CN113636953B - Preparation method of O-/N-alkyl substituted hydroxylamine salt - Google Patents
Preparation method of O-/N-alkyl substituted hydroxylamine salt Download PDFInfo
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- CN113636953B CN113636953B CN202110934598.1A CN202110934598A CN113636953B CN 113636953 B CN113636953 B CN 113636953B CN 202110934598 A CN202110934598 A CN 202110934598A CN 113636953 B CN113636953 B CN 113636953B
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- oxime
- hydroxylamine
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- 150000002443 hydroxylamines Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- 150000002923 oximes Chemical class 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 31
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- -1 nitro, hydroxyl Chemical group 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical class 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical group COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 229940100198 alkylating agent Drugs 0.000 claims 2
- 239000002168 alkylating agent Substances 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 claims 1
- 229940008406 diethyl sulfate Drugs 0.000 claims 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims 1
- 150000008282 halocarbons Chemical class 0.000 claims 1
- 239000003513 alkali Substances 0.000 abstract description 14
- 239000002253 acid Substances 0.000 abstract description 12
- 239000002910 solid waste Substances 0.000 abstract description 8
- 230000007547 defect Effects 0.000 abstract description 7
- 239000000463 material Substances 0.000 abstract description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 abstract description 5
- 238000005265 energy consumption Methods 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 239000012847 fine chemical Substances 0.000 abstract description 2
- 238000006386 neutralization reaction Methods 0.000 abstract description 2
- 239000000575 pesticide Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- 238000004128 high performance liquid chromatography Methods 0.000 description 40
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 33
- 239000002994 raw material Substances 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 16
- 238000005406 washing Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 239000007858 starting material Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000013558 reference substance Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- UGCMJRGHQWYGCF-IZZDOVSWSA-N (ne)-n-[(2,4,6-trimethoxyphenyl)methylidene]hydroxylamine Chemical compound COC1=CC(OC)=C(\C=N\O)C(OC)=C1 UGCMJRGHQWYGCF-IZZDOVSWSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- UIIZGAXKZZRCBN-WEVVVXLNSA-N (ne)-n-[(4-bromophenyl)methylidene]hydroxylamine Chemical compound O\N=C\C1=CC=C(Br)C=C1 UIIZGAXKZZRCBN-WEVVVXLNSA-N 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 5
- RJJVVYVLHWMYAA-WEVVVXLNSA-N chembl202440 Chemical compound COC1=CC(\C=N\O)=CC=C1O RJJVVYVLHWMYAA-WEVVVXLNSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000007069 methylation reaction Methods 0.000 description 5
- 230000011987 methylation Effects 0.000 description 4
- OAAPUCPYMQYBML-UHFFFAOYSA-N n-[(2,4,5-trimethoxyphenyl)methylidene]hydroxylamine Chemical compound COC1=CC(OC)=C(C=NO)C=C1OC OAAPUCPYMQYBML-UHFFFAOYSA-N 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- IHMGDCCTWRRUDX-YVMONPNESA-N (nz)-n-[(2-nitrophenyl)methylidene]hydroxylamine Chemical compound O\N=C/C1=CC=CC=C1[N+]([O-])=O IHMGDCCTWRRUDX-YVMONPNESA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- ORIHZIZPTZTNCU-YVMONPNESA-N salicylaldoxime Chemical compound O\N=C/C1=CC=CC=C1O ORIHZIZPTZTNCU-YVMONPNESA-N 0.000 description 3
- WTLPAVBACRIHHC-VMPITWQZSA-N (ne)-n-[(4-nitrophenyl)methylidene]hydroxylamine Chemical compound O\N=C\C1=CC=C([N+]([O-])=O)C=C1 WTLPAVBACRIHHC-VMPITWQZSA-N 0.000 description 2
- UYTMLDBQFLIQJA-XQRVVYSFSA-N (nz)-n-(furan-2-ylmethylidene)hydroxylamine Chemical compound O\N=C/C1=CC=CO1 UYTMLDBQFLIQJA-XQRVVYSFSA-N 0.000 description 2
- CRBZVDLXAIFERF-UHFFFAOYSA-N 2,4,6-trimethoxybenzaldehyde Chemical compound COC1=CC(OC)=C(C=O)C(OC)=C1 CRBZVDLXAIFERF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;n-methylhydroxylamine;chloride Chemical compound Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 2
- NUXCOKIYARRTDC-UHFFFAOYSA-N o-ethylhydroxylamine;hydron;chloride Chemical compound Cl.CCON NUXCOKIYARRTDC-UHFFFAOYSA-N 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 1
- WHIVNJATOVLWBW-PLNGDYQASA-N (nz)-n-butan-2-ylidenehydroxylamine Chemical compound CC\C(C)=N/O WHIVNJATOVLWBW-PLNGDYQASA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- PXAJQJMDEXJWFB-UHFFFAOYSA-N acetone oxime Chemical compound CC(C)=NO PXAJQJMDEXJWFB-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 150000002547 isoxazolines Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- CPQCSJYYDADLCZ-UHFFFAOYSA-N n-methylhydroxylamine Chemical class CNO CPQCSJYYDADLCZ-UHFFFAOYSA-N 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 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
- 239000000376 reactant Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/10—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of unsubstituted hydrocarbon radicals or of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of N-/O-alkyl substituted hydroxylamine salt, belonging to the technical field of fine chemical industry, pesticide or bulk pharmaceutical chemical industry. The invention reacts N-/O-alkylate of oxime with hydroxylamine inorganic salt to produce N-/O-alkyl substituted hydroxylamine inorganic salt and oxime. The invention provides a method for preparing N-/O-alkyl substituted hydroxylamine salt with high efficiency and environmental protection through the unprecedented hydroxylamine exchange invention, and the oxime can be prepared again to generate N-/O-alkylate of oxime while preparing N-/O-alkyl substituted hydroxylamine inorganic salt, so as to realize material circulation; the reaction process does not need to use equivalent acid or alkali for neutralization, thereby avoiding the defects of using a large amount of acid or alkali and generating inorganic salt solid waste in the existing method and being more environment-friendly. Moreover, the preparation method has mild reaction conditions, and avoids the defects of high pollution and high energy consumption of the traditional process.Wherein R 1、R2 and R are as defined in the claims and the specification.
Description
Technical Field
The invention relates to a preparation method of N-/O-alkyl substituted hydroxylamine salt, belonging to the technical field of fine chemical industry, pesticide or bulk pharmaceutical chemical industry.
Background
N-/O-alkyl-substituted hydroxylamine salts (formula I) are important pharmaceutical and chemical intermediates, and represent compounds of the formula: o-methylhydroxylamine hydrochloride (methoxyamine hydrochloride), N-methylhydroxylamine hydrochloride, O-ethylhydroxylamine hydrochloride (ethoxyamine hydrochloride), O-benzylhydroxylamine hydrochloride, and the like. Wherein, N-alkyl substituted hydroxylamine salt is used for preparing nitrone 1, 3-dipolar body, and various isoxazoline compounds are conveniently constructed through cycloaddition reaction, and have wide application in agriculture; the O-alkyl substituted hydroxylamine salt, the typical compounds methoxylamine hydrochloride and benzyloxy amine hydrochloride, are important medical intermediates for producing raw material medicines such as antibiotic cefuroxime.
Wherein R 1、R2 is independently hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl; ha=hcl, H 2SO4,H3PO4, HBr, HI.
The synthesis method of N-/O-alkyl substituted hydroxylamine salt has different structure, and takes typical compound methoxyamine hydrochloride as an example, and the preparation method mainly comprises the following steps: sulfur dioxide method (hydroxylamine disulfonate method), ethyl acetate protection method, acetoxime/butanone oxime method, benzaldehyde method, etc. The reaction process of the methods requires acid and alkali catalysis to generate inorganic salt solid waste; in the purification process, a method of neutralizing by strong alkali and then salifying again after distilling methoxyamine is adopted, and repeated acid-base neutralization not only generates a large amount of solid waste, but also has potential safety hazards, the free alkali is unstable in property, the high-temperature distillation has explosion risk, and serious safety accidents are listed at home and abroad. The production process is complex, and belongs to typical high-pollution and high-energy-consumption backward processes.
TABLE 1 preparation of methoxyamine hydrochloride
The defects of high pollution and high energy consumption of the existing process and the increasingly strict environmental protection requirements are that a safe, environment-friendly and green method is needed in the industry.
Disclosure of Invention
Aiming at the defects of large consumption of strong acid and strong alkali and prominent three-waste environmental protection problem in the preparation method of the N-/O-alkyl substituted hydroxylamine salt, the invention provides a preparation method of the N-/O-alkyl substituted hydroxylamine salt, which is more environment-friendly, simple in preparation method, free from acid and alkali catalysis, free from using strong acid and strong alkali in the conventional method, free from solid waste from the source and capable of recycling materials.
The invention is realized by the following technical scheme:
The preparation process of N-/O-alkyl substituted hydroxylamine salt includes the following steps:
Reacting the N-/O-alkylate of the oxime with a hydroxylamine salt in a solvent to form an oxime and an N-/O-alkyl hydroxylamine inorganic salt:
Wherein the solvent includes, but is not limited to: organic solvents such as methanol, ethanol, acetonitrile, etc., or mixed solvents of water and the above organic solvents.
Preferably, the solvent is water, methanol-water or ethanol-water mixed solvent.
Wherein:
R 1、R2 is independently hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl or heteroaryl, said heteroaryl containing at least one heteroatom of N, O or S;
The substituent is halogen, halogenated C1-C4 alkyl, C1-C6 alkoxy, nitro, hydroxyl, tert-butoxycarbonyl and benzyloxy;
R is C1-C6 alkyl;
HA＝HCl,H2SO4,H3PO4,HBr,HI。
further, the method comprises the steps of,
R 1、R2 is independently hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl, said heteroaryl containing one O atom;
The substituent is halogen, halogenated C1-C4 alkyl, C1-C4 alkoxy, nitro, hydroxyl, tert-butoxycarbonyl and benzyloxy;
further, the method comprises the steps of,
R 1、R2 is independently hydrogen, unsubstituted or phenyl-substituted C1-C4 alkyl, substituted or unsubstituted phenyl, furyl;
The substituent is halogen, halogenated C1-C4 alkyl, C1-C4 alkoxy, nitro, hydroxyl, tert-butoxycarbonyl and benzyloxy;
r is C1-C4 alkyl;
HA＝HCl,H2SO4,H3PO4,HBr,HI。
taking methoxyamine hydrochloride as an example, the reaction formula is as follows:
Taking N-methyl substituted hydroxylamine as an example, the reaction formula is:
Further, the oxime prepared by the method of the invention can be separated from the reaction liquid by precipitation or by extraction, recrystallization, column chromatography and other methods.
The reactant hydroxylamine is present in the form of a salt, which may be hydroxylamine hydrochloride, sulfate, phosphate, hydrobromic acid, hydroiodic acid and the like, with hydrochloride being preferred.
The reaction temperature is 0 to 100 ℃, preferably 0 to 70 ℃.
The molar ratio of the N-/O-alkylate of oxime to hydroxylamine salt is: 1:0.1-1:10, preferably 1:0.5-1:2.
Experimental results show that under the mild reaction condition, the reaction process of the N-methylate of the aldoxime and hydroxylamine hydrochloride is complete; although the substrate structure applicability and the functional group tolerance of the ammonolysis reaction of the oxime methyl ether and the hydroxylamine hydrochloride are good, the reaction has a reversible balance phenomenon. The product methoxyamine and the raw material hydroxylamine have similar nucleophilicity, and in order to make the equilibrium reaction have application value, the characteristics of good crystallization property and easy separation and purification of oxime can be utilized to precipitate the product oxime from the reaction solution, so as to promote the equilibrium to be carried out to the right; in addition, the defect of incomplete reaction can be overcome by a method of recycling for multiple times.
By taking methoxyamine hydrochloride as an example, oxime methyl ether and NH 2 OH & HCl are subjected to ammonolysis exchange reaction to generate methoxyamine hydrochloride and oxime, and oxime can be prepared into oxime methyl ether by a methylation method to realize material circulation; acid and alkali catalysis is not needed in the reaction process, so that the use of strong acid and strong alkali in the conventional method is avoided, and the generation of solid waste is avoided from the source.
R' is hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl or heteroaryl, said heteroaryl containing at least one heteroatom of N, O or S;
The substituent is halogen, halogenated C1-C4 alkyl, C1-C6 alkoxy, nitro, hydroxyl, tert-butoxycarbonyl and benzyloxy.
Oxime methylation, using conventional methylating agents such as dimethyl sulfate, produces a certain amount of N-methide in addition to O-methide oxime methyl ether. N-methylates, likewise, can undergo hydroxylamine amine exchange reactions to yield N-methylhydroxylamine salts and oximes. The O-and N-methylation reaction selectivities are closely related to the cis/reaction configuration of the starting oxime, with the cis configuration producing predominantly N-methylated products and the trans configuration producing predominantly O-methylated products. Thus, by controlling the configuration of the starting materials, O-and N-methylated oxime products can be selectively formed, and O-and N-methylated hydroxylamine salts can be selectively obtained by hydroxylamine salt exchange. Taking cheap furfural as an example, controlling the cis/trans configuration of an oximation product by changing the acid-base condition of a reaction solution, and taking the trans as a main product when reacting under an alkaline condition; when reacted under acidic conditions, the product oxime is predominantly cis. And further affects the selectivity of the O-and N-reactions of oxime methylation products, the reaction process for selectively producing O-and N-methylated hydroxylamine hydrochloride is as follows:
The beneficial effects are that: compared with the prior art, the invention has the advantages that:
The invention takes oxime N-/O-alkylate as raw material to react with hydroxylamine salt to generate N-/O-alkylated substituted hydroxylamine salt and oxime. The oxime can be prepared into an initial raw material oxime N-/O-alkylate by a literature method, so that material circulation is realized; the reaction does not need acid or alkali catalysis, does not produce inorganic salt solid waste, and is more environment-friendly.
(1) The preparation method of the N-/O-alkyl substituted hydroxylamine salt generates the N-/O-alkylated hydroxylamine salt and simultaneously generates oxime, and the oxime can be prepared into raw material oxime N-/O-alkylate by a document methylation method, thereby realizing material circulation;
(2) The preparation method of the N-/O-alkyl substituted hydroxylamine salt does not need acid or alkali catalysts in the reaction process, avoids the defects of using a large amount of acid or alkali and generating solid waste in the traditional route, and has obvious environmental protection advantage;
(3) The preparation method of the N-/O-alkyl substituted hydroxylamine salt has mild reaction conditions and avoids the defects of high pollution and high energy consumption of the traditional process.
Detailed Description
The present invention is described in further detail below in connection with the examples, but the present invention is not limited to the following examples.
All the raw materials used in the embodiment of the invention are commercial products without special description, and all the used test devices or test instruments are industry conventional instruments and devices.
Example 1:
Equation (c)
3.90G (17.32 mmol,1.00 eq) of 2,4, 6-trimethoxybenzaldehyde oxime methyl ether, 1.41g (20.33 mmol,1.17 eq) of hydroxylamine hydrochloride, 45.04g of ethanol, 7.50g of water, stirring and dissolving at 15 ℃ and generating white precipitate at 20 ℃ and stirring and reacting at 60-70 ℃ for 0.5h. TLC monitored the progress of the reaction (EA: pe=1:1, uv254, r f(-C＝NOH):0.2/Rf(-C＝NOMe):0.5). Cooling to 10-15 ℃, stirring and separating out crystals, carrying out suction filtration, collecting and drying solids to obtain 1.68g (theoretical 3.66g, yield 45.90%, HPLC purity 96.545％,mp:203～204℃,1H NMR(300MHz,DMSO-d6)δ:3.77(6H,s),3.80(3H,s),6.26(2H,s),8.13(OH,s),10.8(1H,s).13C NMR(125MHz,DMSO-d6)δ:55.4,55.8,91.0,102.4,142.4,159.2,161.6.); filtrate is evaporated to dryness, washing with water, filtering, collecting and recovering 2.29g (HPLC purity 90.577％,mp:79～81℃,1H NMR(400MHz,DMSO-d6)8.18(s,1H),6.26(s,1H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.37(s,3H).). filtrate is evaporated to dryness) of unreacted raw material 2,4, 6-trimethoxybenzaldehyde oxime methyl ether, obtaining 0.37g (theoretical 1.45g, yield 25.52%, mp: 149-150 ℃) of solid containing methoxyamine hydrochloride.
Preparing raw materials:
Into a 100ml reaction flask were charged 4.02g (20.49 mmol,1.00 eq), 2.56g (36.92 mmol,1.80 eq) of methoxyamine hydrochloride and 30.0ml of methanol, and the mixture was dissolved by stirring at 15 ℃. TLC monitored (EA: pe=1:1, uv254, r f(-CHO):0.3/Rf(-C＝NOMe):0.5) the progress of the reaction until the starting material was complete. Dropwise adding sodium carbonate/water solution (3.20 g/30.00 g) to generate white precipitate, filtering, washing with water, and drying to obtain 3.90g of 2,4, 6-trimethoxy benzaldehyde methyl ether (theoretical 4.48g, yield 87.05%, mp: 79-81 ℃, HPLC purity) :100％,1H NMR(400MHz,DMSO-d6)8.18(s,1H),6.26(s,1H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.37(s,3H).).
Preparing a reference substance solution:
Adding 0.0790g (0.4027 mmol,1.00 eq), 0.0345g (0.4965 mmol,1.23 eq), 1.0ml methanol and 35-40 ℃ ultrasonic vibration for 30min (10 x 3) into a 4ml sample bottle, detecting complete conversion of raw materials by HPLC, and obtaining the product 2,4, 6-trimethoxybenzaldehyde oxime main peak purity ：99.435％(1HNMR(300MHz,DMSO-d6)δ:3.77(6H,s),3.80(3H,s),6.26(2H,s),8.13(OH,s),10.8(1H,s).13C NMR(125MHz,DMSO-d6)δ:55.4,55.8,91.0,102.4,142.4,159.2,161.6.).
[ -CHO/-c=noh/-c=nome purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
Example 2:
Equation (c)
To a 50ml reaction flask were added 0.5780g (2.5661 mmol,1.00 eq.) of 2,4, 6-trimethoxybenzaldehyde oxime methyl ether, 0.2101g (3.0234 mmol,1.18 eq.) of hydroxylamine hydrochloride, 4ml of methanol, 5ml of water, and the mixture was stirred and dissolved at 15 to 20℃to produce a white precipitate. TLC monitored the progress of the reaction (EA: pe=1:1, uv254, r f(-NOH):0.2/Rf(-C＝NOMe):0.5). The reaction solution at 15-20 ℃ is filtered for 3 hours, washed with water, and the solid is collected, then the raw material 2,4, 6-trimethoxybenzaldehyde oxime methyl ether 0.3313g is recovered (HPLC purity 92.312％,mp:79～81℃,1HNMR(400MHz,DMSO-d6)8.18(s,1H),6.26(s,1H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.37(s,3H).); filtrate is evaporated to dryness to obtain solid, washed with water and filtered, and the solid is collected to obtain 0.1960g of 2,4, 6-trimethoxybenzaldehyde oxime (theoretical 0.4878g, yield 40.1804%, HPLC purity 88.899,mp:203～204℃,1H NMR(300MHz,DMSO-d6)δ:3.77(6H,s),3.80(3H,s),6.26(2H,s),8.13(OH,s),10.8(1H,s).13C NMR(125MHz,DMSO-d6)δ:55.4,55.8,91.0,102.4,142.4,159.2,161.6.); filtrate is evaporated to dryness and washed with dichloromethane), thus obtaining methoxyamine-containing hydrochloride solid 0.1648g (theoretical 0.2143g, yield 76.9015%, mp: 145-150 ℃).
[ -CHO/-c=noh/-c=nome purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
Example 3:
Equation (c)
To a 100ml reaction flask were added 0.9769g (4.3371 mmol,1.00 eq), 0.1503g (2.1628 mmol,0.50 eq) of hydroxylamine hydrochloride, 20.0ml of methanol, 2.5ml of water, stirring and dissolving at 16℃and stirring and reacting at 38-40℃under control of temperature, and TLC was used to monitor the progress of the reaction (EA: PE=1:1, UV254, R f(-C＝NOH):0.5/Rf(-C＝NOMe): 0.6). Cooling to 6 ℃, stirring for crystallization, suction filtering, recovering 0.3700g of unreacted raw material 2,4, 5-trimethoxybenzaldehyde oxime methyl ether (HPLC purity 97.347％,1H NMR(400MHz,DMSO-d6)8.25(s,1H),7.14(s,1H),6.72(s,1H),3.85(s,3H),3.83(s,3H),3.81(s,3H),3.36(s,3H).); filtrate is concentrated to dryness, water is added to 15.0ml, suction filtering is carried out, thus obtaining 0.4170g of 2,4, 5-trimethoxybenzaldehyde oxime and oxime methyl ether mixture (HPLC purity: -C=NOH 8.012%, -C=NOMe 88.038%), filtrate is concentrated to dryness, thus obtaining 0.0881g of methoxyamine hydrochloride solid (theoretical 0.1806g, yield 48.78%, mp: 145-150 ℃).
Preparing raw materials:
To a 50ml reaction flask were added 2.1248g (10.8298 mmol,1.00 eq), 1.3576g (16.2553 mmol,1.50 eq) methoxyamine hydrochloride, 30.0ml methanol, and stirred at 15℃and TLC monitored (EA: PE=1:1, UV254, R f(-CHO):0.4/Rf(-C＝NOMe): 0.6) of the reaction progress until the reaction of the starting materials was complete. 35.0ml of water is added to generate white precipitate, and then the white precipitate is filtered, washed and dried to obtain 1.9700g (theoretical 2.4393g, yield 80.7609% and HPLC purity) of 2,4, 5-trimethoxybenzaldehyde oxime methyl ether 99.509％,1H NMR(400MHz,DMSO-d6)8.25(s,1H),7.14(s,1H),6.72(s,1H),3.85(s,3H),3.83(s,3H),3.81(s,3H),3.36(s,3H).).
Preparing a reference substance solution:
Adding 0.0890g (0.4536 mmol,1.00 eq), 0.0363g (0.5181 mmol,1.14 eq) hydroxylamine hydrochloride, 1.0ml methanol, and 35-40deg.C ultrasonic vibration for 30min (10×3) into a 4ml sample bottle, detecting complete conversion of raw materials by HPLC, and obtaining 2,4, 5-trimethoxybenzaldehyde oxime with main peak HPLC purity Trans or Cis:67.268％/19.665％(1H NMR(400MHz,DMSO-d6)δ＝10.94(s,1H),8.20(s,1H),7.17(s,1H),6.71(s,1H),3.82(s,3H),3.80(s,3H),3.37(s,3H).).
[ -CHO/-c=noh/-c=nome purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
Example 4:
Equation (c)
To a 50ml reaction flask were added 0.7671g (4.2579 mmol,1.00 eq), 0.1483g (2.1341 mmol,0.50 eq) hydroxylamine hydrochloride, 20.0ml methanol, 1.0ml water, and the reaction was stirred at 40℃for 3h, and monitored by TLC (EA: PE=1:3, UV254, R f(-NOH):0.2/Rf(-C＝NOMe): 0.5). Cooling to 5-10 ℃, stirring for crystallization, suction filtering and water washing to obtain 0.537g of solid recovered unreacted raw material 2-nitrobenzaldehyde oxime methyl ether (HPLC purity: minus C=NOMe 99.404%); concentrating the filtrate to dryness, washing with water, and suction filtering to obtain solid 0.3830g (HPLC purity: -C=NOH 13.214%, -C=NOMe 50.459%); the filtrate was concentrated to dryness to give 0.1069g (theoretical 0.1782g, 59.99% yield, mp: 145-150 ℃ C.) of methoxyamine hydrochloride-containing solid.
Preparing raw materials:
to a 50ml reaction flask were added 1.9974g (13.2174 mmol,1.00 eq), 1.6624g (19.9048 mmol,1.51 eq) of methoxyamine hydrochloride, 15.0ml of methanol, and the mixture was stirred at 15℃for 1 hour. TLC monitored (EA: pe=1:3, uv254, r f(-CHO):0.4/Rf(-C＝NOMe):0.5) the progress of the reaction until the starting material was complete. Adding 20.0ml of water into the reaction solution, stirring for crystallization, filtering, washing with water, and drying to obtain 2.2866g (theoretical amount 2.3812g, yield 96.03% and HPLC purity) of 2-nitrobenzaldehyde oxime methyl ether Trans or Cis：96.624％/3.064％,mp:98～100℃,1H NMR(500MHz,CDCl3):δ＝8.62(s,1H),8.06(d,J＝8.0Hz,1H),8.00(d,J＝8.0Hz,1H),7.65(t,J＝7.5Hz,1H),7.55(dt,J＝8.5,1.5Hz,1H),4.04(s,3H)ppm.13C NMR(125MHz,CDCl3):δ＝147.9,144.9,133.4,130.1,128.7,127.3,124.8,62.5ppm.).
Preparing a reference substance solution:
To a 4ml sample bottle were added 0.0720g (0.4764 mmol,1.00 eq), 0.0388g (0.5583 mmol,1.17 eq), 1.0ml methanol, 0.0500g triethylamine (0.4941 mmol,1.04 eq) and 15-20deg.C ultrasound for 20min (10X 2), and the conversion of the raw material was detected by HPLC, the main peak purity of the 2-nitrobenzaldehyde oxime was complete Trans or Cis：70.010％/24.701％.(1H NMR(300MHz,DMSO-d6):δ＝11.78(s,1H,OH),8.40(s,1H,N＝CH),8.04(d,J＝7.8Hz,1H,Ar-H),7.88(d,J＝7.8Hz,1H,Ar-H),7.76(d,J＝7.8Hz,1H,Ar-H),7.67–7.62(m,1H,Ar-H))
[ -CHO/-c=noh/-c=nome purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
Example 5:
Equation (c)
To a 50ml reaction flask were added 0.3731g (2.0710 mmol,1.00 eq), 0.0748g (1.0764 mmol,0.52 eq) hydroxylamine hydrochloride, 15.0ml methanol, 1.0ml water, and the reaction was stirred at 40℃for 3h, and monitored by TLC (EA: PE=1:3, UV254, R f(-NOH):0.5/Rf(-C＝NOMe): 0.6). Cooling to 5-10 ℃, stirring for crystallization, suction filtering, and washing with water to obtain 0.2305g of solid (HPLC purity: minus C=NOMe 99.628%); concentrating the filtrate to dryness, washing with water, and suction filtering, and washing to obtain 0.1520g (HPLC purity, -C=NOH 8.609%, -C=NOMe 89.859%); the filtrate was concentrated to dryness to give 0.0502g (theoretical 0.0899g, yield 55.84%, mp: 145-150 ℃ C.) of methoxyamine hydrochloride-containing solid.
Preparing raw materials:
to a 50ml reaction flask were added 1.9360g (12.8111 mmol,1.00 eq), 1.4160g (16.9546 mmol,1.32 eq) of methoxyamine hydrochloride, 15.0ml of methanol, and the mixture was dissolved by stirring at 15 ℃. TLC monitored (EA: pe=1:3, uv254, r f(-CHO):0.4/Rf(-C＝NOMe):0.6) the progress of the reaction until the starting material was complete. Adding 20.0ml of water into the reaction solution, stirring for crystallization, filtering, washing with water, drying to obtain 2.6843g (theoretical 2.8856g, yield 93.0240% and HPLC purity) of 4-nitrobenzaldehyde oxime methyl ether Trans or Cis：73.780％/25.818％,mp:101～103℃,1H NMR(300MHz,CDCl3),δ8.24(d,2H,JHH＝8.9Hz),8.11(s,2H),7.75(d,2H,JHH＝8.9Hz),4.04(s,3H).).
Preparing a reference substance solution:
0.0600g (0.3970 mmol,1.0 eq) of 4-nitrobenzaldehyde, 0.0367g (0.5281 mmol,1.33 eq) of hydroxylamine hydrochloride, 1.0ml of methanol and 30min (10 x 3) of ultrasonic oscillation at 35-40 ℃ are added into a 4ml sample bottle, and the main peak purity of the 4-nitrobenzaldehyde oxime is detected by HPLC Trans or Cis:72.909％/25.016％(1H NMR(300MHz,DMSO-d6):δ＝11.85(s,1H,OH),8.31(s,1H,N＝CH),8.26(d,JHH＝9.0Hz,2H,Ar-H),7.85(d,JHH＝9.0Hz,2H,Ar-H).).
[ -CHO/-c=noh/-c=nome purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
Example 6:
Equation (c)
2.38G (15.74 mmol,1.0 eq) of 2-hydroxybenzaldehyde oxime methyl ether, 0.55 (7.91 mmol,0.5 eq) of hydroxylamine hydrochloride, 10.0ml of methanol, 5.0ml of water and 40 ℃ were added to a 50ml reaction flask, and the reaction was stirred at 40 ℃ and monitored by TLC (EA: PE=1:3, UV254, R f(-NOH):0.4/Rf(-C＝NOMe):0.7). Cooling to 5-10 ℃, adding 10.0ml of chloroform for extraction, washing with water, concentrating the organic phase until the organic phase is dry, and obtaining 2.13g (HPLC purity: C=NOH 15.446% and C=NOMe 83.861%); the aqueous phase is concentrated to dryness to give 0.64g (theoretical 0.66g, yield 96.96%, mp: 145-150 ℃ C.) of methoxyamine hydrochloride solid.
Preparing raw materials:
2.00g (16.38 mmol,1.00 eq) of 2-hydroxybenzaldehyde, 2.10g (25.14 mmol,1.53 eq) of methoxyamine hydrochloride and 10.0ml of methanol were put into a 50ml reaction flask, and dissolved by stirring at 15 ℃. TLC monitored (EA: pe=1:3, uv254, r f(-CHO):0.6/Rf(-C＝NOMe):0.7) the progress of the reaction until the starting material was complete. Dropwise adding sodium carbonate/water solution, extracting with dichloromethane, washing with water, concentrating the organic phase to obtain 2.38g (theoretical 2.48g, yield 95.97%, HPLC purity) of liquid 2-hydroxybenzaldehyde oxime methyl ether 99.205％,1H NMR(500MHz,DMSO-d6)δ＝9.91(s,1H),8.34(s,1H),7.52–7.47(d,J＝7.7Hz,1H),7.24–7.19(t,JHH＝8.0Hz,1H),6.88–6.84(d,JHH＝8.2Hz,1H),6.83–6.78(t,JHH＝7.6Hz,1H),3.85(s,3H).13C NMR(126MHz,DMSO-d6)δ156.57,146.84,131.82,127.65,119.95,118.12,116.71,62.16.).
Preparing a reference substance solution:
0.0530g (0.4340 mmol,1.00 eq), 0.0331g (0.4763 mmol,1.10 eq), 0.0499g triethylamine, 1.0ml methanol and 35-40 ℃ ultrasonic vibration for 30min (10 x 3) are added into a 4ml sample bottle, the conversion of the raw materials is complete by HPLC detection, and the main peak purity of the 2-hydroxybenzaldehyde oxime is obtained ：97.265％(1H NMR(400MHz,DMSO-d6):δ＝8.33(s,1H),7.49–7.47(dd,1H),7.25–7.21(dd,1H),6.90–6.86(m,2H);13C NMR(100MHz,DMSO-d6):δ＝156.42,147.96,130.93,128.30,119.80,118.72,116.46.).
[ -CHO/-c=noh/-c=nome purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
Example 7:
Equation (c)
2.27G (12.53 mmol,1.00 eq.) of 3-methoxy-4-hydroxybenzaldehyde oxime methyl ether, 0.44g (6.33 mmol,0.50 eq.) of hydroxylamine hydrochloride, 5.0ml of methanol, 5.0ml of water and 5.0ml of water were added to a 50ml reaction flask, and the reaction was monitored by TLC (EA: PE=1:3, UV254, R f(-NOH):0.1/Rf(-C＝NOMe): 0.4). Cooling to 10-15 ℃, adding 10.0ml of dichloromethane for extraction, washing with water, and concentrating the organic phase until the organic phase is dry to obtain 1.86g of 3-methoxy-4-hydroxybenzaldehyde oxime/3-methoxy-4-hydroxybenzaldehyde oxime methyl ether concentrated solution (HPLC purity: C=NOH 9.315%, -C=NOMe 79.046%); the aqueous phase is concentrated to dryness to give 0.51g (theoretical 0.53g, yield 96.22%, mp: 145-150 ℃ C.) of methoxyamine hydrochloride solid.
Preparing raw materials:
Into a 50ml reaction flask were charged 2.0g (13.15 mmol,1.00 eq), 1.60g (19.16 mmol,1.45 eq) of methoxyamine hydrochloride and 10.0ml of methanol, and the mixture was dissolved by stirring at 15 ℃. TLC monitored (EA: pe=1:3, uv254, r f(-CHO):0.2/Rf(-C＝NOMe):0.4) the progress of the reaction until the starting material was complete. Dropwise adding sodium carbonate/water solution, extracting with dichloromethane, washing with water, concentrating the organic phase to obtain 2.27g (theoretical 2.38g, yield 95.38% and HPLC purity) of liquid 3-methoxy-4-hydroxybenzaldehyde oxime methyl ether Trans or Cis:84.232％/12.361％,1H NMR(400MHz,DMSO-d6)δ＝9.50(s,1H),8.07(s,1H),7.17(d,JHH＝2.0Hz,1H),7.00(dd,J1＝2.0Hz,J2＝8.0Hz,1H),6.80(d,JHH＝8.0Hz,1H),3.84(s,3H),3.78(s,3H).).
Preparing a reference substance solution:
3-methoxy-4-hydroxybenzaldehyde 0.0652g (0.4285 mmol,1.00 eq), hydroxylamine hydrochloride 0.0363g (0.5224 mmol,1.22 eq), methanol 1.0ml, ultrasonic vibration at 35-40 ℃ for 30min (10 x 3) are added into a 4ml sample bottle, the conversion of the raw materials is detected by HPLC, and the main peak HPLC purity of the 3-methoxy-4-hydroxybenzaldehyde oxime is obtained Trans or Cis:59.805％/36.046％(1H NMR(400MHz,DMSO-d6)δ＝10.85(s,1H),9.36(s,1H),7.99(s,1H),7.16(d,JHH＝1.8Hz,1H),6.97(dd,JHH＝8.1,1.8Hz,1H),6.77(d,JHH＝8.1Hz,1H),3.77(s,3H).13C NMR(101MHz,DMSO-d6)δ＝148.1,148.0,147.8,124.4,120.5,115.4,109.1,55.4.).
[ -CHO/-c=noh/-c=nome purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
Example 8:
Equation (c)
2.51G (11.73 mmol,1.0 eq) of 4-bromobenzaldehyde oxime methyl ether, 0.49g (7.05 mmol,0.60 eq) of hydroxylamine hydrochloride, 5.0ml of methanol, 5.0ml of water and 3h of reaction were stirred at 45℃and monitored by TLC (EA: PE=1:3, UV254, R f(-NOH):0.5/Rf(-C＝NOMe): 0.7). Cooling to 10-15 ℃, extracting with dichloromethane, washing with water, concentrating an organic phase until the organic phase is dried, and obtaining 2.18g (HPLC purity: C=NOH 18.782% and C=NOMe: 75.119%) of 4-bromobenzaldehyde oxime/4-bromobenzaldehyde oxime methyl ether concentrated solution; the aqueous phase is concentrated to dryness to give 0.48g (theoretical 0.59g, yield 81.36%, mp: 145-150 ℃ C.) of methoxyamine hydrochloride solid.
Preparing raw materials:
Into a 50ml reaction flask were charged 2.13g (11.51 mmol,1.00 eq), 1.40g (16.76 mmol,1.46 eq) of methoxyamine hydrochloride and 10.0ml of methanol, and the mixture was dissolved by stirring at 25 ℃. TLC monitored (EA: pe=1:3, uv254, r f(-CHO):0.5/Rf(-C＝NOMe):0.7) the progress of the reaction until the starting material was complete. Dropwise adding sodium carbonate/water solution, extracting with dichloromethane, washing with water, concentrating the organic phase to dry to obtain 2.51g (theoretical 2.46g, yield 100% and HPLC purity) of liquid 4-bromobenzaldehyde oxime methyl ether Trans or Cis:92.734％/6.145％,1H NMR(CDC13)δ＝3.88(s,3H,CH3),7.33(s,1H,CH＝N-),7.43-8.20(m,4H,ArH).).
Preparing a reference substance solution:
Adding 0.0809g (0.4373 mmol,1.0 eq) of 4-bromobenzaldehyde, 0.0345g (0.4965 mmol,1.14 eq) of hydroxylamine hydrochloride, 1.0ml of methanol and 30min (10 x 3) of ultrasonic oscillation at 35-40 ℃ into a 4ml sample bottle, detecting that the raw materials are completely converted by HPLC, and obtaining the product of the main peak HPLC purity of 4-bromobenzaldehyde oxime Trans or Cis:89.688％/8.167％(1H NMR(300MHz,DMSO-d6):δ＝11.38(s,1H,OH),8.13(s,1H,N＝CH),7.63–7.55(m,4H,Ar-H).).
[ -CHO/-c=noh/-c=nome purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
Example 9:
Equation (c)
1.20G (9.50 mmol,1.00 eq) of furaldehyde oxime N-methide, 0.66g (9.50 mmol,1.00 eq) of hydroxylamine hydrochloride, 10.0ml of water and 0-4 ℃ are added into a 50ml reaction bottle and stirred for reaction, white needle-like precipitate is generated, and TLC monitors the progress of the reaction. The solids were filtered and collected and washed with water to give furfural oxime (1H NMR(400MHz,CD3 OD): δ=7.56 (dd, 1H), 7.40 (s, 1H), 7.27 (d, 1H), 6.56 (m, 1H). The filtrate was concentrated to dryness and washed with methanol to give a white solid containing N-methylhydroxylamine hydrochloride.
Preparing raw materials:
In a 50ml reaction flask, 4.85g (50.40 mmol,1.00 eq), 4.63g (55.45 mmol,1.10 eq), 4.66g (55.45 mmol,1.10 eq) of sodium bicarbonate, 10.0ml of water and stirring were added to react, and TLC was used to monitor the progress of the reaction until the starting material was completely reacted, resulting in a white precipitate. Filtering, collecting solid, and drying to obtain the final product of furaldehyde oxime N-methylated compound 6.32g(1H NMR(300MHz,CDC13)δ＝3.8(s,3H,CH3),6.5,7.4–7.7(m,3H,furan),7.8(m,1H CH).).
Preparing a reference substance:
To a 250ml bottle was added 39.78g (0.57 mmol,1.10 eq), 240ml of water and stirred at 0-5℃and 50.00g (0.50 mmol,1.00 eq) of furfuraldehyde was added dropwise, and after the addition was completed, the reaction was stirred at 0-5℃for 2 hours, and TLC was monitored to monitor the progress of the reaction until the reaction of the starting materials was complete, resulting in a white precipitate. The solid was filtered, collected, washed with water and dried to yield 56.10g (yield 97.06%, HPLC purity 99.346%, 1H NMR(400MHz,CD3 OD) of furfural oxime product delta = 7.56 (dd, 1H), 7.40 (s, 1H), 7.27 (d, 1H), 6.56 (m, 1H).
[ -CHO/-c=noh/-c=nme=o purity analysis method ]
HPLC conditions: water/acetonitrile, C 18 (250X 4.6mm,5 μm), 254nm, 1.0ml/min, 30℃and 20. Mu.l.
As shown by the experimental results, the oxime N-/O-alkylate is taken as a raw material and reacts with hydroxylamine salt to generate N-/O-alkylated substituted hydroxylamine salt and oxime. Preparing oxime as initial material N-/O-alkylate to realize material circulation; the reaction does not need acid or alkali catalysis, does not produce inorganic salt solid waste, and is more environment-friendly.
Claims (9)
1. A process for the preparation of an O-alkyl substituted hydroxylamine salt, characterized in that an O-alkylate of an oxime is reacted with a hydroxylamine salt in a solvent to form an oxime and an O-alkyl hydroxylamine inorganic salt:
wherein,
R 1 is hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl, said heteroaryl containing an O atom;
The substituent is halogen, halogenated C1-C4 alkyl, C1-C4 alkoxy, nitro, hydroxyl, tert-butoxycarbonyl and benzyloxy;
The solvent is methanol, ethanol, acetonitrile or a mixed solvent of water and the organic solvent;
R 2 is hydrogen;
R is C1-C6 alkyl;
HA= HCl，H2SO4,H3PO4，HBr，HI。
2. the method of claim 1, wherein,
R 1 is hydrogen, unsubstituted or phenyl-substituted C1-C4 alkyl, substituted or unsubstituted phenyl,; The substituent is halogen, halogenated C1-C4 alkyl, C1-C6 alkoxy, nitro, hydroxyl, tert-butoxycarbonyl and benzyloxy;
R 2 is hydrogen;
r is C1-C4 alkyl;
HA= HCl,，H2SO4,H3PO4，HBr，HI。
3. The process according to claim 1 or 2, wherein the reaction temperature is from 0 to 100 ℃.
4. The process according to claim 1 or 2, wherein the reaction temperature is from 0 to 70 ℃.
5. The process according to claim 1 or 2, wherein the molar ratio of O-alkylate of oxime to hydroxylamine salt is: 1:0.1-1:10.
6. The process according to claim 1 or 2, wherein the molar ratio of O-alkylate of oxime to hydroxylamine salt is: 1:0.5-1:2.
7. The process according to claim 1 or 2, wherein the product oxime is isolated by precipitation, extraction, recrystallization or column chromatography.
8. The process of any one of claims 1 to 7 wherein the oxime O-alkylate is prepared from the product oxime and an alkylating agent.
9. The process of claim 8 wherein the alkylating agent is dimethyl sulfate, diethyl sulfate, dimethyl carbonate, halogenated hydrocarbon.
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|---|---|---|---|---|
| EP0259850A2 (en) * | 1986-09-12 | 1988-03-16 | BASF Aktiengesellschaft | Method for the production of 0-substituted hydroxylamine hydrochlorides |
| CN101357895A (en) * | 2008-09-19 | 2009-02-04 | 江苏爱利思达清泉化学有限公司 | Method for synthesizing methoxamine hydrochloride |
| CN102976968A (en) * | 2012-12-01 | 2013-03-20 | 张家港市大伟助剂有限公司 | Preparation method for methoxylamine hydrochloride |
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| EP0259850A2 (en) * | 1986-09-12 | 1988-03-16 | BASF Aktiengesellschaft | Method for the production of 0-substituted hydroxylamine hydrochlorides |
| CN101357895A (en) * | 2008-09-19 | 2009-02-04 | 江苏爱利思达清泉化学有限公司 | Method for synthesizing methoxamine hydrochloride |
| CN102976968A (en) * | 2012-12-01 | 2013-03-20 | 张家港市大伟助剂有限公司 | Preparation method for methoxylamine hydrochloride |
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