CN115677463A - Simple preparation method of beta-cyclocitral - Google Patents
Simple preparation method of beta-cyclocitral Download PDFInfo
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- CN115677463A CN115677463A CN202110837238.XA CN202110837238A CN115677463A CN 115677463 A CN115677463 A CN 115677463A CN 202110837238 A CN202110837238 A CN 202110837238A CN 115677463 A CN115677463 A CN 115677463A
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- Prior art keywords
- formula
- reaction
- cyclocitral
- compound
- reagent
- Prior art date
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- MOQGCGNUWBPGTQ-UHFFFAOYSA-N 2,6,6-trimethyl-1-cyclohexene-1-carboxaldehyde Chemical compound CC1=C(C=O)C(C)(C)CCC1 MOQGCGNUWBPGTQ-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 239000000203 mixture Substances 0.000 claims abstract description 47
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 36
- 238000006170 formylation reaction Methods 0.000 claims abstract description 32
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 25
- 230000022244 formylation Effects 0.000 claims abstract description 25
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 25
- 238000003379 elimination reaction Methods 0.000 claims abstract description 19
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 16
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 14
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000007259 addition reaction Methods 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 239000002904 solvent Substances 0.000 claims description 34
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 235000019270 ammonium chloride Nutrition 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- 238000004821 distillation Methods 0.000 claims description 10
- 239000003999 initiator Substances 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000001895 2,6,6-trimethylcyclohex-2-ene-1-carbaldehyde Substances 0.000 claims description 8
- ZVZRJSHOOULAGB-UHFFFAOYSA-N alpha-Cyclocitral Chemical compound CC1=CCCC(C)(C)C1C=O ZVZRJSHOOULAGB-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 230000008707 rearrangement Effects 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 4
- OKNLBTNZLUNRDW-UHFFFAOYSA-N hydrogen peroxide;hydrobromide Chemical compound Br.OO OKNLBTNZLUNRDW-UHFFFAOYSA-N 0.000 claims description 4
- CABDFQZZWFMZOD-UHFFFAOYSA-N hydrogen peroxide;hydrochloride Chemical compound Cl.OO CABDFQZZWFMZOD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- -1 methyl formate alkane Chemical class 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- XLERAVUWMMIYNR-UHFFFAOYSA-M I(=O)(=O)O.[I-].[Na+] Chemical compound I(=O)(=O)O.[I-].[Na+] XLERAVUWMMIYNR-UHFFFAOYSA-M 0.000 claims description 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 235000011116 calcium hydroxide Nutrition 0.000 claims description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- LFVNVDAPBHPGQA-UHFFFAOYSA-N hydrogen peroxide hydroiodide Chemical compound I.OO LFVNVDAPBHPGQA-UHFFFAOYSA-N 0.000 claims description 2
- CBEQRNSPHCCXSH-UHFFFAOYSA-N iodine monobromide Chemical compound IBr CBEQRNSPHCCXSH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- PKIJMLKOTJOFDG-UHFFFAOYSA-N sodium hypochlorite hydrochloride Chemical compound [Na+].Cl.[O-]Cl PKIJMLKOTJOFDG-UHFFFAOYSA-N 0.000 claims description 2
- PVHJZOQELQLRCN-UHFFFAOYSA-M sodium;bromic acid;bromide Chemical compound [Na+].Br.[O-]Br(=O)=O PVHJZOQELQLRCN-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 17
- PSQYTAPXSHCGMF-BQYQJAHWSA-N β-ionone Chemical compound CC(=O)\C=C\C1=C(C)CCCC1(C)C PSQYTAPXSHCGMF-BQYQJAHWSA-N 0.000 description 10
- 239000007789 gas Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- VLRGXXKFHVJQOL-UHFFFAOYSA-N 3-chloropentane-2,4-dione Chemical compound CC(=O)C(Cl)C(C)=O VLRGXXKFHVJQOL-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- SFEOKXHPFMOVRM-UHFFFAOYSA-N (+)-(S)-gamma-ionone Natural products CC(=O)C=CC1C(=C)CCCC1(C)C SFEOKXHPFMOVRM-UHFFFAOYSA-N 0.000 description 5
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 5
- 229940043350 citral Drugs 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- LKOKKQDYMZUSCG-UHFFFAOYSA-N 3,5,5-Trimethyl-3-cyclohexen-1-one Chemical compound CC1=CC(C)(C)CC(=O)C1 LKOKKQDYMZUSCG-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000006385 ozonation reaction Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229930002839 ionone Natural products 0.000 description 2
- 150000002499 ionone derivatives Chemical class 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- DDDIVAXBYDCLRR-FLPUTOKSSA-N (e)-1-[(1r,6r)-2,2,6-trimethylcyclohexyl]but-2-en-1-one Chemical compound C\C=C\C(=O)[C@@H]1[C@H](C)CCCC1(C)C DDDIVAXBYDCLRR-FLPUTOKSSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BGTBFNDXYDYBEY-FNORWQNLSA-N 4-(2,6,6-Trimethylcyclohex-1-enyl)but-2-en-4-one Chemical compound C\C=C\C(=O)C1=C(C)CCCC1(C)C BGTBFNDXYDYBEY-FNORWQNLSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Chemical group 0.000 description 1
- 235000021466 carotenoid Nutrition 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
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- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
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Abstract
The invention provides a simple preparation method of beta-cyclocitral, which comprises the steps of preparing 1, 2-dihalogen-1, 3-trimethylcyclohexane by addition reaction of 1, 3-trimethylcyclohexene and a halogen reagent, then obtaining a mixture of 2-halogeno-1, 3-trimethylcyclohexene and 3-halogeno-2, 4-trimethylcyclohexene by elimination reaction under the action of alkali, obtaining a corresponding Grignard reagent by Grignard reaction of the obtained mixture and magnesium powder, and then preparing the beta-cyclocitral by formylation reaction of the corresponding Grignard reagent and a formylation reagent. The preparation method has the advantages of cheap and easily-obtained raw materials, simple steps, simple operation, safety, environmental protection, easy realization, high reaction atom economy and selectivity, high yield and purity, low product cost and suitability for green industrial production.
Description
Technical Field
The invention relates to a simple preparation method of beta-cyclocitral, belonging to the technical field of fine chemical production.
Background
Beta-cyclocitral, also known as 2, 6-Trimethyl-1-cyclohexene-1-carbaldehyde, known as 2, 6-trimethy-1-cyclohexene-1-carboxaldehyde, CAS number 432-25-7. The beta-cyclocitral has wide application and can be used for preparing various spice compounds such as beta-ionone, vitamin A, retinoic acid, beta-carotene, carotenoid, dihydrodamascone, damascone and the like.
The structural formula of beta-cyclocitral is as follows:
at present, the following two technical routes are mainly adopted for preparing the beta-cyclocitral.
1. Ozonization and reduction hydrolysis method of beta-ionone
The literature of Yunnan chemical industry, 2004, 31 (1), 1-4, takes beta-ionone as a raw material, ozonizes the product in methanol at low temperature, reduces the product by a reducing agent, hydrolyzes the product to prepare beta-cyclocitral, the total yield is 85 percent, the product content is 93 percent, and the reaction process is described as the following synthetic route 1.
The synthetic route 1 has many disadvantages: the raw material beta-ionone is generally prepared by condensing citral and acetone to obtain basic ionone and cyclizing the basic ionone by concentrated sulfuric acid, the price is higher, and the atom economy of the method for reversely synthesizing the beta-cyclocitral by using the beta-ionone with higher price is low; the ozonization reaction temperature is low, the stability of ozonide is poor, and the industrial safe operation is not facilitated; incomplete ozonization conversion, poor ozonization selectivity, low product content and difficult obtaining of high-content products.
2. Imidization and cyclization method of citral
The literature, "chemistry world, 2005, 10, 614" and "college chemical engineering journal, 2011, 25 (3), 538-542" uses citral as a raw material, firstly uses aniline, butylamine, cyclohexylamine, propylamine, methylamine and other primary or secondary amines to protect aldehyde groups to form imine, then cyclizes at low temperature in the presence of a large amount of sulfuric acid, finally hydrolyzes and removes amine to obtain a mixture of alpha-cyclocitral and beta-cyclocitral, and then rearranges under an alkaline condition to prepare the beta-cyclocitral, wherein the total yield is generally 78-85%, and the reaction process is described as the following synthetic route 2.
Although the data of the route are reported more, the citral price of the method is high, the citral imine has poor stability, the cyclization reaction needs to be carried out at low temperature in a large amount of concentrated sulfuric acid (the mass ratio of the concentrated sulfuric acid to the substrate is about 1.5-2.5), the temperature requirement is high, oxidation and polymerization side reactions are easy to generate, a large amount of high-COD acidic wastewater is generated by post-treatment, the environmental protection property is poor, and the requirement of green industrial production cannot be met.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a simple preparation method of beta-cyclocitral. The preparation method has the advantages of cheap and easily-obtained raw materials, simple steps, simple operation, safety, environmental protection, easy realization, high reaction atom economy and selectivity, high yield and purity, low product cost and suitability for green industrial production.
Description of terms:
a compound of formula II: 1, 3-trimethylcyclohexene;
a compound of formula III: 1, 2-dihalo-1, 3-trimethylcyclohexane;
a compound of formula IV: 2-halo-1, 3-trimethylcyclohexene;
a compound of formula V: 3-halo-2, 4-trimethylcyclohexene;
a compound of formula I: beta-cyclocitral.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a preparation method of beta-cyclocitral comprises the following steps:
(1) In a solvent A, a compound shown in a formula II and a halogen reagent are subjected to addition reaction to prepare a compound shown in a formula III; then in a solvent B and under the action of alkali, a mixture of a compound shown in a formula IV and a compound shown in a formula V is obtained through elimination reaction;
wherein, in the structural formulas of the compound of the formula III, the compound of the formula IV and the compound of the formula V, a substituent X is Cl, br or I;
(2) In a solvent C, under the action of an initiator, a mixture of a compound shown in a formula IV and a compound shown in a formula V and magnesium powder are subjected to Grignard reaction to obtain a corresponding Grignard reagent, and then the Grignard reagent and a formylation reagent are subjected to formylation to prepare beta-cyclocitral (I);
according to the present invention, preferably, in step (1), the solvent a is one or a combination of two or more of dichloromethane, dichloroethane, toluene, chlorobenzene, tetrahydrofuran or acetonitrile; the mass ratio of the solvent A to the compound shown in the formula II is (2-15) to 1; preferably, the mass ratio of the solvent A to the compound of the formula II is (4-12): 1.
According to the invention, preferably, the halogen reagent in the step (1) is chlorine, hydrochloric acid-sodium hypochlorite, hydrochloric acid-hydrogen peroxide, bromine, hydrobromic acid-sodium bromate, hydrobromic acid-hydrogen peroxide, iodine chloride, iodine bromide, hydroiodic acid-hydrogen peroxide or hydroiodic acid-sodium iodate; preferably, the halogen reagent is chlorine, hydrobromic acid-hydrogen peroxide, bromine or hydrochloric acid-hydrogen peroxide.
According to the invention, in the step (1), the molar ratio of the compound which is subjected to the halogenation reaction in the halogen reagent to the compound shown in the formula II is preferably (1.0-3.0): 1.
According to the present invention, it is preferable that the temperature of the addition reaction of the compound of formula II and the halogen reagent in step (1) is 0 to 100 ℃; preferably, the temperature of the addition reaction is 20 to 50 ℃. The addition reaction time is 1 to 8 hours; preferably, the addition reaction time is 2 to 6 hours.
According to the present invention, preferably, the solvent B in step (1) is one or a combination of two or more of dichloromethane, dichloroethane, toluene, chlorobenzene, tetrahydrofuran, acetonitrile or water; the mass ratio of the solvent B to the compound shown in the formula II is (3-20) to 1.
According to the present invention, it is preferable that the base in step (1) is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium hydrogencarbonate, calcium hydroxide, sodium sulfite, sodium hydrogensulfite, triethylamine, diisopropylethylamine, pyridine, lutidine or quinoline; the molar ratio of the alkali to the compound shown in the formula II is (1.0-2.0): 1.
According to the present invention, it is preferable that the elimination reaction temperature in step (1) is 0 to 100 ℃; preferably, the elimination reaction temperature is 10 to 50 ℃. The elimination reaction time is 1 to 6 hours; preferably, the elimination reaction time is 2 to 4 hours.
According to the present invention, preferably, in step (1), the addition reaction and the elimination reaction can be carried out in a "one-pot" manner.
According to the present invention, preferably, in the step (1), the reaction solution obtained by the elimination reaction is allowed to stand for layering, and the organic phase is washed with water and distilled to recover the solvent, and then is directly used in the next reaction.
According to the present invention, preferably, in the step (2), the solvent C is one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, methoxycyclopentane, hexane, heptane or toluene; the mass ratio of the solvent C to the mixture of the compound shown in the formula IV and the compound shown in the formula V is (2-10): 1.
According to the present invention, preferably, in the step (2), the initiator is one or a combination of iodine, bromoethane or 1, 2-dibromoethane; the mass of the initiator is 0.5-5.0% of the mass of the mixture of the compound of the formula IV and the compound of the formula V; preferably, the mass of the initiator is 0.5% to 3.0% of the mass of the mixture of the compound of formula IV and the compound of formula v.
According to the present invention, it is preferred that in step (2), the formylation reagent is N, N-dimethylformamide, ethyl formate, methyl formate alkane or hydrogen cyanide; preferably, the formylation agent is N, N-dimethylformamide.
According to the invention, in the step (2), the molar ratio of the magnesium powder, the formylation reagent, the mixture of the compound shown in the formula IV and the compound shown in the formula V is (1.0-1.5) to (1.0-3.5) 1; preferably, the molar ratio of the mixture of magnesium powder, formylating agent, compound of formula IV and compound of formula V is (1.1-1.3): 1.5-2.5): 1.
According to the present invention, it is preferable that, in the step (2), the Grignard reaction temperature is 20 to 60 ℃; preferably, the grignard reaction temperature is 25-45 ℃. The Grignard reaction time is 1 to 5 hours; preferably, the grignard reaction time is 2 to 3 hours. The Grignard reaction is carried out under the protection of inert gas.
According to the present invention, it is preferred that in step (2), the mixture of the compound of formula IV and the compound of formula v is added to the reaction system in two portions, that is: firstly, adding a mixture of the compound of the formula IV and the compound of the formula V into a system containing a solvent B, an initiator and magnesium powder, wherein the total mass of the mixture is 1-10% of the total mass of the compound of the formula IV and the compound of the formula V, and then adding the rest of the mixture of the compound of the formula IV and the compound of the formula V into the system in a dropwise manner.
According to the present invention, it is preferable that, in the step (2), the reaction temperature of the Grignard reagent and the formylation reagent is from-20 to 35 ℃; preferably, the reaction temperature of the grignard reagent and the formylation reagent is 5 to 20 ℃. The reaction time of the grignard reagent and formylation reagent is 0.5 to 5 hours, preferably 1 to 3 hours. The reaction of the Grignard reagent and the formylation reagent is carried out under the protection of inert gas.
According to the present invention, preferably, in step (2), the Grignard reaction and formylation reaction can be carried out in a "one-pot" manner.
According to the present invention, it is preferable that, in the step (2), the formylation reagent is added dropwise to the reaction system containing the Grignard reagent.
According to the present invention, it is preferable that the step (2) further comprises a rearrangement conversion and acidification step after the formylation reaction. Formylating a Grignard reagent and a formylation reagent generated by the mixture of the compound of the formula IV and the compound of the formula V to respectively obtain beta-cyclocitral and alpha-cyclocitral; wherein, the alpha-cyclocitral can be converted into the beta-cyclocitral through rearrangement.
Preferably, the rearrangement conversion is completed by adjusting the pH of the system to 9-10 by using 10-30wt% ammonium chloride aqueous solution and then stirring the system for reaction at 15-35 ℃ for 1-3 hours.
Preferably, the acidification is to adjust the pH of the system to 3-5 by using ammonium chloride aqueous solution with the mass concentration of 10-30 wt%.
According to the present invention, it is preferable that in the step (2), the reaction solution obtained by the reaction of the grignard reagent and the formylation reagent is subjected to the following post-treatment method: adding the reaction solution or the residue obtained after the solvent is recovered from the reaction solution through reduced pressure distillation into a mixture of water and dichloromethane, adjusting the pH value to 9-10 by using an ammonium chloride aqueous solution, stirring and converting for 1-3 hours at 15-35 ℃, and converting alpha-cyclocitral generated by the compound of the formula V into beta-cyclocitral; continuously adjusting pH to 3-5 with ammonium chloride aqueous solution, demixing, extracting water phase with dichloromethane, mixing organic phases, and washing with saturated sodium chloride aqueous solution; and after the organic phase is subjected to reduced pressure distillation to remove the solvent, the organic phase is further subjected to reduced pressure rectification to obtain the beta-cyclocitral (I).
The reaction process of the present invention is depicted as the following scheme 3:
reaction scheme 3
Wherein, in the structural formulas of the compound of the formula III, the compound of the formula IV and the compound of the formula V, the substituent X is Cl, br or I.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a preparation method of beta-cyclocitral, which comprises the steps of preparing 1, 2-dihalogen-1, 3-trimethylcyclohexane by addition reaction of 1, 3-trimethylcyclohexene and a halogen reagent, then obtaining a mixture of 2-halogeno-1, 3-trimethylcyclohexene and 3-halogeno-2, 4-trimethylcyclohexene by elimination reaction under the action of alkali, obtaining a corresponding Grignard reagent by Grignard reaction of the obtained mixture and magnesium powder, and then preparing the beta-cyclocitral by formylation reaction of the Grignard reagent and a formylation reagent.
2. The addition of 1, 3-trimethylcyclohexene and halogen reagent belongs to the classical reaction, the reaction selectivity is only one, the quantitative yield is obtained, and the elimination reaction can be directly carried out without distillation and purification. Selecting proper elimination reaction conditions by utilizing different spatial positions and activities of two halogen atoms of an addition product, wherein the elimination reaction is mainly carried out according to an E1 mechanism, tertiary carbon connected with 1-position halogen easily loses the halogen to form carbocation, hydrogen atoms connected with 2-position carbon atoms have stronger acidity due to the activation of the same carbon halogen, and carbon-carbon double bonds are easily formed between 1, 2-positions, so that the main elimination product 2-halogeno-1, 3-trimethylcyclohexene is obtained; and simultaneously obtaining a 1, 6-site elimination reaction product 3-halogenated-2, 4-trimethylcyclohexene with lower content. The two elimination products can form corresponding Grignard reagent with magnesium powder, the reaction site of Grignard reaction is specific, the activity of the Grignard reagent is proper, and then the Grignard reagent and formylation reagent are subjected to formylation reaction to prepare the beta-cyclocitral.
3. Formylating a Grignard reagent and a formylation reagent generated by a mixture of 2-halo-1, 3-trimethylcyclohexene and 3-halo-2, 4-trimethylcyclohexene to respectively obtain beta-cyclocitral and alpha-cyclocitral; by utilizing the characteristic that alpha-cyclocitral is easy to rearrange and convert into beta-cyclocitral under the alkaline condition, the pH value of a reaction liquid obtained after reaction is adjusted to 9-10 by ammonium chloride aqueous solution for rearrangement conversion, so that the alpha-cyclocitral generated by 3-halogenated-2, 4-trimethylcyclohexene is converted into the beta-cyclocitral, and the high-purity beta-cyclocitral can be obtained even if the 3-halogenated-2, 4-trimethylcyclohexene in the 2-halogenated-1, 3-trimethylcyclohexene and the 3-halogenated-2, 4-trimethylcyclohexene is not separated, and meanwhile, the post-treatment step is simplified.
4. The raw materials used in the method are cheap and easily available, and the cost is low; the method has the advantages of simple steps, mild reaction conditions and easy realization, and the target product can be prepared by only two steps; the production amount of waste water is small, and the method is green, safe and environment-friendly; the related raw materials and intermediate products are stable, the reaction atom economy and selectivity are high, the byproducts are few, the yield and the purity of the target product are high, the yield can reach 92.3 percent, and the method is suitable for green industrial production.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
In the examples, "%" is a mass percentage unless otherwise specified.
The yields in the examples are all molar yields.
The starting materials and reagents used in the examples are commercially available products or can be prepared according to the prior art.
And performing gas phase detection by using Shimadzu gas chromatograph, wherein the model of the instrument is GC-1020PLUS.
The preparation method of the raw material 1, 3-trimethylcyclohexene used in the examples is as follows:
2000 g of tetrahydrofuran and 750.0 g (6 mol) of 40% aqueous hydrazine hydrate solution were added to a 5000 ml four-neck flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, 691.0 g (5 mol) of beta-isophorone was added dropwise at 20 to 25 ℃ for 3 hours, and then the reaction was stirred at 25 to 30 ℃ for 3 hours. 1000 g of dichloromethane were added, the layers were separated, the aqueous layer was extracted twice with 500 g of dichloromethane, the organic phases were combined, dichloromethane and tetrahydrofuran were recovered by atmospheric distillation, and the residue obtained was transferred to a beaker for further use.
In another 1000 ml four-necked flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a distillation apparatus, 200 g of diethylene glycol and 22.5 g (0.4 mol) of potassium hydroxide were charged, heated to an internal temperature of 110 to 120 ℃ and the distillation residue in the resulting beaker was added dropwise while receiving the distillate, and after 5 hours of dropping, the reaction was stirred at 120 to 125 ℃ for 1 hour. 200 g of water was added to the obtained distillate, and the mixture was separated into layers, and the organic phase was dried over 10.0 g of anhydrous sodium sulfate for 3 hours, and then filtered to remove the drying agent, whereby 586.5 g of colorless transparent liquid 1, 3-trimethylcyclohexene was obtained, which had a gas phase purity of 99.8% and a yield based on β -isophorone of 94.6%.
Example 1: preparation of a mixture of 2-chloro-1, 3-trimethylcyclohexene (IV 1) and 3-chloro-2, 4-trimethylcyclohexene (V1)
600 g of 1, 2-dichloroethane, 62.0 g (0.5 mol) of 1, 3-trimethylcyclohexene and a device for absorbing 30% sodium hydroxide aqueous solution were added to a 2000 ml four-neck flask connected with a stirrer, a thermometer, a reflux condenser, a gas-guide tube and a device for absorbing 30% sodium hydroxide aqueous solution, chlorine gas was slowly introduced between 30 ℃ and 45 ℃ and 39.5 g (0.56 mol) of chlorine gas was introduced in total for about 4 hours, after which the mixture was stirred at 45 ℃ to 50 ℃ for 2 hours, cooled to 20 ℃ to 25 ℃, 82.5 g (0.6 mol) of potassium carbonate, 200 g of water, 10.0 g of sodium sulfite, stirred at 30 ℃ to 35 ℃ for 3 hours, and the layers were separated and the organic layer was washed with 50 g of water, and the solvent was recovered by distillation from the organic phase to obtain 72.5 g of pale yellow liquid, and the gas phase area ratios of 2-chloro-1, 3-trimethylcyclohexene (IV 1) and 3-chloro-2, 4-trimethylcyclohexene (1) were 93.3% and 5%, respectively, and 91.5% were used in the step (2) directly.
The nuclear magnetic data of the product obtained are as follows:
1 HNMR(400MHz,CDCl 3 ):δppm
5.13(t,0.1H),3.69(s,0.1H),1.91-1.94(m,1.9H),1.67-1.70(m,3H),1.57-1.60(m,2H),1.47-1.51(m,2H),1.12-1.18(m,6H)。
example 2: preparation of a mixture of 2-chloro-1, 3-trimethylcyclohexene (IV 1) and 3-chloro-2, 4-trimethylcyclohexene (V1)
600 g of 1, 2-dichloroethane, 62.0 g (0.5 mol) of 1, 3-trimethylcyclohexene and 125.0 g (1.2 mol) of 35wt% hydrochloric acid are added to a 2000 ml four-neck flask which is connected with a stirring device, a thermometer, a reflux condenser tube, a constant pressure dropping funnel and a 30% sodium hydroxide aqueous solution absorption device, 68.0 (0.6 mol) of 30wt% hydrogen peroxide is dropped at 40-45 ℃ for about 2 hours, and then the mixture is stirred and reacted for 3 hours at 45-50 ℃. Cooling to 20-25 deg.c, adding 82.5 g (0.6 mol) potassium carbonate, 200 g water, 10.0 g sodium sulfite, stirring at 30-35 deg.c for reaction for 3 hr, demixing, washing the organic layer with 50 g water, distilling the organic phase to recover solvent to obtain 71.1 g yellowish liquid with gas phase area ratio of 2-chloro-1, 3-trimethylcyclohexene (IV 1) and 3-chloro-2, 4-trimethylcyclohexene (v 1) of 89.6% and 9.1%, yield of 89.7%, and direct use in step (2).
Example 3: preparation of a mixture of 2-bromo-1, 3-trimethylcyclohexene (IV 2) and 3-bromo-2, 4-trimethylcyclohexene (V2)
Into a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser, a constant pressure dropping funnel and an absorption device connected to 30% aqueous sodium hydroxide solution, 500 g of dichloromethane, 62.0 g (0.5 mol) of 1, 3-trimethylcyclohexene were added, a mixture of 85.0 g (0.53 mol) of liquid bromine and 200 g of dichloromethane was slowly dropped between 20 ℃ and 25 ℃ for about 2 hours, after which the dropping was completed, and after stirring and reacting at 25 ℃ to 30 ℃ for 2 hours, cooling to 20 ℃ to 25 ℃ and adding 70.5 g (0.7 mol) of triethylamine, 200 g of water, 10.0 g of sodium sulfite, stirring and reacting at 20 ℃ to 25 ℃ for 3 hours, layering, the organic layer was washed with 50 g of water, and the organic phase was distilled to recover the solvent to obtain 97.0 g of light brown liquid, and the gas phase area ratios of 2-bromo-1, 3-trimethylcyclohexene (IV 2) and 3-bromo-2, 4-trimethylcyclohexene (2) were 93.9% and 5.3%, respectively, and used in the step (2.6%) directly.
The nuclear magnetic data of the product obtained are as follows:
1 HNMR(400MHz,CDCl 3 ):δppm
5.09(t,0.1H),3.62(s,0.1H),1.91-1.94(m,1.9H),1.65-1.69(m,3H),1.55-1.59(m,2H),1.47-1.50(m,2H),1.12-1.16(m,6H)。
example 4: preparation of a mixture of 2-bromo-1, 3-trimethylcyclohexene (IV 2) and 3-bromo-2, 4-trimethylcyclohexene (V2)
To a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser, a constant pressure dropping funnel and an absorption device connected to 30% aqueous sodium hydroxide solution, 600 g of 1, 2-dichloroethane, 62.0 g (0.5 mol) of 1, 3-trimethylcyclohexene, 243.0 g (1.2 mol) of 40wt% hydrobromic acid were added, 62.5 g (0.55 mol) of 30wt% hydrogen peroxide was added dropwise at 20 to 30 ℃ and dropwise added after about 2 hours, thereafter, the mixture was stirred at 30 to 35 ℃ for 3 hours, cooled to 20 to 25 ℃, 110.0 g (0.8 mol) of potassium carbonate, 200 g of water, 10.0 g of sodium sulfite, stirred at 40 to 45 ℃ for 3 hours, and the organic layer was washed with 50 g of water, the solvent was recovered by distillation to obtain 95.6 g of light brown liquid, 2-bromo-1, 3-trimethylcyclohexene (IV 2) and 3-bromo-2, 4-trimethylcyclohexene (2) with an area ratio of 91.6% in the gas phase, and a yield of 1.6% for direct use in the step (2.6% yield, 2).
Example 5: preparation of beta-cyclocitral (I)
100 g of tetrahydrofuran, 6.7 g (0.28 mol) of magnesium powder, 0.3 g of iodine and 2.0 g of a mixture of 2-chloro-1, 3-trimethylcyclohexene (IV 1) and 3-chloro-2, 4-trimethylcyclohexene (V1) obtained by the method of example 1 were charged into a 1000 ml four-neck flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser under nitrogen protection, and after initiation of the reaction at 35 to 40 ℃, a mixed solution of 37.6 g (0.25 mol in total) of 2-chloro-1, 3-trimethylcyclohexene (IV 1) and 3-chloro-2, 4-trimethylcyclohexene (V1) and 200 g of tetrahydrofuran was added dropwise at 35 to 40 ℃ for 2 hours, and then the reaction was stirred at 40 to 45 ℃ for 2 hours to obtain a Grignard reagent. Cooling to 10-15 ℃, under the protection of nitrogen, dropwise adding 29.2 g (0.4 mol) of N, N-dimethylformamide, finishing dropwise adding within 1 hour, and stirring and reacting for 3 hours at 15-20 ℃. Distilling under reduced pressure at 40-45 deg.C to recover solvent, adding 100 g water and 200 g dichloromethane into the obtained residue, adjusting pH to 9-10 with 20wt% ammonium chloride aqueous solution, stirring at 20-25 deg.C, and converting for 1.5 hr; the pH was further adjusted to 4-5 with 20wt% aqueous ammonium chloride, the mixture was stirred at 20-25 ℃ for 1 hour, the layers were separated and the aqueous phase was extracted twice with 50 g of dichloromethane. After combining the organic phases, washing was carried out once with 30 g of saturated aqueous sodium chloride solution. After the organic phase is distilled under reduced pressure to remove the extractant, the organic phase is rectified under reduced pressure (60-70 ℃/2-2.5 mmHg) to obtain 36.2 g of colorless transparent liquid beta-cyclocitral (I), the gas phase purity is 99.3 percent, and the yield is 95.1 percent.
The nuclear magnetic data of the product obtained are as follows:
1 HNMR(400MHz,CDCl 3 ):δppm
10.02(s,1H),2.16(t,2H),2.08(s,3H),1.59-1.62(m,2H),1.41-1.45(m,2H),1.18(s,6H)。
example 6: preparation of beta-cyclocitral (I)
Under the protection of nitrogen, 150 g of tetrahydrofuran, 6.7 g (0.28 mol) of magnesium powder, 0.3 g of iodine, 2.0 g of a mixture of 2-bromo-1, 3-trimethylcyclohexene (IV 2) and 3-bromo-2, 4-trimethylcyclohexene (V2) obtained by the method of example 3 were charged into a 1000 ml four-neck flask equipped with a stirrer, a thermometer, a constant pressure dropping funnel and a reflux condenser, and after the initiation of the reaction at 30 to 35 ℃, a mixed solution of 55.5 g (total of 0.25 mol) of a mixture of 2-bromo-1, 3-trimethylcyclohexene (IV 2) and 3-bromo-2, 4-trimethylcyclohexene (V2) and 100 g of tetrahydrofuran was added dropwise at 35 to 40 ℃ for 2 hours, and after that the dropwise addition was completed, the reaction was carried out at 40 to 45 ℃ for 2 hours, a grignard reagent was obtained. Cooling to 10-15 ℃, under the protection of nitrogen, dropwise adding 29.2 g (0.4 mol) of N, N-dimethylformamide, finishing dropwise adding within 1 hour, and stirring and reacting for 2 hours at 10-15 ℃. Distilling under reduced pressure at 40-45 deg.C to recover solvent, adding 100 g water and 200 g dichloromethane into the obtained residue, adjusting pH to 9-10 with 20wt% ammonium chloride aqueous solution, stirring at 20-25 deg.C, and converting for 1.5 hr; the pH was further adjusted to 3-4 with 20wt% aqueous ammonium chloride, the mixture was stirred at 20-25 ℃ for 1 hour, the layers were separated and the aqueous phase was extracted twice with 50 g of dichloromethane. After combining the organic phases, washing was carried out once with 30 g of saturated aqueous sodium chloride solution. After the organic phase is decompressed and distilled to remove the extractant, the organic phase is decompressed and rectified (60-70 ℃/2-2.5 mmHg) to obtain 36.7 g of colorless transparent liquid beta-cyclocitral (I), the purity of the gas phase is 99.7 percent, and the yield is 96.5 percent.
The nuclear magnetic data of the product obtained are as follows:
1 HNMR(400MHz,CDCl 3 ):δppm
10.02(s,1H),2.16(t,2H),2.08(s,3H),1.59-1.62(m,2H),1.41-1.45(m,2H),1.18(s,6H)。
Claims (10)
1. a preparation method of beta-cyclocitral comprises the following steps:
(1) In a solvent A, a compound shown in a formula II and a halogen reagent are subjected to addition reaction to prepare a compound shown in a formula III; then in a solvent B and under the action of alkali, a mixture of a compound shown in the formula IV and a compound shown in the formula V is obtained through elimination reaction;
wherein in the structural formulas of the compound shown in the formula III, the compound shown in the formula IV and the compound shown in the formula V, a substituent X is Cl, br or I;
(2) In a solvent C, under the action of an initiator, carrying out Grignard reaction on a mixture of a compound shown in formula IV and a compound shown in formula V and magnesium powder to obtain a corresponding Grignard reagent, and then carrying out formylation reaction on the Grignard reagent and a formylation reagent to prepare beta-cyclocitral (I);
2. the method for preparing beta-cyclocitral according to claim 1, wherein step (1) comprises one or more of the following conditions:
i. the solvent A is one or the combination of more than two of dichloromethane, dichloroethane, toluene, chlorobenzene, tetrahydrofuran or acetonitrile; the mass ratio of the solvent A to the compound shown in the formula II is (2-15) to 1; preferably, the mass ratio of the solvent A to the compound shown in the formula II is (4-12): 1;
ii. The halogen reagent is chlorine, hydrochloric acid-sodium hypochlorite, hydrochloric acid-hydrogen peroxide, bromine, hydrobromic acid-sodium bromate, hydrobromic acid-hydrogen peroxide, iodine chloride, iodine bromide, hydroiodic acid-hydrogen peroxide or hydroiodic acid-sodium iodate; preferably, the halogen reagent is chlorine, hydrobromic acid-hydrogen peroxide, bromine or hydrochloric acid-hydrogen peroxide;
iii, the molar ratio of the compound which generates the halogenation reaction in the halogen reagent to the compound shown in the formula II is (1.0-3.0): 1;
iv, the temperature of the addition reaction of the compound shown in the formula II and a halogen reagent is 0-100 ℃; preferably, the addition reaction temperature is 20 to 50 ℃.
3. The method for preparing beta-cyclocitral according to claim 1, wherein step (1) comprises one or more of the following conditions:
i. the solvent B is one or the combination of more than two of dichloromethane, dichloroethane, toluene, chlorobenzene, tetrahydrofuran, acetonitrile or water; the mass ratio of the solvent B to the compound shown in the formula II is (3-20): 1;
ii. The alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium bicarbonate, calcium hydroxide, sodium sulfite, sodium bisulfite, triethylamine, diisopropylethylamine, pyridine, lutidine or quinoline; the molar ratio of the alkali to the compound shown in the formula II is (1.0-2.0): 1;
iii, the temperature of the elimination reaction is 0-100 ℃; preferably, the elimination reaction temperature is 10 to 50 ℃.
4. The method for preparing beta-cyclocitral according to claim 1, wherein step (1) comprises one or more of the following conditions:
i. the addition reaction and the elimination reaction can be finished by a one-pot method;
ii. And standing and layering the reaction solution obtained by eliminating the reaction, washing the organic phase with water, distilling to recover the solvent, and directly using the organic phase in the next reaction.
5. The method for preparing beta-cyclocitral according to claim 1, wherein step (2) comprises one or more of the following conditions:
i. the solvent C is one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, methoxycyclopentane, hexane, heptane or toluene; the mass ratio of the solvent C to the mixture of the compound shown in the formula IV and the compound shown in the formula V is (2-10) to 1;
ii. The initiator is one or a combination of iodine, bromoethane or 1, 2-dibromoethane; the mass of the initiator is 0.5-5.0% of the mass of the mixture of the compound of the formula IV and the compound of the formula V; preferably, the mass of the initiator is 0.5-3.0% of the mass of the mixture of the compound of formula IV and the compound of formula V;
iii, the formylation reagent is N, N-dimethylformamide, ethyl formate, methyl formate alkane or hydrogen cyanide; preferably, the formylation reagent is N, N-dimethylformamide;
iv, the molar ratio of the mixture of the magnesium powder, the formylation reagent, the compound of the formula IV and the compound of the formula V is (1.0-1.5): 1.0-3.5): 1; preferably, the molar ratio of the mixture of magnesium powder, formylating agent, compound of formula IV and compound of formula V is (1.1-1.3): 1.5-2.5): 1.
6. The method for preparing beta-cyclocitral according to claim 1, wherein step (2) comprises one or more of the following conditions:
i. the Grignard reaction temperature is 20-60 ℃; preferably, the Grignard reaction temperature is 25-45 ℃;
ii. The reaction temperature of the Grignard reagent and the formylation reagent is-20 to 35 ℃; preferably, the reaction temperature of the grignard reagent and the formylation reagent is 5 to 20 ℃.
7. The method for preparing beta-cyclocitral according to claim 1, wherein step (2) comprises one or more of the following conditions:
i. the mixture of the compound of formula IV and the compound of formula V is added into the reaction system in two times, namely: firstly, adding a mixture of a compound shown in the formula IV and a compound shown in the formula V, wherein the mixture accounts for 1-10% of the total mass of the mixture, and the mixture is added into a system containing a solvent B, an initiator and magnesium powder;
ii. The Grignard reaction and formylation reaction can be completed in a one-pot method;
and iii, adding the formylation reagent into the reaction system containing the Grignard reagent in a dropwise manner.
8. The method for preparing beta-cyclocitral according to claim 1, wherein the formylation in step (2) further comprises rearrangement conversion and acidification steps.
9. The method for preparing beta-cyclocitral according to claim 8, wherein the rearrangement conversion is performed by adjusting pH of the system to 9-10 with 10-30wt% ammonium chloride aqueous solution, and stirring at 15-35 deg.C for 1-3 hr to complete the rearrangement conversion;
and the acidification is to use ammonium chloride aqueous solution with the mass concentration of 10-30wt% to adjust the pH of the system to 3-5.
10. The method for producing β -cyclocitral according to claim 1, wherein in step (2), the reaction solution obtained by reacting the grignard reagent with the formylation reagent is subjected to the following post-treatment method: adding the reaction liquid or residues obtained after the solvent is recovered from the reaction liquid through reduced pressure distillation into a mixture of water and dichloromethane, adjusting the pH value to be 9-10 by using an ammonium chloride aqueous solution, stirring and converting the mixture at 15-35 ℃ for 1-3 hours, and converting alpha-cyclocitral generated by the compound of the formula V into beta-cyclocitral; continuously adjusting pH to 3-5 with ammonium chloride aqueous solution, demixing, extracting water phase with dichloromethane, mixing organic phases, and washing with saturated sodium chloride aqueous solution; and after the organic phase is subjected to reduced pressure distillation to remove the solvent, the organic phase is further subjected to reduced pressure rectification to obtain the beta-cyclocitral (I).
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| CN111484400A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Preparation method of 2-methyl-4- (2,6, 6-trimethylcyclohexene-1-yl) -2-butenal |
| CN111574349A (en) * | 2019-02-18 | 2020-08-25 | 新发药业有限公司 | Preparation method of citral |
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| CN111484400A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Preparation method of 2-methyl-4- (2,6, 6-trimethylcyclohexene-1-yl) -2-butenal |
| CN111574349A (en) * | 2019-02-18 | 2020-08-25 | 新发药业有限公司 | Preparation method of citral |
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| Title |
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| OH, JONG HOON等: "Synthesis of 1-[3-(propylthio)butyryl]-2, 6, 6-trimethylcyclohexene", 《TAEHAN HWAHAKHOE CHI 》, vol. 29, no. 3, pages 311 - 318 * |
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