CN115160210B - Method for synthesizing heterobicyclic compounds - Google Patents
Method for synthesizing heterobicyclic compounds Download PDFInfo
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- CN115160210B CN115160210B CN202210916901.XA CN202210916901A CN115160210B CN 115160210 B CN115160210 B CN 115160210B CN 202210916901 A CN202210916901 A CN 202210916901A CN 115160210 B CN115160210 B CN 115160210B
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- 238000000034 method Methods 0.000 title claims abstract description 69
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 105
- 239000003054 catalyst Substances 0.000 claims abstract description 41
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 35
- -1 heterobicyclic compound Chemical class 0.000 claims abstract description 35
- 230000008569 process Effects 0.000 claims abstract description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 229910052751 metal Inorganic materials 0.000 claims description 16
- 239000002184 metal Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 238000004817 gas chromatography Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 229910018072 Al 2 O 3 Inorganic materials 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 229910004298 SiO 2 Inorganic materials 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002808 molecular sieve Substances 0.000 claims description 5
- 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 5
- 229910021536 Zeolite Inorganic materials 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000010457 zeolite Substances 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 238000004140 cleaning Methods 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 4
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000009471 action Effects 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 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 6
- 239000003814 drug Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 229960000346 gliclazide Drugs 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002351 wastewater Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 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 description 4
- 150000003997 cyclic ketones Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(ii) nitrate Chemical compound [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 101100005280 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cat-3 gene Proteins 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- CSDREXVUYHZDNP-UHFFFAOYSA-N alumanylidynesilicon Chemical compound [Al].[Si] CSDREXVUYHZDNP-UHFFFAOYSA-N 0.000 description 2
- 229940124350 antibacterial drug Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 2
- 229960003702 moxifloxacin Drugs 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(ii) nitrate Chemical compound [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000002910 solid waste Substances 0.000 description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 2
- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4as,7as)-2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 description 1
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 1
- WLDMPODMCFGWAA-UHFFFAOYSA-N 3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1CCCC2C(=O)NC(=O)C21 WLDMPODMCFGWAA-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- PMRVFZXOCRHXFE-FMEJWYFOSA-L Kad 1229 Chemical compound [Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 PMRVFZXOCRHXFE-FMEJWYFOSA-L 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- DCZNCNBYKPIZRQ-UHFFFAOYSA-M sodium;2-ethyl-3-oxobutanoate Chemical compound [Na+].CCC(C(C)=O)C([O-])=O DCZNCNBYKPIZRQ-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to a method for synthesizing heterobicyclic compounds. The method takes the heterobicyclic compound containing carbonyl as a raw material, and prepares the heterobicyclic compound through hydrodeoxygenation reaction under the action of a catalyst. The method for synthesizing the heterobicyclic compound has the advantages of simple process, green route, less pollution in the reaction process, continuous operation and high efficiency.
Description
Technical Field
The application relates to the field of pharmaceutical chemistry synthesis, in particular to a method for synthesizing heterobicyclic compounds.
Background
The heterobicyclic substances have wide application in the field of medicine synthesis and are important medicine intermediates. For example, cis-perhydroisoindole consists of a six-membered carbocyclic ring and a five-membered nitrogen heterocyclic ring. It is a key intermediate for synthesizing mitiglinide calcium. The miglites calcium-resistant medicament is mainly used for treating type II diabetes, has a similar action mechanism to sulfonylurea, has a higher onset speed and a short half-life period, is beneficial to reducing postprandial blood sugar of diabetics, can avoid the hypoglycemia caused by continuous blood sugar reduction, and has the beauty of 'in vitro pancreas'.
Also for example, cis-7-azabicyclo [3.3.0] octane has a molecular structure comprising a five-membered carbocyclic ring and a five-membered azaheterocyclic ring. The gliclazide is an important intermediate in the synthesis process of the gliclazide, and the 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 countries around the world at present.
In addition, the novel broad-spectrum antibacterial drug moxifloxacin has the advantages that the novel broad-spectrum antibacterial drug moxifloxacin is an important intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane and other heterobicyclic substances applied to medicine synthesis, so that the heterobicyclic intermediate has very wide application in the field of modern medicine synthesis.
The method for synthesizing the heterobicyclo substances is mainly obtained by reducing carbonyl in imide by the corresponding imide substances through chemical reducing reagents. For example, in the synthesis of cis-7-azabicyclo [3.3.0] octane and cis-perhydroisoindole, cyclopentane-1, 2-dicarboximide or cyclohexane-1, 2-dicarboximide is generally reduced with lithium aluminum hydride (CN 184096A, WO 2009/140279 A2) to give cis-7-azabicyclo [3.3.0] octane and cis-perhydroisoindole, respectively. However, the lithium aluminum hydride reagent has high risk, high cost and complex reduction post-treatment process, so that the current process has high wastewater amount. In addition, the reduction process (process improvement of the azabicyclo of the gliclazide intermediate, gu Hu, zileuton, research on the synthesis process of gliclazide, liu Yongkuan, university of Zhengzhou treatises, new technical research on the synthesis of gliclazide, lin Yuan, university of Jinan treatises, CN 103183632A) can be realized by using the combination of sodium borohydride or potassium borohydride and Lewis acid, but the problems of wastewater and cost still cannot be solved at present.
In addition, there are reports (The Journal of Organic Chemistry,1977,42,2082-2087) that aza-bicyclo [3.3.0] octane is obtained by reduction of zinc powder after chlorination reaction with phosphorus oxychloride using aza-bicyclo [3.3.0] octane-2-one as raw material, and expensive lithium aluminum hydride and sodium borohydride are omitted in the route, but raw materials are difficult to prepare, phosphorus oxychloride and zinc powder are needed, generation of solid waste in the production process is unavoidable, and economy and environmental protection are still challenged.
There is also a report (US 8,664,408 B2,US 20120316214A1,CN 1741993A) that cis-7-azabicyclo [3.3.0] octane is obtained by directly hydrogenating cyclopentadicarboximide by catalytic hydrogenation, but the reaction temperature is generally above 260 ℃, the reaction pressure is above 20MPa, and the severe reaction conditions greatly increase the risk of the process and have higher requirements on equipment.
In summary, the synthesis process of the heterobicyclic pharmaceutical intermediates at present has the problems of high raw material price, use of dangerous and high-price reducing reagents, more wastewater, solid waste and the like in the production process, intermittent reaction, low reaction concentration and generally low production efficiency.
Disclosure of Invention
In order to solve the problems involved in the above methods, the present application aims to provide a novel method for synthesizing heterobicyclic compounds, which uses a specific catalyst to prepare the heterobicyclic compounds by hydrodeoxygenation under the action of the catalyst by using carbonyl heterobicyclic compounds as raw materials. The method for synthesizing the heterobicyclic compound has the advantages of simple process, easy separation, high yield, no pollution, continuous operation and contribution to industrial production, and the reaction byproducts are only water.
In order to achieve the above object of the present application, the following technical solutions are specifically adopted:
the application provides a method for synthesizing heterobicyclic compounds, which comprises the following steps:
the carbonyl-containing heterobicyclic compound is subjected to hydrogenation reduction and dehydration reaction in the presence of a catalyst and hydrogen to obtain the heterobicyclic compound;
wherein the catalyst is a supported catalyst M/S, M is a metal active component, and S is a carrier;
the reaction temperature is 80-250 ℃, and the reaction pressure is 0.1-8MPa.
Carbonyl-containing heterobicyclo compounds
In the method, carbonyl-containing heterobicyclo compounds are taken as raw materials, wherein the carbonyl-containing heterobicyclo compounds refer to bicyclo compounds containing carbonyl and heteroatoms on the ring, the heteroatoms (including carbonyl) are 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and typical examples are [4-6 membered cyclic ketone ] and [5-6 membered heterocycle ], wherein the heteroatoms of the [5-6 membered heterocycle ] are 1 to 2 heteroatoms selected from nitrogen or oxygen, and the heterocycle is a saturated ring or an unsaturated ring.
In some embodiments, the [4-6 membered cyclic ketone ] and [5-6 membered heterocycle ] is selected from structures of formulas 1-8 below:
wherein n is 1 、n 2 、n 3 、n 4 、n 5 、n 6 、n 7 、n 8 Each independently selected from 0, 1 or 2; m is m 1 、m 2 、m 3 、m 4 、m 5 、m 6 、m 7 、m 8 Each independently selected from 1 or 2;
R 1 、R 2 、R 3 、R 4 each independently selected from hydrogen or C1-C6 alkyl, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl;
represents a single bond or a double bond, and represents a single bond or no bond.
In some embodiments, [4-6 membered cyclic ketone ] and [5-6 membered heterocycle ] is selected from the following compounds:
the carbonyl-containing heterobicyclic compound is subjected to hydrogenation reduction and dehydration reaction to obtain the corresponding heterobicyclic compound.
In some embodiments, the corresponding heterobicyclic compounds after the [4-6 membered cyclic ketone ] and [5-6 membered heterocycle ] reaction are selected from the structures of formulas 9-12 below:
wherein n is 1 、n 2 、n 5 、n 6 Each independently selected from 0, 1 or 2; m is m 1 、m 2 、m 5 、m 6 Each independently selected from 1 or 2;
R 1 、R 2 each independently selected from hydrogen or C1-C6 alkyl, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
Catalyst
In the method, the catalyst is a supported catalyst M/S, M is a metal active component, S is a carrier, namely the catalyst comprises a carrier S and a metal active component M supported on the carrier.
In some embodiments, M is selected from one or more of Cu, ni, co, fe, pd, pt, ru, rh, ir;
preferably, M is selected from one or more of Cu, ni, co, ru, pd, pt;
more preferably, M is selected from one or more of Cu, ni, ru, pd.
In some embodiments, S is selected from activated carbon, ion exchange resins, 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, H. Beta. Manufactured by Tianjin southbound catalyst Co., ltd.);
preferably S is selected from ion exchange resins, 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, H. Beta. Manufactured by Tianjin southbound catalyst Co., ltd.);
more preferably S is selected from 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, H. Beta. Manufactured by Tianjin southbound catalyst Co., ltd.).
Preferably, the metal M comprises 0.5-20wt%, preferably 0.5-10wt%, more preferably 1-8wt% of the catalyst.
Reaction conditions
In the method, the reaction temperature is 80-250 ℃ (for example 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 ℃), and the reaction pressure is 0.1-8MPa (0.1, 0.2, 0.5, 0.6, 0.8, 1,2, 3, 4, 5, 6, 7, 8 MPa).
The process can be carried out with or without solvent.
The solvent can be selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, cyclohexane, n-hexane and n-heptane;
preferably, the solvent is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane;
more preferably, the solvent is selected from one or more of water, methanol, isopropanol, dioxane.
The method mainly takes heterobicyclic ketone as a raw material, and a target product is heterobicyclic, and the principle is as follows:
in one embodiment, a method of synthesizing a heterobicyclic compound comprises the steps of:
1) Loading the catalyst into a fixed bed reactor, heating to a reaction temperature in a hydrogen atmosphere (preferably at 3 ℃/min) for 1-8h to activate the catalyst (the metal active component in the application is a metal simple substance, the hydrogen activation (reduction) process of the catalyst is already described), and after the activation is finished, regulating the system to the reaction pressure;
2) And uniformly mixing the carbonyl-containing heterobicyclo compound with an optional solvent, pumping the mixture into a reactor for reaction, and collecting the mixture after passing through a condenser and a gas-liquid separator to obtain the product.
The reaction temperature in the step 1) is 80-250 ℃;
preferably, the reaction temperature is 100-220 ℃;
more preferably, the reaction temperature is 120-200 ℃.
The reaction pressure in the step 1) is 0.1-8MPa;
preferably, the reaction pressure is 0.5-6MPa;
more preferably, the reaction pressure is 1.0 to 5MPa.
The volume ratio of the carbonyl-containing heterobicyclo compound to the solvent in the step 2) is 1:0.1-1:50;
preferably, the volume ratio is 1:0.5-1:20;
more preferably 1:1 to 1:5; it is emphasized that it is also possible to work without solvent.
In step 2), the reaction feed mass space velocity (calculated as carbonyl-containing heterobicyclic species) is from 0.05 to 8h -1 ；
Preferably, the space velocity of the feed mass is 0.05 to 5h -1 ；
More preferably 0.05-3h -1 。
Wherein the mass flow unit of the carbonyl-containing heterobicyclo is g/min, and the mass unit of the catalyst is g.
In the step 2), the molar ratio of the carbonyl-containing heterobicyclo compound to the hydrogen in the reaction is 1:5-1:100;
preferably, the molar ratio is 1:5 to 1:80;
more preferably 1:5 to 1:40.
In the dehydration reaction, the efficiency of the continuous reaction using a fixed bed is obviously improved compared with that of the continuous reaction using a reaction kettle, mainly because the dehydration reaction is a reversible reaction, and the generated water cannot be timely removed from the system in the reaction kettle, so that the reaction is gradually slowed down.
In another embodiment, a method of synthesizing a heterobicyclic compound comprises the steps of:
1) Cleaning a reaction kettle, adding the catalyst, the carbonyl-containing heterobicyclo compound serving as a reactant and an optional solvent into the reaction kettle, and sealing the reaction kettle.
2) After the air tightness of the reaction kettle is determined by pressure maintaining with nitrogen, the air in the kettle is replaced with nitrogen for three times, the nitrogen in the kettle is replaced with hydrogen for three times, and the hydrogen is filled to the reaction pressure.
3) The reaction vessel was heated to the reaction temperature, the pressure in the reaction vessel was kept constant (hydrogen was charged into the vessel), and a certain reaction time was maintained.
4) After the reaction is finished, cooling, decompressing, replacing hydrogen in the kettle with nitrogen, and detecting a product by using gas chromatography.
The volume ratio of the carbonyl-containing heterobicyclic compound to the solvent in the step 1) is 1:1-1:50;
preferably, the volume ratio is 1:1-1:20;
more preferably 1:1 to 1:10; it is emphasized that it is also possible to work without solvent.
The reaction pressure in the step 2) is 0.5-8.0MPa;
preferably, the reaction pressure is 0.5-6.0MPa;
more preferably, the reaction pressure is 1.0 to 5.0MPa.
The reaction temperature in the step 3) is 80-250 ℃;
preferably, the reaction temperature is 90-200 ℃;
more preferably, the reaction temperature is 120-200 ℃.
The reaction time in the step 3) is 0.5-24h;
preferably, the reaction time is 3-16 hours;
more preferably, the reaction time is 4 to 10 hours.
The beneficial effects are that:
the method for continuously synthesizing the heterobicyclic substances is green in route, capable of continuously producing, high in efficiency, simple in production process, capable of avoiding the use of dangerous and expensive chemical reducing agents due to the fact that the main byproduct is water, and free of generating corrosive waste water. Compared with the traditional method, the method is easy to realize industrial production.
The present application has been described in detail hereinabove, but the above embodiments are merely exemplary in nature and are not intended to limit the present application. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or summary or the following examples.
Detailed Description
The application 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 application as claimed.
Unless otherwise indicated, all materials, reagents, methods and the like used in the examples are those conventionally used in the art.
In the following examples, carbonyl-containing heterobicyclic species, e.g. Obtaining medicine after purchasing; /> Purchased from Enamine MADE Building Blocks; />Purchased from le yan reagent; />Purchasing from a TRC reagent;
deionized water is self-made;
n-heptane, ethyl acetate, 1, 4-dioxane were purchased from national pharmaceutical group chemical reagent company, inc; nickel nitrate, palladium nitrate, ruthenium chloride, copper nitrate were purchased from national pharmaceutical group chemical reagent limited;
the H-ZSM-5 molecular sieve was purchased from Tianjin southbound catalyst Co., ltd;
γ-Al 2 O 3 and SiO 2 Purchased from Qingdao sea wave silica gel desiccant Co., ltd;
high purity nitrogen and high purity hydrogen were purchased from Qingdao de Hai Wei industry Co., ltd.
In the method for preparing the heterobicyclic compound, carbonyl-containing heterobicyclic compound and hydrogen are used as raw materials, and the heterobicyclic compound is obtained through high-temperature and high-pressure reaction under the action of a catalyst. The obtained product was filtered through a 0.22 μm filter and analyzed by Gas Chromatography (GC). Gas chromatography detection conditions: instrument: island GC2010Plus, chromatographic column: intercap-FFAP,30 mX0.25mm X0.25 um, vaporization chamber temperature 250 ℃, FID temperature 300 ℃, column oven temperature program: the temperature is kept at 60 ℃ for 1min, and then the temperature is increased to 230 ℃ at a speed of 15 ℃/min for 10min. The reaction product was characterized by gas chromatography-mass spectrometry (GC-MS). The product was quantitatively determined by Shimazu-GC 2010plus gas chromatography. The correlation calculation formula is as follows:
catalyst preparation examples
Preparation example 1
1) 200g of nickel nitrate was added to the reaction vessel, and 5.0L of water was added for dissolution.
2) 500g of gamma-Al 2 O 3 The carrier (spherical, 3mm diameter) was added to the aqueous metal precursor solution, stirred for 2 hours and evaporated to dryness.
3) Drying the obtained solid at 120 ℃ for 24 hours, and roasting at 550 ℃ for 6 hours to obtain the catalyst 1.
Preparation example 2
1) 200g of nickel nitrate was added to the reaction vessel, and 3.0L of water was added for dissolution.
2) 500g of SiO 2 The carrier (spherical, 3mm diameter) was added to the aqueous metal precursor solution, stirred for 2 hours and evaporated to dryness.
3) Drying the obtained solid at 120 ℃ for 24 hours, and roasting at 550 ℃ for 6 hours to obtain the catalyst 2.
Preparation example 3
1) 200g of nickel nitrate was added to the reaction vessel, and 3.0L of water was added for dissolution.
2) 500g H-ZSM-5 carrier (silicon-aluminum ratio 80, spherical, diameter 3 mm) was added to the above metal precursor aqueous solution, stirred for 2 hours, and then evaporated to dryness.
3) Drying the obtained solid at 120 ℃ for 24 hours, and roasting at 550 ℃ for 6 hours to obtain the catalyst 3.
Preparation example 4
1) 30g of ruthenium chloride was added to the reaction vessel, and 1.0L of water was added for dissolution.
2) 300g H-ZSM-5 carrier (silicon-aluminum ratio 80, spherical, diameter 3 mm) was added to the above metal precursor aqueous solution, stirred for 4 hours, and then evaporated to dryness.
3) Drying the obtained solid at 120 ℃ for 24 hours, and roasting at 550 ℃ for 6 hours to obtain the catalyst 4.
Preparation example 5
1) 200g of copper nitrate was added to the reaction vessel, and 3.0L of water was added for dissolution.
2) 500g of gamma-Al 2 O 3 The carrier (spherical, 3mm diameter) was added to the aqueous metal precursor solution, stirred for 3 hours and evaporated to dryness.
3) Drying the obtained solid at 120 ℃ for 24 hours, and roasting at 550 ℃ for 6 hours to obtain the catalyst 5.
Preparation example 6
1) 10g of palladium nitrate was added to the beaker, and 200ml of water was added thereto and stirred well.
2) 100g of gamma-Al 2 O 3 Adding the powder into the metal precursor solution, stirring for 4 hours, and standing for 24 hours.
3) Evaporating the mixture to dryness, drying the obtained solid at 120 ℃ for 24 hours, and roasting at 550 ℃ for 6 hours to obtain the catalyst 6.
Examples
Examples 1 to 6 (continuous reaction)
1) 200g of catalyst (spherical, 3mm in diameter) was charged into a fixed bed reactor (reaction tube having an inner diameter of 20mm and a length of 100 cm), the temperature was raised from room temperature to 200℃at 3℃per minute under a hydrogen purge of 100ml/min, the catalyst was activated for 4 hours, and then the system pressure was adjusted to the reaction pressure;
2) The carbonyl-containing heterobicyclic compound is pumped into the catalyst bed by a plunger pump for reaction. And collecting the waste water after passing through a condenser and a gas-liquid separator, and performing GC detection. Specific reaction conditions and results are shown in the following table.
Example 7 (batch reaction)
1) The reaction vessel was cleaned, and 50g of the mixture was charged into a 10L reaction vessel2g of catalyst 6, 300g of n-heptane and sealing the reaction kettle.
2) After the air tightness of the reaction kettle is ensured by using nitrogen to be maintained, the air in the kettle is replaced by nitrogen for three times, the nitrogen in the kettle is replaced by hydrogen for three times, and the pressure of the nitrogen is increased to 3MPa.
3) The reaction vessel was heated to 150℃and the pressure in the reaction vessel was maintained constant at 4.5MPa (hydrogen was fed into the vessel) and the reaction time was maintained.
4) After the reaction is finished for 15 hours, cooling and pressure relief are carried out, after hydrogen in the kettle is replaced by nitrogen, the conversion rate is detected by gas chromatography, and the product is obtainedThe selectivity was 96%.
Examples 8 to 20 (continuous reaction)
1) 200g of catalyst (spherical, 3mm in diameter) was charged into a fixed bed reactor (reaction tube having an inner diameter of 20mm and a length of 100 cm), the temperature was raised from room temperature to 200℃at 3℃per minute under a hydrogen purge of 100ml/min, the catalyst was activated for 4 hours, and then the system pressure was adjusted to the reaction pressure;
2) The carbonyl-containing heterobicyclic compound is pumped into the catalyst bed by a plunger pump for reaction. And collecting the waste water after passing through a condenser and a gas-liquid separator, and performing GC detection. Specific reaction conditions and results are shown in the following table.
As can be seen from the results of the examples, the catalyst in the preparation examples has high reactivity to various carbonyl-containing heterobicyclic compounds, and can synthesize heterobicyclic compounds with high selectivity. Compared with the batch kettle type reaction, the continuous type reaction (fixed bed reactor) is easier to obtain higher yield, mainly because a dehydration process exists in the reaction process, and a water removal process is a reversible reaction.
The above embodiments are only for illustrating the technical solution of the present application, and are not limited thereto. Although the application has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some or all of the technical features thereof, without departing from the spirit and scope of the present application as defined in the claims; and such modifications or substitutions are intended to be within the scope of the present application as defined by the claims.
Claims (33)
1. A method for synthesizing heterobicyclic compounds, comprising the steps of:
the carbonyl-containing heterobicyclic compound is subjected to hydrogenation reduction and dehydration reaction in the presence of a catalyst and hydrogen to obtain the heterobicyclic compound; the carbonyl-containing heterobicyclo compound is selected from the structures shown in the following formulas 1-8:
wherein n is 1 、n 2 、n 3 、n 4 、n 5 、n 6 、n 7 、n 8 Each independently selected from 0, 1 or 2; m is m 1 、m 2 、m 3 、m 4 、m 5 、m 6 、m 7 、m 8 Each independently selected from 1 or 2;
R 1 、R 2 、R 3 、R 4 each independently selected from hydrogen or C1-C6 alkyl;
represents a single bond or a double bond, ">Represents a single bond or no;
the heterobicyclic compounds are selected from the structures of the following formulas 9-12:
wherein the catalyst is a supported catalyst M/S, wherein M is a metal active ingredient selected from Cu, ni, pd, ru, S is a carrier selected from gamma-Al 2 O 3 、SiO 2 One of zeolite molecular sieves;
the reaction temperature is 80-250 ℃, and the reaction pressure is 0.1-8MPa.
2. The method according to claim 1, wherein the carbonyl-containing heterobicyclic compound is selected from the group consisting of:
3. the method according to claim 1, wherein the metal active ingredient accounts for 0.5-20wt% of the catalyst.
4. A method according to claim 3, characterized in that the metal active ingredient is present in an amount of 0.5-10wt% of the catalyst.
5. The process according to claim 4, wherein the metal active ingredient is present in an amount of 1 to 8 wt.% of the catalyst.
6. A method according to claim 1 or 2, characterized in that the method comprises the steps of:
1) Loading the catalyst into a fixed bed reactor, heating to a reaction temperature in a hydrogen atmosphere, and maintaining for 1-8h to activate the catalyst, and adjusting the system to the reaction pressure after the activation is finished;
2) And uniformly mixing the carbonyl-containing heterobicyclic compound with an optional solvent, pumping the mixture into a reactor for reaction, and collecting the mixture after passing through a condenser and a gas-liquid separator to obtain the heterobicyclic compound.
7. The method according to claim 6, wherein the reaction temperature in step 1) is 100-220 ℃; the reaction pressure in the step 1) is 0.5-6MPa.
8. The method according to claim 7, wherein the reaction temperature in step 1) is 120-200 ℃; the reaction pressure in the step 1) is 1.0-5MPa.
9. The method according to claim 6, wherein the volume ratio of carbonyl-containing heterobicyclic compound to solvent in step 2) is 1:0.1-1:50.
10. The process according to claim 9, wherein the volume ratio of carbonyl-containing heterobicyclic compound to solvent in step 2) is 1:0.5-1:20.
11. The method according to claim 10, wherein the volume ratio of carbonyl-containing heterobicyclic compound to solvent in step 2) is 1:1-1:5.
12. The process according to claim 6, wherein the reaction feed mass space velocity in step 2) is from 0.05 to 8h -1 。
13. The process according to claim 12, wherein the reaction feed mass space velocity in step 2) is from 0.05 to 5h -1 。
14. The process according to claim 13, wherein the reaction feed mass space velocity in step 2) is from 0.05 to 3h -1 。
15. The process according to claim 6, wherein the molar ratio of carbonyl-containing heterobicyclic compound to hydrogen in the reaction of step 2) is 1:5 to 1:100.
16. The process according to claim 15, wherein the molar ratio of carbonyl-containing heterobicyclic compound to hydrogen in the reaction of step 2) is 1:5 to 1:80.
17. The process according to claim 16, wherein the molar ratio of carbonyl-containing heterobicyclic compound to hydrogen in the reaction of step 2) is from 1:5 to 1:40.
18. The method according to claim 6, wherein the solvent in step 2) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, cyclohexane, n-hexane, n-heptane.
19. The method of claim 18, wherein the solvent in step 2) is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane.
20. The method of claim 19, wherein the solvent in step 2) is selected from one or more of water, methanol, isopropanol, 1, 4-dioxane.
21. The method according to claim 1 or 2, comprising the steps of:
1) Cleaning a reaction kettle, adding the catalyst, the carbonyl-containing heterobicyclo compound serving as a reactant and an optional solvent into the reaction kettle, and sealing the reaction kettle;
2) After the pressure maintaining of the nitrogen is used for determining that the reaction kettle is airtight, replacing the air in the kettle with the nitrogen, replacing the nitrogen in the kettle with the hydrogen, and filling the hydrogen to the reaction pressure;
3) Heating the reaction kettle to a reaction temperature, keeping the pressure in the reaction kettle constant, and keeping a certain reaction time;
4) After the reaction is finished, cooling and pressure relief are carried out, and after hydrogen in the kettle is replaced by nitrogen, the heterobicyclic compound is detected by gas chromatography.
22. The method according to claim 21, wherein the volume ratio of carbonyl-containing heterobicyclo compound to solvent in step 1) is 1:1 to 1:50.
23. The method according to claim 22, wherein the volume ratio of carbonyl-containing heterobicyclo compound to solvent in step 1) is 1:1-1:20.
24. The method according to claim 23, wherein the volume ratio of carbonyl-containing heterobicyclo compound to solvent in step 1) is 1:1-1:10.
25. The method of claim 21, wherein the solvent in step 1) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, cyclohexane, n-hexane, n-heptane.
26. The method of claim 25, wherein the solvent in step 1) is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane.
27. The method of claim 26, wherein the solvent in step 1) is selected from one or more of water, methanol, isopropanol, 1, 4-dioxane.
28. The process according to claim 21, wherein the reaction pressure in step 2) is 0.5-8.0MPa.
29. The process of claim 28, wherein the reaction pressure in step 2) is 0.5-6.0MPa.
30. The process of claim 29, wherein the reaction pressure in step 2) is 1.0-5.0MPa.
31. The method according to claim 21, wherein the reaction temperature in step 3) is 80-250 ℃; the reaction time in step 3) is 0.5 to 24 hours.
32. The method according to claim 31, wherein the reaction temperature in step 3) is 90-200 ℃; the reaction time in the step 3) is 3-16h.
33. The method of claim 32, wherein the reaction temperature in step 3) is 120-200 ℃; the reaction time in step 3) is 4-10h.
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