CN115894186A - Synthetic method of intermediate of limod - Google Patents
Synthetic method of intermediate of limod Download PDFInfo
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- CN115894186A CN115894186A CN202211494320.8A CN202211494320A CN115894186A CN 115894186 A CN115894186 A CN 115894186A CN 202211494320 A CN202211494320 A CN 202211494320A CN 115894186 A CN115894186 A CN 115894186A
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- catalyst
- reaction
- promoter
- dimethoxy
- copper catalyst
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 61
- -1 3, 5-dimethoxy-4-isopropylbenzyl Chemical group 0.000 claims abstract description 44
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 43
- 239000007800 oxidant agent Substances 0.000 claims abstract description 14
- 238000001308 synthesis method Methods 0.000 claims abstract description 13
- ZFQFDCIZQIYJRV-UHFFFAOYSA-N 3,5-dimethoxy-4-propan-2-ylbenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1C(C)C ZFQFDCIZQIYJRV-UHFFFAOYSA-N 0.000 claims abstract description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 70
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 38
- 229910052802 copper Inorganic materials 0.000 claims description 38
- 239000010949 copper Substances 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 29
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 25
- 239000011953 free-radical catalyst Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 20
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 19
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims description 17
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 16
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 10
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- SXTLQDJHRPXDSB-UHFFFAOYSA-N copper;dinitrate;trihydrate Chemical compound O.O.O.[Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O SXTLQDJHRPXDSB-UHFFFAOYSA-N 0.000 claims description 4
- 229940076286 cupric acetate Drugs 0.000 claims description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 4
- 239000005453 ketone based solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 2
- 239000004312 hexamethylene tetramine Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 claims 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 133
- 238000009776 industrial production Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 description 31
- 239000000047 product Substances 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 229940045803 cuprous chloride Drugs 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 239000002699 waste material Substances 0.000 description 5
- ANMATWQYLIFGOK-UHFFFAOYSA-N Iguratimod Chemical compound CS(=O)(=O)NC1=CC=2OC=C(NC=O)C(=O)C=2C=C1OC1=CC=CC=C1 ANMATWQYLIFGOK-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229950003909 iguratimod Drugs 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 206010007269 Carcinogenicity Diseases 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
- 231100000260 carcinogenicity Toxicity 0.000 description 2
- 230000007670 carcinogenicity Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
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- 239000000463 material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
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- 239000000376 reactant Substances 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
- AUDBREYGQOXIFT-UHFFFAOYSA-N (3,5-dimethoxyphenyl)methanol Chemical compound COC1=CC(CO)=CC(OC)=C1 AUDBREYGQOXIFT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZISJNXNHJRQYJO-CMDGGOBGSA-N 5-[(e)-2-phenylethenyl]-2-propan-2-ylbenzene-1,3-diol Chemical compound C1=C(O)C(C(C)C)=C(O)C=C1\C=C\C1=CC=CC=C1 ZISJNXNHJRQYJO-CMDGGOBGSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- VOBHPCGTIVBHHH-UHFFFAOYSA-M C1=CC=NC=C1.[O-2].[O-2].[OH-].[Cr+5] Chemical compound C1=CC=NC=C1.[O-2].[O-2].[OH-].[Cr+5] VOBHPCGTIVBHHH-UHFFFAOYSA-M 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- OBXSGRKNCOCTTM-UHFFFAOYSA-N benzyl diethyl phosphate Chemical class CCOP(=O)(OCC)OCC1=CC=CC=C1 OBXSGRKNCOCTTM-UHFFFAOYSA-N 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- INGGGNUCWJHFKD-UHFFFAOYSA-N chromium;pyridine Chemical compound [Cr].C1=CC=NC=C1 INGGGNUCWJHFKD-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 150000002697 manganese compounds Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000006053 organic reaction Methods 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical class C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
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- 238000001291 vacuum drying Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of a yivinmod intermediate. Specifically, the invention discloses a synthesis method of 3, 5-dimethoxy-4-isopropylbenzaldehyde, which comprises the following steps: in the presence of an oxidizing agent and a catalyst, 3, 5-dimethoxy-4-isopropylbenzyl alcohol is subjected to the following oxidation reaction. The intermediate of the invention has high purity and yield, green and environment-friendly reaction and simple post-treatment, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to a synthetic method of a limod intermediate.
Background
The vitamin mod (Benvitimod) is the first non-hormone novel small molecule chemical drug for treating inflammatory and autoimmune diseases in the world, is separated from symbiotic bacterial metabolites of soil nematodes, and is the first therapeutic aromatic hydrocarbon receptor modulator (TAMA). Pharmacological research shows that the vismod can inhibit the activity of lymphocyte protein tyrosine kinase; has inhibitory effect on the release of inflammatory cytokines associated with psoriasis, migration and infiltration of inflammatory cells, abnormal differentiation and proliferation of keratinocytes, neovascularization and vasodilatation. In 2009 and 9 months, the yivinmod obtains clinical batches, and in 2019 and 5 and 29 months, NMPA approves 1 type of innovative medicine yivinmod cream (euphbiak) to be marketed, and is used for locally treating adult psoriasis vulgaris with light to moderate stability.
The chemical name of the danimod is: 5- [ (E) -2-styryl ] -2-isopropyl-1, 3-benzenediol, having the following structural formula:
in the reported synthetic route of the iguratimod, the skeleton structure is generally synthesized by a Wittig-Horner condensation reaction, which is carried out between substituted diethyl benzylphosphate and substituted benzaldehyde. The key intermediates involved in this route include 3, 5-dimethoxy-4-isopropylbenzaldehyde, which has the following structural formula:
CN101830764A discloses a method for synthesizing stilbene compounds by utilizing Pfitzner-moffatt oxidation reaction, which takes substituted benzyl alcohol as a raw material, and DMSO (dimethyl sulfoxide) is adopted to prepare corresponding substituted benzaldehyde compounds by Pfitzner-moffatt oxidation. After the reaction, water was added, extraction was performed with ethyl acetate, washing was performed with water, and the solvent was removed by rotary evaporation to obtain 8.72g (41.9 mmol) of a product with a yield of 88%. And then preparing a target product stilbene compound such as phenyl-limod (i.e. the vismod) by Wittig-Horner condensation, wherein the specific reaction conditions are as follows:
the Pfitzner-moffatt oxidation uses a mixture of dimethyl sulfoxide (DMSO) and acetic anhydride (activating reagent) as an oxidizing agent to oxidize alcohols to aldehydes via an alkoxy sulfonium ylide intermediate. One of the byproducts generated during the oxidation reaction is dimethyl sulfide, which is toxic and has a foul odor, and when discharged excessively, it adversely affects the ecological environment, so that the method is not suitable for large-scale industrial production.
CN1407978A discloses a method for synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde by using pyridinium chlorochromate as an oxidant. After the reaction was complete, diethyl ether was added, the layers were separated, the black viscous slurry was washed with dry diethyl ether to turn it to a black solid, the combined organic solution was passed through a short pad of Floriaol and the solvent was removed by rotary evaporation to give a slurry which was then crystallized from ethanol/hexane in 75% -80% yield. The reaction yield is not high, the oxidant of the pyridinium chlorochromate has high toxicity and carcinogenicity, and a large amount of chromium-containing waste liquid generated after the reaction can cause environmental pollution, so that the industrial production is difficult to realize.
CN101838173A discloses a method for synthesizing 3, 5-dimethoxy-4-isopropyl benzaldehyde by taking DMSO-sodium bicarbonate as an oxidizing agent. After the reaction is finished, adding water, extracting by ethyl acetate, washing by water, and removing the solvent by rotary evaporation to obtain an oxidation product with the yield of 86%. This reaction is more similar to that of CN101830764A, with DMSO being used as the oxidant, dimethyl sulfide is also produced as a by-product.
CN104003848A discloses a method for synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde by using chromium trioxide pyridinium salt or manganese dioxide as an oxidant. After the reaction is finished, adding water, extracting for 5 times by using ethyl acetate, concentrating the ethyl acetate, separating out a solid, filtering and drying to obtain an oxidation product. The reaction adopts chromium pyridine trioxide or manganese dioxide as an oxidant, the pyridinium chlorochromate has high toxicity and carcinogenicity, the manganese dioxide reacts violently, and harmful wastes are generated, so that the industrial production is difficult to realize.
The prior art does not adopt an environment-friendly and efficient synthesis method, has the defects of low reaction yield, high reagent toxicity and the like, and produces by-products which can cause environmental pollution. When 3, 5-dimethoxy-4-isopropyl benzaldehyde is synthesized, more toxic byproducts are difficult to remove, and the toxic byproducts are purified by adopting separation and purification methods such as recrystallization, extraction or column chromatography, and the like, and the process has the defects of complex separation process, long consumed time and large required solvent amount, and is not suitable for industrial mass production in actual production. In order to better broaden the application of the yivinmod, a process route which is suitable for large-scale production needs to be continuously researched.
Disclosure of Invention
The invention aims to overcome the defects of high production cost, environmental hazard and unsuitability for industrial production in the synthetic method of the key intermediate of the iguratimod in the prior art, and provides a synthetic method of the intermediate of the iguratimod. The intermediate of the iguratimod obtained by the synthesis method has high purity and yield, green and environment-friendly reaction and simple post-treatment, and is suitable for large-scale industrial production. The invention also provides a new crystal form of the intermediate of the yivinmod, which has high purity, is convenient for separation, storage and transportation, and provides great convenience for preparing a high-quality final product (i.e. the yivinmod) and simplifying the process.
The invention solves the technical problems through the following technical scheme:
the invention provides a method for synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde, which comprises the following steps: in the presence of an oxidant and a catalyst, 3, 5-dimethoxy-4-isopropylbenzyl alcohol is subjected to the following oxidation reaction;
the oxidant is oxygen or air;
the catalyst is selected from one or more of a nitroxide free radical catalyst, a copper catalyst and a promoter.
In the oxidation reaction, the oxidizing agent is preferably air.
In the oxidation reaction, the catalyst is preferably a mixture of a nitroxide radical catalyst, a copper catalyst and a promoter.
<xnotran> , 2,2,6,6- (TEMPO), 4- -2,2,6,6- (4-OH-TEMPO), 4- -2,2,6,6- , 4- -2,2,6,6- , 4- -2,2,6,6- 4- -2,2,6,6- , TEMPO / 4-OH-TEMPO, 4-OH-TEMPO. </xnotran>
In the oxidation reaction, the molar amount of the nitroxide radical catalyst is 0.5 to 10%, preferably 1 to 5%, more preferably 1 to 4%, even more preferably 1 to 3%, and most preferably 3%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
In the oxidation reaction, the copper catalyst is selected from one or more of cuprous halide, cupric acetate and cupric nitrate trihydrate, preferably selected from one or more of cuprous chloride (CuCl), cuprous bromide (CuBr), cuprous iodide (CuI), cupric acetate and cupric nitrate trihydrate, more preferably selected from one or more of CuCl, cuBr and CuI, and more preferably CuCl.
In the oxidation reaction, the molar amount of the copper catalyst is 0.5 to 10%, preferably 1 to 5%, more preferably 1 to 4%, even more preferably 1 to 3%, and most preferably 3%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
In the oxidation reaction, the promoter is one or more selected from pyridine, 4-Dimethylaminopyridine (DMAP), N' -Tetramethylethylenediamine (TMEDA), N-methylimidazole, triethylamine (TEA) and hexamethylenetetramine, preferably DMAP and/or TMEDA, more preferably TMEDA.
In the oxidation reaction, the molar amount of the promoter is 1% to 20%, preferably 2% to 10%, more preferably 2% to 8%, even more preferably 2% to 6%, and most preferably 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
In the oxidation reaction, the molar ratio of the nitroxide free radical catalyst, the copper catalyst and the promoter is a conventional molar ratio, and may be 1:0.5 to 2:1 to 5, preferably 1:1 to 1.5:1.5 to 3, more preferably 1:1:2.
in the oxidation reaction, the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5% to 10%, 0.5% to 10% and 1% to 20%, respectively, preferably 1% to 5%, 1% to 5% and 2% to 10%, further preferably 1% to 4%, 1% to 4% and 2% to 8%, more preferably 1% to 3%, 1% to 3% and 2% to 6%, and most preferably 3%, 3% and 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
In the oxidation reaction, the mole ratio of the nitroxide free radical catalyst, the copper catalyst and the promoter is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5-10%, 0.5-10% and 1-20%, respectively, preferably 1-5%, 1-5% and 2-10%, further preferably 1-4%, 1-4% and 2-8%, more preferably 1-3%, 1-3% and 2-6%, most preferably 3%, 3% and 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
In the oxidation reaction, the nitroxide free radical catalyst is TEMPO and/or 4-OH-TEMPO, the copper catalyst is one or more of CuCl, cuBr and CuI, and the promoter is DMAP and/or TMEDA; the mole ratio of the nitroxide free radical catalyst to the copper catalyst to the promoter is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5-10%, 0.5-10% and 1-20%, respectively, preferably 1-5%, 1-5% and 2-10%, further preferably 1-4%, 1-4% and 2-8%, more preferably 1-3%, 1-3% and 2-6%, most preferably 3%, 3% and 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
In the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is CuCl, and the accelerator is TMEDA; the mole ratio of the nitroxide free radical catalyst to the copper catalyst to the promoter is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5-10%, 0.5-10% and 1-20%, respectively, preferably 1-5%, 1-5% and 2-10%, further preferably 1-4%, 1-4% and 2-8%, more preferably 1-3%, 1-3% and 2-6%, most preferably 3%, 3% and 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
The oxidation reaction further comprises a solvent.
The solvent is a solvent which is conventional in the field, as long as the solvent can dissolve reactants and does not react with the reactants; may be selected from one or more of aromatic hydrocarbon solvents (e.g., benzene, toluene or xylene), halogenated hydrocarbon solvents (e.g., dichloromethane, dichloroethane, dichloropropane or chloroform), polar aprotic solvents (e.g., acetonitrile, DMF or DMSO), etheric solvents (e.g., tetrahydrofuran, dioxane or ethylene glycol dimethyl ether) and ketone solvents (e.g., acetone or cyclohexanone), preferably from one or more of polar aprotic solvents, etheric solvents and ketone solvents, further preferably from one or more of dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF) and acetone, more preferably from one or more of acetonitrile, THF and acetone, and most preferably acetonitrile or THF.
The progress of the oxidation reaction can be monitored by detection methods conventional in the art (e.g., TLC, MS, HPLC or NMR, preferably TLC or HPLC), and the end point of the reaction is generally determined by the disappearance or no longer reaction of the starting 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
In the synthesis method, the time of the oxidation reaction is not particularly limited, and generally refers to the time required from the start of the reaction to the completion of most of the conversion of the reaction raw material. By effecting the majority of the conversion, it is meant that the content of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol in the reaction liquid of the oxidation reaction is 15% or less, preferably 10% or less, more preferably 5% or less, still more preferably 1% or less, and most preferably 0.5% or less. The content can be detected by methods conventional in the art, including but not limited to HPLC, TLC, etc.
The temperature of the oxidation reaction is a temperature which is conventional in such a reaction in the art, and may be a low temperature (e.g., 0 ℃), room temperature, or a high temperature, preferably 10 to 40 ℃, more preferably 15 to 35 ℃, and still more preferably room temperature.
And after the oxidation reaction is finished, carrying out post-treatment operation.
The post-treatment comprises the following steps: adding water for quenching.
The quenching can be adding the reaction liquid into water, or adding water into the reaction liquid. The water can be added dropwise, or sequentially in batches, or added in one step integrally.
The quenching is carried out at a suitable temperature. The temperature of the quenching is any temperature in the range of 0 ℃ to room temperature, preferably 0 to 25 ℃, further preferably 0 to 20 ℃, more preferably 0 to 15 ℃, most preferably 0 to 10 ℃.
The post-treatment also comprises the following steps: separating out solid and separating.
The separation is a conventional separation operation, such as filtration or suction filtration.
In the present invention, the yield of the product of the oxidation reaction is 90%, preferably 93%, more preferably 95%, and still more preferably 98%.
In the present invention, the purity of the product of the oxidation reaction is 90%, preferably 95%, more preferably 98%, and still more preferably 99.5%.
In a second aspect, the present invention also provides a crystalline form of 3, 5-dimethoxy-4-isopropylbenzaldehyde as hereinbefore described having an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:9.3 +/-0.2, 10.3 +/-0.2, 11.3 +/-0.2, 13.9 +/-0.2, 15.7 +/-0.2, 17.4 +/-0.2, 18.4 +/-0.2, 18.9 +/-0.2, 20.2 +/-0.2, 20.4 +/-0.2, 20.7 +/-0.2, 22.7 +/-0.2, 25.1 +/-0.2, 25.5 +/-0.2, 25.7 +/-0.2, 27.2 +/-0.2, 27.9 +/-0.2, 28.4 +/-0.2, 29.2 +/-0.2, 29.7 +/-0.2, 30.0 +/-0.2, 31.2 +/-0.2, 32.7 +/-0.2, 33.7 +/-0.2, 34.9 +/-0.2, 36.3 +/-0.2, 39.2 +/-0.2, 40.4 +/-0.2 and 40.5 +/-0.2.
In a third aspect, the present invention also provides a use of 3, 5-dimethoxy-4-isopropylbenzaldehyde or its crystal form as described above for preparing the present vismod compound.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the reaction operation is convenient, the raw materials are common and easy to obtain, the cost is low, the reaction condition is mild, the monitoring is easy, and the yield is high; meanwhile, the complicated conventional post-treatment and purification steps are omitted, and the obtained crystal form product has extremely high purity (> 99.5%). The technical scheme of the invention has the technical effects of one or more of the following effects:
(1) The reaction is mild and easy to monitor: the air oxidation reaction has mild condition and high yield, the reaction process can be conveniently and accurately monitored by observing color change during the reaction, and the reaction is complete from orange to dark blue;
(2) The cost is reduced: the reaction raw materials, the catalyst and the organic solvent are common and easy to obtain, the cost is low, only about 15g of copper catalyst is needed for feeding 1 kg of reaction substrate after the reaction is amplified, the total amount of the reagent is about 70g, and the cost is low;
(3) The reaction method is simple and environment-friendly: the post-treatment operation of the invention does not need complex operations such as filtration, spin drying, extraction, concentration, recrystallization and the like, the reaction solution or the reaction mixture can be crystallized by adding water, solid wastes increasing the burden of environmental protection treatment are not generated in the whole process, only conventional liquid wastes are generated, copper ions in the waste liquid are easy to remove by using inorganic alkali, the waste liquid treatment is simple, and the invention is very suitable for industrial production;
(4) The reaction product has high yield and purity: the reaction yield is over 90 percent, the product can be directly precipitated from the quenched reaction liquid in a crystal form with extremely high purity of more than 99.5 percent after the reaction is finished, and the ideal reaction yield and purity can be obtained with high repeatability even under large-scale feeding.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
The technical solution of the present invention is further illustrated by the following examples. It should be understood that the following examples are only for illustrating and explaining the present invention and are not intended to limit the scope of the present invention. Unless otherwise indicated, the instruments, materials, reagents and the like used in the following examples are all available by conventional commercial means.
Abbreviations and symbols in the context of the present invention have the following meanings:
HPLC conditions: high performance liquid chromatography (talete 3000) in siemmer flight; and (3) chromatographic column: ghost-sniper,4.6mm x 50mm; mobile phase: a buffer solution containing 0.1mol/L of an ammonium acetate buffer (7.7 g of ammonium acetate, 1000ml of water was added to dissolve the ammonium acetate, and the pH was adjusted to 9.0 with ammonia water) as a buffer salt stock solution, a methanol-buffer salt stock solution-water (10; gradient of mobile phase: 70% A/30% B → 10% A/90% B → 70% A/30% B for 45min; wavelength: 205nm.
LC-MS conditions: the model is as follows: agilent liquid chromatography mass spectrometer 1260/6120; an ion source: ESI; sample preparation solvent: and (3) acetonitrile.
XRPD conditions: bruker D8 ADVANCE X-ray powder diffractometer; the measurement conditions were as follows: cuKa40kv 40mA, divergent slit 0.6mm, cable-stayed slit 4.0 °, continuous scan, lynxEye detector, step size: 0.02 °, scan speed, 4 °/min, scan range: 3-60 degrees.
In order to monitor the progress of the reaction uniformly, the controlled sampling time points in the following examples and comparative examples were set to 20 hours after the start of the reaction under various reaction conditions, except for specific indications, but the time for the actual reaction raw materials to complete most of the conversion may be much less than 20 hours, and may vary depending on the scale of the reaction.
Interpretation of terms:
controlling the content of products: in the oxidation reaction process of the present invention, the content of the reaction product 3, 5-dimethoxy-4-isopropylbenzaldehyde in the reaction solution is generally measured by HPLC after the reaction is carried out for a certain period of time after the reaction solution is sampled.
Controlling the content of raw materials: in the oxidation reaction process of the present invention, the content of the reaction raw material (or referred to as reaction substrate) 3, 5-dimethoxy-4-isopropylbenzyl alcohol in the reaction solution is generally measured by sampling the reaction solution and detecting by HPLC after the reaction is carried out for a certain period of time.
Reaction raw materials, reaction substrates: all refer to 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
Example 1
5.00g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol, 123mg of 4-OH-TEMPO, 71mg of CuCl and 166mg of TMEDA are added into a 100mL reaction bottle, 25mL of acetonitrile is added, the reaction bottle is kept in an air environment, the reaction is stirred at 20-25 ℃ for 20 hours, and a sample is taken and monitored by HPLC. After the reaction is finished, the obtained reaction liquid is filtered by 10g of 200-300-mesh silica gel, a filter cake is washed by 20mL of acetonitrile, and the obtained filtrate is subjected to reduced pressure evaporation at 40-50 ℃ to remove the solvent, so that 4.82g of white solid is obtained, the yield is 97.37%, and the HPLC purity is 99.11%.
The results show that: air oxidation is adopted, the reaction condition is mild, the color change of the reaction liquid can be observed during the reaction, the reaction is complete from orange yellow to blue, the reaction process is convenient to monitor, and the reaction yield and the purity are high.
Example 2:
5.00g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol, 123mg of 4-OH-TEMPO, 71mg of CuCl and 166mg of TMEDA are added into a 100mL reaction bottle, 25mL of acetonitrile is added, the reaction bottle is kept in an air environment, the reaction is stirred at 20-25 ℃ and is carried out, a sample is sampled and monitored by HPLC, and the complete conversion of the raw materials is confirmed. And after the reaction is finished, dropwise adding the reaction liquid into 100mL of ice water at the temperature of 0-10 ℃ for quenching, separating out white solid, continuously stirring for 2 hours, performing suction filtration, leaching the filter cake once with 50mL of ice water, performing suction filtration again to obtain 4.97g of wet product, and drying to obtain 4.70g of white solid, wherein the yield is 94.9%, and the HPLC purity is 99.89%.
Structural characterization data for the product:
1 H-NMR(400MHz，CDCl 3 ):δ9.88(s,1H),7.05(s,1H),3.87(s,6H),3.66(dt,J＝13.94,6.72Hz,1H),1.29(d,J＝6.85Hz,6H).
ESI-MS:m/z 209.1[M+H] + 。
the results show that: air oxidation is adopted, the reaction condition is mild, the color change of the reaction liquid can be observed during the reaction, the reaction is complete from orange to blue, and the reaction process is convenient to monitor. The post-treatment is simple and environment-friendly, the conventional operations such as filtration, concentration spin-drying, extraction and the like are not needed, and the product can be directly separated out and obtained from the system with extremely high purity by adopting a water quenching mode on the premise of keeping high yield. A small amount of catalyst used in the reaction is dissolved in water and is easy to remove, the whole preparation process does not generate solid waste, only generates liquid waste which can be treated in a conventional mode, and the method is very suitable for industrial production.
Example 3:
following the same preparation method as in example 2, using TEMPO as a nitroxide radical catalyst, the scale of reaction, reaction conditions and work-up procedure were the same as in example 2, and the results are shown in Table 1.
TABLE 1 screening of nitroxide free radical catalysts
[1] The proportion is as follows: the molar ratio of each nitroxide radical catalyst/copper catalyst/promoter to the reaction raw material is based on the amount of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
The results show that: when TEMPO is used as the nitroxide free radical catalyst, the reaction yield and the product purity are not affected, and an ideal result consistent with 4-OH-TEMPO can be obtained. Based on commercial cost considerations only, 4-OH-TEMPO may be preferred where the reaction yield and product purity do not differ significantly, since 4-OH-TEMPO is cheaper and more readily available than TEMPO.
Example 4:
the reaction solvent was screened in accordance with the same preparation method as in example 2, and the scale of reaction, reaction conditions and working-up operation were the same as in example 2, and the results are shown in Table 2.
TABLE 2 screening of organic solvents
[1] The proportion is as follows: the molar ratio of each nitroxide radical catalyst/copper catalyst/promoter to the reaction raw material is based on the amount of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
The results show that: when acetonitrile and THF are used as organic solvents, the reaction result is better, and the yield and purity of the obtained product are more ideal; when DMSO and DMF are used as organic solvents, detection results of the intermediate control product and the intermediate control raw material show that the reaction process is slow, the raw materials are not completely reacted after 20 hours, and the reaction time still needs to be prolonged; when acetone is used as an organic solvent, the reaction yield is ideal, the product purity is slightly low, and the purity requirement of the next preparation reaction can be met. Therefore, acetonitrile and THF can be preferably used as the organic solvent.
Example 5:
the promoters were screened in organic solvents of acetonitrile and THF according to the same preparation method as in example 2, and the scale of reaction, reaction conditions and working up operation were the same as in example 2, and the reaction time was 20 hours for the acetonitrile group and 28 hours for the THF group, and the results are shown in tables 3 and 4.
TABLE 3 screening of Accelerant acetonitrile groups
[1] The proportion is as follows: the molar ratio of each nitroxide radical catalyst/copper catalyst/promoter to the reaction raw material is based on the amount of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
Table 4 screening of accelerator THF groups
[1] The proportion is as follows: the molar ratio of each nitroxide radical catalyst/copper catalyst/promoter to the reaction raw material is based on the amount of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
The results show that: in acetonitrile and THF organic reaction solvent, TMEDA and DMAP can be used as promoters to completely react, the reaction yield and purity of the TMEDA and the DMAP are both higher, but the reaction rate of the DMAP is slightly slower than that of the TMEDA; when pyridine and TEA are used as the promoters, the control result shows that the reaction of the raw materials is incomplete after 20 hours, and the reaction time needs to be prolonged. Therefore, TMEDA and DMAP are preferably used as the promoter, and TMEDA is more preferred.
Example 6:
the same preparation process as in example 2 was followed, and the types of copper catalysts were screened in an acetonitrile organic solvent, and the scale of reaction, reaction conditions and working up were the same as in example 2, and the results are shown in Table 5.
TABLE 5 screening of copper catalysts
[1] The proportion is as follows: the molar ratio of each nitroxide radical catalyst/copper catalyst/promoter to the reaction raw material is based on the amount of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
The results show that: when CuCl, cuBr and CuI are used as copper catalysts, the reaction yield and the product purity are high.
Example 7:
the catalyst was prepared in the same manner as in example 2 by selecting the proportions of the components, the scale of reaction, the reaction conditions and the working up operation were the same as in example 2, and the results are shown in Table 6.
TABLE 6 screening of the proportions of the catalyst systems
[1] The proportion is as follows: the molar ratio of each nitroxide radical catalyst/copper catalyst/promoter to the reaction raw material is based on the amount of the reaction raw material 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
The results show that: carrying out central control detection 20 hours after the reaction under the conditions of 3%/3%/6%, completely converting reaction raw materials, and having higher reaction yield and product purity; carrying out central control detection 20 hours after the reaction under the conditions of 1%/1%/2%, wherein most of the conversion of the reaction raw materials is not completed, the reaction time is prolonged to 25 hours, the reaction raw materials disappear, and the reaction yield and the product purity are ideal; prolonging the reaction time to 40 hours under the condition of 0.5%/0.5%/1%, completing most of conversion of reaction raw materials, and ensuring that the reaction yield and the product purity meet the requirements; the reaction with the catalyst in the ratio of 0.1%/0.1%/0.2% was completed until a large amount of the starting material was not completely converted after 40 hours. Therefore, catalyst system ratios of 3%/3%/6%, 1%/1%/2%, and 0.5%/0.5%/1% are preferably used, more preferably 3%/3%/6%.
Example 8:
adding 2000g of 3, 5-dimethoxy-4-isopropyl benzyl alcohol into a 20L reaction kettle, adding 10L of acetonitrile, stirring and dispersing, sequentially adding 49.14g of 4-OH-TEMPO, 28.24g of CuCl and 66.32g of TMEDA, flushing a feeding opening with 2L of acetonitrile, supplementing 4L of acetonitrile, promoting dissolution, stirring at room temperature, introducing air into the bottom of a reaction solution by using a gas pipe when most of raw materials are dissolved, changing the reaction solution from orange to dark green after blowing the air for about 9 hours, and completely changing the reaction solution from dark green to dark blue. TLC monitoring is carried out to complete the reaction, the reaction solution is concentrated, the volume of the reaction solution is approximately kept to be 5L, 14L of normal temperature water is added, the mixture is stirred uniformly,
starting refrigeration, setting 0 ℃, starting timing when the internal temperature is lower than 10 ℃, stirring for crystallization for 2 hours, filtering, washing residues in the kettle with 15L of ice water, discharging water, soaking and washing a filter cake for 5 times, draining water, dishing, and vacuum drying (the temperature of an oven is lower than 50 ℃) to obtain a target product which is a white solid, the weight is 1937.23g, the yield is 97.8%, and the HPLC purity is 99.93%.
The obtained target product 3, 5-dimethoxy-4-isopropylbenzaldehyde is in a crystal form, and an X-ray powder diffraction pattern of the target product has diffraction peaks at the following positions of 2 theta: 9.3 + -0.2, 10.3 + -0.2, 11.3 + -0.2, 13.9 + -0.2, 15.7 + -0.2, 17.4 + -0.2, 18.4 + -0.2, 18.9 + -0.2, 20.2 + -0.2, 20.4 + -0.2, 20.7 + -0.2, 22.7 + -0.2, 25.1 + -0.2, 25.5 + -0.2, 25.7 + -0.2, 27.2 + -0.2, 27.9 + -0.2, 28.4 + -0.2, 29.2 + -0.2, 29.7 + -0.2, 30.0 + -0.2, 31.2 + -0.2, 32.7 + -0.2, 33.7 + -0.2, 34.9 + -0.2, 36.3 + -0.2, 39.2 + -0.2, 40.4 + -0.2 and 42.5 + -0.2.
Comparative example 1:
adding 42.00g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol and 160mL of n-heptane into a 500mL reaction bottle, heating at 80 ℃, stirring, adding 25mL of ethyl acetate into the reaction bottle, stirring until the solid is completely dissolved,then MnO is added slowly in portions 2 80.00g, and stirred under reflux with heating overnight. After the reaction was completed, the reaction mixture was cooled to about 40 ℃, 200-300 mesh silica gel was used as a filler, filtered, and the silica gel column was washed with n-heptane/ethyl acetate =8/1 until the product was completely eluted, and rotary evaporated under reduced pressure to give 40.04g of a white solid product with a yield of 96.25%.
The results show that: using MnO 2 Oxidation, although the reaction yield is high, the reaction requires the addition of MnO in the case where the starting material is completely dissolved 2 The system is always in a violent boiling state in the reaction process, the risk of being burnt by high-temperature organic gas is increased during production, and the normal heptane gas is extremely flammable, so the reaction has higher risk in the production process; in addition, black manganese compounds generated in the reaction are easy to agglomerate and adhere to the surface of the reactor, are difficult to remove in other mild ways except heating and pickling, are difficult to treat in industrial production, can generate a large amount of harmful wastes, and have high safety and environmental protection risks.
Comparative example 2:
adding 2.00g of 3, 5-dimethoxy-4-isopropylbenzyl alcohol and 15mL of acetonitrile into a 100mL reaction bottle, stirring at 45 ℃, and dropwise adding Na into the reaction bottle 2 O 8 S 2 2.50g of aqueous solution (7 mL) was stirred for 30 minutes and monitored by TLC to show the disappearance of most of the starting material and the production of a more polar material, which was confirmed to be not the target product by comparison with the standard sample.
The results show that: most of the raw materials of the oxidation reaction in this step are reacted, but the target product is not obtained, presumably because the reaction is excessively oxidized to produce a carboxylic acid, which is not converted into the target product.
Comparative example 3:
adding 3.00g of 3, 5-dimethoxybenzyl alcohol into a three-neck flask, adding 30mL of acetonitrile, stirring for dispersion, sequentially adding 92mg of 4-OH-TEMPO, 52mg of CuCl and 124mg of TMEDA, wherein the color of the reaction solution is gray black, reacting overnight under the air condition, detecting by TLC that the reaction is complete, the system is a dark gray liquid, slowly adding water into the system, almost no change is generated when 15mL of water is added, continuously adding the water, gray liquid drops slowly appear at the beginning, finally adding the water to 30mL for half an hour, continuously stirring, separating out a small amount of gray solid, filtering to obtain off-white solid, the wet weight is 570mg, and a large amount of gray liquid drops exist in the filtrate. The solid was air dried to give 396mg of an off-white solid in about 13% yield and 95.12% purity.
Claims (17)
1. A method for synthesizing 3, 5-dimethoxy-4-isopropylbenzaldehyde is characterized by comprising the following steps: in the presence of an oxidant and a catalyst, carrying out the following oxidation reaction on 3, 5-dimethoxy-4-isopropyl benzyl alcohol;
the oxidant is oxygen or air;
the catalyst is selected from one or more of a nitroxide free radical catalyst, a copper catalyst and a promoter.
2. The method of synthesis of claim 1, wherein the oxidant is air.
3. The synthesis method of claim 1, wherein the catalyst is a mixture of a nitroxide free-radical catalyst, a copper catalyst, and a promoter.
4. <xnotran> 1 , , TEMPO, 4-OH-TEMPO, 4- -2,2,6,6- , 4- -2,2,6,6- , 4- -2,2,6,6- 4- -2,2,6,6- , TEMPO / 4-OH-TEMPO, 4-OH-TEMPO. </xnotran>
5. The synthesis method according to claim 1, wherein the copper catalyst is selected from one or more of cuprous halide, cupric acetate and cupric nitrate trihydrate, preferably from one or more of CuCl, cuBr, cuI, cupric acetate and cupric nitrate trihydrate, more preferably from one or more of CuCl, cuBr and CuI, and more preferably CuCl.
6. The synthesis process according to claim 1, wherein the promoter is selected from one or more of pyridine, DMAP, TMEDA, N-methylimidazole, TEA and hexamethylenetetramine, preferably is DMAP and/or TMEDA, more preferably is TMEDA.
7. The method of claim 1, wherein the nitroxide free radical catalyst is present in a molar amount of 0.5% to 10%, preferably 1% to 5%, more preferably 1% to 4%, even more preferably 1% to 3%, and most preferably 3%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
8. The synthesis method according to claim 1, wherein the molar amount of the copper catalyst is 0.5 to 10%, preferably 1 to 5%, more preferably 1 to 4%, even more preferably 1 to 3%, and most preferably 3% based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
9. The synthesis process according to claim 1, wherein the molar amount of the promoter is 1 to 20%, preferably 2 to 10%, more preferably 2 to 8%, even more preferably 2 to 6%, and most preferably 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
10. The synthesis method of claim 1, wherein the molar ratio of the nitroxide free-radical catalyst, the copper catalyst, and the promoter is 1:0.5 to 2:1 to 5, preferably 1:1 to 1.5:1.5 to 3, more preferably 1:1:2.
11. the synthesis process according to claim 1, wherein the temperature of the oxidation reaction is low, room or high, preferably 10 to 40 ℃, more preferably 15 to 35 ℃, and still more preferably room temperature.
12. The synthesis method according to claim 1, wherein the molar amounts of the nitroxide radical catalyst, the copper catalyst and the promoter in the oxidation reaction are 0.5-10%, 0.5-10% and 1-20%, respectively, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol, preferably 1-5%, 1-5% and 2-10%, more preferably 1-4%, 1-4% and 2-8%, more preferably 1-3%, 1-3% and 2-6%, and most preferably 3%, 3% and 6%.
13. The synthesis method of claim 1, wherein the molar ratio of the nitroxide free radical catalyst, the copper catalyst, and the promoter in the oxidation reaction is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5-10%, 0.5-10% and 1-20%, respectively, preferably 1-5%, 1-5% and 2-10%, further preferably 1-4%, 1-4% and 2-8%, more preferably 1-3%, 1-3% and 2-6%, most preferably 3%, 3% and 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
14. The synthesis method according to claim 1, wherein in the oxidation reaction, the nitroxide free radical catalyst is TEMPO and/or 4-OH-TEMPO, the copper catalyst is one or more selected from CuCl, cuBr and CuI, and the promoter is DMAP and/or TMEDA; the mole ratio of the nitroxide free radical catalyst to the copper catalyst to the promoter is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5-10%, 0.5-10% and 1-20%, respectively, preferably 1-5%, 1-5% and 2-10%, further preferably 1-4%, 1-4% and 2-8%, more preferably 1-3%, 1-3% and 2-6%, most preferably 3%, 3% and 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
15. The synthesis method of claim 1, wherein in the oxidation reaction, the nitroxide free radical catalyst is 4-OH-TEMPO, the copper catalyst is CuCl, and the promoter is TMEDA; the mole ratio of the nitroxide free radical catalyst to the copper catalyst to the promoter is 1:1:2; the molar amounts of the nitroxide free radical catalyst, the copper catalyst and the promoter are 0.5-10%, 0.5-10% and 1-20%, respectively, preferably 1-5%, 1-5% and 2-10%, further preferably 1-4%, 1-4% and 2-8%, more preferably 1-3%, 1-3% and 2-6%, most preferably 3%, 3% and 6%, based on the molar amount of 3, 5-dimethoxy-4-isopropylbenzyl alcohol.
16. The synthetic method of any one of claims 1-15 wherein the oxidation reaction further comprises a solvent; the solvent may be selected from one or more of aromatic hydrocarbon solvents (e.g., benzene, toluene or xylene), halogenated hydrocarbon solvents (e.g., dichloromethane, dichloroethane, dichloropropane or chloroform), polar aprotic solvents (e.g., acetonitrile, DMF or DMSO), ethereal solvents (e.g., THF, dioxane or ethylene glycol dimethyl ether) and ketone solvents (e.g., acetone or cyclohexanone), preferably from one or more of polar aprotic solvents, ethereal solvents and ketone solvents, further preferably from one or more of DMSO, DMF, acetonitrile, THF and acetone, more preferably from one or more of acetonitrile, THF and acetone, and most preferably acetonitrile or THF.
17. The synthesis method according to claim 16, characterized in that after the oxidation reaction is finished, a post-treatment operation is also carried out;
preferably, the post-treatment comprises the following steps: adding water for quenching; and/or, the post-treatment also comprises the following steps: separating out solid and separating; the separation may be filtration or suction filtration.
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| CN101830764A (en) * | 2010-05-05 | 2010-09-15 | 河北科技大学 | Method for synthesizing Stilbene compound by utilizing Pfitzner-moffatt oxidizing reaction |
| CN109096068A (en) * | 2018-07-10 | 2018-12-28 | 嘉兴学院 | The method that mantoquita/bidentate ligand/TEMPO catalytic air oxidation alcohol prepares aldehydes or ketones |
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| CN101830764A (en) * | 2010-05-05 | 2010-09-15 | 河北科技大学 | Method for synthesizing Stilbene compound by utilizing Pfitzner-moffatt oxidizing reaction |
| CN109096068A (en) * | 2018-07-10 | 2018-12-28 | 嘉兴学院 | The method that mantoquita/bidentate ligand/TEMPO catalytic air oxidation alcohol prepares aldehydes or ketones |
Non-Patent Citations (1)
| Title |
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| MINGYU GUAN等: "Practical Organic solvent-free Cu(OAc)2/DMAP/ TEMO-catalyzed aldehyde and imine formation from alcohols under air atmosphere", RSC ADVANCED, vol. 4, no. 80, pages 48778 * |
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