CN103772433A - Synthetic method of chemiluminescence reagent AMPPD for immunization analysis - Google Patents
Synthetic method of chemiluminescence reagent AMPPD for immunization analysis Download PDFInfo
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- CN103772433A CN103772433A CN201210397604.5A CN201210397604A CN103772433A CN 103772433 A CN103772433 A CN 103772433A CN 201210397604 A CN201210397604 A CN 201210397604A CN 103772433 A CN103772433 A CN 103772433A
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- XYIPYISRNJUPBA-UHFFFAOYSA-N [3-(3'-methoxyspiro[adamantane-2,4'-dioxetane]-3'-yl)phenyl] dihydrogen phosphate Chemical compound O1OC2(C3CC4CC(C3)CC2C4)C1(OC)C1=CC=CC(OP(O)(O)=O)=C1 XYIPYISRNJUPBA-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000010189 synthetic method Methods 0.000 title claims abstract description 22
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 7
- 230000003053 immunization Effects 0.000 title abstract 2
- 238000002649 immunization Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 32
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 19
- 230000026731 phosphorylation Effects 0.000 claims abstract description 14
- 238000007539 photo-oxidation reaction Methods 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 238000006467 substitution reaction Methods 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 31
- -1 di(2-ethylhexyl)phosphate propionitrile ester Chemical class 0.000 claims description 25
- 239000000126 substance Substances 0.000 claims description 25
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 18
- 229940125904 compound 1 Drugs 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000002841 Lewis acid Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- 150000007517 lewis acids Chemical class 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 239000011593 sulfur Substances 0.000 claims description 11
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229940125782 compound 2 Drugs 0.000 claims description 9
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 9
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 9
- 229910052753 mercury Inorganic materials 0.000 claims description 9
- 239000011592 zinc chloride Substances 0.000 claims description 9
- 235000005074 zinc chloride Nutrition 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000003018 immunoassay Methods 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical group CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 4
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- CEQFOVLGLXCDCX-WUKNDPDISA-N methyl red Chemical compound C1=CC(N(C)C)=CC=C1\N=N\C1=CC=CC=C1C(O)=O CEQFOVLGLXCDCX-WUKNDPDISA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 3
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 3
- 230000001335 demethylating effect Effects 0.000 claims description 2
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 claims 5
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000017858 demethylation Effects 0.000 abstract 1
- 238000010520 demethylation reaction Methods 0.000 abstract 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 10
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- GQKZBCPTCWJTAS-UHFFFAOYSA-N methoxymethylbenzene Chemical compound COCC1=CC=CC=C1 GQKZBCPTCWJTAS-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000003351 photoxidation Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- WOTBPOGYFGKWIB-UHFFFAOYSA-N C(=O)O.OC=1C=C(C(=O)O)C=CC1 Chemical compound C(=O)O.OC=1C=C(C(=O)O)C=CC1 WOTBPOGYFGKWIB-UHFFFAOYSA-N 0.000 description 1
- BMKCPUBVYYJSFN-WUKNDPDISA-N CO/C(/c1cccc(O)c1)=C1\C2CC34C1CC3CC4C2 Chemical compound CO/C(/c1cccc(O)c1)=C1\C2CC34C1CC3CC4C2 BMKCPUBVYYJSFN-WUKNDPDISA-N 0.000 description 1
- YKUCHDXIBAQWSF-UHFFFAOYSA-N COC(c1cc(O)ccc1)=O Chemical compound COC(c1cc(O)ccc1)=O YKUCHDXIBAQWSF-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 201000008197 Laryngitis Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010035745 Pneumonitis chemical Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 201000009408 aspiration pneumonitis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
The invention discloses a synthetic method of chemiluminescence reagent AMPPD for immunization analysis. 3-methoxy benzaldehyde with cheap price is used as raw material, and six reactions including acetalation, substitution, condensation, demethylation, phosphorylation and photooxidation are carried out, and AMPPD is synthesized efficiently with overall yield of 36%. 3-methoxy benzaldehyde with cheap price is used as raw material, which substantially reduces the cost; the phosphorylation method in the synthesis route is improved, and the yield of the phosphorylation reaction is increased; strict waterless and oxygen-free operation does not related in the synthesis route, and the reaction yield in the synthesis process is high, so the method is suitable for industrial production, and overcomes the disadvantage that the synthesis route at the present market is not easy to be used in large scale production.
Description
Technical field
The present invention relates to the preparation method of chemical illuminating reagent, especially the synthetic method of 4-methoxyl group-4-(3-phosphoric acid acyl phenyl) spiral shell [1,2-dioxane-3,2 '-diamantane] disodium salt (being called for short AMPPD).
Background technology
AMPPD is the chemical luminous substrate of alkaline phosphatase, and in suitable buffered soln, along with the catalytic hydrolysis effect of enzyme, AMPPD resolves into AMP-D, and the latter sends the optical signal that intensity is very high, and its luminous speed depends on the concentration of alkali phosphorus enzyme.In the time that alkali phosphorus enzyme is coupled to the probe of hybridization, the amount of hybrid molecule just can be detected by this system.Be widely used as at present the luminous substrate of chemiluminescence immune assay, there is very high detection sensitivity, be applicable to detect the material of various molecular weight, stable luminous substrate, detected result is stable, reproducible, detect linear wide ranges, do not need special luminous substrate-antigen/antibody connector, convenience, easily use, can apply the advantages such as multiple analytical model (sandwich, competition, antibody test etc.), medically promoting the use of.But because its price is higher, limit its large-scale development and used.The major cause that price is high is comparatively difficulty of this material preparation, synthesis technique complexity.
Its preparation at present mainly contains four routes.
The first synthetic method is one piece of patent (patent No. EP0518387) in Europe, be that raw material is prepared the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund by 2-diamantane ketone and 3-hydroxy-benzoic acid formic acid at metallic compound, then prepare AMPPD(by conventional photoxidation and see formula three), this reaction method flow process is short, efficiency is high, to complete reaction with the catalyst system of Lithium Aluminium Hydride/anhydrous titanous chloride composition but prepare key intermediate crucial catalyzer used, but anhydrous titanous chloride performance is active, belong to spontaneously combustible, meet air and water burning or blast, tool strong and stimulating, to mucous membrane, the upper respiratory tract, eye and skin have strong impulse.After suction, can be because of larynx and bronchial spasm, inflammation, oedema, chemical pneumonitis or pulmonary edema and lethal.After contact, cause burning sensation, cough, pant, laryngitis, breathe hard, have a headache, feel sick, vomiting etc., have not yet to see large-scale production, also there is no the mass-producing supply of commodities of Using such method.
The second synthetic method is one piece of Chinese patent (patent No. 102030779), it improves European patent, in patent, replace this catalyst system of Lithium Aluminium Hydride/anhydrous titanous chloride, used any catalyst system in anhydrous titanium tetrachloride/Lithium Aluminium Hydride, anhydrous titanium tetrachloride/zinc, these the three kinds of combinations of anhydrous titanium tetrachloride/tin instead.The method efficiently solves the shortcoming of the anhydrous titanous chloride that uses high risk, but still will under the condition of absolute anhydrous and oxygen-free, complete in actual building-up process.Therefore, this method is only suitable for a small amount of in laboratory and synthesizes, and is not suitable for industrial production, thereby has limited a large amount of productions of AMPPD.
TiCl
4/ LAH or TiCl
4/ Zn or TiCl
4/ Sn
The third method is to form two keys by the prussiate of diamantane and the Grignard reagent of replacement to obtain the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund, then obtain AMPPD(by conventional photooxidation reaction and see formula two) (United States Patent (USP), the patent No. 4956477; United States Patent (USP), the patent No. 6417380; United States Patent (USP), the patent No. 6124478; European patent, the patent No. 0582317 etc.), the method flow process is oversize, use hypertoxic prussiate, has used Grignard reagent in process simultaneously, makes complicated operation, produces danger, therefore also can not realize the large-scale production of AMPPD.
The 4th kind of synthetic method is one piece of Chinese patent (patent No. 200510021054), in patent, adopting 2-diamantane ketone and 3-dimethyl tertiary butyl siloxy-1-(1 '-p diethylaminobenzoic acid ester group)-benzyl methyl ether is raw material, react by Wittig, obtain [(3-dimethyl tertiary butyl siloxy phenyl) methoxyl group methene alkane] diamantane, obtain AMPPD by photoxidation.The method cost of material is high, and synthesis step is long, and in phosphorylation process, uses the method for phosphorus oxychloride Direct Phosphorylation to be difficult to obtain the disodium salt of solid, extremely affects the recrystallization purifying of final product.
Therefore,, although there has been several pieces of synthetic methods about AMPPD report, do not have at present a kind of suitable method and realizes the industrial production of AMPPD.
Summary of the invention
The object of the invention is to the deficiency for existing AMPPD synthetic method, the new synthetic method of a kind of AMPPD is provided.
In order to achieve the above object, the present invention has adopted following technical scheme:
For a synthetic method of the chemical illuminating reagent AMPPD of immunoassay, the method synthetic route is as follows:
Wherein, in compound 1, R group is methyl or ethyl;
Concrete synthesis step is as follows:
Step a, condensation reaction: in ether solvent, under the effect of alkali, there is condensation reaction with 2-diamantane ketone and obtain compound 2 in compound 1, alkali is any in LDA, LHMDS, n-Butyl Lithium, tert-butyl lithium, potassium tert.-butoxide, sodium tert-butoxide and sodium hydride, the temperature that adds alkali is-80 ℃ ~ 10 ℃, ether solvent is a kind in methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane;
Step b, demethylating reaction: compound 2 reacts and obtains compound 3 with sulfur alcohol sodium under heating condition, sulfur alcohol sodium is with the amount of substance of compound 2 than being 3:1 ~ 0.9:1, and temperature of reaction is 50 ℃ ~ 190 ℃, and reaction solvent is any in DMF, DMSO and THF;
Step c, phosphorylation reaction: compound 3 and 3-hydroxypropionitrile phosphorylation under the effect of acid binding agent, phosphorylation process solvent is any in acetonitrile, tetrahydrofuran (THF), acetonitrile, methyl tertiary butyl ether and methylene dichloride, acid binding agent is any in pyridine, triethylamine, diisopropyl ethyl amine and DMAP, and the mineral alkali when hydrolysis of di(2-ethylhexyl)phosphate propionitrile ester is any in NaOH, sodium carbonate, sodium bicarbonate and sodium hydride;
Steps d, photooxidation reaction: compound 4, under the effect of photooxidation catalyst, is reacted and obtained final product AMPPD by rayed; Light source is high-pressure mercury lamp or the high voltage mercury lamp of power at 200W ~ 2000W, and photooxidation catalyst is any in Methylene blue, methylene blue, tropeolin-D and methyl red, and compound 4 is 100:10 ~ 100:0.001 with the weight feed ratio of catalyzer.
Preferably, compound 1 is synthetic by following method:
R=methyl, ethyl
First there is acetalation: m-methoxybenzaldehyde 5 does under solution, acid catalyzed effect and reacts and obtain compound 6 with methyl alcohol with trimethyl orthoformate, the volume ratio of methyl alcohol and trimethyl orthoformate is 0.1:1 ~ 1:0.1, acid is any in the vitriol oil, concentrated hydrochloric acid, phosphoric acid, acetic acid, p-methyl benzenesulfonic acid monohydrate, ammonium chloride, tartrate and citric acid, m-methoxybenzaldehyde 5 is with sour amount of substance than being 1:0.01 ~ 1:0.5, and this step temperature of reaction is 20 ℃ ~ 95 ℃;
There is again substitution reaction: compound 6 obtains compound 1 with phosphorous acid ester under the katalysis of Lewis acid, and phosphorous acid ester is triethyl-phosphite or trimethyl phosphite.Lewis acid is any in Zinc Chloride Anhydrous, boron trifluoride diethyl etherate, boron trichloride, aluminum trichloride (anhydrous) and FERRIC CHLORIDE ANHYDROUS, and the temperature that adds Lewis acid is-30 ℃ ~ 40 ℃.
Preferably, in the acetalation step of synthetic compound 1, in the time that reaction conditions meets following condition, this reaction can obtain more excellent result: the volume ratio of methyl alcohol and trimethyl orthoformate is 0.9:1 ~ 1.26:1, acid is any in the vitriol oil, acetic acid and p-methyl benzenesulfonic acid monohydrate, m-methoxybenzaldehyde is with sour amount of substance than being 1:0.1, and temperature of reaction is 65 ℃ ~ 80 ℃.In the substitution reaction step of synthetic compound 1, in the time that reaction conditions meets following condition, this reaction can obtain more excellent result: Lewis acid for Zinc Chloride Anhydrous or boron trifluoride diethyl etherate, and it is-20 ℃ ~-5 ℃ that Lewis acid adds fashionable temperature.
Especially, when in the acetalation step of synthetic compound 1, acid is acetic acid, and the volume ratio of methyl alcohol and trimethyl orthoformate is 1:1, and now this reaction can obtain optimum result; In the substitution reaction step of synthetic compound 1, phosphorous acid ester is triethyl-phosphite, and Lewis acid is Zinc Chloride Anhydrous, and now this reaction can obtain optimum result.
Preferably, in the time that step a reaction conditions meets following condition, this step reaction can obtain more excellent result: alkali is LDA or LHMDS, and the temperature that adds alkali is-75 ℃ ~-50 ℃, and solvent is methyl tertiary butyl ether or tetrahydrofuran (THF).
Preferably, in the time that step b reaction conditions meets following condition, this reaction can obtain more excellent result: sulfur alcohol sodium is with the amount of substance of reaction raw materials than being 1.05:1 ~ 2:1, and temperature of reaction is 100 ℃ ~ 140 ℃.
Preferably, in the time that step c reaction conditions meets following condition, this reaction can obtain more excellent result: phosphorylation process solvent is tetrahydrofuran (THF), and acid binding agent is pyridine or triethylamine.
Preferably, in the time that steps d reaction conditions meets following condition, this reaction can obtain more excellent result: the high-pressure mercury lamp that light source is 800W, and photooxidation catalyst is methylene blue, the weight feed ratio of raw material and catalyzer is 100:5 ~ 100:0.1.
Especially,, when alkali in step a is LHMDS, reaction solvent is methyl tertiary butyl ether; In step b, sulfur alcohol sodium is with the amount of substance of compound 2 than being 1.2:1, and reaction solvent is DMF; In step c, the solvent of phosphorylation process is that tetrahydrofuran (THF), alkali are pyridine, and the mineral alkali when hydrolysis of di(2-ethylhexyl)phosphate propionitrile ester is NaOH; In steps d, compound 4 is 197:1 with the weight feed ratio of methylene blue, and now, this synthetic method can obtain optimal result.
The present invention, from low-cost m-methoxybenzaldehyde, greatly reduces cost; In synthetic route, improve the method for phosphorylation, improved the productive rate of phosphorylation reaction; In synthetic route, do not relate to strict anhydrous and oxygen-free operation, in building-up process, reaction yield is all very high, and synthetic total recovery is 36%, and the present invention is suitable for industrial production, has solved existing market synthetic route and has been difficult for amplifying the shortcoming of producing.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic spectrogram of AMPPD;
Fig. 2 is the infrared spectrogram of AMPPD.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is done further to explanation clearly and completely.
Embodiment
The synthetic of 3-methoxyl group-1-in embodiment (1 '-p diethylaminobenzoic acid ester group) benzyl methyl ether 1 can adopt following two-step reaction:
First there is acetalation: by 5136 grams of m-methoxybenzaldehydes (1mol), be dissolved in 200mL methyl alcohol, add successively at normal temperatures (6 grams of trimethyl orthoformate 200mL and acetic acid, 0.1mol) (in other embodiments, the volume ratio of methyl alcohol and trimethyl orthoformate is 0.1:1 ~ 1:0.1, when time in the volume ratio of methyl alcohol and the trimethyl orthoformate scope at 0.9:1 ~ 1.26:1 reacts and can reach a preferably effect, acid such as replaces with at the vitriol oil of amount of substance, concentrated hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid monohydrate, ammonium chloride, tartrate, any in citric acid, m-methoxybenzaldehyde is 1:0.01 ~ 1:0.5 with sour amount of substance ratio).Heating reflux reaction 10 hours (temperature of reaction is controlled at 20 ℃ ~ 95 ℃ in other embodiments) at 65 ℃ ~ 80 ℃, decompression is revolved after desolventizing, adds ethyl acetate, washes twice with saturated sodium bicarbonate solution, and organic layer is washed till neutrality with saturated nacl aqueous solution.Dry filter, concentrated, obtains 1-(dimethoxy-methyl)-6169 grams of 3-anisoles through underpressure distillation, and productive rate is 93%,
1h NMR(300MHz, CDCl
3) δ 3.22(d, 6H), 3.90 (s, 3H), 5.60 (m, 1H), 7.09-7.20 (m, 4H).
Substitution reaction: 1-(dimethoxy-methyl)-6182 grams of 3-anisoles (1mol) occur to be again dissolved in 300mL methylene dichloride, add triethyl phosphate 199 grams (1.2mol) (in other embodiments, triethyl phosphate such as replaces with at the trimethyl phosphite 99 of amount of substance).At-20 ℃ ~-5 ℃, add (204 grams of Zinc Chloride Anhydrouss, tetrahydrofuran solution (150mL) 1.5mol) rises to room temperature reaction 10 hours (in other embodiments naturally, Zinc Chloride Anhydrous such as replaces with at any in boron trifluoride diethyl etherate, boron trichloride, aluminum trichloride (anhydrous) and the FERRIC CHLORIDE ANHYDROUS of amount of substance, adds the temperature of Zinc Chloride Anhydrous to be controlled at-30 ℃ ~ 40 ℃).Use saturated NaHCO
3after washing, anhydrous sodium sulfate drying, is spin-dried for.Underpressure distillation, obtains 1239 grams of 3-methoxyl group-1-(1 '-p diethylaminobenzoic acid ester group) benzyl methyl ethers of oily, yield 83%.
1H?NMR(300MHz,CDCl
3）δ1.20（m,6H）,3.25（s,3H）,3.79(s,3H),4.15(m,4H),4.40(m,1H),7.05(m,2H),7.15(m,2H)。
Obtaining after compound 1, the present embodiment has adopted following four-step reaction to complete the synthetic of AMPPD.
Step a.[(3-p-methoxy-phenyl) methoxyl group methene alkane] diamantane 2 synthetic
By 3-methoxyl group-1-(1 '-p diethylaminobenzoic acid ester group) 1144 grams of benzyl methyl ethers (0.5mol), be dissolved in methyl tertiary butyl ether 400mL (in other embodiments, methyl tertiary butyl ether replaces with isopyknic isopropyl ether, ether, tetrahydrofuran (THF) and 1, any in 4-dioxane), at-75 ℃ ~-50 ℃, add LHMDS(0.5mol) and (75 grams of 2-diamantane ketone, mixing solutions 0.5mol) (in other embodiments, LHMDS such as replaces with at the LDA of amount of substance, n-Butyl Lithium, tert-butyl lithium, potassium tert.-butoxide, any in sodium tert-butoxide and sodium hydride, add the temperature of LHMDS to be controlled at-80 ℃ ~ 10 ℃), after adding, naturally rise to after room temperature, react 10 hours.Add the hydrochloric acid of 2M to make system pH in 4.0 ~ 6.5, separate organic layer dry, obtain 138 grams of target compounds after revolving desolventizing, productive rate 97%, is directly used in the next step.
Step b.[(3-hydroxy phenyl) methoxyl group methene alkane] diamantane 3 synthetic
[(3-p-methoxy-phenyl) methoxyl group methene alkane] diamantane 271 grams (0.25mol) is dissolved in the DMF of 150mL (in other embodiments, DMF replaces with isopyknic DMSO or THF), under normal temperature, drip the tetrahydrofuran solution 500mL(of sulfur alcohol sodium (0.30mol) in other embodiments, sulfur alcohol sodium is 0.9:1 ~ 3:1 with the amount of substance ratio of [(3-p-methoxy-phenyl) methoxyl group methene alkane] diamantane 2, when the amount of substance of sulfur alcohol sodium and [(3-p-methoxy-phenyl) methoxyl group methene alkane] diamantane 2 reacted and can reach an optimum effect than time in the scope at 1.05:1 ~ 2:1), after finishing, react 10 hours (in other embodiments at 100 ℃ ~ 140 ℃, temperature of reaction is controlled at 50 ℃ ~ 190 ℃).Add saturated NH to reaction solution
4cl, separates organic layer and adds anhydrous sodium sulfate drying.After revolving desolventizing, obtain yellow solid, alcohol-water recrystallization obtains 49 grams of white solids, 73%.
1H?NMR（300MHz,CDCl
3）δ1.74-1.96（m,12H）,2.62（m,1H）,3.24(m,1H),3.31（s,3H）,6.98-7.06(m,2H),7.14-7.21(m,2H)。
Synthesizing of step c [(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt 4
By 23 grams of POCl
3(0.15mol) be dissolved in 200mL tetrahydrofuran (THF) (in other embodiments, tetrahydrofuran (THF) replaces with any in isopyknic acetonitrile, methyl tertiary butyl ether and methylene dichloride), add successively [(3-hydroxy phenyl) methoxyl group methene alkane] diamantane 327 grams (0.10mol) and pyridine 24 grams (0.30mol) (in other embodiments, pyridine such as replaces with at any in triethylamine, diisopropyl ethyl amine and the DMAP of amount of substance), react 2 hours.Add 3-hydroxypropionitrile 21 grams (0.30mol) to stir 12 hours.Add after saturated ammonium chloride solution, separate organic layer dry, revolve after desolventizing, the intermediate obtaining is dissolved in 100mL methyl alcohol, add NaOH solution (0.20mol) stirring reaction 12 hours (in other embodiments, NaOH such as replaces with at any in sodium carbonate, sodium bicarbonate and the sodium hydride of amount of substance) of 2M.After revolving desolventizing, use methanol-water recrystallization, obtain 32 grams of white solids, productive rate 81%.
1H?NMR(300MHz,CDCl
3）δ1.77－1.95（m,12H）,2.59（m,1H）,3.20(m,1H),3.30（s,3H）,6.99－7.16(m,4H)。
Steps d .AMPPD's is synthetic
[(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt 439.4 grams (0.10mol) is dissolved in 50mL water, add 0.2 gram of methylene blue to stir (in other embodiments, methylene blue replaces with Methylene blue, any in tropeolin-D and methyl red, [(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt 4 is 100:10 ~ 100:0.001 with the weight feed ratio of methylene blue, when time in the weight feed ratio of [(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt 4 and the methylene blue scope at 100:5 ~ 100:0.1 react can reach an optimum effect), pass into Oxygen Flow.With 800W high-pressure mercury lamp photograph, after 1 hour (in other embodiments, high-pressure mercury lamp replaces with high voltage mercury lamp, and power range is 200W ~ 2000W), suction filtration is removed methylene blue, and decolorizing with activated carbon obtains colourless transparent liquid.After revolving desolventizing, obtain faint yellow solid, obtain 35 grams of white solid AMPPD, productive rate 82% with methanol-water recrystallization.
1H?NMR（300MHz,CDCl
3）δ1.75－1.99（m,12H）,2.63（m,1H）,3.27(m,1H),3.32（s,3H）,7.05－7.25(m,4H)。In Figure of description, the nuclear magnetic spectrogram that Fig. 1 is AMPPD, the infrared spectrogram that Fig. 2 is AMPPD.
Above-described embodiment, from low-cost m-methoxybenzaldehyde, greatly reduces cost; In synthetic route, improve the method for phosphorylation, improved the productive rate of phosphorylation reaction; In synthetic route, do not relate to strict anhydrous and oxygen-free operation, in building-up process, reaction yield is all very high, and synthetic total recovery is 36%, thereby the applicable industrial production of the present invention, has solved existing market synthetic route and has been difficult for amplifying the shortcoming of producing.
It should be noted that; above-described embodiment only as to preferred embodiment of the present invention illustrate; can not be interpreted as limitation of the present invention; all equivalent variations or replacement that all those of ordinary skill in the art make under the prerequisite without prejudice to spirit of the present invention, within the protection domain that is all considered as limiting in claim of the present invention.
Claims (10)
1. for a synthetic method of the chemical illuminating reagent AMPPD of immunoassay, it is characterized in that: the method synthetic route is as follows:
Wherein, in compound 1, R group is methyl or ethyl;
Concrete synthesis step is as follows:
Step a, condensation reaction: in ether solvent, under the effect of alkali, there is condensation reaction with 2-diamantane ketone and obtain compound 2 in compound 1, alkali is any in LDA, LHMDS, n-Butyl Lithium, tert-butyl lithium, potassium tert.-butoxide, sodium tert-butoxide and sodium hydride, while adding alkali, the temperature of system is-80 ℃ ~ 10 ℃, ether solvent is any in methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane;
Step b, demethylating reaction: compound 2 reacts and obtains compound 3 with sulfur alcohol sodium under heating condition, sulfur alcohol sodium is with the amount of substance of compound 2 than being 3:1 ~ 0.9:1, and temperature of reaction is 50 ℃ ~ 190 ℃, and reaction solvent is any in DMF, DMSO and THF;
Step c, phosphorylation reaction: compound 3 and 3-hydroxypropionitrile phosphorylation under the effect of acid binding agent, the solvent of phosphorylation process is any in acetonitrile, tetrahydrofuran (THF), acetonitrile, methyl tertiary butyl ether and methylene dichloride, acid binding agent is any in pyridine, triethylamine, diisopropyl ethyl amine and DMAP, and the mineral alkali when hydrolysis of di(2-ethylhexyl)phosphate propionitrile ester is any in NaOH, sodium carbonate, sodium bicarbonate and sodium hydride;
Steps d, photooxidation reaction: compound 4, under the effect of photooxidation catalyst, is reacted and obtained final product AMPPD by rayed; Light source is high-pressure mercury lamp or the high voltage mercury lamp of power at 200W ~ 2000W, and photooxidation catalyst is any in Methylene blue, methylene blue, tropeolin-D and methyl red, and compound 4 is 100:10 ~ 100:0.001 with the weight feed ratio of catalyzer.
2. according to claim 1 for the synthetic method of the chemical illuminating reagent AMPPD of immunoassay, it is characterized in that: described compound 1 is synthetic by following method:
R=methyl, ethyl
First there is acetalation: m-methoxybenzaldehyde 5 does under solution, acid catalyzed effect and reacts and obtain compound 6 with methyl alcohol with trimethyl orthoformate, the volume ratio of methyl alcohol and trimethyl orthoformate is 0.1:1 ~ 1:0.1, acid is any in the vitriol oil, concentrated hydrochloric acid, phosphoric acid, acetic acid, p-methyl benzenesulfonic acid monohydrate, ammonium chloride, tartrate and citric acid, m-methoxybenzaldehyde 5 is with sour amount of substance than being 1:0.01 ~ 1:0.5, and this step temperature of reaction is 20 ℃ ~ 95 ℃;
There is again substitution reaction: compound 6 obtains compound 1 with phosphorous acid ester under the katalysis of Lewis acid, and phosphorous acid ester is triethyl-phosphite or trimethyl phosphite.Lewis acid is any in Zinc Chloride Anhydrous, boron trifluoride diethyl etherate, boron trichloride, aluminum trichloride (anhydrous) and FERRIC CHLORIDE ANHYDROUS, and while adding Lewis acid, the temperature of system is-30 ℃ ~ 40 ℃.
3. synthetic method according to claim 2, it is characterized in that: in the acetalation step of synthetic described compound 1, the volume ratio of methyl alcohol and trimethyl orthoformate is 0.9:1 ~ 1.26:1, acid is any in the vitriol oil, acetic acid and p-methyl benzenesulfonic acid monohydrate, m-methoxybenzaldehyde is with sour amount of substance than being 1:0.1, and temperature of reaction is 65 ℃ ~ 80 ℃.
4. synthetic method according to claim 2, is characterized in that: in the substitution reaction step of synthetic described compound 1, Lewis acid is Zinc Chloride Anhydrous or boron trifluoride diethyl etherate, and the temperature that Lewis acid adds fashionable system is-20 ℃ ~-5 ℃.
5. synthetic method according to claim 2, is characterized in that: in the acetalation step of synthetic described compound 1, acid is acetic acid, and the volume ratio of methyl alcohol and trimethyl orthoformate is 1:1; In the substitution reaction step of synthetic described compound 1, phosphorous acid ester is triethyl-phosphite, and Lewis acid is Zinc Chloride Anhydrous.
6. synthetic method according to claim 1 and 2, is characterized in that: in described step a, alkali is LDA or LHMDS, and while adding alkali, the temperature of system is-75 ℃ ~-50 ℃, and reaction solvent is methyl tertiary butyl ether or tetrahydrofuran (THF).
7. synthetic method according to claim 1 and 2, is characterized in that: in described step b, sulfur alcohol sodium is with the amount of substance of compound 2 than being 1.05:1 ~ 2:1, and temperature of reaction is 100 ℃ ~ 140 ℃.
8. synthetic method according to claim 1 and 2, is characterized in that: in described step c, the solvent of phosphorylation process is that tetrahydrofuran (THF), acid binding agent are pyridine or triethylamine.
9. synthetic method according to claim 1 and 2, is characterized in that: the high-pressure mercury lamp that in described steps d, light source is 800W, and photooxidation catalyst is methylene blue, compound 4 is 100:5 ~ 100:0.1 with the weight feed ratio of methylene blue.
10. synthetic method according to claim 1 and 2, is characterized in that: in described step a, alkali is LHMDS, and reaction solvent is methyl tertiary butyl ether; In described step b, sulfur alcohol sodium is with the amount of substance of compound 2 than being 1.2:1, and reaction solvent is DMF; In described step c, the solvent of phosphorylation process is that tetrahydrofuran (THF), alkali are pyridine, and the mineral alkali when hydrolysis of di(2-ethylhexyl)phosphate propionitrile ester is NaOH; In described steps d, compound 4 is 197:1 with the weight feed ratio of methylene blue.
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| CN118085323B (en) * | 2024-04-29 | 2024-07-19 | 台州黄岩泽钰新材料科技有限公司 | High-strength degradable polyester composite material and preparation method thereof |
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Application publication date: 20140507 |