CN115232056A - Synthesis method of cis-7-azabicyclo [3.3.0] octane - Google Patents
Synthesis method of cis-7-azabicyclo [3.3.0] octane Download PDFInfo
- Publication number
- CN115232056A CN115232056A CN202210915867.4A CN202210915867A CN115232056A CN 115232056 A CN115232056 A CN 115232056A CN 202210915867 A CN202210915867 A CN 202210915867A CN 115232056 A CN115232056 A CN 115232056A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- product
- catalyst
- storage tank
- 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
- UZHVXJZEHGSWQV-KNVOCYPGSA-N (3as,6ar)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole Chemical compound C1NC[C@H]2CCC[C@H]21 UZHVXJZEHGSWQV-KNVOCYPGSA-N 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 139
- 238000000034 method Methods 0.000 claims abstract description 45
- 230000008569 process Effects 0.000 claims abstract description 21
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 12
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 11
- 238000004227 thermal cracking Methods 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 85
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- 239000003054 catalyst Substances 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 238000003860 storage Methods 0.000 claims description 42
- 238000000926 separation method Methods 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 31
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- 229910018072 Al 2 O 3 Inorganic materials 0.000 claims description 29
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 239000007788 liquid Substances 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 229940125898 compound 5 Drugs 0.000 claims description 23
- 229910004298 SiO 2 Inorganic materials 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 229940125782 compound 2 Drugs 0.000 claims description 20
- 229940126214 compound 3 Drugs 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 19
- 239000002808 molecular sieve Substances 0.000 claims description 19
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 229910021536 Zeolite Inorganic materials 0.000 claims description 18
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 18
- 239000010457 zeolite Substances 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 14
- 229910044991 metal oxide Inorganic materials 0.000 claims description 14
- 150000004706 metal oxides Chemical class 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 229940125904 compound 1 Drugs 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 11
- 239000007789 gas Substances 0.000 claims description 11
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 7
- 150000001336 alkenes Chemical class 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 7
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052684 Cerium Inorganic materials 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229910052769 Ytterbium Inorganic materials 0.000 claims description 6
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 229910052746 lanthanum Inorganic materials 0.000 claims description 6
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 5
- HECLRDQVFMWTQS-RGOKHQFPSA-N 1755-01-7 Chemical compound C1[C@H]2[C@@H]3CC=C[C@@H]3[C@@H]1C=C2 HECLRDQVFMWTQS-RGOKHQFPSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 239000003456 ion exchange resin Substances 0.000 claims description 4
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 4
- 238000011068 loading method Methods 0.000 claims description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 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
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 230000001502 supplementing effect Effects 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 4
- 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 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 229910021193 La 2 O 3 Inorganic materials 0.000 claims description 2
- 229910052765 Lutetium Inorganic materials 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 2
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 claims description 2
- 229940094933 n-dodecane Drugs 0.000 claims description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910052706 scandium Inorganic materials 0.000 claims description 2
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- OZCRKDNRAAKDAN-UHFFFAOYSA-N but-1-ene-1,4-diol Chemical compound O[CH][CH]CCO OZCRKDNRAAKDAN-UHFFFAOYSA-N 0.000 abstract description 7
- 238000005698 Diels-Alder reaction Methods 0.000 abstract description 4
- 238000006703 hydration reaction Methods 0.000 abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 3
- 238000006385 ozonation reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 75
- 239000006227 byproduct Substances 0.000 description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 16
- -1 lithium aluminum hydride Chemical compound 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical group C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 6
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 6
- 238000005086 pumping Methods 0.000 description 6
- 238000010926 purge Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 5
- 229960000346 gliclazide Drugs 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- DCZNCNBYKPIZRQ-UHFFFAOYSA-M sodium;2-ethyl-3-oxobutanoate Chemical compound [Na+].CCC(C(C)=O)C([O-])=O DCZNCNBYKPIZRQ-UHFFFAOYSA-M 0.000 description 5
- 239000002351 wastewater Substances 0.000 description 5
- ARGCQEVBJHPOGB-UHFFFAOYSA-N 2,5-dihydrofuran Chemical compound C1OCC=C1 ARGCQEVBJHPOGB-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- LIBFVQBAZPYQCJ-UHFFFAOYSA-N 2-oxaspiro[3.4]octane-1,3-dione Chemical compound O=C1OC(=O)C11CCCC1 LIBFVQBAZPYQCJ-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- HSJPMRKMPBAUAU-UHFFFAOYSA-N cerium(3+);trinitrate Chemical compound [Ce+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O HSJPMRKMPBAUAU-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- YZFOGXKZTWZVFN-UHFFFAOYSA-N cyclopentane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCCC1 YZFOGXKZTWZVFN-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000011946 reduction process Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- FYDKNKUEBJQCCN-UHFFFAOYSA-N lanthanum(3+);trinitrate Chemical compound [La+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O FYDKNKUEBJQCCN-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 1
- 150000007524 organic acids 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
- UZLYXNNZYFBAQO-UHFFFAOYSA-N oxygen(2-);ytterbium(3+) Chemical compound [O-2].[O-2].[O-2].[Yb+3].[Yb+3] UZLYXNNZYFBAQO-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- HYXGAEYDKFCVMU-UHFFFAOYSA-N scandium oxide Chemical compound O=[Sc]O[Sc]=O HYXGAEYDKFCVMU-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000006200 vaporizer Substances 0.000 description 1
- 229910003454 ytterbium oxide Inorganic materials 0.000 description 1
- 229940075624 ytterbium oxide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing cis-7-azabicyclo [3.3.0] octane. The method takes 1,4-butenediol as a raw material, and synthesizes the cis-7-azabicyclo [3.3.0] octane through the steps of dehydration reaction, diels-Alder reaction, epoxidation hydration reaction, dehydration reaction (esterification reaction and thermal cracking reaction), ozonization reaction, hydrogenation reaction, ammoniation reaction and the like. The method for synthesizing the cis-7-azabicyclo [3.3.0] octane has the advantages of simple process, green route, less pollution in the reaction process, continuous operation in multiple steps and high efficiency.
Description
Technical Field
The invention relates to the field of medicinal chemical synthesis, in particular to a method for synthesizing cis-7-azabicyclo [3.3.0] octane.
Background
Cis-7-azabicyclo [3.3.0] octane is an important intermediate in the field of medicine synthesis, and can be used for synthesizing gliclazide after nitrosation and zinc powder reduction. Gliclazide is a second-generation sulfonylurea oral hypoglycemic agent, has dual functions of reducing blood sugar and improving blood coagulation, and is registered and sold in a plurality of 130 countries all over the world at present.
The currently commonly used method for synthesizing cis-7-azabicyclo [3.3.0] octane mainly uses cyclopentane-1,2-dicarboximide as a raw material, and uses lithium aluminum hydride to reduce two carbonyl groups of cyclopentane-1,2-dicarboximide (CN 1844096A, WO 2009/140279 A2). Because the lithium aluminum hydride reagent has high risk and high cost, the reduction post-treatment process is complex, the amount of wastewater is large, and the cost of the reduction process is always high. In addition, the reduction process can be realized by matching sodium/potassium borohydride with Lewis acid (improved gliclazide intermediate azabicyclo technology, gu Hu, qilu medicine, synthesis technology research of gliclazide, liu Yongkuan, zheng State university academic paper, new synthesis technology research of gliclazide, lin Yuan, jinan university academic paper, CN 103183632A), but the problems of much wastewater and high cost cannot be solved at present. There are also reports of using catalytic hydrogenation method to directly hydrogenate cyclopentane-1,2-dicarboximide to obtain cis-7-azabicyclo [3.3.0] octane (U.S. Pat. No. 8,664,408 b2,2012031624 a1,cn 1741993A), but the reaction temperature is generally above 260 ℃, the reaction pressure is above 20MPa, the harsh reaction conditions greatly increase the risk of the process, and the requirement for equipment is high.
In addition, in the synthesis of the raw material cyclopentane-1,2-dicarboximide, cyclohexanone and urea are mainly used as raw materials to synthesize cyclopentane dicarboxylic acid through multi-step reaction, the cyclopentane dicarboxylic acid is dehydrated to synthesize cyclopentane dicarboxylic anhydride, and the cyclopentane dicarboxylic anhydride is continuously reacted with ammonia to synthesize cyclopentane-1,2-dicarboximide. Bromine is used in the synthesis process, and more halogen-containing waste water is generated. The process has long route, generates more pollution and has larger defects under the current severe environment-friendly situation.
There is also a report on The production of cis-7-azabicyclo [3.3.0] octane by The chlorination of aza [3.3.0] octan-2-one with phosphorus oxychloride followed by zinc powder reduction (The Journal of Organic Chemistry,1977,42,2082-2087). Lithium aluminum hydride and sodium borohydride are not used in the route, but raw materials are difficult to prepare, phosphorus oxychloride and zinc powder are needed, a large amount of waste is inevitably generated in the production process, and the economy and environmental protection are still challenged.
Synthesis of cis-7-azabicyclo [3.3.0] octane from aza-cyclo [3.3.0] octane-2-one
In summary, the existing synthesis process of cis-7-azabicyclo [3.3.0] octane faces the problems of expensive raw materials, need of using dangerous and expensive reducing reagents, more waste water and solid waste generated in the production process, and the like. And the processes are all intermittent reactions, the reaction concentration is low, and the production efficiency is generally low.
Disclosure of Invention
In order to solve the problems involved in the above methods, the present invention aims to provide a method for synthesizing cis-7-azabicyclo [3.3.0] octane. The method takes 1,4-butenediol as a raw material, and synthesizes the cis-7-azabicyclo [3.3.0] octane through the steps of dehydration reaction, diels-Alder reaction, epoxidation hydration reaction, dehydration reaction (esterification reaction and thermal cracking reaction), ozone oxidation reaction, hydrogenation reaction, ammoniation reaction and the like under the action of a catalyst. The method for synthesizing the cis-7-azabicyclo [3.3.0] octane has the advantages of simple process, easy separation, continuous operation in multiple steps, high yield, reduction of three-waste discharge and contribution to industrial production.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the invention provides a method for synthesizing cis-7-azabicyclo [3.3.0] octane, which comprises the following steps:
(1) Introducing the compound 1 (1,4-butenediol) into a fixed bed reactor filled with a catalyst for dehydration reaction, condensing and carrying out gas-liquid separation on a product, then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain a compound 2 (2,5-dihydrofuran);
(2) Adding the compound 2 and conjugated olefin into a high-pressure reaction kettle, maintaining pressure after replacing air in the kettle with nitrogen to ensure that the reaction kettle is not leak, heating for reaction, cooling after the reaction is finished, relieving pressure, and rectifying a product to obtain a compound 3;
(3) Mixing the compound 3 with an oxidant, performing epoxidation reaction, adding alkali for hydrolysis, and extracting to obtain a compound 4;
(4) Introducing the compound 4 into a fixed bed reactor filled with a catalyst for dehydration reaction, condensing and carrying out gas-liquid separation on a product, then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain a compound 5;
or mixing the compound 4 with acetic anhydride, adding a catalyst, heating for esterification, and distilling to obtain a compound 8; mixing the compound 8 with a solvent, introducing the mixture into a fixed bed reactor for thermal cracking reaction, condensing and separating a product from gas and liquid, and then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain a compound 5;
(5) Mixing the compound 5 with a solvent, introducing ozone into the mixture, introducing nitrogen into the mixture after the raw materials completely react, and distilling the mixture after the nitrogen is purged to obtain a compound 6;
(6) Adding the compound 6 and a catalyst into a high-pressure reaction kettle, replacing air in the kettle with nitrogen, then replacing with hydrogen, then filling hydrogen, heating for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure does not continuously decrease, and rectifying after the reaction is finished to obtain a compound 7;
(7) Dissolving the compound 7 in an optional solvent, respectively introducing the compound and ammonia gas into a fixed bed reactor filled with a catalyst for reaction, condensing and separating the product from gas and liquid, then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain the product cis-7-azabicyclo [3.3.0] octane.
Step (1)
In the step, compound 1 is dehydrated and cyclized under the action of the catalyst, and compound 2 is obtained.
In some embodiments, the catalyst of step (1) is selected from the group consisting of activated carbon, ion exchange resin, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, hbeta) manufactured by Tianjin Minuate catalyst Co., ltd.;
preferably, said catalyst of step (1) is selected from γ -Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, hbeta) manufactured by Tianjin Minuate catalyst Co., ltd.;
more preferably, said catalyst of step (1) is selected from γ -Al 2 O 3 、SiO 2 And zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, and Hbeta manufactured by Tianjin Kanghua catalyst Co., ltd.).
In some embodiments, the reaction temperature of step (1) is from 100 to 400 ℃, preferably from 120 to 300 ℃, more preferably from 120 to 280 ℃.
In some embodiments, the mass space velocity of said compound 1 (1,4-butenediol) of step (1) is from 0.1 to 5h -1 Preferably 0.3 to 3 hours -1 More preferably 0.5 to 1.5h -1 。
Wherein the unit of the mass flow of 1,4-butylene glycol is g/min, and the unit of the catalyst mass is g.
Step (2)
In this step, the compound 2 and the conjugated olefin undergo a diels-alder reaction to produce a compound 3.
In some embodiments, the compound 2 (2,5-dihydrofuran) to conjugated olefin of step (2) is in a molar ratio of 1:5 to 5:1, e.g., 1:5, 2:5, 3:5, 4:5, 1:1, 2:1, 3:1, 4:1, 5:1.
In some embodiments, the conjugated olefin of step (2) is selected from one or more of cyclopentadiene and dicyclopentadiene.
In some embodiments, the reaction temperature of step (2) is 140 to 260 ℃, preferably 160 to 220 ℃, more preferably 160 to 200 ℃.
In some embodiments, the reaction time of step (2) is from 10min to 10h, preferably from 30min to 5h, more preferably from 30min to 3h.
Step (3)
In the step, the compound 3 and an oxidant undergo epoxidation reaction to generate an epoxy compound, and the epoxy compound is hydrolyzed to generate a compound 4 after alkali is added.
In some embodiments, the oxidizing agent of step (3) is selected from one or more of peroxyformic acid, peroxyacetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid.
In some embodiments, the molar ratio of compound 1 to oxidant in step (3) is 1.1 to 1:3.
In some embodiments, the epoxidation reaction temperature of step (3) is from-10 to 40 ℃, preferably from 0 to 30 ℃, more preferably from 0 to 20 ℃.
In some embodiments, the epoxidation reaction time of step (3) is from 30min to 10h, preferably from 30min to 6h, more preferably from 30min to 3h.
In some embodiments, in step (3), compound 3, the organic acid, hydrogen peroxide and the catalyst are mixed and then subjected to epoxidation reaction, and the organic acid peroxide is unstable and needs to be prepared on the spot. In the step, formic acid, hydrogen peroxide and sulfuric acid are mixed to prepare the peroxyformic acid. Sulfuric acid is a catalyst in the process of making peroxyformic acid.
In some embodiments, the base of step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
In some embodiments, the hydrolysis temperature of step (3) is 20-70 ℃.
Step (4)
In this step, the process of compound 4 to compound 5 may be one of the following methods:
the method comprises the following steps: the compound 4 is dehydrated under the action of a catalyst.
In some embodiments, the catalyst for the dehydration reaction of step (4) is selected from Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、Yb 2 O 3 、Y 2 O 3 、La 2 O 3 、Sc 2 O 3 One or more of (a).
In some embodiments, the dehydration reaction temperature of step (4) is 350-550 ℃.
In some embodiments, the dehydration reaction feed space velocity of step (4) is from 0.05 to 1.0h -1 。
The second method comprises the following steps: and (3) carrying out esterification reaction on the compound 4 and acetic anhydride under the action of a catalyst to obtain a compound 8, and further carrying out thermal cracking to obtain a compound 5.
In some embodiments, the molar ratio of compound 4 to acetic anhydride of step (4) is 1.2 to 1:6.
In some embodiments, the esterification catalyst of step (4) is selected from one or more of sulfuric acid, phosphoric acid, hydrochloric acid, amberlyst-15, amberlyst-35.
In some embodiments, the esterification reaction temperature of step (4) is from 40 to 90 ℃.
In some embodiments, the esterification reaction time of step (4) is from 30min to 10h.
In some embodiments, the solvent for the thermal cracking reaction of step (4) is selected from one or more of tetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, ethyl acetate.
In some embodiments, the thermal cracking reaction temperature of step (4) is 300 to 600 ℃, preferably 300 to 550 ℃, more preferably 350 to 450 ℃.
Step (5)
In this step, the compound 5 and ozone are subjected to an ozone oxidation reaction to produce a compound 6.
In some embodiments, the solvent of step (5) is selected from one or more of methanol, ethanol, dichloromethane, dichloroethane, water, formic acid, acetic acid.
In some embodiments, the reaction temperature of step (5) is selected from-20 to 30 ℃.
In some embodiments, the mass concentration of said compound 5 of step (5) in the solvent is 10 to 50wt%, preferably 10 to 40wt%, more preferably 20 to 30wt%.
Step (6)
In this step, compound 6 is hydrogenated under the action of a catalyst to produce compound 7.
In some embodiments, the catalyst of step (6) is a supported catalyst M/S, M is a metal active component, and S is a support, i.e. the catalyst comprises a support S and a metal active component M supported on the support.
In some embodiments, M is selected from one or more of Cu, ni, co, ru, pd, pt;
preferably, M is selected from one or more of Cu, ni, co and Ru;
more preferably, M is selected from one or more of Cu, ni and Ru.
In some embodiments, S is selected from activated carbon, ion exchange resin, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, hbeta) manufactured by Tianjin Minuate catalyst Co., ltd.;
preferably, S is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, hbeta) manufactured by Tianjin south catalyst Ltd.;
more preferably, S is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 And zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, hbeta) manufactured by Tianjin Minmade catalyst, inc.
In some embodiments, the catalyst of step (6) is added in an amount of 3 to 10t% of compound 6.
In some embodiments, the reaction temperature of step (6) is in the range of 100 to 250 ℃, preferably 120 to 200 ℃, more preferably 150 to 200 ℃.
In some embodiments, said reaction pressure of step (6) is from 0.1 to 8MPa, preferably from 2 to 6MPa, more preferably from 3 to 5MPa.
Step (7)
In the step, the compound 7 is subjected to amination reaction under the action of a catalyst to generate a product cis-7-azabicyclo [3.3.0] octane.
In some embodiments, the catalyst of step (7) is a supported metal oxide catalyst, i.e., the catalyst comprises a support and a metal oxide supported on the support.
In some embodiments, the metal active component corresponding to the metal oxide is selected from one or more of scandium, yttrium, lanthanum, cerium, ytterbium, lutetium;
preferably, the metal active component corresponding to the metal oxide is selected from one or more of yttrium, lanthanum, cerium and ytterbium;
more preferably, the metal active component corresponding to the metal oxide is selected from one or more of lanthanum, cerium and ytterbium.
In some embodiments, the support is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, hbeta) manufactured by Tianjin Minuate catalyst Co., ltd.;
preferably, the support is selected from gamma-Al 2 O 3 、SiO 2 、ZrO 2 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, hbeta) manufactured by Tianjin Minuate catalyst Co., ltd.;
more preferably, the support is selected from gamma-Al 2 O 3 、SiO 2 And zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35 manufactured by Tianjin Miniaturization catalyst Co., ltd.).
In some embodiments, the loading of the metal oxide in the supported metal oxide catalyst (evaporation of the precursor solution after impregnation and complete loading of the metal on the surface of the support) is 0.1 to 5wt%, for example 0.1, 0.2, 0.5, 0.6, 0.8, 1,2, 3, 4, 5%, preferably 0.1 to 3wt%, more preferably 0.1 to 1wt%.
In some embodiments, the reaction temperature of step (7) is 180 to 550 ℃, preferably 220 to 450 ℃, more preferably 250 to 450 ℃.
Step (7) may be carried out with or without a solvent.
In some embodiments, the solvent of step (7) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, dioxane, cyclohexane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane;
preferably, the solvent of step (7) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, cyclohexane, n-hexane, and n-heptane;
more preferably, the solvent of step (7) is selected from one or more of methanol, ethanol, propanol, cyclohexane, n-hexane, and n-heptane.
In some embodiments, the volume ratio of compound 7 to solvent of step (7) is 1.
In some embodiments, the mass space velocity of said compound 7 of step (7) is from 0.01 to 10h -1 Preferably 0.01 to 5h -1 More preferably 0.02 to 3 hours -1 。
In some embodiments, the molar ratio of compound 7 to ammonia of step (7) is 1:5-1, 100, preferably 1:5-1, more preferably 1.
In some embodiments, the reaction pressure of step (7) is from 0.1 to 3.0MPa, preferably from 0.1 to 2.0MPa, more preferably from 0.1 to 1.0MPa.
Has the advantages that:
the invention provides a method for synthesizing cis-7-azabicyclo [3.3.0] octane, which has the advantages of green reaction route, continuous production in multiple steps, high efficiency, simple process operation, main byproduct of water, avoidance of use of dangerous and expensive chemical reduction reagent, and no generation of corrosive wastewater. Compared with the traditional method, the method is easy to realize industrial production.
The present invention has been described in detail hereinabove, but the above embodiments are merely illustrative in nature and are not intended to limit the present invention. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or the summary or the following examples.
Detailed Description
The present invention is further illustrated by the following examples, which are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention.
The starting materials, reagents, methods and the like used in the examples are those conventional in the art unless otherwise specified.
In the following examples, 1,4-butenediol, dicyclopentadiene, purchased from Roen reagent, deionized water, formic acid, methanol, acetic anhydride, sodium hydroxide, tetrahydrofuran, 1,4-dioxane, cerium nitrate, lanthanum nitrate, ytterbium oxide, cerium oxide, scandium oxide, purchased from national pharmaceutical group chemical reagent, inc.; gamma-Al 2 O 3 And SiO 2 Purchased from Qingdao sea wave silica gel desiccant, inc.; the H-ZSM-5 series molecular sieves were purchased from Tianjin south China catalyst, inc.; raney Ni catalyst was purchased from ShanghaineKai New materials science and technology Co., ltd; high-purity nitrogen, high-purity ammonia gas and high-purity hydrogen gas are purchased from great science and technology limited of Qingdao De Hai.
In the method for synthesizing cis-7-azabicyclo [3.3.0] octane according to the invention, 1,4-butenediol is used as a raw material, and the cis-7-azabicyclo [3.3.0] octane is synthesized through dehydration reaction, diels-alder reaction, epoxidation hydration reaction, dehydration reaction (esterification reaction, thermal cracking reaction), ozonization reaction, hydrogenation reaction and ammoniation reaction. The product obtained in each step was passed through a 0.22 μm filter and analyzed by Gas Chromatography (GC). Gas chromatography detection conditions: the instrument comprises the following steps: shimadzu GC2010Plus, column: intercap-FFAP,30m × 0.25mm × 0.25 μm, vaporizer temperature 250 ℃, FID temperature 300 ℃, column oven temperature program: keeping at 60 deg.C for 1min, and heating to 230 deg.C at 15 deg.C/min for 10min. The product was qualitatively analyzed by gas chromatography-mass spectrometry (GC-MS). The product was quantified by Shimazu-GC 2010plus gas chromatography. The correlation calculation formula is as follows:
example 1
1. The fixed bed reactor was charged with 20g of gamma-Al 2 O 3 The catalyst is heated to 240 ℃ under the nitrogen flow rate of 50ml/min, and the compound 1 (1,4-butenediol) is added for 0.8h -1 Pumping the mixture into a reactor for reaction at the airspeed, condensing the product, separating gas from liquid, then feeding the product into a storage tank, rectifying the product in the storage tank, taking 62-66 ℃ fraction to obtain a product compound 2, wherein the yield is 77%, the main byproduct is crotonaldehyde, the mass yield is 1%, and the rest byproduct is mainly water.
2. Adding 1.0kg of compound 2 and 1.0kg of cyclopentadiene into a 5L high-pressure reaction kettle, maintaining the pressure after replacing the air in the kettle with nitrogen to ensure that the reaction kettle is airtight, heating to 180 ℃ for reaction for 10 hours, cooling after the reaction is finished, relieving the pressure, rectifying the product to obtain 1.79kg of compound 3, wherein the separation yield is 92%. The remaining by-product was a gum.
3. 1890g of formic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added to the flask, and stirred at 10 ℃ for 30min to obtain peroxyformic acid. 700g of Compound 3 was slowly added dropwise to the above mixture while controlling the reaction temperature not to exceed 20 ℃. After the dropwise addition, the reaction was continued for 1 hour with stirring to obtain an intermediate. Then, saturated sodium hydroxide solution is dripped until the system is alkaline, and the internal temperature is controlled to be not higher than 30 ℃ in the dripping process. After the completion of the dropwise addition, ethyl acetate was added and extracted three times (1000 ml each), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and then filtered to remove ethyl acetate, whereby 810g of Compound 4 was obtained in an isolated yield of 93%.
4. 20g Yb were fed into a fixed bed reactor 2 O 3 Heating the catalyst to 350 ℃ in a nitrogen atmosphere, keeping the temperature for 2h to activate the catalyst, and then adding the compound 4 for 0.1h -1 The air speed of the reaction kettle is introduced into the reactor for reaction, the product enters a storage tank after condensation and gas-liquid separation, the product in the storage tank is rectified to obtain a compound 5, and the separation yield is 83%.
5. 300g of compound 5 and 1200g of methanol are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than-10 ℃, after the raw materials completely react, nitrogen is introduced for purging for 30min, the methanol is distilled off, 260 ℃ fractions are taken to obtain 287g of compound 6, and the separation yield is 91%.
6. 250g of Compound 6 was mixed with 12.5g of Ru/. Gamma. -Al 2 O 3 (the load of Ru is 5%) is added into a 500ml high-pressure reaction kettle, after the air in the kettle is replaced by nitrogen for three times, the hydrogen is replaced for three times, then 3MPa hydrogen is filled, the reaction kettle is heated to 180 ℃ for reaction, the hydrogen is continuously supplemented into the reaction kettle until the pressure does not continuously decrease, and after the reaction is finished, the product is obtainedAnd distilling to obtain fraction at 145-150 deg.c to obtain 188g of compound 7 in 93% yield.
7. 150g of compound 7 and ammonia gas (150 ml/min) are respectively introduced into a fixed bed reactor filled with 10g of La-H-ZSM-5, the reaction temperature is 280 ℃, and the space velocity is 0.08H -1 The product enters a storage tank after condensation and gas-liquid separation, and is rectified to obtain 165 ℃ fraction to obtain 135g of the product cis-7-azabicyclo [3.3.0]]Octane, isolated in 90% yield.
Example 2
1. A fixed bed reactor was charged with 20g of gamma-Al 2 O 3 Catalyst, heating to 240 ℃ under nitrogen flow rate of 50ml/min, and taking compound 1 for 0.8h -1 Pumping the mixture into a reactor for reaction at the airspeed, condensing the product, separating gas from liquid, then feeding the product into a storage tank, rectifying the product in the storage tank, taking 62-66 ℃ fraction to obtain a product compound 2, wherein the yield is 77%, the main byproduct is crotonaldehyde, the mass yield is 1%, and the rest byproduct is mainly water.
2. Adding 1.0kg of compound 2 and 1.0kg of cyclopentadiene into a 5L high-pressure reaction kettle, maintaining the pressure after replacing the air in the kettle with nitrogen to ensure that the reaction kettle is airtight, heating to 180 ℃ for reaction for 10 hours, cooling after the reaction is finished, relieving the pressure, rectifying the product to obtain 1.79kg of compound 3, wherein the separation yield is 92%. The remaining by-product was a gum.
3. 1890g of formic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added to the flask, and stirred at 10 ℃ for 30min to obtain peroxyformic acid. 700g of Compound 3 was slowly added dropwise to the above mixture while controlling the reaction temperature not to exceed 20 ℃. After the dropwise addition, the reaction was continued for 1 hour with stirring to obtain an intermediate. Then, saturated sodium hydroxide solution is dripped until the system is alkaline, and the internal temperature is controlled to be not higher than 30 ℃ in the dripping process. After the completion of the dropwise addition, ethyl acetate was added and extracted three times (1000 ml each), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and then filtered to remove ethyl acetate, whereby 810g of Compound 4 was obtained in an isolated yield of 93%.
4. Adding 10g of Sc into a fixed bed reactor 2 O 3 Heating the catalyst to 350 ℃ in a nitrogen atmosphere, keeping the temperature for 2h to activate the catalyst, and then adding the compound 4 for 0.1h -1 The reaction is carried out by introducing the airspeed of the reaction vessel, the product enters a storage tank after condensation and gas-liquid separation, and the product in the storage tank is rectified to obtain a compound 5 with the separation yield of 88%.
5. 300g of compound 5 and 1200g of methanol are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than-10 ℃, after the raw materials completely react, nitrogen is introduced for purging for 30min, the methanol is distilled off, 260 ℃ fractions are taken to obtain 287g of compound 6, and the separation yield is 91%.
6. 250g of compound 6 was mixed with 12.5g of Ni/gamma-Al 2 O 3 (Ni load is 5%) is added into a 500ml high pressure reaction kettle, after the air in the kettle is replaced by nitrogen for three times, the hydrogen is used for replacing for three times, then 3MPa hydrogen is filled, and then the mixture is addedHeating to 180 ℃ for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure is not reduced continuously, after the reaction is finished, rectifying the product to obtain fraction of 145-150 ℃ to obtain 188g of compound 7, and the separation yield is 92%.
7. 150g of compound 7 and ammonia gas (150 ml/min) are respectively introduced into a fixed bed reactor filled with 10g of La-H-ZSM-5, the reaction temperature is 280 ℃, and the space velocity is 0.08H -1 The product is condensed and enters a storage tank after gas-liquid separation, and the product is rectified to obtain 165 ℃ fraction to obtain 135g of cis-7-azabicyclo [3.3.0]Octane, isolated in 90% yield.
Example 3
1. The fixed bed reactor was charged with 20g of gamma-Al 2 O 3 Catalyst, heating to 240 ℃ under nitrogen flow of 50ml/min, compound 1 is added for 0.8h -1 Pumping the mixture into a reactor for reaction at the airspeed, condensing the product, separating gas from liquid, then feeding the product into a storage tank, rectifying the product in the storage tank, taking a fraction at 62-66 ℃ to obtain a product compound 2, wherein the yield is 75%, the main byproduct is crotonaldehyde, the mass yield is 2%, and the rest byproduct is mainly water.
2. Adding 1.0kg of compound 2 and 1.0kg of cyclopentadiene into a 5L high-pressure reaction kettle, maintaining the pressure after replacing the air in the kettle with nitrogen to ensure that the reaction kettle is airtight, heating to 180 ℃ for reaction for 10 hours, cooling after the reaction is finished, relieving the pressure, rectifying the product to obtain 1.79kg of compound 3, wherein the separation yield is 92%. The remaining by-product was a gum.
3. 1890g of formic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added to the flask, and stirred at 10 ℃ for 30min to obtain peroxyformic acid. 700g of Compound 3 was slowly added dropwise to the above mixture while controlling the reaction temperature not to exceed 20 ℃. After the dropwise addition, the reaction was continued for 1 hour with stirring to obtain an intermediate. Then, saturated sodium hydroxide solution is dripped until the system is alkaline, and the internal temperature is controlled to be not higher than 30 ℃ in the dripping process. After the completion of the dropwise addition, ethyl acetate was added and extracted three times (1000 ml each), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and then filtered to remove ethyl acetate, whereby 810g of Compound 4 was obtained in an isolated yield of 93%.
4. 500g of compound 4 and 1500g of acetic anhydride are mixed in a 5L flask, 5g of sulfuric acid is added, the mixture is heated to 80 ℃ to react for 10h, and 725g of compound 8 is obtained by distillation with the isolation yield of 97%.
700g of the compound 8 and 700g of tetrahydrofuran are mixed and then introduced into a fixed bed reactor heated to 450 ℃, products enter a storage tank after condensation and gas-liquid separation, and the products are rectified to obtain 322g of the compound 5, wherein the separation yield is 87%.
5. 300g of compound 5 and 1200g of methanol are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than-10 ℃, after the raw materials completely react, nitrogen is introduced for purging for 30min, the methanol is distilled off, 260 ℃ fractions are taken to obtain 287g of compound 6, and the separation yield is 91%.
6. 250g of Compound 6 was mixed with 12.5g of Ru/. Gamma. -Al 2 O 3 (the loading amount of Ru is 5%) is added into a 500ml high-pressure reaction kettle, after the air in the kettle is replaced by nitrogen for three times, the hydrogen is replaced for three times, then 3MPa hydrogen is filled, the reaction kettle is heated to 180 ℃ for reaction, hydrogen is continuously supplemented into the reaction kettle until the pressure does not continuously decrease, after the reaction is finished, a product is rectified, a fraction of 145 ℃ to 150 ℃ is taken, 188g of a compound 7 is obtained, and the separation yield is 93%.
7. 150g of compound 7 and ammonia gas (150 ml/min) are respectively introduced into a fixed bed reactor filled with 10g of La-H-ZSM-5, the reaction temperature is 280 ℃, and the space velocity is 0.08H -1 The product is condensed and enters a storage tank after gas-liquid separation, and the product is rectified to obtain 165 ℃ fraction to obtain 135g of cis-7-azabicyclo [3.3.0]]Octane, isolated in 90% yield.
Example 4
1. The fixed bed reactor was charged with 20g H-ZSM-5 (Si/Al = 80) catalyst and the temperature was raised to 240 ℃ under a nitrogen flow of 50ml/min, compound 1 was allowed to stand for 0.8h -1 Pumping the mixture into a reactor for reaction at the airspeed, condensing the product, separating gas from liquid, then feeding the product into a storage tank, rectifying the product in the storage tank, taking 62-66 ℃ fraction to obtain a product compound 2, wherein the yield is 77%, the main byproduct is crotonaldehyde, the mass yield is 1%, and the rest byproduct is mainly water.
2. Adding 1.0kg of compound 2 and 1.0kg of cyclopentadiene into a 5L high-pressure reaction kettle, maintaining pressure after replacing air in the kettle with nitrogen to ensure that the reaction kettle is airtight, heating to 200 ℃ for reaction for 5 hours, cooling after the reaction is finished, relieving pressure, rectifying the product to obtain 1.60kg of compound 3, wherein the separation yield is 82%. The remaining by-product was a gum.
3. 1890g of acetic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added to the flask, and stirred at 10 ℃ for 30min to obtain peracetic acid. 700g of Compound 3 was slowly added dropwise to the above mixture while controlling the reaction temperature not to exceed 20 ℃. After the dropwise addition, the reaction was continued for 1 hour with stirring to obtain an intermediate. Then, saturated sodium hydroxide solution is dripped until the system is alkaline, and the internal temperature is controlled to be not higher than 30 ℃ in the dripping process. After the completion of the dropwise addition, ethyl acetate was added and extracted three times (1000 ml each), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and then filtered to remove ethyl acetate to obtain 800g of compound 4 in an isolated yield of 91%.
4. 500g of Compound 4 was mixed with 1500g of acetic anhydride in a 5L flask, 5g of Amberlyst-35 was added, the mixture was heated to 80 ℃ to react for 10 hours, and 730g of Compound 8 was obtained by distillation with an isolation yield of 98%.
700g of the compound 8 and 700g of tetrahydrofuran are mixed and then introduced into a fixed bed reactor heated to 400 ℃, the product is condensed and subjected to gas-liquid separation and then enters a storage tank, the product is rectified to obtain 330g of the compound 5, and the separation yield is 89%.
5. 300g of the compound 5, 600g of dichloromethane and 600g of methanol are mixed in a 5L flask, then ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than-20 ℃, after the raw materials completely react, nitrogen is introduced for purging for 30min, then methanol and dichloromethane are distilled off, and a fraction at 260 ℃ is taken to obtain 285g of the compound 6, and the separation yield is 91%.
6. Adding 250g of compound 6 and 12.5g of Ni/H-ZSM-5 (the load of Ru is 5%) into a 500ml high-pressure reaction kettle, replacing air in the kettle with nitrogen for three times, replacing the air with hydrogen for three times, then filling 3MPa hydrogen, heating to 200 ℃ for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure does not continuously decrease, after the reaction is finished, rectifying the product to obtain fraction at 145-150 ℃ to obtain 180g of compound 7, and the separation yield is 90%.
7. 150g of Compound 7 and 150g of ammonia gas (150 ml/min) were separately introduced into a chamber containing 10g of Ce-gamma-Al 2 O 3 In the fixed bed reactor, the reaction temperature is 280 ℃, and the space velocity is 0.05h -1 The product enters a storage tank after condensation and gas-liquid separation, and is rectified to obtain a fraction of 165 ℃ to obtain 130g of cis-7-azabicyclo [3.3.0]]Octane, isolated in 87% yield.
Example 5
1. A fixed bed reactor was charged with 20g of Nb 2 O 3 Catalyst, heating to 240 ℃ under nitrogen flow rate of 50ml/min, and taking compound 1 for 0.8h -1 Pumping the mixture into a reactor for reaction at the airspeed, condensing the product, separating gas from liquid, then feeding the product into a storage tank, rectifying the product in the storage tank, taking a fraction at 62-66 ℃ to obtain a product compound 2, wherein the yield is 75%, the main byproduct is crotonaldehyde, the mass yield is 3%, and the rest byproduct is mainly water.
2. Adding 1.0kg of compound 2 and 1.0kg of cyclopentadiene into a 5L high-pressure reaction kettle, maintaining pressure after replacing air in the kettle with nitrogen to ensure that the reaction kettle is airtight, heating to 200 ℃ for reaction for 5 hours, cooling after the reaction is finished, relieving pressure, rectifying the product to obtain 1.60kg of compound 3, wherein the separation yield is 82%. The remaining by-product was a gum.
3. 1890g of acetic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added to the flask, and stirred at 10 ℃ for 30min to obtain peracetic acid. 700g of Compound 3 was slowly added dropwise to the above mixture while controlling the reaction temperature not to exceed 20 ℃. After the dropwise addition, the reaction was continued for 1 hour with stirring to obtain an intermediate. Then, saturated sodium hydroxide solution is dripped until the system is alkaline, and the internal temperature is controlled to be not higher than 30 ℃ in the dripping process. After the completion of the dropwise addition, ethyl acetate was added and extracted three times (1000 ml each), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and then filtered to remove ethyl acetate, whereby 800g of Compound 4 was obtained in an isolated yield of 91%.
4. 500g of Compound 4 was mixed with 1500g of acetic anhydride in a 5L flask, 5g of sulfuric acid was added, the mixture was heated to 80 ℃ and reacted for 10 hours, 725g of Compound 8 was obtained by distillation, and the isolation yield was 97%.
700g of the compound 8 and 700g of 1, 4-dioxane are mixed and then introduced into a fixed bed reactor heated to 400 ℃, products enter a storage tank after being condensed and separated from gas and liquid, and the products are rectified to obtain 328g of the compound 5, wherein the separation yield is 88%.
5. 300g of compound 5 and 1200g of dichloroethane are mixed in a 5L flask, then ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than 10 ℃, after the raw materials completely react, nitrogen is introduced for purging for 30min, the dichloroethane is distilled off, 282g of compound 6 is obtained from 260 ℃ fraction, and the separation yield is 90%.
6. 250g of Compound 6 was mixed with 12.5g of Ni/Nb 2 O 3 (the load of Ru is 5%) is added into a 500ml high-pressure reaction kettle, after the air in the kettle is replaced by nitrogen for three times, the hydrogen is replaced by hydrogen for three times, then 3MPa hydrogen is filled, the reaction kettle is heated to 180 ℃ for reaction, hydrogen is continuously supplemented into the reaction kettle until the pressure is not reduced continuously, after the reaction is finished, the product is rectified, the fraction at 145-150 ℃ is taken, 176g of compound 7 is obtained, and the separation yield is 88%.
7. 150g of Compound 7 and 150g of ammonia gas (150 ml/min) were separately introduced into a reactor containing 10g of gamma-Al 2 O 3 In the fixed bed reactor, the reaction temperature is 350 ℃, and the space velocity is 0.05h -1 The product is condensed and enters a storage tank after gas-liquid separation, and the product is rectified to obtain 165 ℃ fraction to obtain 125g of cis-7-azabicyclo [3.3.0]Octane, isolated in 83% yield.
Example 6
1. The fixed bed reactor is filled with 20g Amberlyst-35 catalyst, the temperature is raised to 120 ℃ under the nitrogen flow rate of 50ml/min, and the compound 1 is heated for 0.5h -1 Pumping the mixture into a reactor for reaction at the airspeed, condensing the product, separating the gas from the liquid, then feeding the product into a storage tank, rectifying the product in the storage tank, taking a fraction at 62-66 ℃ to obtain a compound 2, wherein the yield is 71%, the main byproduct is crotonaldehyde, the mass yield is 5%, and the rest byproduct is mainly water.
2. Adding 1.0kg of compound 2 and 1.0kg of dicyclopentadiene into a 5L high-pressure reaction kettle, maintaining the pressure after replacing the air in the kettle with nitrogen to ensure that the reaction kettle is airtight, heating to 200 ℃ for reaction for 5 hours, cooling after the reaction is finished, relieving the pressure, rectifying the product to obtain 1.60kg of compound 3, wherein the separation yield is 82%. The remaining by-product was a gum.
3. 1890g of acetic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added to the flask, and stirred at 10 ℃ for 30min to obtain peracetic acid. 700g of Compound 3 was slowly added dropwise to the above mixture while controlling the reaction temperature not to exceed 20 ℃. After the dropwise addition, the reaction was continued for 1 hour with stirring to obtain an intermediate. Then, saturated sodium hydroxide solution is dripped until the system is alkaline, and the internal temperature is controlled to be not higher than 30 ℃ in the dripping process. After the completion of the dropwise addition, ethyl acetate was added and extracted three times (1000 ml each), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and then filtered to remove ethyl acetate, whereby 800g of Compound 4 was obtained in an isolated yield of 91%.
4. 500g of compound 4 and 1000g of acetic anhydride are mixed in a 5L flask, 5g of sulfuric acid is added, the mixture is heated to 80 ℃ to react for 10h, 720g of compound 8 is obtained by distillation, and the isolation yield is 97%.
700g of the compound 8 and 700g of toluene are mixed and then introduced into a fixed bed reactor heated to 400 ℃, the product is condensed and subjected to gas-liquid separation and then enters a storage tank, the product is rectified to obtain 330g of the compound 5, and the separation yield is 89%.
5. 300g of compound 5 and 1200g of dichloroethane are mixed in a 5L flask, then ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than 10 ℃, after the raw materials completely react, nitrogen is introduced for purging for 30min, the dichloroethane is distilled off, 282g of compound 6 is obtained from 260 ℃ fraction, and the separation yield is 90%.
6. 250g of Compound 6 was mixed with 12.5g of Ni/Nb 2 O 3 (the load of Ru is 5%) is added into a 500ml high-pressure reaction kettle, after the air in the kettle is replaced by nitrogen for three times, the hydrogen is replaced by hydrogen for three times, then 3MPa hydrogen is filled, the reaction kettle is heated to 180 ℃ for reaction, hydrogen is continuously supplemented into the reaction kettle until the pressure is not reduced continuously, after the reaction is finished, the product is rectified, the fraction at 145-150 ℃ is taken, 176g of compound 7 is obtained, and the separation yield is 88%.
7. 150g of the compound 7 and 150ml/min ammonia gas are respectively introduced into a fixed bed reactor filled with 10g H-ZSM-5, the reaction temperature is 350 ℃, and the space velocity is 0.05h -1 The product enters a storage tank after condensation and gas-liquid separation, and is rectified to obtain 165 ℃ fraction to obtain 131g of cis-7-azabicyclo [3.3.0]Octane, isolated in 87% yield.
The above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same. While the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: modifications may be made to the embodiments described above, or equivalents may be substituted for some or all of the features thereof without departing from the spirit and scope of the invention as defined by the claims; but such modifications or substitutions are intended to be included within the scope of the present invention as defined in the appended claims.
Claims (10)
1. A method for synthesizing cis-7-azabicyclo [3.3.0] octane is characterized by comprising the following steps:
(1) Introducing the compound 1 into a fixed bed reactor filled with a catalyst for dehydration reaction, condensing and carrying out gas-liquid separation on a product, then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain a compound 2;
(2) Adding the compound 2 and conjugated olefin into a high-pressure reaction kettle, maintaining pressure after replacing air in the kettle with nitrogen to ensure that the reaction kettle is not leak, heating for reaction, cooling after the reaction is finished, relieving pressure, and rectifying a product to obtain a compound 3;
(3) Mixing the compound 3 with an oxidant, performing epoxidation reaction, adding alkali for hydrolysis, and extracting to obtain a compound 4;
(4) Introducing the compound 4 into a fixed bed reactor filled with a catalyst for dehydration reaction, condensing and carrying out gas-liquid separation on a product, then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain a compound 5;
or mixing the compound 4 with acetic anhydride, adding a catalyst, heating for esterification, and distilling to obtain a compound 8; mixing the compound 8 with a solvent, introducing the mixture into a fixed bed reactor for thermal cracking reaction, condensing and separating a product from gas and liquid, and then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain a compound 5;
(5) Mixing the compound 5 with a solvent, introducing ozone into the mixture, introducing nitrogen into the mixture after the raw materials completely react, and distilling the mixture after the nitrogen is purged to obtain a compound 6;
(6) Adding the compound 6 and a catalyst into a high-pressure reaction kettle, replacing air in the kettle with hydrogen after replacing the air with nitrogen, then filling hydrogen, heating for reaction, continuously supplementing the hydrogen into the reaction kettle until the pressure does not continuously decrease, and rectifying after the reaction is finished to obtain a compound 7;
(7) Dissolving the compound 7 in an optional solvent, respectively introducing the compound and ammonia gas into a fixed bed reactor filled with a catalyst for reaction, condensing and separating the product from gas and liquid, then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain the product cis-7-azabicyclo [3.3.0] octane.
2. The process according to claim 1, characterized in that the catalyst of step (1) is selected from activated carbon, ion exchange resins, γ -Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves;
preferably, the catalyst of step (1) is selected from γ -Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves;
more preferably, said catalyst of step (1) is selected from γ -Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves;
preferably, the reaction temperature of step (1) is 100 to 400 ℃, preferably 120 to 300 ℃, more preferably 120 to 260 ℃;
preferably, the mass space velocity of the compound 1 in the step (1) is 0.1-5h -1 Preferably 0.3 to 3 hours -1 More preferably 0.5-1.5h -1 。
3. The method of claim 1, wherein the molar ratio of compound 2 to conjugated olefin of step (2) is 1:5-5:1;
preferably, the conjugated olefin of step (2) is selected from one or more of cyclopentadiene and dicyclopentadiene;
preferably, the reaction temperature of step (2) is 140 to 260 ℃, preferably 160 to 220 ℃, more preferably 160 to 200 ℃;
preferably, the reaction time of step (2) is 10min to 10h, preferably 30min to 5h, more preferably 30min to 3h.
4. The process of claim 1, wherein the oxidizing agent of step (3) is selected from one or more of peroxyformic acid, peroxyacetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid;
preferably, the molar ratio of said compound 3 to oxidant of step (3) is 1.1 to 1:3;
preferably, the epoxidation reaction temperature of step (3) is from-10 to 40 ℃, preferably from 0 to 30 ℃, more preferably from 0 to 20 ℃;
preferably, the epoxidation reaction time of step (3) is 30min to 10h, preferably 30min to 6h, more preferably 30min to 3h;
preferably, the base of step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate;
preferably, the temperature of said hydrolysis by addition of a base in step (3) is 20-70 ℃.
5. The method according to claim 1, wherein the catalyst for the dehydration reaction of step (4) is selected from Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、Yb 2 O 3 、Y 2 O 3 、La 2 O 3 、Sc 2 O 3 One or more of (a);
preferably, the dehydration reaction temperature of the step (4) is 350-550 ℃;
preferably, the feeding space velocity of the dehydration reaction in the step (4) is 0.05-1.0h -1 。
6. The process of claim 1, wherein the molar ratio of compound 4 to acetic anhydride of step (4) is 1.2 to 1:6;
preferably, the catalyst of the esterification reaction of the step (4) is selected from one or more of sulfuric acid, phosphoric acid, hydrochloric acid, amberlyst-15 and Amberlyst-35;
preferably, the esterification reaction temperature of the step (4) is 40-90 ℃;
preferably, the esterification reaction time of the step (4) is 30min-10h;
preferably, the solvent for the thermal cracking reaction of step (4) is selected from one or more of tetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, and ethyl acetate;
preferably, the thermal cracking reaction temperature of step (4) is 300 to 600 ℃, preferably 300 to 550 ℃, and more preferably 350 to 450 ℃.
7. The process according to claim 1, wherein the solvent of step (5) is selected from one or more of methanol, ethanol, dichloromethane, dichloroethane, water, formic acid, acetic acid;
preferably, the reaction temperature of step (5) is selected from-20 to 30 ℃;
preferably, the mass concentration of the compound 5 of the step (5) in the solvent is 10 to 50wt%, preferably 10 to 40wt%, more preferably 20 to 30wt%.
8. The method according to claim 1, wherein the catalyst of step (6) is a supported catalyst comprising a carrier S and a metal active ingredient M supported on the carrier;
m is selected from one or more of Cu, ni, co, ru, pd and Pt;
preferably, M is selected from one or more of Cu, ni, co and Ru;
more preferably, M is selected from one or more of Cu, ni and Ru;
s is selected from activated carbon, ion exchange resin, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves;
preferably, S is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves;
more preferably, S is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves;
preferably, the adding amount of the catalyst in the step (6) is 3-10t% of the compound 6;
preferably, the reaction temperature of step (6) is 100 to 250 ℃, preferably 120 to 200 ℃, more preferably 150 to 200 ℃;
preferably, said reaction pressure of step (6) is from 0.1 to 8MPa, preferably from 2 to 6MPa, more preferably from 3 to 5MPa.
9. The method according to claim 1, wherein the catalyst of step (7) is a supported metal oxide catalyst comprising a carrier and a metal oxide supported on the carrier;
preferably, the metal active component corresponding to the metal oxide is selected from one or more of scandium, yttrium, lanthanum, cerium, ytterbium and lutetium;
preferably, the metal active component corresponding to the metal oxide is selected from one or more of yttrium, lanthanum, cerium and ytterbium;
more preferably, the metal active component corresponding to the metal oxide is selected from one or more of lanthanum, cerium and ytterbium;
preferably, the support is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves;
preferably, the support is selected from gamma-Al 2 O 3 、SiO 2 、ZrO 2 、Nb 2 O 5 One or more of zeolite molecular sieves;
more preferably, the support is selected from gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves;
preferably, the supported metal oxide catalyst has a metal oxide loading of 0.1 to 5wt%, preferably 0.1 to 3wt%, more preferably 0.1 to 1wt%.
10. The process according to claim 9, wherein the reaction temperature of step (7) is 180-550 ℃, preferably 220-450 ℃, more preferably 250-450 ℃;
preferably, the solvent of step (7) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, dioxane, cyclohexane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, and n-dodecane;
preferably, the solvent of step (7) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, cyclohexane, n-hexane, and n-heptane;
more preferably, the solvent of step (7) is selected from one or more of methanol, ethanol, propanol, cyclohexane, n-hexane, n-heptane;
preferably, the volume ratio of the compound 7 to the solvent in step (7) is 1;
preferably, the mass space velocity of the compound 7 in the step (7) is 0.01 to 10h -1 Preferably 0.01 to 5h -1 More preferably 0.02 to 3 hours -1 ；
Preferably, the molar ratio of the compound 7 to ammonia of step (7) is 1:5-1, preferably 1:5-1, 80, more preferably 1;
preferably, said reaction pressure of step (7) is 0.1 to 3.0MPa, preferably 0.1 to 2.0MPa, more preferably 0.1 to 1.0MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210915867.4A CN115232056B (en) | 2022-08-01 | 2022-08-01 | Synthesis method of cis-7-azabicyclo [3.3.0] octane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210915867.4A CN115232056B (en) | 2022-08-01 | 2022-08-01 | Synthesis method of cis-7-azabicyclo [3.3.0] octane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115232056A true CN115232056A (en) | 2022-10-25 |
| CN115232056B CN115232056B (en) | 2024-01-26 |
Family
ID=83677413
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210915867.4A Active CN115232056B (en) | 2022-08-01 | 2022-08-01 | Synthesis method of cis-7-azabicyclo [3.3.0] octane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115232056B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005049568A1 (en) * | 2003-11-24 | 2005-06-02 | Potluri Ramesh Babu | A process for industrially viable preparation of (s,s,s) phenylmethyl-2-azabicyclo-[3.3.0]-octane-3-carboxylate tosylate |
| CN112851563A (en) * | 2020-12-30 | 2021-05-28 | 安徽金鼎医药股份有限公司 | Synthesis process of N-amino-3-azabicyclo [3,3,0] octane hydrochloride |
-
2022
- 2022-08-01 CN CN202210915867.4A patent/CN115232056B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005049568A1 (en) * | 2003-11-24 | 2005-06-02 | Potluri Ramesh Babu | A process for industrially viable preparation of (s,s,s) phenylmethyl-2-azabicyclo-[3.3.0]-octane-3-carboxylate tosylate |
| CN112851563A (en) * | 2020-12-30 | 2021-05-28 | 安徽金鼎医药股份有限公司 | Synthesis process of N-amino-3-azabicyclo [3,3,0] octane hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115232056B (en) | 2024-01-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20170107164A1 (en) | Composite metal catalyst composition, and method and apparatus for preparing 1,4-cyclohexanedimethanol using same | |
| CN105237434A (en) | Method for producing cyclohexanone oxime | |
| CN106187776B (en) | Process for producing dimethyl 1, 4-cyclohexanedicarboxylate and process for producing 1, 4-cyclohexanedimethanol | |
| CN115232056B (en) | Synthesis method of cis-7-azabicyclo [3.3.0] octane | |
| CN110078627B (en) | High-yield synthesis of H6Method for MDA | |
| CN103804143B (en) | High concentration 3 hydroxy methyl propionate Hydrogenation is for the technique of 1,3 propylene glycol | |
| CN105541542A (en) | Technique for continuously producing decahydronaphthalene from industrial naphthalene | |
| CN107501053A (en) | A kind of green synthesis method by the step alcohol ether of alkene one | |
| CN108516939A (en) | A kind of preparation method of high anti-body 4,4 '-diamino-dicyclohexyl methane of content | |
| CN111393402B (en) | N & lt/EN & gt acid/quaternary ammonium salt composite catalytic CO 2 Method for preparing cyclic carbonate by cycloaddition with epoxide | |
| CN113527062B (en) | Method and system for preparing 1, 3-propylene glycol from glycerol | |
| CN110862302B (en) | Method for preparing 1, 4-butanediol by combining slurry bed hydrogenation and fixed bed hydrogenation | |
| CN114409504B (en) | Method for preparing 1, 4-butanediol by hydrogenating 1, 4-butynediol | |
| CN115197048A (en) | Preparation method of hydrogenated bisphenol A | |
| CN115108962B (en) | Method for continuously synthesizing azabicyclo compound | |
| CN112661618B (en) | Copper catalysis preparation method of cyclopentanone | |
| CN112279783B (en) | Method for preparing 3-hydroxypropionitrile under supercritical condition | |
| CN112661619B (en) | Method for preparing cyclopentanone | |
| CN114671750B (en) | Four-ring aerospace fuel, precursor thereof and preparation method thereof | |
| CN114805098B (en) | Method for synthesizing 5-amino-1-amyl alcohol by using furfural as initial raw material | |
| CN114716325B (en) | Method for continuously preparing triethylamine | |
| CN115806495B (en) | Method for co-producing propylene glycol methyl ether and isopropanolamine | |
| CN103889967A (en) | Method for producing cis-rose oxide | |
| CN109942530B (en) | Method for simply and conveniently preparing bulgur and intermediate thereof | |
| CN116410057A (en) | Two-stage reaction, separation and purification method for synthesizing 1, 4-butanediol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |