CN109046352A - A kind of method that catalysis prepares tumor vessel blocking agent pharmaceutical intermediate - Google Patents
A kind of method that catalysis prepares tumor vessel blocking agent pharmaceutical intermediate Download PDFInfo
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- CN109046352A CN109046352A CN201810770556.7A CN201810770556A CN109046352A CN 109046352 A CN109046352 A CN 109046352A CN 201810770556 A CN201810770556 A CN 201810770556A CN 109046352 A CN109046352 A CN 109046352A
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- China
- Prior art keywords
- alumina hydrotalcite
- nickel magnesia
- cuprous oxide
- acid
- magnesia
- Prior art date
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- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title abstract description 14
- 206010028980 Neoplasm Diseases 0.000 title abstract description 11
- 239000002981 blocking agent Substances 0.000 title abstract description 7
- 239000012450 pharmaceutical intermediate Substances 0.000 title abstract description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 96
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 46
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 claims abstract description 43
- 229960001545 hydrotalcite Drugs 0.000 claims abstract description 43
- 229910001701 hydrotalcite Inorganic materials 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims abstract description 35
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229940112669 cuprous oxide Drugs 0.000 claims abstract description 31
- 239000000463 material Substances 0.000 claims abstract description 28
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 22
- JLDSOYXADOWAKB-UHFFFAOYSA-N aluminium nitrate Chemical compound [Al+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O JLDSOYXADOWAKB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- CCVYRRGZDBSHFU-UHFFFAOYSA-N (2-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1O CCVYRRGZDBSHFU-UHFFFAOYSA-N 0.000 claims description 34
- FFFIRKXTFQCCKJ-UHFFFAOYSA-N 2,4,6-trimethylbenzoic acid Chemical compound CC1=CC(C)=C(C(O)=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-N 0.000 claims description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 17
- QYJPSWYYEKYVEJ-FDGPNNRMSA-L copper;(z)-4-oxopent-2-en-2-olate Chemical compound [Cu+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O QYJPSWYYEKYVEJ-FDGPNNRMSA-L 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000010949 copper Substances 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- 229910052802 copper Inorganic materials 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 230000033228 biological regulation Effects 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- XEUCQOBUZPQUMQ-UHFFFAOYSA-N Glycolone Chemical compound COC1=C(CC=C(C)C)C(=O)NC2=C1C=CC=C2OC XEUCQOBUZPQUMQ-UHFFFAOYSA-N 0.000 claims 1
- RQQDJYROSYLPPK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 Chemical compound N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 RQQDJYROSYLPPK-UHFFFAOYSA-N 0.000 claims 1
- 230000006641 stabilisation Effects 0.000 claims 1
- 238000011105 stabilization Methods 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 25
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- 150000002989 phenols Chemical class 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000003197 catalytic effect Effects 0.000 description 12
- 239000012535 impurity Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- XGOYIMQSIKSOBS-UHFFFAOYSA-N vadimezan Chemical compound C1=CC=C2C(=O)C3=CC=C(C)C(C)=C3OC2=C1CC(O)=O XGOYIMQSIKSOBS-UHFFFAOYSA-N 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 229950008737 vadimezan Drugs 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000000654 additive Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-dimethylbenzene Natural products CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000004411 aluminium Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- ATTFYOXEMHAYAX-UHFFFAOYSA-N magnesium nickel Chemical compound [Mg].[Ni] ATTFYOXEMHAYAX-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YSJWNEDBIWZWOI-UHFFFAOYSA-N 2-hydroxy-3,4-dimethylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(O)=C1C YSJWNEDBIWZWOI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000004066 vascular targeting agent Substances 0.000 description 2
- -1 3,6- dioxaheptyl Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- CDMOJOBQGOLJLJ-UHFFFAOYSA-N CC1=C2OC=3C=CCC(C3C(C2=CC=C1C)=O)=O Chemical compound CC1=C2OC=3C=CCC(C3C(C2=CC=C1C)=O)=O CDMOJOBQGOLJLJ-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- RALVJOGGCCWZDG-UHFFFAOYSA-N acetic acid;chlorobenzene Chemical compound CC(O)=O.ClC1=CC=CC=C1 RALVJOGGCCWZDG-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- YAVVGPBYBUYPSR-UHFFFAOYSA-N benzene;oxygen Chemical compound [O].C1=CC=CC=C1 YAVVGPBYBUYPSR-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010916 retrosynthetic analysis Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
- B01J23/72—Copper
-
- B01J35/394—
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
Abstract
The invention belongs to catalysis material technical fields, and in particular to a kind of method that catalysis prepares tumor vessel blocking agent pharmaceutical intermediate 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid.The present invention is with Ni (NO3)2·6H2O、Al(NO3)3·9H2O and Mg (NO3)2·6H2O is that raw material prepares nickel magnesia-alumina hydrotalcite, then prepares nickel magnesia-alumina hydrotalcite as supported carrier cuprous oxide using nickel magnesia-alumina hydrotalcite and supports cuprous oxide material；The present invention supports the fragrant halogen of cuprous oxide material catalysis using nickel magnesia-alumina hydrotalcite and phenol analog derivative prepares tumor vessel blocking agent pharmaceutical intermediate 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid；Catalyst system high income of the present invention, reaction temperature is low, is suitble to industrialized production.
Description
Technical field
The invention belongs to catalysis material technical fields, and in particular to a kind of catalysis is prepared among tumor vessel blocking agent drug
The method of body.
Background technique
Tumor vessel blocking agent (vascular disrupting agents, VDAs) is that one kind can be quickly and selective broken
For bad malignant tumour new vessels to reach the drug for the treatment of cancer purpose, Vadimezan (ASA404, DMXAA) is chemical entitled
5,6- dimethyl Oxoxanthone -4- acetic acid are small molecule tumor vessel disrupting agent, are used for and other drugs partner treatment advanced stage
Lung cancer and other tumours.2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid be synthesis Vadimezan (ASA404,
DMXAA key intermediate), 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid is two aryl oxide structures, according to inverse conjunction
It can be synthesized by corresponding fragrant halogen compound and containing phenolic compounds at analysis, structural formula and retrosynthetic analysis are as follows:
European Journal of Medicinal Chemistry 37 (2002) 825-828, An improved
With 3,4- dimethyl -2- iodo in synthesis of 5,6-dimethylxanthenone-4-acetic acid (DMXAA)
Benzoic acid is raw material, is initially formed the potassium salt form of benzoic acid, is then made in the catalysis of CuCl/ tri- (3,6- dioxaheptyl) amine
2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid, crude yield 87%, then to isolating are generated with lower reaction
Crude product recrystallized using ethyl acetate/methanol mixed system, yield 71%, comprehensive yield is only 61.8%, and
Iodate raw material preparation cost is high, so the route is not suitable for production amplification.
China Medicine University's Chen Guohua in 2011 et al. (Chinese Journal of Pharmaceuticals, 2011,42 (4): 248-250, tumour
The synthesis of vascular disrupting agents vadimezan) use 3,4- dimethyl -2 hydroxybenzoic acid and o-chlorobenzene acetic acid in K2CO3/CuCl/
The catalytic action of the composite catalyst of KI/TBAB is reacted in next step, yield 79%；But react raw materials used 3,4- dimethyl-
2 hydroxybenzoic acid also needs multistep reaction preparation.
Liu Xuefeng (Chinese Journal of Pharmaceuticals, 2015,46 (3): the easy synthesis of 238-239, Vadimezan) in 2015
A kind of synthetic method of simplicity is disclosed, which is raw material using bromo- 3, the 4- mesitylenic acid of 2- and o-hydroxy phenylacetic acid,
2- [(2- carboxymethyl) phenoxy group] -3,4- dimethyl benzene first is prepared under DBU/ pyridine/Cu/CuI Diversity catalytic action
Acid, yield 72%；The route is easy to get relative to above two method raw material, and route is short, is suitble to GMP requirement, but crude yield
Only 72%, purity and color be not high, and the crude product prepared influences subsequent bulk pharmaceutical chemicals even across active carbon decoloring also yellowly
The coloration of Vadimezan.
So developing a kind of using the bromo- 3,4- mesitylenic acid of 2- and o-hydroxy phenylacetic acid as the synthesis of raw material high-efficient simple
Method has great importance to synthesize 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid.
Summary of the invention
The purpose of the present invention is overcoming deficiency in the prior art, the present invention provides a kind of nickel magnesia-alumina hydrotalcite and supports oxygen
Change copper product to be catalyzed the method for preparing 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid；The present invention uses nickel magnesium
Aluminium houghite be carrier, its surface in situ formed cuprous oxide active component, catalysis bromo- 3, the 4- mesitylenic acid of 2- with
O-hydroxy phenylacetic acid reaction generates 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid.Catalyst system yield of the present invention
Up to 90% or more, product is white powdery solids, has excellent appearance, and catalyst can be recycled and apply, and reduce
Production cost.
According to an aspect of the present invention, the present invention provides a kind of nickel magnesia-alumina hydrotalcites to support cuprous oxide material
Preparation method includes the following steps:
1) preparation of nickel magnesia-alumina hydrotalcite:
By 5mmol Ni (NO3)2·6H2O、30mmol Al(NO3)3·9H2O and 10mmol Mg (NO3)2·6H2O is dissolved in
It stirs evenly to form the first mixed liquor in 400ml distilled water；
First mixed liquor is warming up to 70-80 DEG C to be stirred, the sodium hydroxide and 0.4mol/ of 0.6mol/L is then added dropwise
L sodium carbonate composition alkaline mixed solution, control alkaline mixed solution dripping quantity regulation system pH maintain 10.2-10.5 it
Between, pH stops that alkaline mixed solution is added dropwise after stablizing, and then insulation reaction 6-8h is cooled to room temperature, filter, and filter cake uses purified water
Washing is to filtrate at drying to constant weight obtains nickel magnesia-alumina hydrotalcite at 70-80 DEG C after neutrality；
2) copper component supports:
Cupric acetylacetonate is dissolved in toluene, nickel magnesia-alumina hydrotalcite ultrasound, back flow reaction 18-24h is added；Decompression is de-
Except ethylene glycol ultrasonic disperse is added in toluene, it is warming up at 150-160 DEG C and reacts 2h, cooling, filtering, dry nickel magnesia-alumina neatly
Stone barbell carries cuprous oxide material and (is abbreviated as Cu2O/LDH)；The present invention uses nickel magnesia-alumina hydrotalcite for carrier, and cupric is born
It is downloaded in nickel magnesia-alumina hydrotalcite, then uses ethylene glycol that cupric is reduced to monovalence copper for reducing agent, keep monovalence oxidation sub-
Copper is distributed more uniform on carrier, and catalytic activity is higher.
Preferably, 5-20mmol cupric acetylacetonate is added in step 2) in every gram of nickel magnesia-alumina hydrotalcite；It is further excellent
It is selected as that 15mmol cupric acetylacetonate is added in every gram of nickel magnesia-alumina hydrotalcite；
According to another aspect of the present invention, the present invention provides a kind of nickel magnesia-alumina hydrotalcites to support cuprous oxide material
Purposes be catalyzed fragrant halogen under the action of solvent and alkali and react two aryl oxides of generation with phenolic substances.
Preferably, the fragrant halogen of the catalysis, which react two aryl oxides of generation with phenolic substances and refers to, is catalyzed bromo- 3, the 4- dimethyl benzene of 2-
Formic acid is reacted with o-hydroxy phenylacetic acid generates 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid, and reaction equation is such as
Shown in Scheme 1:
Preferably, the solvent is N,N-Dimethylformamide (DMF), pyridine, quinoline, dimethyl sulfoxide, nitrobenzene, second
The mixing of one or both of glycol, diethylene glycol dimethyl ether, dioxane and tetrahydrofuran (THF)；
Preferably, the alkali is one of triethylamine, potassium carbonate or cesium carbonate；4-dimethylaminopyridine can also be used
(DMAP), the alkali such as 11 carbon -7- alkene (DBU) of 1,8- diazabicylo realize the effect of alkali in the present invention；
Preferably, it is calculated according to molar ratio, the molar ratio of the o-hydroxy phenylacetic acid and bromo- 3, the 4- mesitylenic acid of 2-
For 1.05-1.30:1；
Preferably, bromo- 3, the 4- mesitylenic acid of the 2- is reacted with o-hydroxy phenylacetic acid generates 2- [(2- carboxymethyl) benzene
Oxygroup] -3,4- mesitylenic acid reaction temperature be 90-120 DEG C；
Preferably, it is calculated according to weight ratio, it is bromo- 3, the 4- bis- of 2- that the nickel magnesia-alumina hydrotalcite, which supports cuprous oxide material,
The 5%wt-20wt% of methyl benzoic acid weight.
The present invention provides the preparation methods that a kind of nickel magnesia-alumina hydrotalcite supports cuprous oxide material, can using the material
It is effectively catalyzed fragrant halogen and substance containing phenol produces two aryl oxides, to prepare tumor vessel blocking agent pharmaceutical intermediate 2- [(2- carboxylic first
Base) phenoxy group] -3,4- mesitylenic acid, compared with method in the prior art, catalysis process of the present invention has following excellent
Point:
1) catalyst system of the present invention is simple, high catalytic efficiency, and reaction conversion can be completed at 100 DEG C or so；
2) present invention using with layer dihydroxy composite oxide of metal nickel magnesia-alumina hydrotalcite as carrier, on its surface and
Duct internal in-situ supported active copper, is evenly distributed, substantially increases the catalytic activity of cuprous oxide.
Detailed description of the invention
Fig. 1 is the transmission electron microscope figure that nickel magnesia-alumina hydrotalcite prepared by the present invention supports cuprous oxide material, figure
Middle black dot represents cuprous oxide.
Fig. 2 is the 1H-NMR spectrogram of 2- prepared by the present invention [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid, molten
Agent is deuterated DMSO.
Specific embodiment
In order to make the objectives, technical solutions and advantages of the present invention clearer, With reference to embodiment, to this
Invention is further described.It should be understood that these descriptions are merely illustrative, and it is not intended to limit the scope of the invention.
HPLC chromatogram analysis condition in embodiment: chromatographic column, Zorbax Exlipse XDB-C18,4.6 × 250mm × 5 μ
m；Mobile phase A (phosphate aqueous solution of 0.1%V), Mobile phase B (acetonitrile), flow velocity 1.0ml/min, Detection wavelength 220nm, by table 1
Middle gradient is eluted:
1 HPLC eluent gradient elution program of table
Raw materials and reagents: the raw materials used bromo- 3,4- mesitylenic acid of 2- is that (Chinese Medicine industry is miscellaneous according to the prior art
Will, 2015,46 (3): the easy synthesis of 238-239, Vadimezan) in introduction made by oneself obtained by, through silica gel column chromatography into
Row purifying, purity 99.89%；Remaining raw material is commercially available conventional reagent.
Embodiment 1
One, it prepares nickel magnesia-alumina hydrotalcite and supports cuprous oxide material and (be abbreviated as Cu2O/LDH)
1) preparation of nickel magnesia-alumina hydrotalcite:
By 5mmol Ni (NO3)2·6H2O、30mmol Al(NO3)3·9H2O and 10mmol Mg (NO3)2·6H2O is dissolved in
It stirs evenly to form the first mixed liquor in 400ml distilled water；
First mixed liquor is warming up to 70-80 DEG C to be stirred, the sodium hydroxide and 0.4mol/ of 0.6mol/L is then added dropwise
L sodium carbonate composition alkaline mixed solution, control alkaline mixed solution dripping quantity regulation system pH maintain 10.2-10.5 it
Between, pH stops that alkaline mixed solution is added dropwise after stablizing, and then insulation reaction 6-8h is cooled to room temperature, filter, and filter cake uses purified water
Washing is to filtrate at drying to constant weight obtains nickel magnesia-alumina hydrotalcite (being abbreviated as LDH) at 70-80 DEG C after neutrality；
2) copper component supports:
Cupric acetylacetonate (0-20mmol) is dissolved in 100ml toluene, 1.0g nickel magnesia-alumina hydrotalcite ultrasound is added, returns
Stream reaction 18-24h；100ml ethylene glycol ultrasonic disperse is added in removed under reduced pressure toluene, is warming up at 150-160 DEG C and reacts 2h, drops
Temperature, filtering are dried at 60 DEG C to constant weight to obtain nickel magnesia-alumina hydrotalcite and support cuprous oxide material and (are abbreviated as Cu2O/LDH)。
Two, nickel magnesia-alumina hydrotalcite supports cuprous oxide material and (is abbreviated as Cu2O/LDH catalytic performance test) uses
The nickel magnesia-alumina hydrotalcite that different cupric acetylacetonate additive amounts are prepared supports cuprous oxide material as catalyst 2-
Bromo- 3,4- mesitylenic acid is reacted with o-hydroxy phenylacetic acid generates 2- [(2- carboxymethyl) phenoxy group] -3,4- dimethyl benzene first
Acid, the method is as follows:
Bromo- 3, the 4- mesitylenic acid (2.30g, 10mmol) of 2-, o-hydroxy phenylacetic acid are added in parallel projects instrument
(1.83g, 12mmol), catalyst (0.23g, 10%wt), Anhydrous potassium carbonate (2.76g, 20mmol), the heating of 30ml solvent DMF
Back flow reaction, detects reaction solution using HPLC, stops when no longer changing to bromo- 3, the 4- mesitylenic acid concentration of substrate 2- anti-
It answers, counts reaction time, bromo- 3, the 4- mesitylenic acid of substrate 2-, target product 2- [(2- carboxymethyl) benzene oxygen in reaction solution
Base] -3,4- mesitylenic acid and its impurity three area percentage (o-hydroxy phenylacetic acid and its peak of solvent DMF not into
Row integral statistics), the nickel magnesia-alumina hydrotalcite that different cupric acetylacetonate additive amounts are prepared supports cuprous oxide material conduct
The catalytic effect of catalyst is shown in Table 2:
2 cupric acetylacetonate additive amount of table supports the influence of cuprous oxide material catalytic performance to nickel magnesia-alumina hydrotalcite
Note: cupric acetylacetonate additive amount refers to that nickel magnesia-alumina hydrotalcite supports in cuprous oxide material preparation process every gram
The molal quantity of cupric acetylacetonate is added in nickel magnesia-alumina hydrotalcite；Impurity refers to the bromo- 3,4- mesitylenic acid of 2- and adjacent hydroxyl
Base phenylacetic acid intramolecular condensation and its with target product 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid occur into
One step side reaction, the impurity counted in table 2 under impurity item are each impurity summation.
For result above with the increase of cupric acetylacetonate additive amount, it is sub- that the nickel magnesia-alumina hydrotalcite prepared supports oxidation
The catalytic activity of copper product enhances；When in every gram of nickel magnesia-alumina hydrotalcite be added cupric acetylacetonate 15mmol when catalytic effect most
It is good, the nickel magnesia-alumina hydrotalcite prepared under this material proportion support cuprous oxide material transmission electron microscope picture as shown in Figure 1,
Cuprous oxide is highly dispersed on carrier as can be seen from Figure.
Embodiment 1-A
In order to verify carrier of the present invention to the effect of catalyst, the present invention uses grade cuprous oxide (Shandong West Asia
Learn Industrial Co., Ltd) substitution nickel magnesia-alumina hydrotalcite support cuprous oxide material catalysis the bromo- 3,4- mesitylenic acid of 2- with
O-hydroxy phenylacetic acid reaction generates 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid, the method is as follows:
Bromo- 3, the 4- mesitylenic acid (2.30g, 10mmol) of 2-, o-hydroxy phenylacetic acid are added in 100ml three-necked flask
(1.83g, 12mmol), grade cuprous oxide (0.23g, 10%wt), Anhydrous potassium carbonate (2.76g, 20mmol), 30ml solvent
DMF heating reflux reaction detects reaction solution using HPLC, and reaction reaches balance after 6h, bromo- 3, the 4- diformazan of substrate 2- in reaction solution
The area percentage of yl benzoic acid, target product 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid and its impurity three
Than being respectively 38.2%, 61.5%, 0.3%；It is poor to show that its catalytic activity compared with nickel magnesia-alumina hydrotalcite supports cuprous oxide material.
Embodiment 2
15mmol cupric acetylacetonate is added as optimal proportion in every gram of nickel magnesia-alumina hydrotalcite of establishment and prepares nickel magnesium
After aluminium houghite supports cuprous oxide material as catalyst, the present invention does solvent type, the type of alkali in catalysis reaction
It advanced optimizes, the method is as follows:
Bromo- 3, the 4- mesitylenic acid (2.30g, 10mmol) of 2-, o-hydroxy phenylacetic acid are added in parallel projects instrument
(low boiling point is reacted at (1.83g, 12mmol), catalyst (0.23g, 10%wt), alkali (20mmol), 100-120 DEG C of 30ml solvent
Back flow reaction is taken in 100 DEG C of solvents), reaction solution is detected using HPLC, to bromo- 3, the 4- mesitylenic acid concentration of substrate 2-
Stop reaction when no longer changing, counts bromo- 3, the 4- mesitylenic acid of substrate 2-, target product 2- [(2- carboxylic first in reaction solution
Base) phenoxy group] -3,4- mesitylenic acid and its impurity three area percentage, differential responses system the results are shown in Table 3 institutes
Show:
Influence of the type of 3 solvent of table and its alkali to reaction
The above result shows that best as alkali effect as solvent, cesium carbonate using dioxane.
Embodiment 3
15mmol cupric acetylacetonate is added as optimal proportion in determining every gram of nickel magnesia-alumina hydrotalcite and prepares nickel magnesium
Aluminium houghite support cuprous oxide material as catalyst, cesium carbonate as alkali, dioxane as solvent when, the present invention couple
Catalyst amount is further optimized: method is as follows:
Bromo- 3, the 4- mesitylenic acid (2.30g, 10mmol) of 2-, o-hydroxy phenylacetic acid are added in parallel projects instrument
(1.83g, 12mmol), catalyst (0.12-0.69g, 5.0-30%wt), cesium carbonate (15mmol), the reflux of 30ml dioxane
Reaction detects reaction solution using HPLC, stops reaction, system when no longer changing to bromo- 3, the 4- mesitylenic acid concentration of substrate 2-
Count the bromo- 3,4- mesitylenic acid of substrate 2-, target product 2- [(2- carboxymethyl) phenoxy group] -3,4- dimethyl benzene in reaction solution
Formic acid and its area percentage of impurity three, differential responses system the results are shown in Table shown in 4:
Influence of 4 catalyst amount of table to reaction
The above result shows that with the increase of catalyst amount, the conversion ratio of substrate is continuously increased, when catalyst amount is
Bromo- 3, the 4- mesitylenic acid weight of 2- 15% when, the substrate transformation rate reaches maximum, continues growing the dosage of catalyst, instead
And impurity content greatly increases；So catalyst amount control is 15% or so.
Embodiment 4
Bromo- 3, the 4- mesitylenic acid (229.1g, 1mol) of substrate 2-, neighbour are sequentially added in 30L double-layer glass reaction kettle
Hydroxyl phenylacetic acid (182.6g, 1.2mol), catalyst (34.4g, 15%wt), cesium carbonate (423.6g, 1.3mol), 10L dioxy
Six rings are stirred at reflux reaction；
It is analyzed after back flow reaction 4h using HPLC detection reaction solution and (counts and calculate by area percentage: substrate
3.8%, target product 95.7%, impurity 0.5%), continue back flow reaction 2h and extract reaction solution progress HPLC analysis (by area percentage
Calculated than statistics: substrate 0.1%, target product 99.2%, impurity 0.7%), stop reaction and be cooled to 20-30 DEG C, is then added dropwise
Aperture is used to divide for 0.45 micron of organic filtering with microporous membrane after the aqueous solution of citric acid stirring 20-30min of 1L0.1mol/L
Catalyst is separated out, filtrate is obtained；
Filtrate is adjusted to pH=3.2-3.5 and is transferred in 50L crystallization kettle using citric acid and is heated to 50-60 DEG C at uniform
Then the aqueous solution of 20%V methanol is added dropwise in solution using peristaltic pump into crystallization kettle, stop being added dropwise when system occurs muddy
The aqueous solution of 20%V methanol, insulated and stirred 30-60min, the aqueous solution for then proceeding to be added dropwise 20%V methanol are used into solution
HPLC detection target product 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid stops being added dropwise when no longer reducing, finally
40 DEG C are cooled to by 50 DEG C with the rate of temperature fall of 1 DEG C/min, 20 DEG C is cooled to by 40 DEG C with the rate of temperature fall of 3 DEG C/min, filters,
269.1g white solid 2- [(2- carboxymethyl) phenoxy group] -3,4- two is dried in vacuo to obtain at 45 DEG C after 0 DEG C of acetone elution filter cake
Methyl benzoic acid, yield 89.6%, it is 99.86% that HPLC, which detects purity,；1H-NMR[(CD3)2SO]:δ12.39(s,2H,
CO2H),7.64(d,1H),7.26(dd,1H),7.20(d,1H),7.07(m,1H),6.90(dd,1H),6.08(d,1H),
3.71(m,2H),2.37(s,3H,CH3),2.00(s,3H,CH3)。
Embodiment 5
Carry out recovery is dried after using acetone supersound washing to the catalyst that embodiment 4 is isolated, reaction condition is same
Embodiment 4, experimental scale are bromo- 3, the 4- mesitylenic acid 20mmol of substrate 2-, and recovery three times, counts each reaction liquid
Response situation it is as shown in table 5:
5 catalyst recovery of table is formed
The above result shows that catalyst circulation of the present invention apply three times after its catalytic performance compared with fresh catalyst without bright
Significant difference is different, i.e., recovery can be achieved in later period production amplification reduces production cost.
Although embodiments of the present invention are described in detail, it should be understood that, without departing from of the invention
In the case where spirit and scope, embodiments of the present invention can be made with various changes, replacement and change.
Claims (10)
1. the preparation method that a kind of nickel magnesia-alumina hydrotalcite supports cuprous oxide material, characterized by the following steps:
1) preparation of nickel magnesia-alumina hydrotalcite:
By 5mmol Ni (NO3)2·6H2O、30mmol Al(NO3)3·9H2O and 10mmol Mg (NO3)2·6H2O is dissolved in
It stirs evenly to form the first mixed liquor in 400ml distilled water；
First mixed liquor is warming up to 70-80 DEG C be stirred, the sodium hydroxide and 0.4mol/L of 0.6mol/L is then added dropwise
The alkaline mixed solution of sodium carbonate composition, the dripping quantity regulation system pH for controlling alkaline mixed solution are maintained between 10.2-10.5, pH
Stop that alkaline mixed solution is added dropwise after stabilization, then insulation reaction 6-8h is cooled to room temperature, filter, and filter cake is using purifying water washing
To filtrate at drying to constant weight obtains nickel magnesia-alumina hydrotalcite at 70-80 DEG C after neutrality；
2) copper component supports:
Cupric acetylacetonate is dissolved in toluene, nickel magnesia-alumina hydrotalcite ultrasound, back flow reaction 18-24h is added；Removed under reduced pressure first
Ethylene glycol ultrasonic disperse is added in benzene, is warming up at 150-160 DEG C and reacts 2h, and cooling filters, is dry that nickel magnesia-alumina hydrotalcite is carried on a shoulder pole
Carry cuprous oxide material.
2. preparation method according to claim 1, it is characterised in that: be added in every gram of nickel magnesia-alumina hydrotalcite in step 2
5-20mmol cupric acetylacetonate.
3. preparation method according to claim 2, it is characterised in that: be added in every gram of nickel magnesia-alumina hydrotalcite in step 2
15mmol cupric acetylacetonate.
4. a kind of any one of claim 1-3 nickel magnesia-alumina hydrotalcite supports the purposes of cuprous oxide material, feature exists
In: under the action of solvent and alkali, it is catalyzed fragrant halogen and reacts two aryl oxides of generation with phenolic substances.
5. purposes according to claim 4, it is characterised in that: the fragrant halogen of the catalysis is reacted with phenolic substances generates two aryl oxides
Refer to that the catalysis bromo- 3,4- mesitylenic acid of 2- is reacted with o-hydroxy phenylacetic acid and generates 2- [(2- carboxymethyl) phenoxy group] -3,4-
Mesitylenic acid, reaction equation is as shown in Scheme 1:
。
6. purposes according to claim 5, it is characterised in that: the solvent is N,N-Dimethylformamide, pyridine, quinoline
Quinoline, dimethyl sulfoxide, nitrobenzene, ethylene glycol, diethylene glycol dimethyl ether, one or both of dioxane and tetrahydrofuran are mixed
It closes.
7. purposes according to claim 5, it is characterised in that: the alkali is one in triethylamine, potassium carbonate or cesium carbonate
Kind.
8. purposes according to claim 5, it is characterised in that: calculated according to molar ratio, the o-hydroxy phenylacetic acid and 2-
The molar ratio of bromo- 3,4- mesitylenic acid is 1.05-1.30:1.
9. purposes according to claim 5, it is characterised in that: bromo- 3, the 4- mesitylenic acid of the 2- and o-hydroxy
The reaction temperature that acetic acidreaction generates 2- [(2- carboxymethyl) phenoxy group] -3,4- mesitylenic acid is 90-120 DEG C.
10. purposes according to claim 5, it is characterised in that: calculated according to weight ratio, the nickel magnesia-alumina hydrotalcite load
Carry the 5%wt-20wt% that cuprous oxide material is the bromo- 3,4- mesitylenic acid weight of 2-.
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| US20130291431A1 (en) * | 2012-05-01 | 2013-11-07 | Mississippi State University | Composition and methods for improved fuel production |
| CN103623821A (en) * | 2013-11-28 | 2014-03-12 | 常州大学 | Method for preparing supported cuprous oxide catalyst |
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| WO2012089081A1 (en) * | 2010-12-28 | 2012-07-05 | 上海杰事杰新材料(集团)股份有限公司 | Nano particle/polyamide composite material, preparation method therefor, and use thereof |
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