邻二甲苯、间二甲苯、对二甲苯、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、1,2-二氯乙烷、乙腈、丙腈、甲基叔丁基醚、异丙醚、二氧六环、乙二醇二甲醚、甲醇、乙醇、异丙醇中的任一种、两种或多种的组合;或者上述具有水溶性的溶剂与水构成的混合物溶剂;
根据本发明的制备方法,催化氢化步骤反应可以在催化剂的存在下进行,所述催化剂选自铂-碳、钯-碳、镍;
根据本发明的制备方法,催化氢化步骤的反应可以在氢源的存在下进行,所述的氢源可以是氢气、环己烯、甲酸铵中的任一种、两种或多种的组合。
根据本发明的制备方法,水解步骤反应的温度为-20℃~150℃,优选为 0℃~100℃;
根据本发明的制备方法,水解步骤的反应在碱性条件下水解或酸性条件下水解;
根据本发明的制备方法,水解步骤的反应在碱性条件下水解使用的碱为有机碱或无机碱,所述碱选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、叔丁醇钠、叔丁醇钾、叔丁醇镁、碳酸钠、碳酸钾、碳酸铯、硼氢化钠、硼氢化钾、乙二胺、丙二胺、丁二胺中的任一种、两种或多种的组合;
根据本发明的制备方法,水解步骤的反应在酸性条件下水解使用的酸为无机酸,所述无机酸例如为盐酸、硫酸、磷酸中的任一种、两种或多种的组合。
根据本发明的制备方法,水解步骤反应中化合物(13)与使用的碱或酸的摩尔比为1:1~10;优选为1:3~5;
根据本发明,所述式(1)所示光学纯环氨基醇的制备方法还包括化合物(12) 的制备,包括:
将化合物(14)与环戊二烯发生氧化加成反应,得到化合物(12)。
上述制备方法中,所述氧化加成反应是化合物(14)先被氧化剂氧化后再与环戊二烯发生双烯加成反应。所述氧化加成反应的温度为-20℃~150℃,优选为-10℃~100℃,例如为0℃~30℃;
上述制备方法中,氧化加成反应使用的溶剂可以是甲苯、邻二甲苯、间二甲苯、对二甲苯、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、1,2-二氯乙烷、乙腈、丙腈、甲基叔丁基醚、异丙醚、二氧六环、乙二醇二甲醚、甲醇、乙醇、异丙醇中的任一种、两种或多种的组合,或者上述可与水混溶的溶剂与水构成的混合溶剂;
上述制备方法中,氧化加成反应在氧化剂的存在下进行,所述氧化剂选自高碘酸盐、金属卤盐、金属卤盐与吡啶构成的组合物、金属卤盐与过氧化物和/ 或吡啶构成的组合物、钛/钒酸酯、钛/钒酸酯与过氧化物构成的组合物;
当使用金属卤盐、金属卤盐与吡啶构成的组合物、或钛/钒酸酯时,所述反应在氧气气氛或含氧气的气氛中进行,例如在空气气氛中进行。
优选地,所述氧化加成步骤在如下条件下进行:高碘酸钠、三氯化铁-双氧水、三氯化铁-叔丁基过氧化氢、三氯化铁-氧气、三氯化铁-空气、三氯化钌-双氧水、三氯化钌-叔丁基过氧化氢、三氯化钌-氧气、三氯化钌-空气、氯化镍-双氧水、氯化镍-叔丁基过氧化氢、氯化镍-氧气、氯化镍-空气、氯化铜-双氧水、氯化铜-叔丁基过氧化氢、氯化铜-氧气、氯化铜-空气、氯化亚铜-双氧水、氯化亚铜-叔丁基过氧化氢、氯化亚铜-氧气、氯化亚铜-空气、氯化亚铜-吡啶-双氧水、氯化亚铜-吡啶-叔丁基过氧化氢、氯化亚铜-吡啶-氧气、氯化亚铜-吡啶-空气、四异丙基钛酸酯-双氧水、四异丙基钛酸酯-叔丁基过氧化氢、四异丙基钛酸酯-氧气、四异丙基钛酸酯-空气、三异丙基钒酸酯-双氧水、三异丙基钒酸酯-叔丁基过氧化氢、三异丙基钒酸酯-氧气、三异丙基钒酸酯-空气。
根据本发明,所述式(1)所示光学纯环氨基醇的制备方法还包括化合物(14) 的制备,包括:
化合物(15)与固体光气、羟胺盐酸盐反应得到化合物(14)。
上述制备方法中,优选在碱性条件下进行,反应使用的碱优选为有机碱,例如为三乙胺、N,N-二异丙基乙胺、N,N-二甲基苯胺、吡啶、2,6-二甲基吡啶、 2-甲基吡啶、3-甲基吡啶、4-甲基吡啶。
上述制备方法中,化合物(15):碱:固体光气:羟胺盐酸盐的摩尔比为 1:1~10:0.3~1:1~5,优选为1:3~6:0.4~0.6:1~1.5。
上述制备方法中,所述反应温度为-20℃~150℃,优选为-10℃~50℃,例如为0℃~5℃。
上述制备方法中,所述反应的溶剂可以是甲苯、邻二甲苯、间二甲苯、对二甲苯四氢呋喃、2-甲基四氢呋喃、二氯甲烷、1,2-二氯乙烷、乙腈、丙腈、甲基叔丁基醚、异丙醚、二氧六环、乙二醇二甲醚中的任一种、两种或多种的组合;
本发明还提供式(2)所示光学纯环氨基醇的盐的制备方法,包括:
将化合物(1)与化合物HX反应得到化合物(2);其中化合物HX为有机酸或无机酸。
优选地,所述化合物(1)通过上述方法制备。
根据本发明的制备方法,成盐步骤反应温度为-20℃~150℃,优选为 0℃~100℃;例如为0℃~5℃。
上述制备方法中,成盐步骤使用的溶剂可以是甲苯、邻二甲苯、间二甲苯、对二甲苯、四氢呋喃、2-甲基四氢呋喃、二氯甲烷、1,2-二氯乙烷、乙腈、丙腈、甲基叔丁基醚、异丙醚、二氧六环、乙二醇二甲醚、甲醇、乙醇、异丙醇的中的任一种或其组合;
上述制备方法中,所述化合物HX可以是甲酸、醋酸、草酸、苯甲酸、琥珀酸、富马酸、盐酸、氢溴酸、氢碘酸中的任一种或其组合。
上述制备方法中,成盐步骤中化合物(1)与化合物HX的摩尔比为1:1~10;优选为1:1~5。
在一个具体的技术方案中,化合物(1)的制备方法包括下述步骤:
1)酰胺化:D-(-)-樟脑内磺酰胺(15)与固体光气和羟胺盐酸盐发生酰胺化反应,制得化合物(14);其中,樟脑内磺酰胺(15):碱:固体光气:羟胺盐酸盐的摩尔比为1:1~10:0.3~1:1~5;
2)氧化加成:在氧化剂条件下,化合物(14)与环戊二烯发生不对称双烯加成,制得化合物(12);其中,化合物(14):氧化剂:环戊二烯的摩尔比为1:1~5:1~10;
3)催化氢化:化合物(12)经催化氢化制备化合物(13);
4)水解:化合物(13)经水解制得化合物(1);
与现有技术相比,本发明具有下述有益技术效果:
1)原料价廉易得:本发明技术使用的环戊二烯和羟胺盐都是廉价易购得的化工原料,手性诱导试剂樟脑内磺酰胺可方便定量回收循环使用;现有技术则使用了价格昂贵的文斯内脂、保护剂、格式试剂和过氧酸。
2)原子经济合成路线:本发明技术仅经酰胺化、氧化加成、水解、氢化、成盐五个简短易操作步骤;现有技术则经光学拆分、钯碳氢化还原、氨基保护、格氏试剂开环、过氧酸氧化、碱水解、酸去保护、酸成盐八个步骤;光学拆分步骤,理论上仅有50%的收率,原子很不经济;
3)高效环保:本发明技术的多个中间体不需要分离纯化,可直接投入下一步反应;仅有的两个纯化分离步骤,也是简单的重结晶;易于工业化大生产。
本发明所述化合物的化学名称为:
化合物(1):(1R,3S)-3-氨基环戊醇;
化合物(2):(1R,3S)-3-氨基环戊醇有机/无机酸盐;
化合物(3):(2R,5S,13aR)-8-羟基-7,9-二氧代-N-(2,4,6-三氟苄基)- 2,3,4,5,7,9,13,13a-八氢-2,5-甲桥吡啶并(1’,2’:4,5)吡嗪并(2,1-b)(1,3)氧氮杂庚烷 -10-甲酰胺;
混合物(4):1-(2,2-二甲氧基乙基)-3-甲氧基-4-氧-5-羧基-1,4-二氢吡啶基-2-甲酸甲酯;
化合物(5):2,4,6-三氟苄胺;
化合物(6):(+/-)-2-氮杂二环(2.2.1)庚-5-烯-3-酮;(1R,4S)-2-氮杂二环(2.2.1) 庚-5-烯-3-酮;
化合物(7):(1S,4R)-2-氮杂二环(2.2.1)庚-3-酮;
化合物(8):(1S,4R)-3-氧代-2-氮杂二环(2.2.1)庚-3-甲酸叔丁酯;
化合物(9):(1S,3R)-(3-乙酰环戊基)-氨甲酸叔丁酯;
化合物(10):(1R,3S)-3-叔丁氧酰胺环戊醇醋酸酯;
混合物(11):(1S,3R)-(3-羟基环戊基)-氨甲酸叔丁酯;
化合物(12):N-((1S,4R)-2-氧代-3-氮杂二环(2.2.1)庚-5-烯)-N’–(D-(-)-樟脑内磺酰胺)羰基
化合物(13):N-((1R,3S)-3-氨基环戊醇)-N’–(D-(-)-樟脑内磺酰胺)羰基;
化合物(14):N-羟胺-N’-(D-(-)-樟脑内磺酰胺)羰基;
化合物(15):D-(-)-樟脑内磺酰胺;
除非另有说明,本发明涉及液体与液体之间的百分比时,所述的百分比为体积/体积百分比;本发明涉及液体与固体之间的百分比时,所述百分比为体积/ 重量百分比;本发明涉及固体与液体之间的百分比时,所述百分比为重量/体积百分比;其余为重量/重量百分比。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1化合物(14)的制备
1)于室温和搅拌条件下,将323克D-(-)-樟脑内磺酰胺(15)和220克固体光气分散于5升二氯甲烷中,待料液温度降至0~5℃时,控温10℃以下,缓缓滴加610克三乙胺;滴加完毕,控制5~10℃搅拌30分钟,然后回流搅拌2小时;
2)分批加入120克盐酸羟胺,继续回流搅拌3小时;降至室温,缓缓加入 2升5%盐酸水溶液;加完后,室温下搅拌30分钟,然后静置分层;
3)分出的有机相经1升水洗涤后,减压浓缩去除溶剂,得化合物(14)的粗品415克;该粗品不需要进一步纯化,直接用于下一步反应;
实施例2化合物(12)的制备
1)室温搅拌条件下,将200克环戊二烯加入到实施例1所得的415克粗品与3升甲醇和2升水所组成的混合液中,待料液温度降至0~5℃时,控温5℃以下,分批加入350克高碘酸钠;加毕,于0~5℃继续搅拌5小时(TLC监测反应完成);
2)滤除不溶物,滤液减压浓缩除去挥发物;加入3升乙酸乙酯和1升水,于室温下搅拌30分钟,然后静置分层;
3)分出的有机相经1升水洗涤后,减压浓缩去除溶剂,得化合物(12)的粗品;
4)粗品经甲基叔丁醚重结晶得化合物(12)的光学纯品,白色固体475克,以D-(-)-樟脑内磺酰胺(15)计总收率93%;
实施例3化合物(12)的制备
1)室温搅拌条件下,将120克环戊二烯、15克氯化亚铜和5克吡啶加入到再次按实施例1步骤制得的415克化合物(14)粗品与3升甲醇和2升水所组成的混合液中,控温25℃以下通入空气,继续搅拌至反应完成(TLC监测反应完成约需10小时);
2)减压浓缩除去挥发物;加入3升乙酸乙酯和1升水,于室温下搅拌30 分钟,然后静置分层;
3)分出的有机相,经1升水洗涤后,减压浓缩去除溶剂,得化合物(12) 的粗品;含氯化亚铜的水相用于下一次套用;
4)粗品经甲基叔丁醚重结晶得化合物(12)的光学纯品,白色固体;
5)490克,以D-(-)-樟脑内磺酰胺(15)计总收率97%;
实施例4化合物(13)的制备
1)将170克化合物(12)溶于500毫升的甲醇,室温、搅拌、钯-碳-氢气条件下,催化氢化6小时;
2)过滤回收钯-碳,滤液即是化合物(13)的甲醇溶液;不需要进一步纯化,直接进行下一步使用;
实施例5化合物(13)的制备
1)室温搅拌条件下,将170克化合物(12)、100克甲酸铵和2克10%钯- 碳分散到500毫升的甲醇中,然后升温搅拌回流6小时;
2)反应液温度降至室温,过滤回收钯-碳,滤液即是化合物(13)的甲醇溶液;不需要进一步纯化,直接进行下一步使用;
实施例6化合物(1)的制备
1)室温搅拌下,将60克氢氧化钠加入到实施例4所得的含化合物(13) 的甲醇溶中,然后升温搅拌回流5小时(TLC监测反应完成);降温至室温,用15%盐酸调节溶液酸碱性(pH~1)至有固体析出;
2)控温10~15℃搅拌下,缓缓加入1升水;然后于0~5℃下继续搅拌1小时;
3)过滤,滤饼用100毫升20%的异丙醇-水洗涤,50~60℃下减压干燥,得 107克D-(-)-樟脑内磺酰胺(15),循环用于制备化合物(14);
4)合并的滤减压浓缩至200毫升,用氨水调节溶液酸碱性(pH~8),二氯甲烷萃取(3x200毫升);将合并的二氯甲烷层减压浓缩至干,即得化合物(1) 的粗品;
5)该粗品不需要进一步纯化;溶于100毫升异丙醇,直接进行下一步使用;
实施例7化合物(1)的制备
1)室温搅拌下,将33克乙二胺加入到实施例5所得的含化合物(13)的甲醇溶中,然后升温搅拌回流5小时(TLC);降温至室温,用15%盐酸调节溶液酸碱性(pH~1)至有固体析出;
2)控温10~15℃搅拌下,缓缓加入1升水;然后于0~5℃下继续搅拌1小时;
3)过滤,滤饼用100毫升20%的异丙醇-水洗涤,50~60℃下减压干燥,得107克D-(-)-樟脑内磺酰胺(15),可循环用于制备化合物(14);
4)合并的滤减压浓缩至200毫升,用氨水调节溶液酸碱性(pH~8),二氯甲烷萃取(3x200毫升);将合并的二氯甲烷层减压浓缩至干,即得化合物(1) 的粗品;
5)该粗品不需要进一步纯化;溶于100毫升异丙醇,直接进行下一步使用;
实施例8化合物(2)的制备(富马酸盐)
1)室温搅拌下,将65克富马酸加入到实施例6所得的含化合物(1)的醇溶中;搅拌升温至溶清;然后降温;室温搅拌2小时,10℃搅拌3小时,0~5℃下搅拌1小时;
2)过滤,滤饼用50毫升丙酮洗涤,50~60℃下减压干燥,即得化合物(2) 的富马酸盐;
3)101克,白色固体,以化合物(12)计总收率93%;99.97ee%
1H-NMR(DMSO-d6,400MHz):δ1.84-1.94(m,1H),1.94-2.08(m,3H),2.11-2.19 (m,1H),2.22-2.30(m,1H),3.47-3.57(m,1H),4.2-4.34(m,1H),5.02(brs,1H),6.33 (d,J=12Hz,1H),6.78(d,J=12Hz,1H),8.21(brs,4H)ppm;13C-NMR(DMSO-d6, 75MHz):δ30.2,32.5,43.4,49.6,71.0,120.6,127.7,169.1,171.0ppm;m/z 102(M+H);
实施例9化合物(2)的制备(苯甲酸盐)
1)室温搅拌下,将65克苯甲酸加入到实施例7所得的含化合物(1)的醇溶中;搅拌升温至溶清;然后降温;室温搅拌2小时,10℃搅拌3小时,0~5℃下搅拌1小时;
2)过滤,滤饼用50毫升丙酮洗涤,50~60℃下减压干燥,即得化合物(2) 的苯甲酸盐;
3)105克,白色固体,以化合物(12)计总收率95%;99.98ee%
1H-NMR(DMSO-d6,400MHz):δ1.65-1.79(m,1H),2.02-2.10(m,1H),2.10-2.19 (m,2H),2.21-2.30(m,1H),3.46-3.58(m,1H),4.10-4.20(m,1H),4.98(brs,1H), 7.45-7.58(m,3H),7.82-7.92(m,2H),8.20(brs,3H)ppm;13C-NMR(DMSO-d6,75 MHz):δ30.2,32.5,43.4,49.6,71.0,127.8,129.5,130.3,136.3,172.6ppm;m/z 102(M+H);
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述的制备方法,其特征在于,所述催化氢化步骤的反应在催化剂的存在下进行,所述催化剂选自铂-碳、钯-碳、镍。
3.根据权利要求1或2所述的制备方法,其特征在于,所述催化氢化步骤的反应在氢源存在下进行,所述的氢源是氢气、环己烯、甲酸铵中的任一种、两种或多种的组合。
4.根据权利要求1-3任一项所述的制备方法,其特征在于,所述水解步骤的反应在碱性条件下水解或酸性条件下水解;
优选地,水解步骤的反应在碱性条件下水解使用的碱为有机碱或无机碱,所述碱例如选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铯、叔丁醇钠、叔丁醇钾、叔丁醇镁、碳酸钠、碳酸钾、碳酸铯、硼氢化钠、硼氢化钾、乙二胺、丙二胺、丁二胺中的任一种、两种或多种的组合;
优选地,水解步骤的反应在酸性条件下水解使用的酸为无机酸,所述无机酸例如为盐酸、硫酸、磷酸中的任一种、两种或多种的组合。
6.根据权利要求5所述的制备方法,其特征在于,所述氧化加成反应在氧化剂的存在下进行,所述氧化剂例如选自高碘酸盐、金属卤盐、金属卤盐与吡啶构成的组合物、金属卤盐与过氧化物和/或吡啶构成的组合物、钛/钒酸酯、钛/钒酸酯与过氧化物构成的组合物。
7.根据权利要求6所述的制备方法,其特征在于,当使用金属卤盐、金属卤盐与吡啶构成的组合物、或钛/钒酸酯时,所述反应在氧气气氛或含氧气的气氛中进行。
8.根据权利要求1-7任一项所述的制备方法,其特征在于,所述式(1)所示光学纯环氨基醇的制备方法还包括化合物(14)的制备,包括:
将化合物(15)与固体光气、羟胺盐酸盐反应得到化合物(14)。
9.根据权利要求8所述的制备方法,其特征在于,所述反应在碱性条件下进行,反应使用的碱优选为有机碱;例如为三乙胺、N,N-二异丙基乙胺、N,N-二甲基苯胺、吡啶、2,6-二甲基吡啶、2-甲基吡啶、3-甲基吡啶、4-甲基吡啶。
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