CN107001192A - 方法 - Google Patents
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- CN107001192A CN107001192A CN201580061201.5A CN201580061201A CN107001192A CN 107001192 A CN107001192 A CN 107001192A CN 201580061201 A CN201580061201 A CN 201580061201A CN 107001192 A CN107001192 A CN 107001192A
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- 238000000034 method Methods 0.000 title claims description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- -1 benzene compound Chemical class 0.000 claims abstract description 16
- 238000007306 functionalization reaction Methods 0.000 claims abstract description 15
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract 6
- 238000006243 chemical reaction Methods 0.000 claims description 20
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 10
- 230000006315 carbonylation Effects 0.000 claims description 6
- 238000005810 carbonylation reaction Methods 0.000 claims description 6
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 claims description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000003205 fragrance Substances 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical group 0.000 description 6
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- KDVYCTOWXSLNNI-UHFFFAOYSA-N 4-t-Butylbenzoic acid Chemical compound CC(C)(C)C1=CC=C(C(O)=O)C=C1 KDVYCTOWXSLNNI-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- SDQFDHOLCGWZPU-UHFFFAOYSA-N lilial Chemical compound O=CC(C)CC1=CC=C(C(C)(C)C)C=C1 SDQFDHOLCGWZPU-UHFFFAOYSA-N 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 235000013599 spices Nutrition 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
- 241000755716 Convallaria Species 0.000 description 3
- 235000009046 Convallaria majalis Nutrition 0.000 description 3
- 241000234269 Liliales Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000007515 enzymatic degradation Effects 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- OCKPCBLVNKHBMX-UHFFFAOYSA-N butylbenzene Chemical compound CCCCC1=CC=CC=C1 OCKPCBLVNKHBMX-UHFFFAOYSA-N 0.000 description 2
- 238000007265 chloromethylation reaction Methods 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000526 short-path distillation Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SDHYGAUOCHFYSR-UHFFFAOYSA-N 1-methyl-3-(2-methylpropyl)benzene Chemical class CC(C)CC1=CC=CC(C)=C1 SDHYGAUOCHFYSR-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
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241001340526 Chrysoclista linneella Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical group CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 description 1
- UAEPNZWRGJTJPN-UHFFFAOYSA-N Methylcyclohexane Natural products CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 244000170916 Paeonia officinalis Species 0.000 description 1
- 235000006484 Paeonia officinalis Nutrition 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 229910002090 carbon oxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 101150016253 cmr2 gene Proteins 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N ethyl ethylene Natural products CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- 230000004129 fatty acid metabolism Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 238000007163 homologation reaction Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 150000005172 methylbenzenes Chemical class 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical class CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
- C11B9/00—Essential oils; Perfumes
- C11B9/0061—Essential oils; Perfumes compounds containing a six-membered aromatic ring not condensed with another ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/30—Compounds having groups
- C07C43/307—Compounds having groups having acetal carbon atoms bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/228—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings, e.g. phenylacetaldehyde
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/542—Alkylated benzaldehydes
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Abstract
二烷基苯化合物的区域‑选择性官能化,其中在位置(a)官能化的化合物与在位置(b)官能化的化合物的比例为至少70:30,更特别地是至少80:20,还更特别地是至少85:15,以及还更特别地是至少90:10,其特征在于取代基R是异丁基。
Description
本发明一般地涉及制备香料原料的方法和在这些方法中所使用的或在这些方法过程中所制备的关键中间体。
具有铃兰气味特征的化合物作为香料成分是特别寻求的。这些化合物是花香香基中的重要成分,并且可以作为许多类型的香料产物的协调剂(harmonizer)。这种类型的化合物广泛用于个人护理和消费者护理产品以及精细香料,以产生令人愉快的气味或掩盖令人不快的气味。
因其铃兰气味香型而被广泛认可的极佳香料成分是LilialTM或3-(4-叔丁基苯基)-2-甲基丙醛(CAS 80-54-6)。这种化合物在精细香料以及个人和家庭护理产品中广泛使用。然而,鉴于近期发现它对雄性大鼠和狗的生殖器官具有毒性作用,因此其使用是有争议的。在小鼠、豚鼠和灵长类动物的研究中没有发现任何影响,然而,根据全球协调系统(Global Harmonized System)(GHS)分类系统,该化合物被归类为CMR2材料。对于CMR第2类材料,有必要确定所要使用的量对消费者是无害的。鉴于LilialTM的监管情况,其正在被其他香料成分所替代。
WO2010105873解决了替代LilialTM的问题,所提出的解决方案在于使用在香料制造人调色板上通常发现的已知成分的混合物,以便重现与LilialTM基本相似的特征。
同样地,WO2009027957提出了一种解决方案,其在于来自香料制造人调色板的已知香料成分组合的制品。
WO2013045301还提出了LilialTM替代品的解决方案,其在于选择成分的混合物,所述成分包括化合物LilyfloreTM和某些茚满基丙醛化合物与其它次要加香成分的组合。
申请人最近发现了一种新颖的化合物,其可以用作香料组合物和精细香料和消费品中的香料成分,以赋予所述组合物、香料和产品期望的铃兰气味特征。更具体地,这种新型化合物具有气味特征,这可以被香料制造人认识和认可,因为它们非常使人联想到LilialTM的气味。此外,所述新化合物不受围绕LilialTM的任何毒性问题的影响。因此,这种新型化合物可以作为LilialTM的简单替代品。
该新化合物描述在共同待决的专利申请PCT/EP/2014059427(其全部内容通过引用并入本文)中,由式(I)定义,
式(I)化合物具有至少与LilialTM一样好的基本上类似的气味特征和性能特征。因此,与现有技术提议的与基于已知成分混合物的LilialTM替代品相反,本发明提供了基于单一化合物的LilialTM替代品。这具有明显优点,代表了替代品问题的经济有效的解决方案,而且还使得香料制造人的创意过程更简单。
围绕LilialTM的监管问题源于其在大鼠和狗中被酶促降解为叔丁基苯甲酸(t-BBA)的事实。叔丁基苯甲酸已知可以在体外抑制葡萄糖合成和脂肪酸合成(McCune等,ArchBiochem Biophys(1982)214(1):124-133)。
已知叔丁基苯甲酸在雄性大鼠中引起睾丸效应(Hunter等,FoodCosmet.Toxicol.1965,3:289-298;Cagen等,J.Am.Coll.Toxicol.1989,8(5):1027-1038)。
申请人最近发现,式(I)化合物不易于酶促降解为其苯甲酸衍生物。虽然申请人不打算受任何特定理论的束缚,但据信苯甲酸衍生物是发生代谢活动级联的关键中间体,导致雄性生殖毒性和雄性大鼠精子形成减少。更具体地,认为叔丁基苯甲酸和相关的支链烷基取代的苯甲酸与大鼠细胞中的辅酶A结合,与该辅因子形成硫酯。进而,认为该硫酯抑制负责大鼠细胞中脂肪酸代谢的其它酶,并且就是这一对CoA依赖性反应的干扰导致了观察到的生殖毒性。
申请人惊奇地发现,在环上在与具有醛官能团的基团相邻的位置上含有取代基、例如甲基取代基的芳基取代的烷醛化合物不易于酶促降解为其相应的苯甲酸衍生物,这提供了迄今为止本领域中未知的深刻见解。这种深刻见解使得申请人能够开发式(I)化合物及其结构相关的衍生物,从而将新型香料成分添加到香料成分的调色板中,所述新型香料成分不仅其本身有用,而且适合作为LilialTM的替代品。
然而,尽管式(I)化合物(和结构上相关的衍生物)作为香料的吸引力,并且尽管其相对简单的化学结构,但是申请人发现使用工业上可放大的化学来制备是复杂和昂贵的。复杂性源于该化合物是三取代的芳基化合物的事实。一方面,三取代的芳基起始材料是稀少和昂贵的,而另一方面,官能化具有三个取代基的芳环通常需要冗长和复杂的合成。
因此,仍然存在提供经济的和工业上可放大的合成式(I)化合物的需要。
在其研究过程中,申请人考虑了大量可能的合成式(I)化合物的路线。确定在以经济的方式合成化合物(I)期间甲基取代基不能添加到环中。甲基取代基必须存在于容易获得的原料中。间二甲苯代表了这样一种便宜且容易获得的原料,并且可以容易地在其一个甲基取代基上同系化,以在形成式(I)化合物的过程中提供关键的中间体(化合物II)。如果要实现经济上可行和工业上可放大的合成,这个关键中间件将需要在环上进行官能化。
因此,本发明在第一方面提供了在环上位置(a)区域-选择性官能化烷基甲苯化合物(II)的方法,
其中取代基R是异丁基。
在本发明的另一方面,提供了形成式(I)化合物的方法,
所述方法包括在环上位置(a)区域-选择性官能化3-甲基-1-异丁基苯(化合物II)的步骤。
“区域选择性”是指官能化主要在环上的位置(a)而不是位置(b)。更具体地,“区域选择性”是指比例(a):(b)是至少70:30,更特别地是至少80:20,还更特别地是至少85:15,更特别地是至少90:10。
在本发明的另一方面,提供了在化合物(I)的合成中3-甲基-1-异丁基苯(化合物II)作为中间体的用途。
如上所述,申请人发现,对于形成化合物(I)的经济上可行和工业上可放大的方法,甲基已经位于可获得的起始原料上是至关重要的。该发现确定化合物(II)(3-甲基-1-异丁基苯)在任何方法中是关键中间体,并且该化合物的官能化必定以这种高的区域选择性进行。
然而,通过关键中间体化合物(II)制备式(I)化合物的想法是反直觉的,因为现有技术明确地表达了对这样做的偏见。具体来说,Rao等人在Indian Journal of Chemistry,第16B卷,1978年5月中将醛官能团引入3-甲基-1-异丁基苯(该文中为IIIe)。所产生的化合物为2-异丁基-4-甲基苯甲醛(IIIg),这表明异丁基将醛官能团定位到相对于异丁基的邻位,而不是对位。换句话说,异丁基对于相对于它的对位位置而言并不促进高的区域选择性。
申请人自己的发现(总结在下表1中)令人惊讶地与Rao等人不一致。在一氧化碳(约40bar)和三氟甲磺酸存在下,在1-丁基-3-甲基苯化合物的羰基化中,发现叔丁基和仲丁基环取代基在选择性地定位羰基化到与丁基取代基对位的环位置时完全无效。然而,比叔丁基和仲丁基取代基基本上更有效的正丁基取代基当与异丁基取代基相比时效果较差。
表1:
根据本发明,3-甲基-1-异丁基苯(化合物II)可以根据已知方法从3-异丁基-1-甲基环己-1-烯(化合物(Ia))来制备。特别地,使用固定在氧化铝或碳上的钯催化剂可以使(Ia)在减压下脱氢。脱氢可以在室温或升高的温度下进行,优选在200℃下进行。
可以引入到3-甲基-1-异丁基苯(化合物II)对位(相对于异丁基)的官能团的选择可以是非常多变的。
区域选择性地引入苯甲醛官能团是本发明的优选实施方案。该官能团的引入可以通过几种方式实现。一种方法是先将化合物(II)氯甲基化,之后将1-氯甲基-2-甲基-4-异丁基苯转化为2-甲基-4-异丁基苯甲醛。然而,由于与方法效率有关的原因,化合物(II)的氯甲基化不是本发明的优选实施方案。
通过羰基化将苯甲醛官能团直接引入环是本发明的优选实施方案。
在本发明的一个具体实施方案中,该反应可以在高压釜中在约40至60大气压的一氧化碳下在6.8摩尔当量的三氟甲磺酸中进行。羰基化将提供区域异构体的混合物,其可以含有70%,更特别地是80%(或甚至更高量)的化合物(III)。
或者,该反应可以在本领域通常已知的条件下在HF/BF3中进行。这种反应通常被称为“三菱”化学。US3,962,343中描述了三菱化学的代表性实例,将其通过引用并入本文。
在本发明的另一个实施方案中,式(II)化合物可以在本领域通常已知的反应条件下溴化。
可操作的反应条件是在10℃下,在0.05摩尔当量铁粉的存在下,用1摩尔当量的溴处理纯(II)。
在本发明的另一个实施方案中,式(II)化合物可直接转化为式(I)化合物。
用于该转化的反应条件是本领域通常已知的,并且可以在-70℃下在二氯甲烷中使化合物(II)与四氯化钛和式(V)化合物进行反应而进行。用稀硫酸水解中间体乙酸烯醇酯,提供在区域异构体的混合物中达到40%的(VI)。
式(III)化合物可以使用本领域通常已知的Muller Conradi-Pieroh条件转化为化合物(VI)。
特定的反应条件包括用原甲酸三甲酯处理将苯甲醛(III)转化为二甲基缩醛,然后在室温下在催化三氟化硼醚合物的存在下与乙基乙烯基醚反应。中间体乙氧基甲氧基缩醛在5%HCl存在下水解,得到(VI)。
在起始材料中包含甲基取代基的另一个优点是,与使用的固体4-异丁基苯甲醛不同,例如,作为合成众所周知的香料成分 的起始原料,化合物(III)中的甲基取代基的存在使得化合物成为液体,这使得它更容易在工业规模上处理。
此后,式(VI)化合物可以被氢化以提供式(I)化合物。氢化条件通常是本领域众所周知的,并且包括使用5%的钯/碳在500mbar压力下催化氢化丙烯醛侧链中的双键。
上述化合物(IV)可以根据以下反应方案进一步转化:
反应方案(a)描述了化合物(IV)转化为化合物(I)。该反应可以通过在仲胺存在下由钯催化的(IV)与烯丙醇的Heck反应来进行,随后使用本领域通常已知的条件氧化所得丙醇的侧链,得到化合物(I)。
反应方案(b)描述了使烯丙基醚与式(IV)化合物在Heck条件下反应以得到化合物(VII)和(VIII)的混合物的类似方法。本领域技术人员将预期化合物(VII)和(VIII)的混合物的酸水解将得到化合物(IX)和所需化合物(I)的混合物,因此,通过该混合物进行的合成路线初看之下显得是没有前途的。
然而,使申请人惊讶的是,酸性水解后,化合物(VII)和(VIII)都转化为化合物(I),表明水解得到化合物(I)之前,(VII)进行酸介导的双键迁移生成(VIII)。
因此,本发明的另一方面提供形成式(I)化合物的方法,其包括形成化合物(VII)和(VIII)的混合物的步骤。
当以与区域异构体的混合物(特别是与2-异丁基-4-甲基苯甲醛(X)的混合物)形式获得化合物(III)时,难以通过蒸馏分离它们。然而,可以通过蒸馏相应的二烷基缩醛,优选相应的二甲基缩醛(IIIa+Xa)或二乙基缩醛(IIIb+Xb)来促进化合物(III)的分离。这通过比较GC分离中保留时间的增加差异来证明,这表明通过蒸馏改善分离(图1)。
因此,式(III)化合物的相应的二烷基缩醛,特别是式(III)化合物的二乙基缩醛(其为化合物(IIIb))是用于制备所需式(I)化合物的有用中间体,并构成本发明的另一方面。
通过用原甲酸三乙酯和催化量的BF3·Et2O处理,在第一步a)中将区域异构体(III)和(X)的混合物转化成相应的二乙基缩醛(IIIb+Xb)的混合物。在第二步骤b)中,在粗反应混合物的中和后,进行蒸馏以基本上纯形式获得二乙基缩醛(IIIb)。式(IIIb)化合物可以水解成式(III)化合物,或以与上述类似的方式直接转化成式(VI)化合物。
或者,BF3·Et2O可以被对甲苯磺酸(pTSA)代替,并且在除去不需要的异构体之后,即使在pTSA存在的情况下也可以进行Müller-Cunradi反应。因此,缩醛形成、蒸馏和Müller-Cunradi反应可以作为“一锅”过程进行。
因此,在另一方面,本发明提供了一种纯化或分离化合物(III)的方法,并由此提高了在进一步反应中获得的产物特别是式(I)化合物的纯度。
现在以下是一系列实施例,用于进一步说明本发明。
实施例1:3-(4-异丁基-2-甲基苯基)丙醛的合成
A)3-异丁基甲苯(II)
将新鲜蒸馏的3-和5-异丁基-1-甲基环己-1-烯(700g,4.6mol)的混合物垂直通过填充有100g钯/氧化铝颗粒(Aldrich,art.205745)的玻璃管(2×50cm)并加热至200℃。将环己烯在32mbar下以2ml/min的速率通过柱。将粗(II)浓缩并收集在柱底部的接收器中。将含有90%的(II)和10%的1-异丁基-3-甲基环己烷的产物通过在50cm填充柱上蒸馏(bp.105℃,88mbar)来纯化,得到纯的(II)(566g,83%收率)。
1H-NMR(400MHz,CDCl3):δ=7.24(dd,J=7.58Hz,1H),7.05(m,3H),2.52(d,J=7.07Hz,2H),2.41(s,3H),1.94(m,1H),0.99(d,J=6.82Hz,6H)ppm。13C-NMR(400MHz,CDCl3):δ=141.7(s),137.6(s),130.0(d),128.0(d),126.4(d),126.2(d),45.5(t),30.3(d),22.5(2q),21.5(q)ppm。GC/MS(EI):148(M+,26),106(42),105(100),103(8),91(18),79(7),77(11),43(8),41(8),39(8)。
B)2-甲基-4-异丁基溴化物(IV)
用氮气冲洗反应器,并添加(II)(5440g,36.7mol)。在搅拌下添加铁粉(102g,1.8mol)和碘(1g)。将混合物冷却至10℃,并在10℃下用6小时逐滴添加溴(5860g,36.7mol)。在添加期间,产生必须通过适当方式吸收的1摩尔当量的氢溴酸。添加之后,将反应物在室温下搅拌1小时,然后用10升NaOH 2M洗涤。将混合物用己烷萃取两次,然后将有机层合并,用水和盐水洗涤并真空浓缩。短程蒸馏(120℃,8mbar)得到(IV)(4580g,55%收率)。
1H-NMR(400MHz,CDCl3):δ=7.46(d,J=8.07Hz,1H),7.06(s,1H),6.87(d,J=8.07Hz,1H),2.45(d,J=7.09Hz,2H),2.42(s,3H),1.88(m,1H),0.95(d,J=6.60Hz,6H)ppm。13C-NMR(400MHz,CDCl3):δ=141.0(s),137.2(s),132.0(d),131.7(d),128.3(d),122.0(s),44.7(t),30.1(d),22.9(q),22.3(2q)ppm。GC/MS(EI):228(M+,20),226(M+,20),186(21),185(97),184(23),183(100),105(19),104(14),103(17),77(13)。
C)2-甲基-4-异丁基苯甲醛(III)
将镁屑(171g,7mol)置于反应器中并用THF覆盖。添加少量(6ml)(IV),并通过温和加热引发反应。将剩余的(IV)(1589g,7mol)与THF(3l)混合并逐滴添加,同时保持温和回流(70-85℃)而无需外部加热。添加完后,将混合物在回流下再搅拌1小时。将反应混合物冷却至10℃,并在1小时内逐滴添加二甲基甲酰胺(566g,7.7mol),保持温度低于30℃。将反应混合物搅拌1小时,然后用冰冷的HCl(2M)淬灭。将混合物用己烷萃取,合并有机层,用水和盐水洗涤。将溶液用MgSO4干燥并真空浓缩。用100cm填充柱蒸馏(b.p.105℃,2.5mbar),得到纯(III)(592g,收率48%)。
1H-NMR(400MHz,CDCl3):δ=10.22(s,1H),7.71(d,J=7.82Hz,1H),7.14(d,J=7.58Hz,1H),7.04(s,1H),2.65(s,3H),2.50(d,J=7.34Hz,2H),1.91(m,1H),0.92(d,J=6.85Hz,6H)ppm。13C-NMR(400MHz,CDCl3):δ=192.3(d),148.2(s),140.5(s),132.6(d),132.3(d),132.2(s),127.1(d),45.4(t),30.1(d),22.4(2q),19.6(q)ppm。GC/MS(EI):176(M+,53),134(100),133(38),106(14),105(70),103(14),91(37),77(19),43(30),41(14)。
D)3-(4-异丁基-2-甲基苯基)丙烯-2-醛(VI)
向反应器中装入(III)(1kg,5.68mol)、甲醇(400ml)和原甲酸三甲酯(900g,8.49mol)。将反应混合物冷却至-10℃,并添加盐酸(37%,1g)。反应放热并将温度升至25℃,将混合物搅拌30分钟。将反应用乙酸钠(20g)淬灭并通过真空蒸馏除去挥发物。将残余的缩醛装入第二反应器中,并添加三氟化硼乙醚合物(1g),并在4小时内逐滴添加乙基乙烯基醚(538g,7.5mol),同时保持温度在25-30℃。将反应物质用饱和碳酸钠(500ml)淬灭。将得到的粗甲氧基乙氧基缩醛在90℃下用含有盐酸(37%,50g)的水(500ml)水解5小时。将中间体(VI)在120℃下短程蒸馏。
1H-NMR(400MHz,CDCl3):δ=9.87(s,1H),7.78(d,J=15.89Hz,1H),7.55(d,J=8.31,1H),7.06(m,1H),6.96(m,1H),6.68(m,1H),2.50(s,2H),2.49(s,3H),1.88(m,1H),0.94(d,J=6.60Hz,6H)ppm。13C-NMR(400MHz,CDCl3):δ=194.0(d),150.4(d),145.5(s),137.8(s),131.9(d),130.3(s),128.7(d),127.5(d),126.7(d),45.3(t),30.1(d),22.40(2q),19.8(q)ppm。GC/MS(EI):202(M+,8),187(42),159(31),145(100),141(13),131(30),129(20),128(22),116(18),115(34)。
E)3-(4-异丁基-2-甲基苯基)丙醛(I)
将蒸馏的(VI)装入高压釜,并添加异丙醇(200ml)。在0.5bar氢气压力下,将不饱和醛用钯/碳(5%)氢化。将混合物过滤并真空浓缩。通过在50cm填充柱上蒸馏(沸点116℃,0.05mbar)纯化粗产物,得到产物(I)(926g,80%收率,基于(III))。
气味:花香,醛香,青香,橡胶味,铃兰醛味,水味。
1H-NMR(400MHz,CDCl3):δ=9.88(t,J=1.5Hz,1H),7.07(d,J=7.6Hz,1H),7.0-6.95(m,2H),2.98-2.93(m,2H),2.79-2.74(m,2H),2.46(d,J=7.1Hz,2H),2.33(s,3H),1.95-1.82(m,1H),0.95(d,J=6.6Hz,6H)ppm。13C-NMR(400MHz,CDCl3):δ=202.2(d),140.2(s),136(s),135.9(s),131.6(d),128.6(d),127.3(d),45.4(t),44.6(t),30.6(d),25.5(t),22.9(q),19.7(q)ppm。GC/MS(EI):204(M+,23),161(100),147(26),143(49),119(84),118(34),117(33),115(33),105(59),91(36)。
实施例2:1-(二乙氧基甲基)-4-异丁基-2-甲基苯(IIIb)的合成
将(III)和(X)的混合物85:15(200g,1.13mol)放入反应器中,并添加三氟硼烷THF配合物(1g,0.01mol)。在25-30℃下用20分钟添加原甲酸三乙酯(200g,1.35mol),同时用冰浴冷却。将深红色反应混合物搅拌10分钟,然后添加三乙胺(2ml,0.01mol),并将含有(IIIb)和(Xb)的混合物在填充有丝网圆柱体(2×3mm)的30cm柱上蒸馏,得到纯的(IIIb)(b.p 100℃,2.6mbar,197g,69%收率)。
1H-NMR(400MHz,CDCl3):δ=7.46(d,J=7.83Hz,1H),6.96(dd,J=7.58,1.47Hz,1H),6.93(s,1H),5.54(s,1H),3.56(m,4H),2.42(d,J=7.09Hz,2H),2.35(s,3H),1.84(dt,J=13.39,6.88x(2)Hz,1H),1.22(t,J=7.09x(2)Hz,6H),0.89(d,J=6.60Hz,6H)ppm。13C-NMR(400MHz,CDCl3):δ=141.7(s),135.8(s),134.1(s),131.3(d),126.2(2d),100.2(d),61.3(2t),45.1(t),30.2(d),22.4(2q),18.9(q),15.25(2q)ppm。GC/MS(EI):250(M+,1),206(15),205(100),177(27),162(8),134(10),105(22),103(8),91(13),57(10),29(7)。
Claims (7)
1.二烷基苯化合物的区域-选择性官能化,
其中在位置(a)官能化的化合物与在位置(b)官能化的化合物的比例为至少70:30,更特别地为至少80:20,还更特别地为至少85:15,以及还更特别地为至少90:10,其特征在于取代基R是异丁基。
2.根据权利要求1的区域-选择性官能化,其中所述反应是将苯甲醛官能团引入到位置(a)的羰基化反应。
3.根据权利要求2的区域-选择性羰基化,其中所述羰基化反应使用HF/BF3和一氧化碳进行。
4.形成式(I)化合物的方法,
包括区域-选择性官能化二烷基苯化合物的步骤,
其中在位置(a)官能化的化合物与在位置(b)官能化的化合物的比例为至少70:30,更特别地为至少80:20,还更特别地为至少85:15,以及还更特别地为至少90:10,并且其中取代基R是异丁基。
5.形成式(I)化合物的方法,
包括以下步骤:-
A)
B)
和
C)氢化化合物(Ⅵ)以提供化合物(I)。
6.权利要求5的方法,其中将化合物(III)转化为相应的二烷基缩醛用于纯化,然后进一步转化为化合物(I)。
7.式IIIb的化合物,
在形成式(I)化合物的方法中作为有用的中间体。
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